Publications by authors named "Pamela M Vacek"

106 Publications

Compliance and Fidelity With an Injury Prevention Exercise Program in High School Athletics.

Sports Health 2021 Sep 7:19417381211043120. Epub 2021 Sep 7.

McClure Musculoskeletal Research Center, Department of Orthopaedics and Rehabilitation, Larner College of Medicine, University of Vermont, Burlington, Vermont.

Background: Use of injury prevention programs (IPPs) by high school athletes has increased but their success in reducing injury depends on program compliance and fidelity of exercise performance.

Hypothesis: Compliance with the 11+ IPP and exercise performance fidelity by high school athletic teams depend on sex, sport, and level of play.

Study Design: Secondary analyses of data from a randomized controlled trial (RCT).

Level Of Evidence: Level 2.

Methods: The 11+ IPP was implemented by 100 male and female high school athletic teams (American football, soccer, basketball, and lacrosse). Team compliance and fidelity with the program were evaluated by direct observation of warm-up routines and a weekly online survey completed by coaches. Differences in compliance and fidelity due to sport, sex, and level of play were assessed by analysis of variance.

Results: Coaches reported that their teams performed the full IPP an average of 1.45 times per week, and 28% of observed warm-ups included all exercises in the IPP. Compliance differed by sport but not by level of play or the athletes' sex. At the end of the season, cueing was observed 19% of the time and differed by sport. Good technique was observed 66% of the time and varied by level of play.

Conclusion: Team compliance with the IPP varied by sport and was below the recommended number of sessions per week needed to reduce injury. Removal of implementation barriers and improved support from coaches are needed at all levels of play for IPPs to be effective.

Clinical Relevance: Clinical and sports practitioners intending to implement an IPP at the high school level should anticipate and address barriers that affect program compliance and fidelity of exercise performance. Frequent follow-up and instruction may be necessary for successful adoption of the IPP.
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http://dx.doi.org/10.1177/19417381211043120DOI Listing
September 2021

Articular cartilage thickness changes differ between males and females 4 years following anterior cruciate ligament reconstruction.

J Orthop Res 2021 Jul 20. Epub 2021 Jul 20.

Department of Rehabilitation and Movement Science, College of Nursing and Health Sciences, University of Vermont, Burlington, Vermont, USA.

Anterior cruciate ligament injury and reconstruction (ACLR) affects articular cartilage thickness profiles about the tibial, femoral, and patellar surfaces; however, it's unclear whether the magnitudes of change in cartilage thickness, as well as the locations and areas over which these changes occur, differ between males and females. This is important to consider as differences exist between the sexes with regard to knee biomechanics, patellofemoral pain, and anatomic alignment, which influence risk of an index and repeated injury. Subjects underwent ACLR with a bone-patella tendon-bone autograft. At 4-year follow-up, they had asymptomatic knees; however, significant ACL injured-to-contralateral normal knee differences in articular cartilage thickness values were observed. Both thickening and thinning of cartilage occurred about the tibiofemoral and patellofemoral joints, relative to matched control subjects with normal knees. Further, the location of the areas and magnitudes of thickening and thinning were different between females and males. Thickening (swelling) of articular cartilage is an early finding associated with the onset of posttraumatic osteoarthritis (PTOA). Therefore, the increases in cartilage thickness that were observed in this cohort may represent early signs of the onset of PTOA that occur prior to the patient developing symptoms and radiographic evidence of this disease. The different locations of areas that underwent a change in cartilage thicknesses between males and females suggest that each sex responds differently to knee ligament trauma, reconstruction, rehabilitation, and return to activity, and indicates that sex-specific analysis should be utilized in studies of PTOA.
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http://dx.doi.org/10.1002/jor.25142DOI Listing
July 2021

Predictive validity of the Seasonal Beliefs Questionnaire for discriminating between seasonal and nonseasonal major depressive disorder.

Psychol Assess 2021 Apr 18;33(4):369-374. Epub 2021 Mar 18.

University of Vermont Larner College of Medicine.

The Seasonal Beliefs Questionnaire (SBQ) is a 26-item self-report measure of a winter seasonal affective disorder (SAD)-specific cognitive vulnerability consisting of maladaptive thoughts about the seasons, light availability, and weather conditions. In a known groups comparison, currently depressed adults with SAD had significantly higher SBQ scores than currently depressed adults with nonseasonal major depressive disorder (MDD) and healthy controls, and the MDD group had significantly higher SBQ scores than controls. Using that database, this study explored the predictive validity of using an SBQ cutoff score to differentiate SAD from MDD. Receiver operator characteristic curve analyses used SBQ total score to predict SAD versus MDD, SAD versus control, and MDD versus control status. The SBQ subscale combined score, derived from multivariable logistic regression with SBQ subscales, was examined as an alternative predictor. SBQ total score with a cutpoint of 132 had good predictive ability for distinguishing SAD from MDD (C-statistic = .792, sensitivity = .798, specificity = .794). The SBQ subscale combination score slightly improved predictive ability for the SAD/MDD distinction (C-statistic = .813), with better sensitivity (.930) but worse specificity (.571). In contrast, the score on a generic measure of depressogenic cognitive vulnerability, the Dysfunctional Attitudes Scale, was poor for differentiating SAD from MDD. SBQ total score was excellent in discriminating SAD cases from controls with a cutpoint of 121 (C-statistic = .962, sensitivity = .939, specificity .873), but had poor sensitivity for discriminating MDD cases from controls. Results support using the SBQ to screen for probable SAD in practice settings. (PsycInfo Database Record (c) 2021 APA, all rights reserved).
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http://dx.doi.org/10.1037/pas0000984DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8352370PMC
April 2021

Downregulation of epithelial DUOX1 in chronic obstructive pulmonary disease.

JCI Insight 2021 01 25;6(2). Epub 2021 Jan 25.

Department of Pathology and Laboratory Medicine, Larner College of Medicine, University of Vermont, Burlington, Vermont, USA.

Chronic obstructive pulmonary disease (COPD) is a chronic respiratory disease characterized by small airway remodeling and alveolar emphysema due to environmental stresses such as cigarette smoking (CS). Oxidative stress is commonly implicated in COPD pathology, but recent findings suggest that one oxidant-producing NADPH oxidase homolog, dual oxidase 1 (DUOX1), is downregulated in the airways of patients with COPD. We evaluated lung tissue sections from patients with COPD for small airway epithelial DUOX1 protein expression, in association with measures of lung function and small airway and alveolar remodeling. We also addressed the impact of DUOX1 for lung tissue remodeling in mouse models of COPD. Small airway DUOX1 levels were decreased in advanced COPD and correlated with loss of lung function and markers of emphysema and remodeling. Similarly, DUOX1 downregulation in correlation with extracellular matrix remodeling was observed in a genetic model of COPD, transgenic SPC-TNF-α mice. Finally, development of subepithelial airway fibrosis in mice due to exposure to the CS-component acrolein, or alveolar emphysema induced by administration of elastase, were in both cases exacerbated in Duox1-deficient mice. Collectively, our studies highlight that downregulation of DUOX1 may be a contributing feature of COPD pathogenesis, likely related to impaired DUOX1-mediated innate injury responses involved in epithelial homeostasis.
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http://dx.doi.org/10.1172/jci.insight.142189DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7934842PMC
January 2021

Collagen Organization in Relation to Ductal Carcinoma Pathology and Outcomes.

Cancer Epidemiol Biomarkers Prev 2021 01 20;30(1):80-88. Epub 2020 Oct 20.

Carbone Cancer Center, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, Wisconsin.

Background: There is widespread interest in discriminating indolent from aggressive ductal carcinoma (DCIS). We sought to evaluate collagen organization in the DCIS tumor microenvironment in relation to pathologic characteristics and patient outcomes.

Methods: We retrieved fixed tissue specimens for 90 DCIS cases within the population-based Vermont DCIS Cohort. We imaged collagen fibers within 75 μm of the tumor/stromal boundary on hematoxylin and eosin-stained slides using multiphoton microscopy with second-harmonic generation. Automated software quantified collagen fiber length, width, straightness, density, alignment, and angle to the tumor/stroma boundary. Factor analysis identified linear combinations of collagen fiber features representing composite attributes of collagen organization.

Results: Multiple collagen features were associated with DCIS grade, necrosis pattern, or periductal fibrosis ( < 0.05). After adjusting for treatments and nuclear grade, risk of recurrence (defined as any second breast cancer diagnosis) was lower among cases with greater collagen fiber width [hazard ratio (HR), 0.57 per one standard deviation increase; 95% confidence interval (CI), 0.39-0.84] and fiber density (HR, 0.60; 95% CI, 0.42-0.85), whereas risk was elevated among DCIS cases with higher fiber straightness (HR, 1.47; 95% CI, 1.05-2.06) and distance to the nearest two fibers (HR, 1.47; 95% CI, 1.06-2.02). Fiber length, alignment, and fiber angle were not associated with recurrence ( > 0.05). Five composite factors were identified, accounting for 72.4% of the total variability among fibers; three were inversely associated with recurrence (HRs ranging from 0.60 to 0.67; ≤ 0.01).

Conclusions: Multiple aspects of collagen organization around DCIS lesions are associated with recurrence risk.

Impact: Collagen organization should be considered in the development of prognostic DCIS biomarker signatures.
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http://dx.doi.org/10.1158/1055-9965.EPI-20-0889DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7855820PMC
January 2021

Application of convolutional neural networks to breast biopsies to delineate tissue correlates of mammographic breast density.

NPJ Breast Cancer 2019 19;5:43. Epub 2019 Nov 19.

2Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD USA.

Breast density, a breast cancer risk factor, is a radiologic feature that reflects fibroglandular tissue content relative to breast area or volume. Its histology is incompletely characterized. Here we use deep learning approaches to identify histologic correlates in radiologically-guided biopsies that may underlie breast density and distinguish cancer among women with elevated and low density. We evaluated hematoxylin and eosin (H&E)-stained digitized images from image-guided breast biopsies ( = 852 patients). Breast density was assessed as global and localized fibroglandular volume (%). A convolutional neural network characterized H&E composition. In total 37 features were extracted from the network output, describing tissue quantities and morphological structure. A random forest regression model was trained to identify correlates most predictive of fibroglandular volume ( = 588). Correlations between predicted and radiologically quantified fibroglandular volume were assessed in 264 independent patients. A second random forest classifier was trained to predict diagnosis (invasive vs. benign); performance was assessed using area under receiver-operating characteristics curves (AUC). Using extracted features, regression models predicted global ( = 0.94) and localized ( = 0.93) fibroglandular volume, with fat and non-fatty stromal content representing the strongest correlates, followed by epithelial organization rather than quantity. For predicting cancer among high and low fibroglandular volume, the classifier achieved AUCs of 0.92 and 0.84, respectively, with epithelial organizational features ranking most important. These results suggest non-fatty stroma, fat tissue quantities and epithelial region organization predict fibroglandular volume. The model holds promise for identifying histological correlates of cancer risk in patients with high and low density and warrants further evaluation.
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http://dx.doi.org/10.1038/s41523-019-0134-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6864056PMC
November 2019

Risk Factors Associated With a Noncontact Anterior Cruciate Ligament Injury to the Contralateral Knee After Unilateral Anterior Cruciate Ligament Injury in High School and College Female Athletes: A Prospective Study.

Am J Sports Med 2019 12 5;47(14):3347-3355. Epub 2019 Nov 5.

McClure Musculoskeletal Research Center, Department of Orthopedics and Rehabilitation, Robert Larner M.D. College of Medicine, University of Vermont, Burlington, Vermont, USA.

Background: The incidence of contralateral anterior cruciate ligament (CACL) injuries after recovery from a first-time anterior cruciate ligament (ACL) disruption is high in women; however, little is known about the risk factors associated with this trauma.

Hypothesis: Patient characteristics, strength, anatomic alignment, and neuromuscular characteristics of the contralateral uninjured leg at the time of the first ACL trauma are associated with risk of subsequent CACL injury, and these risk factors are distinct from those for a first-time ACL injury.

Study Design: Case-control study; Level of evidence, 3.

Methods: Sixty-one women who suffered a first-time noncontact ACL injury while participating in high school or college sports and underwent measurement of potential risk factors on their contralateral limb soon after the initial ACL injury and before reconstruction were followed until either a CACL injury or an ACL graft injury occurred, or until the last date of contact.

Results: Follow-up information was available for 55 (90.0%) of the 61 athletes and 11 (20.0%) suffered a CACL injury. Younger age, decreased participation in sport before the first ACL disruption, decreased anterior stiffness of the contralateral knee, and increased hip anteversion were associated with increases in the risk of suffering a CACL injury.

Conclusion: A portion of CACL injury risk factors were modifiable (time spent participating in sport and increasing anterior knee stiffness with bracing), while others were nonmodifiable (younger age and increased hip anteversion). The relationship between younger age at the time of an initial ACL injury and increased risk of subsequent CACL trauma may be explained by younger athletes having more years available to be exposed to at-risk activities compared with older athletes. A decrease of anterior stiffness of the knee is linked to decreased material properties and width of the ACL, and this may explain why some women are predisposed to bilateral ACL trauma while others only suffer the index injury. The risk factors for CACL injury are unique to women who suffer bilateral ACL trauma compared with those who suffer unilateral ACL trauma. This information is important for the identification of athletes who may benefit from risk reduction interventions.
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http://dx.doi.org/10.1177/0363546519886260DOI Listing
December 2019

Using Digital Pathology to Understand Epithelial Characteristics of Benign Breast Disease among Women Undergoing Diagnostic Image-Guided Breast Biopsy.

Cancer Prev Res (Phila) 2019 12 23;12(12):861-870. Epub 2019 Oct 23.

Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, Maryland.

Delayed terminal duct lobular unit (TDLU) involution is associated with elevated mammographic breast density (MD). Both are independent breast cancer risk factors among women with benign breast disease (BBD). Prior digital analyses of normal breast tissues revealed that epithelial nuclear density (END) and TDLU involution are inversely correlated. Accordingly, we examined associations of END, TDLU involution, and MD in BBD clinical biopsies. This study included digitized images of 262 representative image-guided hematoxylin and eosin-stained biopsies from 224 women diagnosed with BBD, enrolled within the cross-sectional BREAST-Stamp project that were visually assessed for TDLU involution (TDLU count/100 mm, median TDLU span and median acini count per TDLU). A digital algorithm estimated nuclei count per unit epithelial area, or END. Single X-ray absorptiometry of prebiopsy ipsilateral craniocaudal digital mammograms measured global and localized MD surrounding the biopsy region. Adjusted ordinal logistic regression models assessed relationships between tertiles of TDLU and END measures. Analysis of covariance examined mean differences in MD across END tertiles. TDLU measures were positively associated with increasing END tertiles [TDLU count/100 mm, OR: 3.42, 95% confidence interval (CI), 1.87-6.28; acini count/TDLU, OR: 2.40, 95% CI, 1.39-4.15]. END was significantly associated with localized, but not, global MD. Relationships were most apparent among patients with nonproliferative BBD. These findings suggest that quantitative END reflects different but complementary information to the histologic information captured by visual TDLU and radiologic MD measures and merits continued evaluation in assessing cellularity of breast parenchyma to understand the etiology of BBD.
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http://dx.doi.org/10.1158/1940-6207.CAPR-19-0120DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7357278PMC
December 2019

Relationship of circulating insulin-like growth factor-I and binding proteins 1-7 with mammographic density among women undergoing image-guided diagnostic breast biopsy.

Breast Cancer Res 2019 07 23;21(1):81. Epub 2019 Jul 23.

National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.

Background: Mammographic density (MD) is a strong breast cancer risk factor that reflects fibroglandular and adipose tissue composition, but its biologic underpinnings are poorly understood. Insulin-like growth factor binding proteins (IGFBPs) are markers that may be associated with MD given their hypothesized role in breast carcinogenesis. IGFBPs sequester IGF-I, limiting its bioavailability. Prior studies have found positive associations between circulating IGF-I and the IGF-I:IGFBP-3 ratio and breast cancer risk. We evaluated the associations of IGF-I, IGFBP-3, and six other IGFBPs with MD.

Methods: Serum IGF measures were quantified in 296 women, ages 40-65, undergoing diagnostic image-guided breast biopsy. Volumetric density measures (MD-V) were assessed in pre-biopsy digital mammograms using single X-ray absorptiometry. Area density measures (MD-A) were estimated by computer-assisted thresholding software. Age, body mass index (BMI), and BMI-adjusted linear regression models were used to examine associations of serum IGF measures with MD. Effect modification by BMI was also assessed.

Results: IGF-I and IGFBP-3 were not strongly associated with MD after BMI adjustment. In multivariable analyses among premenopausal women, IGFBP-2 was positively associated with both percent MD-V (β = 1.49, p value = 0.02) and MD-A (β = 1.55, p value = 0.05). Among postmenopausal women, positive relationships between IGFBP-2 and percent MD-V (β = 2.04, p = 0.003) were observed; the positive associations between IGFBP-2 and percent MD-V were stronger among lean women (BMI < 25 kg/m) (β = 5.32, p = 0.0002; p interaction = 0.0003).

Conclusions: In this comprehensive study of IGFBPs and MD, we observed a novel positive association between IGFBP-2 and MD, particularly among women with lower BMI. In concert with in vitro studies suggesting a dual role of IGFBP-2 on breast tissue, promoting cell proliferation as well as inhibiting tumorigenesis, our findings suggest that further studies assessing the role of IGFBP-2 in breast tissue composition, in addition to IGF-1 and IGFBP-3, are warranted.
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http://dx.doi.org/10.1186/s13058-019-1162-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6651938PMC
July 2019

A measure of cognitions specific to seasonal depression: Development and validation of the Seasonal Beliefs Questionnaire.

Psychol Assess 2019 Jul 28;31(7):925-938. Epub 2019 Mar 28.

Medical Biostatistics Unit, University of Vermont College of Medicine.

We introduce the Seasonal Beliefs Questionnaire (SBQ), a self-report inventory of maladaptive thoughts about the seasons, light availability, and weather conditions, proposed to constitute a unique cognitive vulnerability to winter seasonal affective disorder (SAD; Rohan, Roecklein, & Haaga, 2009). Potential items were derived from a qualitative analysis of self-reported thoughts during SAD-tailored cognitive-behavioral therapy (CBT-SAD) and subsequently refined based on qualitative feedback from 48 SAD patients. In the psychometric study (N = 536 college students), exploratory and confirmatory factor analyses pruned the items to a 26-item scale with a 5-factor solution, demonstrating good internal consistency, convergent and divergent validity, and 2-week test-retest reliability. In a known groups comparison, the SBQ discriminated SAD patients (n = 86) from both nonseasonal major depressive disorder (MDD) patients (n = 30) and healthy controls (n = 110), whereas a generic measure of depressogenic cognitive vulnerability (the Dysfunctional Attitudes Scale [DAS]) discriminated MDD patients from the other groups. In a randomized clinical trial comparing CBT-SAD with light therapy (N = 177), SBQ scores improved at twice the rate in CBT-SAD than in light therapy. Greater change in SBQ scores during CBT-SAD, but not during light therapy, was associated with a lower risk of depression recurrence 2 winters later. In contrast, DAS scores improved comparably during CBT-SAD and light therapy, and DAS change was unrelated to recurrence following either treatment. These results support using the SBQ as a brief assessment tool for a SAD-specific cognitive vulnerability and as a treatment target in CBT-SAD. (PsycINFO Database Record (c) 2019 APA, all rights reserved).
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http://dx.doi.org/10.1037/pas0000715DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7988399PMC
July 2019

Radiographic-based measurement of tibiofemoral joint space width and magnetic resonance imaging derived articular cartilage thickness are not related in subjects at risk for post traumatic arthritis of the knee.

J Orthop Res 2019 05 28;37(5):1052-1058. Epub 2019 Mar 28.

Department Orthopedics and Rehabilitation, Robert Larner M.D. College of Medicine, University of Vermont, Burlington, Vermont.

Joint space width (JSW), measured as the distance between the femoral and tibial subchondral bone margins on two-dimensional weight-bearing radiographs, is the initial imaging modality used in clinical settings to diagnose and evaluate the progression of osteoarthritis (OA). While, JSW is the only structural outcome approved by the FDA for studying the treatment of this disease in phase III clinical trials, recent reports suggest that magnetic resonance imaging (MRI)-based measurements of OA changes are superior due to increased sensitivity and specificity to the structural changes associated with progression of this disease. In the current study, we examined the relationship between radiographic JSW and MRI-derived articular cartilage thickness in subjects 4 years post anterior cruciate ligament reconstruction (ACLR) who were at increased risk for the onset and early progression of post-traumatic OA, and in uninjured subjects with normal knees (Control). In both ACLR and Control groups, there were large measurement biases, wide limits of agreement, and poor correlation between the two measurement techniques. Clinical significance: The finding from this study suggest that the two methods of examining changes associated with the onset and early progression of PTOA either characterize different structures about the knee and should not be used interchangeably, or two-dimensional JSW measurements are not sensitive to small changes in articular cartilage thickness. © 2019 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res.
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http://dx.doi.org/10.1002/jor.24283DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6499682PMC
May 2019

Longitudinal study of t-cell somatic mutations conferring glycosylphosphatidylinositol-anchor deficiency in gulf war I veterans exposed to depleted uranium.

Environ Mol Mutagen 2019 07 27;60(6):494-504. Epub 2019 Mar 27.

Occupational Health Program, Department of Medicine, University of Maryland School of Medicine, Baltimore, Maryland.

Fifty Veterans of the first Gulf War in 1991 exposed to depleted uranium (DU) were studied for glycosylphosphatidylinositol-anchor (GPIa) deficient T-cell mutants on three occasions during the years 2009, 2011, and 2013. GPIa deficiency was determined in two ways: cloning assays employing aerolysin selection and cytometry using the FLAER reagent for positive staining of GPIa cell surface proteins. Subsequent molecular analyses of deficient isolates recovered from cloning assays (Nicklas JA et al. [2019]: Environ Mol Mutagen) revealed apparent incomplete selection in some cloning assays, necessitating correction of original data to afford a more realistic estimate of GPIa deficient mutant frequency (MF) values. GPIa deficient variant frequencies (VFs) determined by cytometry were determined in the years 2011 and 2013. A positive but nonsignificant association was observed between MF and VF values determined on the same blood samples during 2013. Exposure to DU had no effect on either GPIa deficient MF or VFs. Environ. Mol. Mutagen. 60:494-504, 2019. © 2019 Wiley Periodicals, Inc.
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http://dx.doi.org/10.1002/em.22281DOI Listing
July 2019

Molecular analysis of glycosylphosphatidylinositol anchor deficient aerolysin resistant isolates in gulf war i veterans exposed to depleted uranium.

Environ Mol Mutagen 2019 07 28;60(6):470-493. Epub 2019 Mar 28.

Department of Pathology, University of Vermont College of Medicine, Burlington, Vermont.

During the First Gulf War (1991) over 100 servicemen sustained depleted uranium (DU) exposure through wound contamination, inhalation, and shrapnel. The Department of Veterans Affairs has a surveillance program for these Veterans which has included genotoxicity assays. The frequencies of glycosylphosphatidylinositol anchor (GPIa) negative (aerolysin resistant) cells determined by cloning assays for these Veterans are reported in Albertini RJ et al. (2019: Environ Mol Mutagen). Molecular analyses of the GPIa biosynthesis class A (PIGA) gene was performed on 862 aerolysin-resistant T-lymphocyte recovered isolates. The frequencies of different types of PIGA mutations were compared between high and low DU exposure groups. Additional molecular studies were performed on mutants that produced no PIGA mRNA or with deletions of all or part of the PIGA gene to determine deletion size and breakpoint sequence. One mutant appeared to be the result of a chromothriptic event. A significant percentage (>30%) of the aerolysin resistant isolates, which varied by sample year and Veteran, had wild-type PIGA cDNA (no mutation). As described in Albertini RJ et al. (2019: Environ Mol Mutagen), TCR gene rearrangement analysis of these isolates indicated most arose from multiple T-cell progenitors (hence the inability to find a mutation). It is likely that these isolates were the result of failure of complete selection against nonmutant cells in the cloning assays. Real-time studies of GPIa resistant isolates with no PIGA mutation but with a single TCR gene rearrangement found one clone with a PIGV deletion and several others with decreased levels of GPIa pathway gene mRNAs implying mutation in other GPIa pathway genes. Environ. Mol. Mutagen. 60:470-493, 2019. © 2019 Wiley Periodicals, Inc.
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http://dx.doi.org/10.1002/em.22283DOI Listing
July 2019

Detection Rates for Benign and Malignant Diagnoses on Breast Cancer Screening With Digital Breast Tomosynthesis in a Statewide Mammography Registry Study.

AJR Am J Roentgenol 2019 03 23;212(3):706-711. Epub 2019 Jan 23.

1 Department of Surgery, University of Vermont, 1 S Prospect St, UHC Rm 4425, Burlington, VT 05401.

Objective: The objective of our study was to determine whether detection rates of specific benign and malignant diagnoses differ for breast cancer screening with digital breast tomosynthesis (DBT) versus full-field digital mammography (FFDM) alone.

Materials And Methods: We analyzed observational data from the Vermont Breast Cancer Surveillance System, including 86,349 DBT screening examinations and 97,378 FFDM screening examinations performed at eight radiology facilities in Vermont that adopted DBT screening during 2012-2016. We determined the most severe diagnosis made within 6 months after positive screening examinations. Multivariable-adjusted logistic regression was used to compare detection rates for specific diagnoses on DBT versus FFDM.

Results: Compared with FFDM, DBT had a lower recall rate (adjusted odds ratio [OR], 0.81; 95% CI, 0.77-0.85) but comparable biopsy rate (OR = 1.05; 95% CI, 0.93-1.17), benign biopsy rate (OR = 1.12; 95% CI, 0.97-1.29), and cancer detection rate (OR = 0.94; 95% CI, 0.78-1.14). Among benign diagnoses, DBT and FFDM had comparable detection rates for nonproliferative lesions (OR = 1.19; 95% CI, 0.92-1.53), fibroepithelial proliferations (OR = 1.24; 95% CI, 0.85-1.81), proliferative lesions without atypia (OR = 1.13; 95% CI, 0.90-1.42), atypical lesions (OR = 0.77; 95% CI, 0.43-1.38), and lobular carcinoma in situ (LCIS) (OR = 0.92; 95% CI, 0.53-1.61). Among malignant diagnoses, DBT and FFDM had comparable detection rates for ductal carcinoma in situ (OR = 1.05; 95% CI, 0.70-1.57) and invasive breast cancer (OR = 0.92; 95% CI, 0.74-1.13), with no statistically significant differences in detection of invasive ductal carcinoma (OR = 0.83; 95% CI, 0.66-1.06), invasive lobular carcinoma (OR = 1.11; 95% CI, 0.59-2.07), or invasive mixed ductal-lobular carcinoma (OR = 1.49; 95% CI, 0.65-3.39).

Conclusion: Compared with FFDM, breast cancer screening with DBT has a lower recall rate while detecting a similar distribution of benign and malignant diagnoses.
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http://dx.doi.org/10.2214/AJR.18.20255DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6386608PMC
March 2019

Time-varying risks of second events following a DCIS diagnosis in the population-based Vermont DCIS cohort.

Breast Cancer Res Treat 2019 Feb 17;174(1):227-235. Epub 2018 Nov 17.

University of Vermont Cancer Center, University of Vermont, Burlington, VT, USA.

Purpose: Long-term disease-free survival patterns following surgical, radiation, and endocrine therapy treatments for ductal carcinoma in situ (DCIS) are not well characterized in general US practice.

Methods: We identified 1252 women diagnosed with DCIS in Vermont during 1994-2012 using data from the Vermont Breast Cancer Surveillance System, a statewide registry of breast imaging and pathology records. Poisson regression and Cox regression with time-varying hazards were used to evaluate disease-free survival among self-selected treatment groups.

Results: With 7.8 years median follow-up, 192 cases experienced a second breast cancer diagnosis. For women treated with breast-conserving surgery (BCS) alone, the annual rate of second events decreased from 3.1% (95% CI 2.2-4.2%) during follow-up years 1-5 to 1.7% (95% CI 0.7-3.5%) after 10 years. In contrast, the annual rate of second events among women treated with BCS plus adjuvant radiation therapy increased from 1.8% (95% CI 1.1-2.6%) during years 1-5 to 2.8% (95% CI 1.6-4.7%) after 10 years (P < 0.05 for difference in trend compared to BCS alone). Annual rates of second events also increased over time among women treated with BCS plus adjuvant radiation and endocrine therapy (P = 0.01 for difference in trend compared to BCS alone). The rate of contralateral events increased after 10 years for all groups with adjuvant treatments. The rate of second events did not vary over time among women who underwent ipsilateral mastectomy (P = 0.62).

Conclusions: Long-term risk of a second event after DCIS varies over time in a manner dependent on initial treatment.
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http://dx.doi.org/10.1007/s10549-018-5048-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6420371PMC
February 2019

Exposure‒response relationships for silicosis and its progression in industrial sand workers.

Scand J Work Environ Health 2019 05 18;45(3):280-288. Epub 2018 Nov 18.

Medical Biostatistics Unit, University of Vermont Larner College of Medicine, 105 Carrigan Dr., Burlington, VT 05405, USA.

Objectives This study aimed to characterize the relationship between radiographic silicosis and exposure to respirable quartz and determine how exposure affects disease progression. Methods Surveillance chest radiographs from a cohort of 1902 workers were examined to identify 67 cases of radiographic silicosis and 167 matched controls. Exposures were estimated by linking work histories to a job exposure matrix (JEM) based on samples collected by the participating companies and historical estimates. Conditional logistic regression was used to examine exposure‒response relationships. Sequential radiographs from silicosis cases were used to assess associations between exposure and disease progression. Results Risk of silicosis increased with cumulative exposure [odds ratio (OR) 1.43 per 1 mg/m years, 95% confidence interval (CI) 1.23-1.66], average exposure concentration (OR 1.30 per 0.10 mg/m , 95% CI 1.11-1.51) and net exposure duration (OR 1.10 per year, 95% CI 1.05-1.16). Multivariate analyses indicated that the risk associated with cumulative exposure varied depending on exposure duration and concentration. Analysis of the time worked at differing exposure levels indicated that exposures ≤0.05 mg/m were not significantly associated with silicosis risk after adjustment for years worked at higher concentrations. Disease progression was related to subsequent exposure concentration, with a yearly increase in small opacity profusion of 0.052 subcategory per each 0.10 mg/m increase in concentration. Conclusions Workers with longer exposure at lower concentrations were at higher risk for silicosis than those with the same cumulative exposure who worked for a shorter time at higher concentrations. The rate of silicosis progression was related to subsequent exposure concentration.
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http://dx.doi.org/10.5271/sjweh.3786DOI Listing
May 2019

Retrospective Assessment of Respirable Quartz Exposure for a Silicosis Study of the Industrial Sand Industry.

Ann Work Expo Health 2018 10;62(8):1021-1032

West Virginia University, School of Medicine, Section of Pulmonary and Critical Care, Morgantown, WV, USA.

Background: In 2016, the OSHA PEL for crystalline silica was reduced, renewing interest in evaluating risk of silicosis from occupational exposures. The industrial sand industry, which deals with high-purity quartz sands, is the setting for a current epidemiologic investigation of silicosis risk and progression. In support of that investigation, respirable quartz (RQ) exposures were retrospectively estimated for 67 workers with silicosis and 167 matched control workers from 21 industrial sand plants, in which some started work as early as 1929.

Methods: A job exposure matrix (JEM) was constructed by integrating a modern (post-1970) RQ exposure database containing more than 40000 measurements with archival particle count exposure data from a 1947 survey. A simulation algorithm was used to develop a conversion factor to convert the archival particle count data into modern measures of RQ by randomly generating 100000 virtual dust particles of varying diameters corresponding to the size distributions of 14 archival particle size distribution samples. The equivalent respirable mass and particle counts of the virtual particles were calculated, totalled, and ratioed to derive the conversion factor. The JEM was integrated with individual job histories to calculate average and cumulative exposure for each case and control. Multiple exposure estimates were derived for unprotected exposures as well as for exposures adjusted for estimated respiratory protective equipment use and efficiency.

Results: The mean of the count to respirable mass conversion factors derived from 14 archival particle size samples was 157 µg m-3 per mppcf (SD: 42; range: 96-263) with no statistical difference across process areas (drying, screening, vibrating, binning, bulk loading, bagging), P = 0.29. The JEM demonstrated an industry-wide decrease in prevailing exposures to RQ of up to about 2 orders of magnitude from the distant (1929) to the recent (2012) past. Unadjusted cumulative exposures for cases and controls were statistically different (P < 0.001) with respective medians (range) of 3764 µg m-3 year (221-25121) and 1595 µg m-3 year (0-16446). Adjustment of exposure for use of respiratory protection showed modest reductions in estimated exposure: median adjusted cumulative exposures assuming a protection factor of 5 were 86% and 77% of the unadjusted values for cases and controls, respectively.

Conclusions: The industrial sand industry offers a unique setting for examination of silicosis risk because of the high silica content of industrial sand and a long history of radiographic silicosis surveillance of industry workers. However, the great majority of silicosis cases in this industry are found among former workers and are associated with exposures occurring in the distant past, which necessitates extensive retrospective exposure assessment and increases the likelihood of exposure misclassification. Nonetheless, the estimated cumulative exposures for silicosis cases and controls in this work were significantly different, with the median cumulative exposure for cases being more than twice that of their matched controls.
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http://dx.doi.org/10.1093/annweh/wxy064DOI Listing
October 2018

Using deep convolutional neural networks to identify and classify tumor-associated stroma in diagnostic breast biopsies.

Mod Pathol 2018 10 13;31(10):1502-1512. Epub 2018 Jun 13.

Mayo Clinic, Jacksonville, FL, USA.

The breast stromal microenvironment is a pivotal factor in breast cancer development, growth and metastases. Although pathologists often detect morphologic changes in stroma by light microscopy, visual classification of such changes is subjective and non-quantitative, limiting its diagnostic utility. To gain insights into stromal changes associated with breast cancer, we applied automated machine learning techniques to digital images of 2387 hematoxylin and eosin stained tissue sections of benign and malignant image-guided breast biopsies performed to investigate mammographic abnormalities among 882 patients, ages 40-65 years, that were enrolled in the Breast Radiology Evaluation and Study of Tissues (BREAST) Stamp Project. Using deep convolutional neural networks, we trained an algorithm to discriminate between stroma surrounding invasive cancer and stroma from benign biopsies. In test sets (928 whole-slide images from 330 patients), this algorithm could distinguish biopsies diagnosed as invasive cancer from benign biopsies solely based on the stromal characteristics (area under the receiver operator characteristics curve = 0.962). Furthermore, without being trained specifically using ductal carcinoma in situ as an outcome, the algorithm detected tumor-associated stroma in greater amounts and at larger distances from grade 3 versus grade 1 ductal carcinoma in situ. Collectively, these results suggest that algorithms based on deep convolutional neural networks that evaluate only stroma may prove useful to classify breast biopsies and aid in understanding and evaluating the biology of breast lesions.
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http://dx.doi.org/10.1038/s41379-018-0073-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6752036PMC
October 2018

Comparative effectiveness of incorporating a hypothetical DCIS prognostic marker into breast cancer screening.

Breast Cancer Res Treat 2018 Feb 28;168(1):229-239. Epub 2017 Nov 28.

University of Vermont Cancer Center, Burlington, VT, USA.

Purpose: Due to limitations in the ability to identify non-progressive disease, ductal carcinoma in situ (DCIS) is usually managed similarly to localized invasive breast cancer. We used simulation modeling to evaluate the potential impact of a hypothetical test that identifies non-progressive DCIS.

Methods: A discrete-event model simulated a cohort of U.S. women undergoing digital screening mammography. All women diagnosed with DCIS underwent the hypothetical DCIS prognostic test. Women with test results indicating progressive DCIS received standard breast cancer treatment and a decrement to quality of life corresponding to the treatment. If the DCIS test indicated non-progressive DCIS, no treatment was received and women continued routine annual surveillance mammography. A range of test performance characteristics and prevalence of non-progressive disease were simulated. Analysis compared discounted quality-adjusted life years (QALYs) and costs for test scenarios to base-case scenarios without the test.

Results: Compared to the base case, a perfect prognostic test resulted in a 40% decrease in treatment costs, from $13,321 to $8005 USD per DCIS case. A perfect test produced 0.04 additional QALYs (16 days) for women diagnosed with DCIS, added to the base case of 5.88 QALYs per DCIS case. The results were sensitive to the performance characteristics of the prognostic test, the proportion of DCIS cases that were non-progressive in the model, and the frequency of mammography screening in the population.

Conclusion: A prognostic test that identifies non-progressive DCIS would substantially reduce treatment costs but result in only modest improvements in quality of life when averaged over all DCIS cases.
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http://dx.doi.org/10.1007/s10549-017-4582-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5963699PMC
February 2018

IL-1/inhibitory κB kinase ε-induced glycolysis augment epithelial effector function and promote allergic airways disease.

J Allergy Clin Immunol 2018 08 3;142(2):435-450.e10. Epub 2017 Nov 3.

Department of Pathology and Laboratory Medicine, University of Vermont College of Medicine, Burlington, Vt. Electronic address:

Background: Emerging studies suggest that enhanced glycolysis accompanies inflammatory responses. Virtually nothing is known about the relevance of glycolysis in patients with allergic asthma.

Objectives: We sought to determine whether glycolysis is altered in patients with allergic asthma and to address its importance in the pathogenesis of allergic asthma.

Methods: We examined alterations in glycolysis in sputum samples from asthmatic patients and primary human nasal cells and used murine models of allergic asthma, as well as primary mouse tracheal epithelial cells, to evaluate the relevance of glycolysis.

Results: In a murine model of allergic asthma, glycolysis was induced in the lungs in an IL-1-dependent manner. Furthermore, administration of IL-1β into the airways stimulated lactate production and expression of glycolytic enzymes, with notable expression of lactate dehydrogenase A occurring in the airway epithelium. Indeed, exposure of mouse tracheal epithelial cells to IL-1β or IL-1α resulted in increased glycolytic flux, glucose use, expression of glycolysis genes, and lactate production. Enhanced glycolysis was required for IL-1β- or IL-1α-mediated proinflammatory responses and the stimulatory effects of IL-1β on house dust mite (HDM)-induced release of thymic stromal lymphopoietin and GM-CSF from tracheal epithelial cells. Inhibitor of κB kinase ε was downstream of HDM or IL-1β and required for HDM-induced glycolysis and pathogenesis of allergic airways disease. Small interfering RNA ablation of lactate dehydrogenase A attenuated HDM-induced increases in lactate levels and attenuated HDM-induced disease. Primary nasal epithelial cells from asthmatic patients intrinsically produced more lactate compared with cells from healthy subjects. Lactate content was significantly higher in sputum supernatants from asthmatic patients, notably those with greater than 61% neutrophils. A positive correlation was observed between sputum lactate and IL-1β levels, and lactate content correlated negatively with lung function.

Conclusions: Collectively, these findings demonstrate that IL-1β/inhibitory κB kinase ε signaling plays an important role in HDM-induced glycolysis and pathogenesis of allergic airways disease.
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http://dx.doi.org/10.1016/j.jaci.2017.08.043DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6278819PMC
August 2018

Geometric Characteristics of the Knee Are Associated With a Noncontact ACL Injury to the Contralateral Knee After Unilateral ACL Injury in Young Female Athletes.

Am J Sports Med 2017 Dec 13;45(14):3223-3232. Epub 2017 Oct 13.

Department of Orthopaedics and Rehabilitation, University of Vermont, Burlington, Vermont, USA.

Background: Contralateral anterior cruciate ligament (CACL) injury after recovery from a first-time ACL rupture occurs at a high rate in young females; however, little is known about the risk factors associated with bilateral ACL trauma.

Hypothesis: The geometric characteristics of the contralateral knee at the time of the initial ACL injury are associated with risk of suffering a CACL injury in these female athletes.

Study Design: Case-control study; Level of evidence, 3.

Methods: Sixty-two female athletes who suffered their first noncontact ACL injury while participating in sports at the high school or college level were identified, and geometry of the femoral notch, ACL, tibial spines, tibial subchondral bone, articular cartilage surfaces, and menisci of the contralateral, uninjured, knee was characterized in 3 dimensions. We were unable to contact 7 subjects and followed the remaining 55 until either a CACL injury or an ACL graft injury occurred or, if they were not injured, until the date of last contact (mean, 34 months after their first ACL injury). Cox regression was used to identify risk factors for CACL injury.

Results: Ten (18.2%) females suffered a CACL injury. Decreases of 1 SD in femoral intercondylar notch width (measured at its outlet and anterior attachment of the ACL) were associated with increases in the risk of suffering a CACL injury (hazard ratio = 1.88 and 2.05, respectively). Likewise, 1 SD decreases in medial-lateral width of the lateral tibial spine, height of the medial tibial spine, and thickness of the articular cartilage located at the posterior region of the medial tibial compartment were associated with 3.59-, 1.75-, and 2.15-fold increases in the risk of CACL injury, respectively.

Conclusion: After ACL injury, subsequent injury to the CACL is influenced by geometry of the structures that surround the ACL (the femoral notch and tibial spines). This information can be used to identify individuals at increased risk for CACL trauma, who might benefit from targeted risk-reduction interventions.
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http://dx.doi.org/10.1177/0363546517735091DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6533631PMC
December 2017

Characterization of Prepractice Injury Prevention Exercises of High School Athletic Teams.

Sports Health 2017 Nov/Dec;9(6):511-517. Epub 2017 Oct 6.

Department of Orthopaedics & Rehabilitation, University of Vermont Larner College of Medicine, Burlington, Vermont.

Background: Static and dynamic exercises are performed before activity to decrease injury risk and increase performance. Although evidence supports using dynamic over static stretching and performing Fédération Internationale de Football Association (FIFA) 11+ as a dynamic prepractice routine, we do not know the frequency at which these exercises are utilized in high school populations.

Hypothesis: We hypothesize that there is a wide variety of preparticipation exercises performed by high school athletes, and that few high school teams perform FIFA 11+ as an injury prevention program in its entirety.

Study Design: Observational study.

Level Of Evidence: Level 4.

Methods: High school prepractice routines were observed for 185 teams (football, soccer, basketball, and lacrosse) over 1 season. The percentages of team warm-up routines that included components of FIFA 11+ were calculated, and the chi-square test was used to compare sex, sport, and level of competition.

Results: Of a total 644 warm-up observations, 450 (69.9%) included only non-FIFA 11+ exercises, 56 (8.7%) included at least 1 FIFA 11+ exercise, and 38 (5.9%) included only jogging; 69 (10.6%) consisted only of sport-specific activities. The type of warm-up differed significantly between males and females ( P = 0.002), sports ( P < 0.001), and level of competition ( P < 0.001). Static stretching and athletes stretching on their own were observed in 14% and 15% of all observations. No team performed the FIFA 11+ injury prevention routine in its entirety.

Conclusion: The type of warm-up differed by sex, sport, and level of competition. Static stretching was performed more frequently than anticipated, and an entire FIFA 11+ warm-up was never performed.

Clinical Relevance: We need to identify the exercises that decrease injury and increase performance and better inform the athletic population about the risks and benefits of static and dynamic warm-up programs.
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http://dx.doi.org/10.1177/1941738117733981DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5665116PMC
November 2017

Frequencies of micronucleated reticulocytes, a dosimeter of DNA double-strand breaks, in infants receiving computed tomography or cardiac catheterization.

Mutat Res 2017 08 20;820:8-18. Epub 2017 May 20.

Departments of Pathology and Laboratory Medicine (RJA, VEW), Pediatrics (JAN), Medicine (LKAL), and Medical Biostatistics (PMV), Robert Larner College of Medicine, University of Vermont, Burlington, VT 05405 USA.

The use of computed tomography (CT scans) has increased dramatically in recent decades, raising questions about the long-term safety of CT-emitted x-rays especially in infants who are more sensitive to radiation-induced effects. Cancer risk estimates for CT scans typically are extrapolated from models; therefore, new approaches measuring actual DNA damage are needed for improved estimations. Hence, changes in a dosimeter of DNA double-strand breaks, micronucleated reticulocytes (MN-RETs) measured by flow cytometry, were investigated in mice and infants exposed to CT scans. In male C57BL/6N mice (6-8 weeks-of-age), there was a dose-related increase in MN-RETs in blood samples collected 48h after CT scans delivering targeted exposures of 1-130 cGy x-rays (n=5-10/group, r=0.994, p=0.01), with significant increases occurring at exposure levels as low as 0.83 cGy x-rays compared to control mice (p=0.002). In paired blood specimens from infants with no history of a prior CT scan, there was no difference in MN-RET frequencies found 2h before (mean, 0.10±0.07%) versus 48h after (mean, 0.11±0.05%) a scheduled CT scan/cardiac catheterization. However, in infants having prior CT scan(s), MN-RET frequencies measured at 48h after a scheduled CT scan (mean=0.22±0.12%) were significantly higher than paired baseline values (mean, 0.17±0.07%; p=0.032). Increases in baseline (r=0.722, p<0.001) and 48-h post exposure (r=0.682, p<0.001) levels of MN-RETs in infants with a history of prior CT scans were significantly correlated with the number of previous CT scans. These preliminary findings suggest that prior CT scans increase the cellular responses to subsequent CT exposures. Thus, further investigation is needed to characterize the potential cancer risk from single versus repeated CT scans or cardiac catheterizations in infants.
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http://dx.doi.org/10.1016/j.mrgentox.2017.05.006DOI Listing
August 2017

Relationship between geometry of the extensor mechanism of the knee and risk of anterior cruciate ligament injury.

J Orthop Res 2017 05 12;35(5):965-973. Epub 2016 Dec 12.

McClure Musculoskeletal Research Center, Department of Orthopedics and Rehabilitation, College of Medicine, University of Vermont, Burlington, Vermont.

The complex inter-segmental forces that are developed across an extended knee by body weight and contraction of the quadriceps muscle group transmits an anteriorly directed force on the tibia that strain the anterior cruciate ligament (ACL). We hypothesized that a relationship exists between geometry of the knees extensor mechanism and the risk of sustaining a non-contact ACL injury. Geometry of the extensor mechanism was characterized using MRI scans of the knees of 88 subjects that suffered their first non-contact ACL injury and 88 matched control subjects with normal knees that were on the same team. The orientation of the patellar tendon axis was measured relative to the femoral flexion-extension axis to determine the extensor moment arm (EMA), and relative to tibial long axis to measure coronal patellar tendon angle (CPTA) and sagittal patellar tendon angle (SPTA). Associations between these parameters and ACL injury risk were tested with and without adjustment for flexion and internal rotation position of the tibia relative to the femur during MRI data acquisition. After adjustment for internal rotation position of the tibia relative to the femur there were no associations between EMA, CPTA, and SPTA and risk of suffering an ACL injury. However, increased internal rotation position of the tibia relative to the femur was significantly associated with increased risk of ACL injury in female athletes both in univariate analysis (Odds Ratio = 1.16 per degree of internal rotation of the tibia, p = 0.002), as well as after adjustment for EMA, CPTA, and SPTA.: © 2016 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 35:965-973, 2017.
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http://dx.doi.org/10.1002/jor.23366DOI Listing
May 2017

Lung-cancer mortality among Vermont granite workers: factors influencing exposure-response evaluation.

Occup Environ Med 2017 03 7;74(3):211-217. Epub 2016 Nov 7.

Department of Mathematics and Statistics, University of Vermont, Burlington, Vermont, USA.

Objective: To understand why 2 studies relating crystalline silica exposure to lung-cancer mortality in Vermont granite workers yielded conflicting results.

Methods: Data used in the 2 studies were linked to identify discrepancies. Mortality data and employment histories from the earlier study were revised based on data obtained in the later study. SMR were computed and Poisson regressions corresponding to those in the earlier study were performed using the original and revised data. Analyses were repeated with the addition of workers omitted from the earlier study.

Results: After correction of incomplete mortality and employment information in the original data, the overall SMR for the cohort in the earlier study increased from 1.17 (95% CI 1.03 to 1.36) to 1.39 (95% CI 1.22 to 1.59), and was similar to the SMR of 1.37 observed in the later study (95% CI 1.23 to 1.52). The exposure-response relationship was attenuated, particularly when person-years in all exposure categories were included in the analysis. Inclusion of additional workers had a smaller impact on the SMRs but further attenuated the exposure-response relationship.

Conclusions: Differing results from the 2 studies are partly attributable to incomplete vital status and work history information used in the earlier study, as well as differences in cohort inclusion criteria. However, differences in length of follow-up and other factors likely play a larger role.
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http://dx.doi.org/10.1136/oemed-2015-103527DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5520268PMC
March 2017

Relation of Serum Estrogen Metabolites with Terminal Duct Lobular Unit Involution Among Women Undergoing Diagnostic Image-Guided Breast Biopsy.

Horm Cancer 2016 12 2;7(5-6):305-315. Epub 2016 May 2.

Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD, USA.

Higher levels of circulating estrogens and estrogen metabolites (EMs) have been associated with higher breast cancer risk. In breast tissues, reduced levels of terminal duct lobular unit (TDLU) involution, as reflected by higher numbers of TDLUs and acini per TDLU, have also been linked to elevated breast cancer risk. However, it is unknown whether reduced TDLU involution mediates the risk associated with circulating EMs. In a cross-sectional analysis of 94 premenopausal and 92 postmenopausal women referred for clinical breast biopsy at an academic facility in Vermont, we examined the associations of 15 EMs, quantified using liquid chromatography-tandem mass spectrometry, with the number of TDLUs and acini count/TDLU using zero-inflated Poisson regression with a robust variance estimator and ordinal logistic regression models, respectively. All analyses were stratified by menopausal status and adjusted for potential confounders. Among premenopausal women, comparing the highest vs. the lowest tertiles, levels of unconjugated estradiol (risk ratio (RR) = 1.74, 95 % confidence interval (CI) = 1.06-2.87, p trend = 0.03), 2-hydroxyestrone (RR = 1.74, 95 % CI = 1.01-3.01, p trend = 0.04), and 4-hydroxyestrone (RR = 1.74, 95 % CI = 0.99-3.06, p trend = 0.04) were associated with significantly higher TDLU count. Among postmenopausal women, higher levels of estradiol (RR = 2.09, 95 % CI = 1.01-4.30, p trend = 0.04) and 16α-hydroxyestrone (RR = 2.27, 95 % CI = 1.29-3.99, p trend = 0.02) were significantly associated with higher TDLU count. Among postmenopausal women, higher levels of EMs, specifically conjugated estrone and 2- and 4-pathway catechols, were also associated with higher acini count/TDLU. Our data suggest that higher levels of serum EMs are generally associated with lower levels of TDLU involution.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5088060PMC
http://dx.doi.org/10.1007/s12672-016-0265-2DOI Listing
December 2016

Relationship of Predicted Risk of Developing Invasive Breast Cancer, as Assessed with Three Models, and Breast Cancer Mortality among Breast Cancer Patients.

PLoS One 2016 25;11(8):e0160966. Epub 2016 Aug 25.

Division of Cancer Epidemiology and Genetics, Bethesda, United States of America.

Purpose: Breast cancer risk prediction models are used to plan clinical trials and counsel women; however, relationships of predicted risks of breast cancer incidence and prognosis after breast cancer diagnosis are unknown.

Methods: Using largely pre-diagnostic information from the Breast Cancer Surveillance Consortium (BCSC) for 37,939 invasive breast cancers (1996-2007), we estimated 5-year breast cancer risk (<1%; 1-1.66%; ≥1.67%) with three models: BCSC 1-year risk model (BCSC-1; adapted to 5-year predictions); Breast Cancer Risk Assessment Tool (BCRAT); and BCSC 5-year risk model (BCSC-5). Breast cancer-specific mortality post-diagnosis (range: 1-13 years; median: 5.4-5.6 years) was related to predicted risk of developing breast cancer using unadjusted Cox proportional hazards models, and in age-stratified (35-44; 45-54; 55-69; 70-89 years) models adjusted for continuous age, BCSC registry, calendar period, income, mode of presentation, stage and treatment. Mean age at diagnosis was 60 years.

Results: Of 6,021 deaths, 2,993 (49.7%) were ascribed to breast cancer. In unadjusted case-only analyses, predicted breast cancer risk ≥1.67% versus <1.0% was associated with lower risk of breast cancer death; BCSC-1: hazard ratio (HR) = 0.82 (95% CI = 0.75-0.90); BCRAT: HR = 0.72 (95% CI = 0.65-0.81) and BCSC-5: HR = 0.84 (95% CI = 0.75-0.94). Age-stratified, adjusted models showed similar, although mostly non-significant HRs. Among women ages 55-69 years, HRs approximated 1.0. Generally, higher predicted risk was inversely related to percentages of cancers with unfavorable prognostic characteristics, especially among women 35-44 years.

Conclusions: Among cases assessed with three models, higher predicted risk of developing breast cancer was not associated with greater risk of breast cancer death; thus, these models would have limited utility in planning studies to evaluate breast cancer mortality reduction strategies. Further, when offering women counseling, it may be useful to note that high predicted risk of developing breast cancer does not imply that if cancer develops it will behave aggressively.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0160966PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4999085PMC
July 2017

Relationships between mammographic density, tissue microvessel density, and breast biopsy diagnosis.

Breast Cancer Res 2016 08 23;18(1):88. Epub 2016 Aug 23.

Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.

Background: Women with high levels of mammographic density (MD) have a four- to six-fold increased risk of developing breast cancer; however, most neither have a prevalent tumor nor will they develop one. Magnetic resonance imaging (MRI) studies suggest that background parenchymal enhancement, an indicator of vascularity, is related to increased breast cancer risk. Correlations of microvessel density (MVD) in tissue, MD and biopsy diagnosis have not been defined, and we investigated these relationships among 218 women referred for biopsy.

Methods: MVD was determined by counting CD31-positive vessels in whole sections of breast biopsies in three representative areas; average MVD was transformed to approximate normality. Using digital mammograms, we quantified MD volume with single X-ray absorptiometry. We used linear regression to evaluate associations between MVD and MD adjusted for age and body mass index (BMI) overall, and stratified by biopsy diagnosis: cases (in situ or invasive cancer, n = 44) versus non-cases (non-proliferative or proliferative benign breast disease, n = 174). Logistic regression adjusted for age, BMI, and MD was used to calculate odds ratios (ORs) and 95 % confidence intervals (CIs) for associations between MVD and biopsy diagnosis. We also assessed whether the MVD-breast cancer association varied by MD.

Results: MVD and MD were not consistently associated. Higher MVD was significantly associated with higher odds of in situ/invasive disease (ORAdjusted = 1.69, 95 % CI = 1.17-2.44). MVD-breast cancer associations were strongest among women with greater non-dense volume.

Conclusions: Increased MVD in tissues is associated with breast cancer, independently of MD, consistent with MRI findings suggestive of its possible value as a radiological cancer biomarker.
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http://dx.doi.org/10.1186/s13058-016-0746-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4995674PMC
August 2016

Geometric Risk Factors Associated With Noncontact Anterior Cruciate Ligament Graft Rupture.

Am J Sports Med 2016 Oct 11;44(10):2537-2545. Epub 2016 Aug 11.

Department of Orthopaedics and Rehabilitation, University of Vermont, Burlington, Vermont, USA

Background: Anterior cruciate ligament (ACL) graft rupture occurs at a high rate, especially in young athletes. The geometries of the tibial plateau and femoral intercondylar notch are risk factors for first-time ACL injury; however, little is known about the relationship between these geometries and risk of ACL graft rupture.

Hypothesis: The geometric risk factors for noncontact graft rupture are similar to those previously identified for first-time noncontact ACL injury, and sex-specific differences exist.

Study Design: Case-control study; Level of evidence, 3.

Methods: Eleven subjects who suffered a noncontact ACL graft rupture and 44 subjects who underwent ACL reconstruction but did not experience graft rupture were included in the study. Using magnetic resonance imaging, the geometries of the tibial plateau subchondral bone, articular cartilage, meniscus, tibial spines, and femoral notch were measured. Risk factors associated with ACL graft rupture were identified using Cox regression.

Results: The following were associated with increased risk of ACL graft injury in males: increased posterior-inferior-directed slope of the articular cartilage in the lateral tibial plateau measured at 2 locations (hazard ratio [HR] = 1.50, P = .029; HR = 1.39, P = .006), increased volume (HR = 1.45, P = .01) and anteroposterior length (HR = 1.34, P = .0023) of the medial tibial spine, and increased length (HR = 1.18, P = .0005) and mediolateral width (HR = 2.19, P = .0004) of the lateral tibial spine. In females, the following were associated with increased risk of injury: decreased volume (HR = 0.45, P = .02) and height (HR = 0.46, P = .02) of the medial tibial spine, decreased slope of the lateral tibial subchondral bone (HR = 0.72, P = .01), decreased height of the posterior horn of the medial meniscus (HR = 0.09, P = .001), and decreased intercondylar notch width at the anterior attachment of the ACL (HR = 0.72, P = .02).

Conclusion: The geometric risk factors for ACL graft rupture are different for males and females. For females, a decreased femoral intercondylar notch width and a decreased height of the posterior medial meniscus were risk factors for ACL graft rupture that have also been found to be risk factors for first-time injury. There were no risk factors in common between ACL graft injury and first-time ACL injury for males.
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http://dx.doi.org/10.1177/0363546516657525DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6604045PMC
October 2016

Influence of Age and Comorbidity on Colorectal Cancer Screening in the Elderly.

Am J Prev Med 2016 09 22;51(3):e67-75. Epub 2016 Jun 22.

Kaiser Permanente Division of Research, Oakland, California.

Introduction: Expert recommendations differ for colorectal cancer screening in the elderly. Recent studies suggest that healthy adults aged >75 years may benefit from screening. This study examined screening use and follow-up, and how they varied by health status within age strata, among a large cohort of elderly individuals in community settings.

Methods: A population-based, longitudinal cohort study was conducted among health plan members aged 65-89 years enrolled during 2011-2012 in three integrated healthcare systems participating in the Population-Based Research Optimizing Screening through Personalized Regimens consortium. Comorbidity measurements used the Charlson index. Analyses, conducted in 2015, comprised descriptive statistics and multivariable modeling that estimated age by comorbidity-specific percentages of patients for two outcomes: colorectal cancer screening uptake and follow-up of abnormal fecal blood tests.

Results: Among 846,267 patients, 72% were up-to-date with colorectal cancer screening. Of patients with a positive fecal blood test, 65% received follow-up colonoscopy within 3 months. Likelihood of being up-to-date and receiving timely follow-up was significantly lower for patients aged ≥76 years than their younger counterparts (p<0.001). Comorbidity was less influential than age and more strongly related to timely follow-up than being up-to-date. In all age groups, considerable numbers of patients with no/low comorbidity were not up-to-date or did not receive timely follow-up.

Conclusions: In three integrated healthcare systems, many older, relatively healthy patients were not screening up-to-date, and some relatively young, healthy patients did not receive timely follow-up. Findings suggest a need for re-evaluating age-based screening guidelines and improving screening completion among the elderly.
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http://dx.doi.org/10.1016/j.amepre.2016.04.018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4992638PMC
September 2016
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