Demographic characteristics and trends of cell phone use while driving citations in selected states in the United States, 2010-2020.

OBJECTIVE: Distracted driving is a leading cause of motor vehicle crashes, and cell phone use is a major source of in-vehicle distraction. Many states in the United States have enacted cell phone use laws to regulate drivers' cell phone use behavior to enhance traffic safety. Numerous studies have examined the effects of such laws on drivers' cell phone use behavior based on self-reported and roadside observational data. However, little was known about who actually violated the laws at the enforcement level. This study sought to uncover the demographic characteristics of drivers cited for cell phone use while driving and whether these characteristics changed over time since the enactment of cell phone laws. METHODS: We acquired useable traffic citation data for 7 states in the United States from 2010 to 2020 and performed descriptive and regression analyses. RESULTS: Male drivers were cited more for cell phone use while driving. Handheld and texting bans were associated with a greater proportion of cited drivers aged 40 and above, compared to texting-only bans. Trends in the citations issued based on drivers' age group following the enactment of different cell phone laws were also uncovered. The proportion of citations issued to drivers aged 60 and above increased over time but the temporal trend remained insignificant when population effect was considered. CONCLUSIONS: This study examined the demographic characteristics of drivers cited for cell phone use while driving in selected states with texting-only bans or handheld and texting bans. The results reveal policy-based differences in trends in the proportion of citations issued to drivers in different age groups.

Preclinical Characterization of the Anti-Leukemia Activity of the CD33/CD16a/NKG2D Immune-Modulating TriNKET® CC-96191.

Increasing efforts are focusing on natural killer (NK) cell immunotherapies for AML. Here, we characterized CC-96191, a novel CD33/CD16a/NKG2D immune-modulating TriNKET®. CC-96191 simultaneously binds CD33, NKG2D, and CD16a, with NKG2D and CD16a co-engagement increasing the avidity for, and activation of, NK cells. CC-96191 was broadly active against human leukemia cells in a strictly CD33-dependent manner, with maximal efficacy requiring the co-engagement of CD16a and NKG2D. A frequent CD33 single nucleotide polymorphism, R69G, reduced CC-96191 potency but not maximal activity, likely because of reduced CD33 binding. Similarly, the potency, but not the maximal activity, of CC-96191 was reduced by high concentrations of soluble CD33; in contrast, the soluble form of the NKG2D ligand MICA did not impact activity. In the presence of CD33+ AML cells, CC-96191 activated NK cells but not T cells; while maximum anti-AML efficacy was similar, soluble cytokine levels were 10- to >100-fold lower than with a CD33/CD3 bispecific antibody. While CC-96191-mediated cytolysis was not affected by ABC transporter proteins, it was reduced by anti-apoptotic BCL-2 family proteins. Finally, in patient marrow specimens, CC-96191 eliminated AML cells but not normal monocytes, suggesting selectivity of TriNKET-induced cytotoxicity toward neoplastic cells. Together, these findings support the clinical exploration of CC-96191 as in NCT04789655.

A comparison of licensed driver counts from the Federal Highway Administration and driver licensing agencies in 11 states.

Objective: Those who study motor vehicle crashes may rely on counts of licensed drivers to estimate crash, injury, or fatality rates. These counts may be obtained from the U.S. Department of Transportation Federal Highway Administration's (FHWA) annual Highway Statistics Series or directly from state driver licensing agencies. However, previous studies have questioned the accuracy of these counts provided by the FHWA.Methods: To investigate this issue, we compared counts of licensed drivers from the FHWA and state licensing agencies in 11 states, categorized by sex and age group, from 2013 through 2017. We then assessed the impact of any potential differences by fitting two sets of Poisson regression models to estimate age- and sex-based driver fatality rate ratios. One set of models used counts from the FHWA as the offset and the other used counts from state licensing agencies.Results: Our analysis found that the differences between FHWA and state counts varied markedly. Seven states had substantial differences for at least one age group that spanned the entire study period. In several cases, these differences in license counts were large enough to produce directly contradictory driver fatality rate ratio estimates when comparing age groups.Conclusions: These findings highlight the continued concern regarding the accuracy of licensed driver counts from the FHWA and extend previous studies by illustrating the impact of using FHWA counts on statistical inference. We recommend against using these data for traffic safety research or policy evaluation. Nevertheless, we acknowledge the need for a centralized, easily accessible database for licensed driver data.

Molecular features of luminal breast cancer defined through spatial and single-cell transcriptomics.

BACKGROUND: Intratumour heterogeneity is a hallmark of most solid tumours, including breast cancers. We applied spatial transcriptomics and single-cell RNA-sequencing on patient-derived xenografts (PDXs) to profile spatially resolved cell populations within oestrogen receptor-positive (ER+ ) breast cancer and to elucidate their importance in oestrogen-dependent tumour growth. METHODS: Two PDXs of 'ER-high' breast cancers with opposite oestrogen-mediated growth responses were investigated: oestrogen-suppressed GS3 (80-100% ER) and oestrogen-dependent SC31 (40-90% ER) models. The observation was validated via single-cell analyses on an 'ER-low' PDX, GS1 (5% ER). The results from our spatial and single-cell analyses were further supported by a public ER+ breast cancer single-cell dataset and protein-based dual immunohistochemistry (IHC) of SC31 examining important luminal cancer markers (i.e., ER, progesterone receptor and Ki67). The translational implication of our findings was assessed by clinical outcome analyses on publicly available cohorts. RESULTS: Our space-gene-function study revealed four spatially distinct compartments within ER+ breast cancers. These compartments showed functional diversity (oestrogen-responsive, proliferative, hypoxia-induced and inflammation-related). The 'proliferative' population, rather than the 'oestrogen-responsive' compartment, was crucial for oestrogen-dependent tumour growth, leading to the acquisition of luminal B-like features. The cells expressing typical oestrogen-responsive genes like PGR were not directly linked to oestrogen-dependent proliferation. Dual IHC analyses demonstrated the distinct contribution of the Ki67+ proliferative cells toward oestrogen-mediated growth and their response to a CDK4/6 inhibitor. The gene signatures derived from the proliferative, hypoxia-induced and inflammation-related compartments were significantly correlated with worse clinical outcomes, while patients with the oestrogen-responsive signature showed better prognoses, suggesting that this compartment would not be directly associated with oestrogen-dependent tumour progression. CONCLUSIONS: Our study identified the gene signature in our 'proliferative' compartment as an important determinant of luminal cancer subtypes. This 'proliferative' cell population is a causative feature of luminal B breast cancer, contributing toward its aggressive behaviours.

Radiomic analysis of the proximal femur in osteoporosis women using 3T MRI.

Introduction: Osteoporosis (OP) results in weak bone and can ultimately lead to fracture. MRI assessment of bone structure and microarchitecture has been proposed as method to assess bone quality and fracture risk in vivo. Radiomics provides a framework to analyze the textural information of MR images. The purpose of this study was to analyze the radiomic features and its abilityto differentiate between subjects with and without prior fragility fracture. Methods: MRI acquisition was performed on n = 45 female OP subjects: 15 with fracture history (Fx) and 30 without fracture history (nFx) using a high-resolution 3D Fast Low Angle Shot (FLASH) sequence at 3T. Second and first order radiomic features were calculated in the trabecular region of the proximal femur on T1-weighted MRI signal of a matched dataset. Significance of the feature's predictive ability was measured using Wilcoxon test and Area Under the ROC (AUROC) curve analysis. The features were correlated DXA and FRAX score. Result: A set of three independent radiomic features (Dependence Non-Uniformity (DNU), Low Gray Level Emphasis (LGLE) and Kurtosis) showed significant ability to predict fragility fracture (AUROC DNU = 0.751, p < 0.05; AUROC LGLE = 0.729, p < 0.05; AUROC Kurtosis = 0.718, p < 0.05) with low to moderate correlation with FRAX and DXA. Conclusion: Radiomic features can measure bone health in MRI of proximal femur and has the potential to predict fracture.

Total Hip Arthroplasty is the Most Effective Treatment for Atraumatic Subchondral Insufficiency Fractures of the Femoral Head.

BACKGROUND: Subchondral insufficiency fracture of the femoral head (SIFH) is a relatively newly used diagnosisfollowing an insidious onset of hip pain in individuals without apparent antecedent trauma. The aim of this study was to investigate the outcomes of a consecutive series of patients with SIFH treated at one institution. METHODS: A total of 93 patients aged 23 to 91 years who were treated for SIFH in the outpatient clinics at one academic, urban medical center between August 2012 and August 2019 were identified. The diagnosis was made by magnetic resonance imaging or radiograph of the hip and was confirmed by a radiologist specialized in orthopedic surgery. Patient demographics, injury history, duration of pain, treatment type, and persistence of pain were recorded. RESULTS: Sixty-five (69.9%) patients with a mean age of 64.2 ± 9.4 years ultimately underwent total hip arthroplasty (THA). Twenty-eight (30.1%) patients chose no surgical intervention. Patients who underwent THA had less pain at their final follow-up appointment than patients who elected non-operative treatment (p < 0.001). At their final follow-up appointments, 92.9% of patients treated non-operatively reported pain, compared to only 13.8% of patients who underwent THA who had pain. Age, body mass index, and duration of pain prior to initial complaint did not affect presence of continued pain at final follow-up appointments, regardless of treatment type (p > 0.05). CONCLUSION: In the majority of patients, SIFH is often not sufficiently managed with non-operative treatments. Pain reported among patients with confirmed or suspected SIFH is usually severe and interferes with patients' ability to perform their activities of daily life. Total hip arthroplasty seems to be the most reliable method of treatment for this condition. Physicians who treat patients with SIFH should counsel them as to the expectations of recovery and the potential for poorer outcome if treated without THA.

Lifestyle Related Cancer Risk and Protective Behaviors Vary among a Convenient Sample of Physically Active, Young-to-Middle-Aged Adults 18-49.

It is an assumption that physically active adults lead an overall healthy lifestyle. To examine this assumption, we administered a cross-sectional, web-based survey to a sample of young-to-middle-aged US adults between 18 and 49 who self-reported participation in at least one recreational sporting event in the past month. Logistic regressions were conducted to examine demographic characteristics associated with cancer risk and protective behaviors. Gender was represented equally (N = 938), and the average age was 32 years (SD: 8.4). Most participants reported >three days of moderate- to high-intensity physical activity (79%), but not meeting fruit and vegetable consumption guidelines (78%). Many reported current tobacco use (32%), binge drinking at least once in the past 30 days (62%), and suboptimal sun protection use (67%). Participation in lifestyle-related cancer risk and protective behaviors varied based on age, sex, education, routine doctor visits, perceived overall health, health-information-seeking behavior (how participants obtained health information), or team-based sport participation in regression models. Future interventions should be tailored to address varied cancer risk profiles among even physically active adults to encourage multiple healthy behavior changes.

Prediction of total knee replacement using deep learning analysis of knee MRI.

Current methods for assessing knee osteoarthritis (OA) do not provide comprehensive information to make robust and accurate outcome predictions. Deep learning (DL) risk assessment models were developed to predict the progression of knee OA to total knee replacement (TKR) over a 108-month follow-up period using baseline knee MRI. Participants of our retrospective study consisted of 353 case-control pairs of subjects from the Osteoarthritis Initiative with and without TKR over a 108-month follow-up period matched according to age, sex, ethnicity, and body mass index. A traditional risk assessment model was created to predict TKR using baseline clinical risk factors. DL models were created to predict TKR using baseline knee radiographs and MRI. All DL models had significantly higher (p < 0.001) AUCs than the traditional model. The MRI and radiograph ensemble model and MRI ensemble model (where TKR risk predicted by several contrast-specific DL models were averaged to get the ensemble TKR risk prediction) had the highest AUCs of 0.90 (80% sensitivity and 85% specificity) and 0.89 (79% sensitivity and 86% specificity), respectively, which were significantly higher (p < 0.05) than the AUCs of the radiograph and multiple MRI models (where the DL models were trained to predict TKR risk using single contrast or 2 contrasts together as input). DL models using baseline MRI had a higher diagnostic performance for predicting TKR than a traditional model using baseline clinical risk factors and a DL model using baseline knee radiographs.

Identification and characterization of a proliferative cell population in estrogen receptor-positive metastatic breast cancer through spatial and single-cell transcriptomics.

Background: Intratumor heterogeneity is a hallmark of most solid tumors, including breast cancers. We applied spatial transcriptomics and single-cell RNA-sequencing technologies to profile spatially resolved cell populations within estrogen receptor-positive (ER + ) metastatic breast cancers and elucidate their importance in estrogen-dependent tumor growth. Methods: Spatial transcriptomics and single-cell RNA-sequencing were performed on two patient-derived xenografts (PDXs) of "ER-high" metastatic breast cancers with opposite estrogen-mediated growth responses: estrogen-suppressed GS3 (80-100% ER) and estrogen-stimulated SC31 (30-75% ER) models. The analyses included samples treated with and without 17ß-estradiol. The findings were validated via scRNA-seq analyses on "ER-low" estrogen-accelerating PDX, GS1 (5% ER). The results from our spatial and single-cell analyses were further supported by the analysis of a publicly available single cell dataset and a protein-based dual immunohistochemical (IHC) evaluation using three important clinical markers [i.e., ER, progesterone receptor (PR), and Ki67]. The translational implication of these results was assessed by clinical outcome analyses on public breast cancer cohorts. Results: Our novel space-gene-function study revealed a "proliferative" cell population in addition to three major spatially distinct compartments within ER + metastatic breast cancers. These compartments showed functional diversity (i.e., estrogen-responsive, proliferative, hypoxia-induced, and inflammation-related). The "proliferative ( MKI67 + )" population, not "estrogen-responsive" compartment, was crucial for estrogen-dependent tumor growth, leading to the acquisition of luminal B features. The cells with induction of typical estrogen-responsive genes such as PGR were not directly linked to estrogen-dependent proliferation. Additionally, the dual IHC analyses demonstrated the distinct contribution of the Ki67 + proliferative cells toward estrogen-mediated growth and their response to palbociclib, a CDK4/6 inhibitor. The gene signatures developed from the proliferative, hypoxia-induced, and inflammation-related compartments were significantly correlated with worse clinical outcomes, while patients with the high estrogen-responsive scores showed better prognosis, confirming that the estrogen-responsive compartment would not be directly associated with estrogen-dependent tumor progression. Conclusions: For the first time, our study elucidated a "proliferative" cell population distinctly distributed in ER + metastatic breast cancers. They contribute differently toward progression of these cancers, and the gene signature in the "proliferative" compartment is an important determinant of luminal cancer subtypes.

Age-Dependent Changes in Knee Cartilage T1 , T2 , and T1p Simultaneously Measured Using MRI Fingerprinting.

BACKGROUND: Magnetic resonance fingerprinting (MRF) techniques have been recently described for simultaneous multiparameter cartilage mapping of the knee although investigation of their ability to detect early cartilage degeneration remains limited. PURPOSE: To investigate age-dependent changes in knee cartilage T1 , T2 , and T1p relaxation times measured using a three-dimensional (3D) MRF sequence in healthy volunteers. STUDY TYPE: Prospective. SUBJECTS: The study group consisted of 24 healthy asymptomatic human volunteers (15 males with mean age 34.9 ± 14.4 years and 9 females with mean age 44.5 ± 13.1 years). FIELD STRENGTH/SEQUENCE: A 3.0 T gradient-echo-based 3D-MRF sequence was used to simultaneously create proton density-weighted images and T1 , T2 , and T1p maps of knee cartilage. ASSESSMENT: Mean global cartilage and regional cartilage (lateral femur, lateral tibia, medial femur, medial tibia, and patella) T1 , T2 , and T1ρ relaxation times of the knee were measured. STATISTICAL TESTS: Kruskal-Wallis tests were used to compared cartilage T1 , T2 , and T1ρ relaxation times between different age groups, while Spearman correlation coefficients was used to determine the association between age and cartilage T1 , T2 , and T1ρ relaxation times. The value of P < 0.05 was considered statistically significant. RESULTS: Higher age groups showed higher global and regional cartilage T1 , T2 , and T1ρ . There was a significant difference between age groups in global cartilage T2 and T1ρ but no significant difference (P = 0.13) in global cartilage T1. Significant difference was also present between age groups in cartilage T2 and T1ρ for medial femur cartilage and medial tibia cartilage. There were significant moderate correlations between age and T2 and T1ρ for global cartilage (R2  = 0.63-0.64), medial femur cartilage (R2  = 0.50-0.56), and medial tibia cartilage (R2  = 0.54-0.66). CONCLUSION: Cartilage T2 and T1p relaxation times simultaneously measured using a 3D-MRF sequence in healthy volunteers showed age-dependent changes in knee cartilage, primarily within the medial compartment.

Hazardous alcohol use and HIV indicators in six African countries: results from the Population-based HIV Impact Assessments, 2015-2017.

INTRODUCTION: Hazardous alcohol use (HAU), defined as a pattern of alcohol consumption that increases the risk of harmful consequences for the user or others, is associated with an elevated risk of human immunodeficiency virus (HIV) infection and poor health outcomes. We describe the association between people living with HIV (PLHIV) who report HAU and key HIV indicators. Gaps in current literature in estimating HAU on HIV outcomes at the regional level of Eastern and Southern Africa still exist and our analysis aims to address this issue. METHODS: We used weighted pooled data (2015-2017) from the nationally representative Population-based HIV Impact Assessments among adults who provided written consent aged 18-59 years from Eswatini, Malawi, Namibia, Tanzania, Zambia and Zimbabwe. We estimated differences in the prevalence of HIV infection and The Joint United Nations Programme on HIV and AIDS (UNAIDS) 90-90-90 indicators between PLHIV by HAU status using log-binomial regression, stratified by sex. HAU was determined using the Alcohol Use Identification Test-Consumption. RESULTS: Among the 9755 women and 4444 men who tested HIV positive, 6.6% of women and 21.8% of men engaged in HAU. Women who reported HAU were more likely to be HIV positive (adjusted prevalence ratio [aPR] = 1.31, 95% CI: 1.18-1.46) compared to those who did not report HAU. For the UNAIDS 90-90-90 targets, women who engaged in HAU were more likely to be unaware of their HIV-positive status (aPR = 1.22, 95% CI: 1.01-1.47) and not on antiretroviral therapy (ART) (aPR = 1.73, 95% CI: 1.26-2.37). Men who engaged in HAU were more likely to be unaware of their HIV-positive status (aPR = 1.56, 95% CI 1.39-1.76) and not on ART (aPR = 1.72, 95% CI: 1.30-2.29). No difference in viral load suppression, defined as <1000 copies/ml of HIV RNA, was seen by sex. CONCLUSIONS: PLHIV who engage in HAU were more likely to have suboptimal outcomes along the HIV care continuum when compared to those who did not engage in HAU. Targeted interventions, such as alcohol screening for HAU in HIV testing and treatment settings and HIV prevention efforts in alcohol-based venues, may help countries reach HIV epidemic control by 2030.

3D magnetic resonance fingerprinting for rapid simultaneous T1, T2, and T1ρ volumetric mapping of human articular cartilage at 3 T.

Quantitative MRI can detect early biochemical changes in cartilage; however, the conventional techniques only measure one parameter (e.g., T1 , T2 , and T1ρ ) at a time while also being comparatively slow. We implemented a 3D magnetic resonance fingerprinting (3D-MRF) technique for simultaneous, volumetric mapping of T1 , T2 , and T1ρ in knee articular cartilage in under 9 min. It is evaluated on 11 healthy volunteers (mean age: 53 ± 9 years), five mild knee osteoarthritis (OA) patients (Kellgren-Lawrence (KL) score: 2, mean age: 60 ± 4 years), and the National Institute of Standards and Technology (NIST)/International Society for Magnetic Resonance in Medicine (ISMRM) system phantom. Proton density image, and T1 , T2, T1ρ relaxation times, and B1 + were estimated in the NIST/ISMRM system phantom as well as in the human knee medial and lateral femur, medial and lateral tibia, and patellar cartilage. The repeatability and reproducibility of the proposed technique were assessed in the phantom using analysis of the Bland-Altman plots. The intrasubject repeatability was assessed with the coefficient of variation (CV) and root mean square CV (rmsCV). The Mann-Whitney U test was used to assess the difference between healthy subjects and mild knee OA patients. The Bland-Altman plots in the NIST/ISMRM phantom demonstrated an average difference of 0.001% ± 015%, 1.2% ± 7.1%, and 0.47% ± 3% between two scans from the same 3-T scanner (repeatability), and 0.002% ± 015%, 0.62% ± 10.5%, and 0.97% ± 14% between the scans acquired on two different 3-T scanners (reproducibility) for T1 , T2 , and T1ρ , respectively. The in vivo knee study showed excellent repeatability with rmsCV less than 1%, 2%, and 1% for T1 , T2 , and T1ρ , respectively. T1ρ relaxation time in the mild knee OA patients was significantly higher (p < 0.05) than in healthy subjects. The proposed 3D-MRF sequence is fast, reproducible, robust to B1 + inhomogeneity, and can simultaneously measure the T1 , T2 , T1ρ , and B1 + volumetric maps of the knee joint in a single scan within a clinically feasible scan time.

Methods for conducting trends analysis: roadmap for comparing outcomes from three national HIV Population-based household surveys in Kenya (2007, 2012, and 2018).

BACKGROUND: For assessing the HIV epidemic in Kenya, a series of independent HIV indicator household-based surveys of similar design can be used to investigate the trends in key indicators relevant to HIV prevention and control and to describe geographic and sociodemographic disparities, assess the impact of interventions, and develop strategies. We developed methods and tools to facilitate a robust analysis of trends across three national household-based surveys conducted in Kenya in 2007, 2012, and 2018. METHODS: We used data from the 2007 and 2012 Kenya AIDS Indicator surveys (KAIS 2007 and KAIS 2012) and the 2018 Kenya Population-based HIV Impact Assessment (KENPHIA 2018). To assess the design and other variables of interest from each study, variables were recoded to ensure that they had equivalent meanings across the three surveys. After assessing weighting procedures for comparability, we used the KAIS 2012 nonresponse weighting procedure to revise normalized KENPHIA weights. Analyses were restricted to geographic areas covered by all three surveys. The revised analysis files were then merged into a single file for pooled analysis. We assessed distributions of age, sex, household wealth, and urban/rural status to identify unexpected changes between surveys. To demonstrate how a trend analysis can be carried out, we used continuous, binary, and time-to-event variables as examples. Specifically, temporal trends in age at first sex and having received an HIV test in the last 12 months were used to demonstrate the proposed analytical approach. These were assessed with respondent-specific variables (age, sex, level of education, and marital status) and household variables (place of residence and wealth index). All analyses were conducted in SAS 9.4, but analysis files were created in Stata and R format to support additional analyses. RESULTS: This study demonstrates trends in selected indicators to illustrate the approach that can be used in similar settings. The incidence of early sexual debut decreased from 11.63 (95% CI: 10.95-12.34) per 1,000 person-years at risk in 2007 to 10.45 (95% CI: 9.75-11.2) per 1,000 person-years at risk in 2012 and to 9.58 (95% CI: 9.08-10.1) per 1,000 person-years at risk in 2018. HIV-testing rates increased from 12.6% (95% CI: 11.6%-13.6%) in 2007 to 56.1% (95% CI: 54.6%-57.6%) in 2012 but decreased slightly to 55.6% [95% CI: 54.6%-56.6%) in 2018. The decrease in incidence of early sexual debut could be convincingly demonstrated between 2007 and 2012 but not between 2012 and 2018. Similarly, there was virtually no difference between HIV Testing rates in 2012 and 2018. CONCLUSIONS: Our approach can be used to support trend comparisons for variables in HIV surveys in low-income settings. Independent national household surveys can be assessed for comparability, adjusted as appropriate, and used to estimate trends in key indicators. Analyzing trends over time can not only provide insights into Kenya's progress toward HIV epidemic control but also identify gaps.

Osteoporosis Imaging.

Osteoporosis is the most common disease affecting bones worldwide. Dual x-ray absorptiometry (DXA) is the current reference standard for assessing bone health and, combined with other clinical parameters, provides a good estimation of fracture risk. DXA-based Trabecular Bone Score (TBS) can provide complementary indirect information about bone microarchitecture, which also deteriorates osteoporosis. QCT can provide a 3-D volumetric assessment of bone mineral density (BMD), and FEA of computed tomography (CT) images of bone can provide estimates of bone strength, which have the potential to add value, beyond BMD, for fracture risk assessment. Magnetic resonance imaging (MRI) of bone microarchitecture is an additional promising alternative to the assessment of BMD, and there is evidence that microarchitectural parameters could 1 day have benefits for diagnosing osteoporosis beyond BMD and/or FRAX. Assessment of bone via MRI also provides insight into other bone tissue properties (cortical porosity, marrow fat) that are altered in osteoporosis and that DXA cannot assess. Overall, bone health cannot be characterized solely by one parameter. Current imaging techniques/modalities in combination with advanced image processing hold the potential to provide a comprehensive understanding of the pathologic changes that occur in bone tissue in the setting of osteoporosis and pave the way for new imaging methods to diagnose, monitor, and predict osteoporosis.

Computed Tomography-Based Stiffness Measures of Trabecular Bone Microstructure: Cadaveric Validation and In Vivo Application.

Osteoporosis causes bone fragility and elevates fracture risk. Applications of finite element (FE) analysis (FEA) for assessment of trabecular bone (Tb) microstructural strength at whole-body computed tomography (CT) imaging are limited due to challenges with Tb microstructural segmentation. We present a nonlinear FEA method for distal tibia CT scans evading binary segmentation of Tb microstructure, while accounting for bone microstructural distribution. First, the tibial axis in a CT scan was aligned with the FE loading axis. FE cubic mesh elements were modeled using image voxels, and CT intensity values were calibrated to ash density defining mechanical properties at individual elements. For FEA of an upright volume of interest (VOI), the bottom surface was fixed, and a constant displacement was applied at each vertex on the top surface simulating different loading conditions. The method was implemented and optimized using the ANSYS software. CT-derived computational modulus values were repeat scan reproducible (intraclass correlation coefficient [ICC] ≥ 0.97) and highly correlated (r ≥ 0.86) with the micro-CT (µCT)-derived values. FEA-derived von Mises stresses over the segmented Tb microregion were significantly higher (p < 1 × 10-11) than that over the marrow space. In vivo results showed that both shear and compressive modulus for males were higher (p < 0.01) than for females. Effect sizes for different modulus measures between males and females were moderate-to-high (≥0.55) and reduced to small-to-negligible (<0.40) when adjusted for pure lean mass. Among body size and composition attributes, pure lean mass and height showed highest (r ∈ [0.45 0.56]) and lowest (r ∈ [0.25 0.39]) linear correlation, respectively, with FE-derived modulus measures. In summary, CT-based nonlinear FEA provides an effective surrogate measure of Tb microstructural stiffness, and the relaxation of binary segmentation will extend the scope for FEA in human studies using in vivo imaging at relatively low-resolution. © 2022 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.

Associations between TERT Promoter Mutations and Survival in Superficial Spreading and Nodular Melanomas in a Large Prospective Patient Cohort.

Survival outcomes in melanoma and their association with mutations in the telomerase reverse transcriptase gene TERT promoter remain uncertain. In addition, few studies have examined whether these associations are affected by a nearby common germline polymorphism or vary on the basis of melanoma histopathological subtype. We analyzed 408 primary tumors from a prospective melanoma cohort for somatic TERT-124[C>T] and TERT-146[C>T] mutations, the germline polymorphism rs2853669, and BRAFV600 and NRASQ61 mutations. We tested the associations between these variants and clinicopathologic factors and survival outcomes. TERT-124[C>T] was associated with thicker tumors, ulceration, mitoses (>0/mm2), nodular histotype, and CNS involvement. In a multivariable model controlling for the American Joint Committee on Cancer stage, TERT-124[C>T] was an independent predictor of shorter recurrence-free survival (hazard ratio = 2.58, P = 0.001) and overall survival (hazard ratio = 2.47, P = 0.029). Patients with the germline variant and TERT-124[C>T]-mutant melanomas had significantly shorter recurrence-free survival than those lacking either or both sequence variants (P < 0.04). The impact of the germline variant appeared to be more pronounced in superficial spreading than in nodular melanoma. No associations were found between survival and TERT-146[C>T], BRAF, or NRAS mutations. These findings strongly suggest that TERT-124[C>T] mutation is a biomarker of aggressive primary melanomas, an effect that may be modulated by rs2853669.

Finite element analysis of trabecular bone microstructure using CT imaging and continuum mechanical modeling.

PURPOSE: Osteoporosis is a bone disease associated with enhanced bone loss, microstructural degeneration, and fracture-risk. Finite element (FE) modeling is used to estimate trabecular bone (Tb) modulus from high-resolution three-dimensional (3-D) imaging modalities including micro-computed tomography (CT), magnetic resonance imaging (MRI), and high-resolution peripheral quantitative CT (HR-pQCT). This paper validates an application of voxel-based continuum finite element analysis (FEA) to predict Tb modulus from clinical CT imaging under a condition similar to in vivo imaging by comparing with measures derived by micro-CT and experimental approaches. METHOD: Voxel-based continuum FEA methods for CT imaging were implemented using linear and nonlinear models and applied on distal tibial scans under a condition similar to in vivo imaging. First, tibial axis in a CT scan was aligned with the coordinate z-axis at 150 µm isotropic voxels. FEA was applied on an upright cylindrical volume of interests (VOI) with its axis coinciding with the tibial bone axis. Voxel volume, edge, and vertex elements and their connectivity were defined as per the isotropic image grid. A calibration phantom was used to calibrate CT numbers in Hounsfield unit to bone mineral density (BMD) values, which was then converted into calcium hydroxyapatite (CHA) density. Mechanical properties at each voxel volume element was defined using its ash-density defined on CT-derived CHA density. For FEA, the bottom surface of the cylindrical VOI was fixed and a constant displacement was applied along the z-direction at each vertex element on the top surface to simulate a physical axial compressive loading condition. Finally, a Poisson's ratio of 0.3 was applied, and Tb modulus (MPa) was computed as the ratio of average von Mises stress (MPa) of volume elements on the top surface and the applied displacement. FEA parameters including mesh element size, substep number, and different tolerance values were optimized. RESULTS: CT-derived Tb modulus values using continuum FEA showed high linear correlation with the micro-CT-derived reference values (r ∈ [0.87 0.90]) as well as experimentally measured values (r ∈ [0.80 0.87]). Linear correlation of computed modulus with their reference values using continuum FEA with linear modeling was comparable with that obtained by nonlinear modeling. Nonlinear continuum FEA-based modulus values (mean of 1087.2 MPa) showed greater difference from their reference values (mean of 1498.9 MPa using micro-CT-based FEA) as compared with linear continuum methods. High repeat CT scan reproducibility (intra-class correlation [ICC] = 0.98) was observed for computed modulus values using both linear and nonlinear continuum FEA. It was observed that high stress regions coincide with Tb microstructure as fuzzily characterized by BMD values. Distributions of von Mises stress over Tb microstructure and marrow regions were significantly different (p < 10-8 ). CONCLUSION: Voxel-based continuum FEA offers surrogate measures of Tb modulus from CT imaging under a condition similar to in vivo imaging that alleviates the need for segmentation of Tb and marrow regions, while accounting for bone distribution at the microstructural level. This relaxation of binary segmentation will extend the scope of FEA application to assess mechanical properties of bone microstructure at relatively low-resolution imaging.

Single-Cell Transcriptomics Identifies Heterogeneity of Mouse Mammary Gland Fibroblasts With Distinct Functions, Estrogen Responses, Differentiation Processes, and Crosstalks With Epithelium.

Fibroblasts have been shown to be one of the essential players for mammary gland organization. Here, we identify two major types of mouse mammary gland fibroblasts through single-cell RNA sequencing analysis: Dpp4 + fibroblasts and Dpp4 - fibroblasts. Each population exhibits unique functional characteristics as well as discrete localization in normal mouse mammary glands. Remarkably, estrogen, a crucial mediator of mammary gland organization, alters the gene expression profiles of fibroblasts in a population-specific manner, without distinct activation of estrogen receptor signaling. Further integrative analysis with the inclusion of five other publicly available datasets reveals a directional differentiation among the mammary gland fibroblast populations. Moreover, the combination with the mouse mammary epithelium atlas allows us to infer multiple potential interactions between epithelial cells and fibroblasts in mammary glands. This study provides a comprehensive view of mouse mammary gland fibroblasts at the single-cell level.

Fatty Acid Composition of Proximal Femur Bone Marrow Adipose Tissue in Subjects With Systemic Lupus Erythematous Using 3 T Magnetic Resonance Spectroscopy.

BACKGROUND: Systemic lupus erythematosus (SLE) is a chronic, inflammatory disease with common musculoskeletal manifestations, notably reductions in bone quality. Bone marrow adipose tissue composition and quantity has been previously linked to bone quality and may play a role in SLE pathophysiology but has not been thoroughly studied. PURPOSE: To use magnetic resonance spectroscopy (MRS) to investigate bone marrow adipose tissue quantity and composition in proximal femur subregions of untreated SLE patients compared to controls and treated patients. STUDY TYPE: Prospective. SUBJECTS: A total of 64 female subjects: 28 SLE, 15 glucocorticoid (GC)-treated SLE and 21 matched controls. FIELD STRENGTH/SEQUENCE: Stimulated echo acquisition mode (STEAM) sequence at 3 T. ASSESSMENT: MRS was performed at multiple echo times in the femoral neck and trochanter regions and fatty acids (FA) composition was computed. STATISTICAL TESTS: Intergroup comparisons were carried out using ANOVA. A P value < 0.05 was considered statistically significant. RESULTS: SLE patients had significantly higher saturated FA compared to controls in both the femoral neck (+0.12) and trochanter (+0.11), significantly lower monounsaturated FA in the trochanter compared to controls (-0.05), and significantly lower polyunsaturated FA in the femoral neck compared to both controls (-0.07) and SLE patients on GC therapy (-0.05). DATA CONCLUSION: SLE patients have altered proximal femur marrow fat metabolism, which may reflect a manifestation of, or play a role in, the altered inflammatory response of these patients. EVIDENCE LEVEL: 2 TECHNICAL EFFICACY: Stage 2.

Lower extremity injuries in U.S. national fencing team members and U.S. fencing Olympians.

INTRODUCTION: Fencing is growing rapidly in popularity and competitiveness with fencers beginning at a younger age and competing in more tournaments. Even though fencing has a low risk of time-loss injury, fencers are inevitably going to experience injuries if proper athletic training and prevention does not occur. We aim to describe and compare the lower extremity injuries experienced by fencers that have trained at the highest level in the sport. We hypothesized that athletes who fenced longer would suffer more knee and hip injuries and report lower IKDC and HOS scores. METHODS: This is an epidemiology study distributed to members of the U.S. national team and Olympic team from 1980 to 2018. The electronic survey included questions regarding age, weapon, number of years fencing, number of national and Olympic teams, injuries on the dominant and nondominant hip and knee, time missed due to injury, and methods for treatment. The survey also included the International Knee Demographic Committee (IKDC) and Hip Outcome Score (HOS). RESULTS: There were 153 national team members between July 1980 and July 2018, 110 with contact information. A total of 77 athletes submitted the survey, consisting of 30 females and 47 males. Female fencers had more hip injuries and lower IKDC and HOS scores than their male counterparts. In total, there were 71 injuries to the dominant (front) knee and 28 injuries to the nondominant (back) knee. There were 32 dominant hip injuries and 5 nondominant hip injuries. Saber fencers reported the most dominant and nondominant hip and knee injuries. CONCLUSION: The intense, repetitive and asymmetrical movements involved in fencing affect the weight bearing leg and the nondominant leg in all weapons. Special attention should be paid to female fencers as they experience more hip and knee injuries resulting in impaired joint function.