Perimenopausal and Menopausal Mammary Glands In A 4-Vinylcyclohexene Diepoxide Mouse Model.

As both perimenopausal and menopausal periods are recognized critical windows of susceptibility for breast carcinogenesis, development of a physiologically relevant model has been warranted. The traditional ovariectomy model causes instant removal of the entire hormonal repertoire produced by the ovary, which does not accurately approximate human natural menopause with gradual transition. Here, we characterized the mammary glands of 4-vinylcyclohexene diepoxide (VCD)-treated animals at different time points, revealing that the model can provide the mammary glands with both perimenopausal and menopausal states. The perimenopausal gland showed moderate regression in ductal structure with no responsiveness to external hormones, while the menopausal gland showed severe regression with hypersensitivity to hormones. Leveraging the findings on the VCD model, effects of a major endocrine disruptor (polybrominated diphenyl ethers, PBDEs) on the mammary gland were examined during and after menopausal transition, with the two exposure modes; low-dose, chronic (environmental) and high-dose, subacute (experimental). All conditions of PBDE exposure did not augment or compromise the macroscopic ductal reorganization resulting from menopausal transition and/or hormonal treatments. Single-cell RNA sequencing revealed that the experimental PBDE exposure during the post-menopausal period caused specific transcriptomic changes in the non-epithelial compartment such as Errfi1 upregulation in fibroblasts. The environmental PBDE exposure resulted in similar transcriptomic changes to a lesser extent. In summary, the VCD mouse model provides both perimenopausal and menopausal windows of susceptibility for the breast cancer research community. PBDEs, including all tested models, may affect the post-menopausal gland including impacts on the non-epithelial compartments.

Census tract-level social vulnerability and gonorrhea rates in central Ohio: results from the STD Surveillance Network, 2020-2021.

BACKGROUND: Gonorrhea remains a significant burden in central Ohio, particularly in socially disadvantaged communities. This study evaluates gonorrhea case rates and changes from 2020 to 2021, focusing on geographic patterns associated with social vulnerability. METHODS: We analyzed gonorrhea case data from the Columbus STD Surveillance Network (SSuN) for 2020 and 2021. Cases were linked to census tracts and categorized into low (0-0.66) or high (0.67-1.0) vulnerability groups based on the CDC/ATSDR social vulnerability index (SVI). We mapped gonorrhea case rates per 100,000 population, stratified by SVI group, and compared changes using Jenks natural breaks to determine cutpoints. High case rates were defined as ≥605 (2020) and ≥ 532 (2021). A change in case rates was defined as <154 (decrease/no change) or ≥ 154 (increase). Demographic factors were summarized for both years. RESULTS: In 2020 and 2021, nearly half of high SVI tracts had high gonorrhea rates, compared to about 4-7% of low SVI tracts. Median rates in high SVI tracts were approximately five times higher than in low SVI tracts, with rates 546 and 598 per 100,000 in 2020 and 2021, compared to 98 and 104 per 100,000, respectively. Gonorrhea rates increased in 23 (9%) of low SVI tracts and 37 (25%) of high SVI tracts. Demographic characteristics remained consistent between the two years. CONCLUSIONS: Gonorrhea rates increased in central Ohio between 2020 and 2021, with higher burdens in high SVI census tracts. Understanding the dynamics of social vulnerability at the community level is crucial for targeting limited STD resources effectively.

Regulatory T Cells in Tumor-Associated Tertiary Lymphoid Structures Suppress Anti-tumor T Cell Responses.

Infiltration of regulatory T (Treg) cells into many tumor types correlates with poor patient prognoses. However, mechanisms of intratumoral Treg cell function remain to be elucidated. We investigated Treg cell function in a genetically engineered mouse model of lung adenocarcinoma and found that Treg cells suppressed anti-tumor responses in tumor-associated tertiary lymphoid structures (TA-TLSs). TA-TLSs have been described in human lung cancers, but their function remains to be determined. TLSs in this model were spatially associated with >90% of tumors and facilitated interactions between T cells and tumor-antigen-presenting dendritic cells (DCs). Costimulatory ligand expression by DCs and T cell proliferation rates increased in TA-TLSs upon Treg cell depletion, leading to tumor destruction. Thus, we propose that Treg cells in TA-TLSs can inhibit endogenous immune responses against tumors, and targeting these cells might provide therapeutic benefit for cancer patients.

Quadriceps muscle quality and quantity following tibial plateau fracture repair.

PURPOSE: To investigate the qualitative and quantitative changes seen in quadriceps muscles [QM] following tibial plateau fracture and surgery. METHODS: A consecutive series of patients with an isolated tibial plateau fracture presenting to a single academic center were enrolled and prospectively followed. Bilateral knee MRIs were performed preoperatively and 3 and 12 months postoperatively to assess quantity and quality of the quadriceps muscles. All patients underwent tibial plateau operative repair and were made non-weight-bearing for 10 weeks postoperatively then advanced to weight-bearing as tolerated. Functional status assessed via the short musculoskeletal functional assessment (SMFA); knee range of motion [ROM]; vastus medialis oblique [VMO] and vastus lateralis [VL] muscle quantity (axial width, cross sectional area [CSA] and volume) on injured and contralateral limb; VMO, sartorius, semi-membranous and biceps femoris [BF] muscle quality (fat and water content, and proton density fat fraction). All muscle quantitative and qualitative measurements were compared across all time points. RESULTS: Ten patients were included in the final analysis, 6 males and 4 females, with average age of 43.62 ± 16.3 years. While the VMO and VL axial width and CSA were significantly decreased at 3 months preoperatively, this was not statistically significant. There was no significant difference between any QM quantitative measurements at any time points. There was no difference in fat content, water content or PDFF at any time point for the VMO, sartorius, semi-membranous and BF muscles. Regression analysis also showed no association between 12-month SMFA scores and knee ROM with VMO/VL CSA at 1 year. CONCLUSIONS: QM quantity and quality do not significantly change at 3 months and 1 year postoperatively following tibial plateau fracture surgery. LEVEL OF EVIDENCE: Prognostic Level II.

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.

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.

Simultaneous bilateral T1 , T2 , and T1ρ relaxation mapping of the hip joint with magnetic resonance fingerprinting.

Quantitative MRI can detect early biochemical changes in cartilage, but its bilateral use in clinical routines is challenging. The aim of this prospective study was to demonstrate the feasibility of magnetic resonance fingerprinting for bilateral simultaneous T1 , T2 , and T1ρ mapping of the hip joint. The study population consisted of six healthy volunteers with no known trauma or pain in the hip. Monoexponential T1 , T2 , and T1ρ relaxation components were assessed in femoral lateral, superolateral, and superomedial, and inferior, as well as acetabular, superolateral, and superomedial subregions in left and right hip cartilage. Aligned ranked nonparametric factorial analysis was used to assess the side's impact on the subregions. Kruskal-Wallis and Wilcoxon tests were used to compare subregions, and coefficient of variation to assess repeatability. Global averages of T1 (676.0 ± 45.4 and 687.6 ± 44.5 ms), T2 (22.5 ± 2.6 and 22.1 ± 2.5 ms), and T1ρ (38.2 ± 5.5 and 38.2 ± 5.5 ms) were measured in the left and right hip, and articular cartilage, respectively. The Kruskal-Wallis test showed a significant difference between different subregions' relaxation times regardless of the hip side (p < 0.001 for T1 , p = 0.012 for T2 , and p < 0.001 for T1ρ ). The Wilcoxon test showed that T1 of femoral layers was significantly (p < 0.003) higher than that for acetabular cartilage. The experiments showed excellent repeatability with CVrms of 1%, 2%, and 4% for T1 , T2 , and T1ρ, respectively. It was concluded that bilateral T1 , T2 , and T1ρ relaxation times, as well as B1+ maps, can be acquired simultaneously from hip joints using the proposed MRF sequence.

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.

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.

Clinical and Laboratory Findings in Patients With Potential Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Reinfection, May-July 2020.

BACKGROUND: We investigated patients with potential severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) reinfection in the United States during May-July 2020. METHODS: We conducted case finding for patients with potential SARS-CoV-2 reinfection through the Emerging Infections Network. Cases reported were screened for laboratory and clinical findings of potential reinfection followed by requests for medical records and laboratory specimens. Available medical records were abstracted to characterize patient demographics, comorbidities, clinical course, and laboratory test results. Submitted specimens underwent further testing, including reverse transcription polymerase chain reaction (RT-PCR), viral culture, whole genome sequencing, subgenomic RNA PCR, and testing for anti-SARS-CoV-2 total antibody. RESULTS: Among 73 potential reinfection patients with available records, 30 patients had recurrent coronavirus disease 2019 (COVID-19) symptoms explained by alternative diagnoses with concurrent SARS-CoV-2 positive RT-PCR, 24 patients remained asymptomatic after recovery but had recurrent or persistent RT-PCR, and 19 patients had recurrent COVID-19 symptoms with concurrent SARS-CoV-2 positive RT-PCR but no alternative diagnoses. These 19 patients had symptom recurrence a median of 57 days after initial symptom onset (interquartile range: 47-76). Six of these patients had paired specimens available for further testing, but none had laboratory findings confirming reinfections. Testing of an additional 3 patients with recurrent symptoms and alternative diagnoses also did not confirm reinfection. CONCLUSIONS: We did not confirm SARS-CoV-2 reinfection within 90 days of the initial infection based on the clinical and laboratory characteristics of cases in this investigation. Our findings support current Centers for Disease Control and Prevention (CDC) guidance around quarantine and testing for patients who have recovered from COVID-19.