Evolution of peripheral nerve changes in early multiple sclerosis-a longitudinal MR neurography study.

Objectives: Multiple sclerosis (MS) is a demyelinating disorder of the central nervous system. Increasing evidence indicates additional peripheral nerve involvement in early and chronic disease stages. To investigate the evolution of peripheral nerve changes in patients first diagnosed with MS using quantitative MR neurography. Materials and methods: This prospective study included 19 patients with newly diagnosed MS according to the revised McDonald criteria (16 female, mean 30.2 ± 7.1 years) and 19 age-/sex-matched healthy volunteers. High-resolution 3 T MR neurography of the sciatic nerve using a quantitative T2-relaxometry sequence was performed, which yielded the biomarkers of T2 relaxation time (T2app) and proton spin density (PSD). Follow-up scans of patients were performed after median of 12 months (range 7-16). Correlation analyses considered clinical symptoms, intrathecal immunoglobulin synthesis, nerve conduction study, and lesion load on brain and spine MRI. Results: Patients showed increased T2app and decreased PSD compared to healthy controls at initial diagnosis and follow-up (p < 0.001 each). Compared to the initial scan, T2app further increased in patients at follow-up (p = 0.003). PSD further declined by at least 10% in 9/19 patients and remained stable in another 9/19 patients. Correlation analyses did not yield significant results. Conclusion: Peripheral nerve involvement in MS appears at initial diagnosis and continues to evolve within 1 year follow-up with individual dynamics. Quantitative MRN provides non-invasive biomarkers to detect and monitor peripheral nerve changes in MS.

Isolation of Diverse Simian Arteriviruses Causing Hemorrhagic Disease.

Genetically diverse simian arteriviruses (simarteriviruses) naturally infect geographically and phylogenetically diverse monkeys, and cross-species transmission and emergence are of considerable concern. Characterization of most simarteriviruses beyond sequence analysis has not been possible because the viruses fail to propagate in the laboratory. We attempted to isolate 4 simarteriviruses, Kibale red colobus virus 1, Pebjah virus, simian hemorrhagic fever virus, and Southwest baboon virus 1, by inoculating an immortalized grivet cell line (known to replicate simian hemorrhagic fever virus), primary macaque cells, macrophages derived from macaque induced pluripotent stem cells, and mice engrafted with macaque CD34+-enriched hematopoietic stem cells. The combined effort resulted in successful virus isolation; however, no single approach was successful for all 4 simarteriviruses. We describe several approaches that might be used to isolate additional simarteriviruses for phenotypic characterization. Our results will expedite laboratory studies of simarteriviruses to elucidate virus-host interactions, assess zoonotic risk, and develop medical countermeasures.

Survival by sex and HIV status in patients with anal cancer in the USA between 2001 and 2019: a retrospective cohort study.

BACKGROUND: The risk of anal cancer is increased among people with HIV, particularly men who have sex with men. Estimating survival by HIV status and sex and identifying groups at high risk is crucial for documenting prognostic differences between populations. We aimed to compare all-cause and anal cancer-specific survival in patients with anal cancer with and without HIV, stratified by sex, and to identify predictors of survival, stratified by HIV status. METHODS: In this retrospective cohort study, we used data from the HIV/AIDS Cancer Match Study of 13 population-based HIV and cancer registries throughout the USA. We included individuals aged 20-79 years diagnosed with invasive anal cancer between 2001 and 2019. To estimate associations between HIV status and both all-cause and anal cancer-specific mortality overall, we used Cox proportional hazards models, adjusting for year of and age at diagnosis, sex, race and ethnicity, histology, cancer stage, region, and treatment. We also calculated sex-specific adjusted hazard ratios (HRs). By HIV status, we identified characteristics associated with mortality. Models among people with HIV were further adjusted for AIDS status and HIV transmission risk group. FINDINGS: Between Jan 1, 2001, and Dec 31, 2019, 1161 (43·6%) of 2662 patients with anal cancer and HIV and 7722 (35·4%) of 21 824 patients without HIV died. HIV was associated with a 1·35 times (95% CI 1·24-1·47) increase in all-cause mortality among male patients and a 2·47 times (2·10-2·90) increase among female patients. Among patients with HIV, all-cause mortality was increased among non-Hispanic Black individuals (adjusted HR 1·19, 95% CI 1·04-1·38), people with AIDS (1·36, 1·10-1·68), people who inject drugs (PWID; 1·49, 1·17-1·90), patients with adenocarcinoma (2·74, 1·82-4·13), and those with no or unknown surgery treatment (1·34, 1·18-1·53). HIV was associated with anal cancer-specific mortality among female patients only (1·52, 1·18-1·97). Among patients with HIV, anal cancer-specific mortality was increased among patients with adenocarcinoma (3·29, 1·89-5·72), those with no or unknown treatment (1·59, 1·17-2·17), and PWID (1·60, 1·05-2·44). INTERPRETATION: HIV was associated with all-cause mortality among patients with anal cancer, especially women. Anal cancer-specific mortality was elevated among female patients with HIV. As screening for anal cancer becomes more widespread, examining the effects of screening on survival by HIV status and sex is crucial. FUNDING: US National Cancer Institute Intramural Research Program.

Microstructural changes of peripheral nerves in early multiple sclerosis: A prospective magnetic resonance neurography study.

BACKGROUND AND PURPOSE: Multiple sclerosis (MS) is a demyelinating disorder of the central nervous system (CNS). However, there is increasing evidence of peripheral nerve involvement. This study aims to characterize the pattern of peripheral nerve changes in patients with newly diagnosed MS using quantitative magnetic resonance (MR) neurography. METHODS: In this prospective study, 25 patients first diagnosed with MS according to the revised McDonald criteria (16 female, mean age = 32.8 ± 10.6 years) and 14 healthy controls were examined with high-resolution 3-T MR neurography of the sciatic nerve using diffusion kurtosis imaging (DKI; 20 diffusional directions, b = 0, 700, 1200 s/mm2 ) and magnetization transfer imaging (MTI). In total, 15 quantitative MR biomarkers were analyzed and correlated with clinical symptoms, intrathecal immunoglobulin synthesis, electrophysiology, and lesion load on brain and spine MR imaging. RESULTS: Patients showed decreased fractional anisotropy (mean = 0.51 ± 0.04 vs. 0.56 ± 0.03, p < 0.001), extra-axonal tortuosity (mean = 2.32 ± 0.17 vs. 2.49 ± 0.17, p = 0.008), and radial kurtosis (mean = 1.40 ± 0.23 vs. 1.62 ± 0.23, p = 0.014) and higher radial diffusivity (mean = 1.09 ∙ 10-3 mm2 /s ± 0.16 vs. 0.98 ± 0.11 ∙ 10-3 mm2 /s, p = 0.036) than controls. Groups did not differ in MTI. No significant association was found between MR neurography markers and clinical/laboratory parameters or CNS lesion load. CONCLUSIONS: This study provides further evidence of peripheral nerve involvement in MS already at initial diagnosis. The characteristic pattern of DKI parameters indicates predominant demyelination and suggests a primary coaffection of the peripheral nervous system in MS. This first human study using DKI for peripheral nerves shows its potential and clinical feasibility in providing novel biomarkers.

Barriers to gBRCA Testing in High-Risk HER2-Negative Early Breast Cancer.

Despite the OlympiA trial demonstrating that early-stage, high-risk, HER2- germline BRCA1 and BRCA2 mutation (gBRCAm) positive breast cancer patients can benefit from PARPi in the adjuvant setting, the gBRCA testing rate in early-stage HR+/HER2- patients remains suboptimal compared to that in early-stage TNBC patients. To better understand the perceived barriers associated with gBRCA testing in HR+/HER2- disease, a quantitative survey was conducted across stakeholders (n = 430) including medical oncologists, surgeons, nurses, physician assistants, payers, and patients. This study revealed that while payers claim to cover gBRCA testing, poor clinician documentation and overutilization are key challenges. Therefore, payers place utilization management controls on gBRCA testing due to their impression that clinicians overtest. These controls have led to healthcare professionals experiencing payer pushback in the form of reimbursement limitations and denials. The perceived challenges to gBRCA testing stem from the lack of consensus dictating which patients are high risk and should be tested. While payers define high risk based on the CPS + EG score from the OlympiA trial, HCPs adopt a broader definition including genomic risk scores, lymph node involvement, and tumor grade and size. A dialogue to harmonize risk classification and testing eligibility across stakeholders is critical to address this disconnect and increase gBRCA testing in appropriate patients.

Peripheral nerve involvement in hereditary spastic paraplegia characterized by quantitative magnetic resonance neurography.

BACKGROUND AND OBJECTIVES: Hereditary spastic paraplegias (HSPs) are heterogenous genetic disorders. While peripheral nerve involvement is frequent in spastic paraplegia 7 (SPG7), the evidence of peripheral nerve involvement in SPG4 is more controversial. We aimed to characterize lower extremity peripheral nerve involvement in SPG4 and SPG7 by quantitative magnetic resonance neurography (MRN). METHODS: Twenty-six HSP patients carrying either the SPG4 or SPG7 mutation and 26 age-/sex-matched healthy controls prospectively underwent high-resolution MRN with large coverage of the sciatic and tibial nerve. Dual-echo turbo-spin-echo sequences with spectral fat-saturation were utilized for T2-relaxometry and morphometric quantification, while two gradient-echo sequences with and without an off-resonance saturation rapid frequency pulse were applied for magnetization transfer contrast (MTC) imaging. HSP patients additionally underwent detailed neurologic and electroneurographic assessments. RESULTS: All microstructural (proton spin density [ρ], T2-relaxation time, magnetization transfer ratio) and morphometric (cross-sectional area) quantitative MRN markers were decreased in SPG4 and SPG7 indicating chronic axonopathy. ρ was superior in differentiating subgroups and identifying subclinical nerve damage in SPG4 and SPG7 without neurophysiologic signs of polyneuropathy. MRN markers correlated well with clinical scores and electroneurographic results. CONCLUSIONS: MRN characterizes peripheral nerve involvement in SPG4 and SPG7 as a neuropathy with predominant axonal loss. Evidence of peripheral nerve involvement in SPG4 and SPG7, even without electroneurographically manifest polyneuropathy, and the good correlation of MRN markers with clinical measures of disease progression, challenge the traditional view of the existence of HSPs with isolated pyramidal signs and suggest MRN markers as potential progression biomarkers in HSP.

Simultaneous Multislice Accelerated TSE for Improved Spatiotemporal Resolution and Diagnostic Accuracy in Magnetic Resonance Neurography: A Feasibility Study.

OBJECTIVES: This study aims to evaluate the utility of simultaneous multislice (SMS) acceleration for routine magnetic resonance neurography (MRN) at 3 T. MATERIALS AND METHODS: Patients with multiple sclerosis underwent MRN of the sciatic nerve consisting of a standard fat-saturated T2-weighted turbo spin echo (TSE) sequence using integrated parallel acquisition technique (PAT2) acceleration and 2 T2 TSE sequences using a combination of PAT-SMS acceleration (1) to reduce scan time (PAT2-SMS2; SMS-TSE FAST ) and (2) for time neutral increase of in-plane resolution (PAT1-SMS2; SMS-TSE HR ). Acquisition times were 5:29 minutes for the standard T2 TSE, 3:12 minutes for the SMS-TSE FAST , and 5:24 minutes for the SMS-TSE HR . Six qualitative imaging parameters were analyzed by 2 blinded readers using a 5-point Likert scale and T2 nerve lesions were quantified, respectively. Qualitative and quantitative image parameters were compared, and both interrater and intrarater reproducibility were statistically assessed. In addition, signal-to-noise ratio/contrast-to-noise ratio (CNR) was obtained in healthy controls using the exact same imaging protocol. RESULTS: A total of 15 patients with MS (mean age ± standard deviation, 38.1 ± 11 years) and 10 healthy controls (mean age, 29.1 ± 7 years) were enrolled in this study. CNR analysis was highly reliable (intraclass correlation coefficient, 0.755-0.948) and revealed a significant CNR decrease for the sciatic nerve for both SMS protocols compared with standard T2 TSE (SMS-TSE FAST /SMS-TSE HR , -39%/-55%; P ≤ 0.01). Intrarater and interrater reliability of qualitative image review was good to excellent (κ: 0.672-0.971/0.617-0.883). Compared with the standard T2 TSE sequence, both SMS methods were shown to be superior in reducing pulsatile flow artifacts ( P < 0.01). Ratings for muscle border sharpness, detailed muscle structures, nerve border sharpness, and nerve fascicular structure did not differ significantly between the standard T2 TSE and the SMS-TSE FAST ( P > 0.05) and were significantly better for the SMS-TSE HR than for standard T2 TSE ( P < 0.001). Muscle signal homogeneity was mildly inferior for both SMS-TSE FAST ( P > 0.05) and SMS-TSE HR ( P < 0.001). A significantly higher number of T2 nerve lesions were detected by SMS-TSE HR ( P ≤ 0.01) compared with the standard T2 TSE and SMS-TSE FAST , whereas no significant difference was observed between the standard T2 TSE and SMS-TSE FAST . CONCLUSIONS: Implementation of SMS offers either to substantially reduce acquisition time by over 40% without significantly impeding image quality compared with the standard T2 TSE or to increase in-plane resolution for a high-resolution approach and improved depiction of T2 nerve lesions while keeping acquisition times constant. This addresses the specific needs of MRN by providing different imaging approaches for 2D clinical MRN.

Teaching vulval anatomy in the twenty-first century: The Australian experience.

Anatomy has often been regarded as an immutable discipline where everything that needs to be known is known. This article focuses on the teaching of vulval anatomy, the diversification of gender in contemporary society, and the increasing popularity of the Female Genital Cosmetic Surgery (FGCS) industry. The binary language and singular structural arrangements contained in lectures and chapters on "female genital anatomy" are nowadays rendered exclusive and incomplete. A series of 31 semi-structured interviews with Australian anatomy teachers identified barriers and facilitators for teaching vulval anatomy to contemporary student cohorts. Barriers included lack of connection to contemporary clinical practice, time and technical difficulty involved in regularly updating online presentations, the crowded curriculum, personal sensitivity to teaching vulval anatomy, and reluctance to introduce inclusive terminology. Facilitators included lived experience, regular use of social media, and institutional initiatives toward inclusivity including the support of queer colleagues.

Quantification and Proximal-to-Distal Distribution Pattern of Tibial Nerve Lesions in Relapsing-Remitting Multiple Sclerosis : Assessment by MR Neurography.

PURPOSE: Recent studies suggest an involvement of the peripheral nervous system (PNS) in multiple sclerosis (MS). Here, we characterize the proximal-to-distal distribution pattern of peripheral nerve lesions in relapsing-remitting MS (RRMS) by quantitative magnetic resonance neurography (MRN). METHODS: A total of 35 patients with RRMS were prospectively included and underwent detailed neurologic and electrophysiologic examinations. Additionally, 30 age- and sex-matched healthy controls were recruited. 3T MRN with anatomical coverage from the proximal thigh down to the tibiotalar joint was conducted using dual-echo 2­dimensional relaxometry sequences with spectral fat saturation. Quantification of PNS involvement was performed by evaluating microstructural (proton spin density (ρ), T2-relaxation time (T2app)), and morphometric (cross-sectional area, CSA) MRN markers in every axial slice. RESULTS: In patients with RRMS, tibial nerve lesions at the thigh and the lower leg were characterized by a decrease in T2app and an increase in ρ compared to controls (T2app thigh: p < 0.0001, T2app lower leg: p = 0.0040; ρ thigh: p < 0.0001; ρ lower leg: p = 0.0098). An additional increase in nerve CSA was only detectable at the thigh, while the semi-quantitative marker T2w-signal was not altered in RRMS in both locations. A slight proximal-to-distal gradient was observed for T2app and T2-signal, but not for ρ. CONCLUSION: PNS involvement in RRMS is characterized by a decrease in T2app and an increase in ρ, occurring with proximal predominance at the thigh and the lower leg. Our results indicate microstructural alterations in the extracellular matrix of peripheral nerves in RRMS and may contribute to a better understanding of the pathophysiologic relevance of PNS involvement.

Peripheral Nerve Involvement at First Diagnosis of Multiple Sclerosis: A Prospective MR Neurography Study.

OBJECTIVES: The aim of this study was to assess peripheral nerve involvement in patients with multiple sclerosis (MS) at first clinical presentation using quantitative magnetic resonance (MR) neurography in correlation with clinical, laboratory, electrophysiological, and central nervous MR imaging data. MATERIALS AND METHODS: In this prospective monocentric study, 30 patients first diagnosed with MS according to the McDonald criteria (19 women; mean age, 32.4 ± 8.8 years) and 30 age- and sex-matched healthy volunteers were examined with high-resolution 3 T MR neurography using a dual-echo T2-relaxometry sequence covering the tibial and peroneal nerves from proximal thigh to distal calf. Magnetic resonance biomarkers of T2 relaxation time (T2 app ), proton spin density (PSD), and nerve cross-sectional area (CSA) were correlated with clinical symptoms, intrathecal immunoglobulin (Ig) synthesis, nerve conduction study, and lesion load on brain and spine MR imaging. The diagnostic accuracy of MR biomarkers was assessed using receiver-operating characteristic curves. RESULTS: Diffuse nerve changes were detected along the tibial and peroneal nerves in MS patients, who showed decreased PSD ( P < 0.001), increased T2 app ( P < 0.001), and smaller tibial nerve CSA ( P < 0.001) compared with healthy subjects. Tibial PSD was identified as best parameter separating patients from controls (area under the curve = 0.876). Intrathecal IgG and IgM synthesis correlated with PSD values ( r = -0.44, P = 0.016, and r = -0.42, P = 0.022). Contrast-enhancement of brain or spine lesions was related to larger tibial and peroneal CSA ( P < 0.001, P = 0.033). Abnormal electrophysiology correlated with higher tibial and peroneal T2 app ( P < 0.001 and P = 0.033), lower tibial and peroneal PSD ( P = 0.018 and P = 0.002), and smaller peroneal CSA ( P < 0.001). CONCLUSIONS: Quantitative MR neurography reveals peripheral nerve changes in patients with initial diagnosis of MS. Correlation of imaging findings with intrathecal immunoglobulin synthesis may indicate a primary coaffection of the peripheral nervous system in MS.

Methadone prescribed as an analgesic by a specialist palliative medicine team in an acute hospital inpatient setting: retrospective study.

Emerging evidence suggests that methadone has a specific role in the management of treatment resistant cancer-related pain. OBJECTIVES: To investigate the utilisation pattern, safety and efficacy of methadone prescribed as an analgesic for the management of complex cancer-related pain in an acute hospital inpatient setting. METHODS: A retrospective longitudinal observational study of patients prescribed methadone as an analgesic between April 2020 and July 2021 was performed.Changes in coprescribed baseline opioid, use of breakthrough opioid analgesic, patient rated pain scores and adverse side effects were analysed. RESULTS: 16 patients with complex cancer-related treatment resistant pain who were prescribed methadone were included in the study. Of the 16 patients, 14 patients had metastatic disease. Pain was classified in 14 patients as mixed nociceptive-neuropathic and in 2 patients as neuropathic. 13 patients were coprescribed methadone with a pre-established opioid. Methadone was associated with a statistically significant decrease in both opioid breakthrough analgesic by 61%±28% (p<0.001), and coprescribed opioid by 17%±12% (p=0.015). Patient rated pain scores were also significantly decreased (p<0.001). CONCLUSION: Methadone appears to have a specific role in the management of complex cancer pain, neuropathic pain, opioid-tolerance and opioid-induced hyperalgesia, which may be attributable to N-methyl-D-aspartate receptor antagonism.

Impact of HIV on Anal Squamous Cell Carcinoma Rates in the United States, 2001-2015.

BACKGROUND: Incidence of anal squamous cell carcinoma (SCC) has increased in the United States. People living with HIV (PLWH) have an elevated risk of anal SCC, and changes in the number of anal SCCs among PLWH may have influenced general population trends. METHODS: Data were obtained from a linkage of HIV and cancer registries in 12 US regions. The proportion of anal SCCs occurring among PLWH was estimated by sex, age group, and race and ethnicity. To assess the impact of anal SCCs among PLWH on general population trends, annual percent changes (APCs) in incidence rates including and excluding anal SCCs among PLWH were estimated. RESULTS: Between 2001 and 2015, 14.5% of 16 110 anal SCC diagnoses occurred in PLWH. In 2013-2015, 35% of anal SCCs among men occurred in PLWH, but only 2% among women. The proportion of anal SCCs among PLWH was highest among 20- to 49-year-olds and Black and Hispanic individuals. General population anal SCC trends among men were strongly influenced by anal SCCs among PLWH: rates increased 4.6%/y (95% confidence interval [CI] = 1.4% to 8.0%) from 2001 to 2009 followed by a statistically non-significant decline (APC = -2.7%/y, 95% CI = -7.1% to 2.0%) from 2009 to 2015, but without anal SCCs among PLWH, rates were stable (APC = 0.7%/y, 95% CI = -0.8% to 2.3%). Anal SCC rates among women increased 3.8%/y (95% CI = 3.2% to 4.4%) during 2001-2012 and then declined statistically non-significantly (APC = -3.8%/y, 95% CI = -6.9% to -0.6%), and anal SCCs among PLWH had little impact on these trends. CONCLUSIONS: During 2001-2015, anal SCCs among PLWH contributed strongly to changes in incidence trends in the general US population among men, but not women.

New context, new content-Rethinking genital anatomy in textbooks.

It has been widely claimed that reductions in allocated teaching time and the widespread implementation of short-cut teaching methodologies have led to a shortfall in anatomy knowledge among graduating doctors. This decline in knowledge is evident in the failure of anatomy content to prepare graduates for contemporary clinical practice. The implications for postgraduate surgical training are addressed in the numerous extracurricular anatomy courses available to surgical candidates. This paper focuses on genital diversity and its relevance to non-surgical graduates, thus highlighting another potential impact of this knowledge shortfall on frontline clinic consultations. As the gender revolution and female genital cosmetic surgery industry flourish, nothing in contemporary anatomy textbooks addresses issues of diversification of female genitalia nor gives medical graduates a realistic view of what is normal regarding female genital appearance.

R-scale for pulmonary fibrosis: a simple, visual tool for the assessment of health-related quality of life.

RATIONALE: Patients with idiopathic pulmonary fibrosis (IPF) experience impaired health-related quality of life (HRQoL). Several tools have been developed to objectively assess HRQoL in this patient population, but none are in use in routine clinical practice. OBJECTIVES: To develop a rapid, specific tool that can be used for patients with IPF during routine clinic visits. METHODS: A novel and simple five-item numerical rating scale was developed and compared with two other previously validated tools. 100 consecutive patients with IPF managed at a centre for interstitial lung disease were recruited to complete the Raghu scale for pulmonary fibrosis (R-Scale-PF), King's Brief Interstitial Lung Disease questionnaire (K-BILD), and the EuroQol Five-Dimensional Five-Level questionnaire (EQ-5D-5L) in addition to pulmonary function and 6-min walk tests. MEASUREMENTS AND MAIN RESULTS: All 100 patients successfully completed the three HRQoL tools with 53 completing them again at follow-up visits. Internal consistency was high (Cronbach's α 0.825) with minimal floor/ceiling effect. Concurrent validity of the R-Scale-PF was moderate to high compared with the K-BILD (r=-0.713) and the EQ-5D-5L (r=-0.665). Concurrent validity was moderate with physiologic measures (forced vital capacity, r=-0.307, 6-min walking distance, r=-0.383). The R-Scale-PF demonstrated good known-groups validity when comparing scores across stages of disease severity. CONCLUSIONS: The R-Scale-PF correlates well with the K-BILD and EQ-5D-5L. It is hoped that this novel simple numerical rating scale tool, subject to validation in patients from other centres, will provide an opportunity to objectively measure HRQoL in routine clinical practice for patients with IPF.

Racial disparities in mortality outcomes among women diagnosed with breast cancer in Maryland: Impact of cardiovascular disease and clinical characteristics.

BACKGROUND: Although racial disparities in breast cancer (BC) mortality have been well documented in the United States, little is known about the impact of coexisting cardiovascular disease (CVD) and other clinical factors on Black-White survival disparities after the diagnosis of BC. This study examined the associations of race, CVD, and clinical factors at diagnosis with the hazard of BC and CVD-related mortality among patients with BC identified from the Maryland Cancer Registry. METHODS: A total of 36,088 women (25,181 Whites and 10,907 Blacks) diagnosed with incident invasive BC between 2007 and 2017 were included. Subdistribution hazard ratios (sdHRs) for CVD-related and BC mortality were estimated with Fine and Gray regression models, which accounted for the influence of competing events. RESULTS: After a median follow-up of 5.8 years, 8019 deaths occurred; 3896 were BC deaths, and 1167 deaths were CVD-related. Black women had a higher hazard of BC mortality (sdHR, 1.66; 95% confidence interval [CI], 1.55-1.77) and CVD mortality (sdHR, 1.33; 95% CI, 1.17-1.51) in comparison with White women. Associations with CVD mortality were significantly stronger among Black women aged 50 to 59 years (sdHR, 2.86; 95% CI, 1.84-4.44; P for interaction < .001). Among Black women with CVD, the hazard of BC death was 41% higher in comparison with White women. By treatment, a significant association with CVD mortality was observed only among Black women undergoing surgery and radiation (sdHR, 1.61; 95% CI, 1.22-2.13). CONCLUSIONS: Clinicians should consider the impact of younger age, preexisting CVD, and BC treatments among Black patients. Early identification of those at risk for worse survival may improve surveillance and outcomes.

Racialized Economic Segregation and Breast Cancer Mortality among Women in Maryland.

BACKGROUND: Our objective was to determine the association between racialized economic segregation and the hazard of breast cancer mortality in Maryland. METHODS: Among 35,066 women (24,540 White; 10,526 Black) diagnosed with incident invasive breast cancer in Maryland during 2007 to 2017, exposure to racialized economic segregation was measured at the census tract level using Index of Concentration at the Extremes metrics. HRs and 95% confidence intervals (CI) were estimated using Cox proportional hazards regression for the association between racialized economic segregation and the hazard of breast cancer mortality, accounting for clustering at the census tract level. Models were adjusted for age and stratified by race, median age (<60 years, ≥60 years), and clinical characteristics. RESULTS: Overall, the hazard of breast cancer mortality was 1.84 times as high (95% CI, 1.64-2.06) for the least privileged quintile of racialized economic segregation compared with the most privileged quintile. This association differed significantly (P interaction< 0.05) by race and age, with 1.20 (95% CI, 0.90-1.60) times the hazard of breast cancer mortality for Black women versus 1.66 (95% CI, 1.41-1.95) times the hazard for White women, and with greater hazards for younger women (HR, 2.17; 95% CI, 1.83-2.57) than older women (HR, 1.62; 95% CI, 1.40-1.88). CONCLUSIONS: Our results suggest that breast cancer survival disparities exist in Maryland among women residing in the least privileged census tracts with lower income households and higher proportions of Black residents. IMPACT: Our findings provide new insights into the breast cancer mortality disparities observed among women in Maryland.

Reference Intervals for Total T4 and Free T4 in Cynomolgus Macaques (Macaca fascicularis) and Rhesus Macaques (Macaca mulatta).

Thyroid diseases, associated with either increased or decreased concentrations of circulating thyroid hormones, are prevalent in both human and veterinary populations. Hypothyroidism is a differential diagnosis for many medical problems as the disease presents with nonspecific clinical signs that can include lethargy, weight gain, cold intolerance, and dermatologic manifestations such as alopecia. Alopecia is a frequently reported problem in captive nonhuman primates (NHP), and hypothyroidism is considered to be a differential diagnosis. However, thyroid function test results in NHP using total T4 (TT4) and free T4 (FT4) assays are difficult to interpret without accurate reference intervals (RI) for comparison. As a consequence, hypothyroidism may be underdiagnosed in these species. The objective of this study was to establish RI for TT4 and FT4 in healthy populations of cynomolgus macaques ( n = 133; age range 2.6 to 24.7 y) and rhesus macaques ( n = 172; age range 0.8 to 31.0 y). Serum samples were collected across a 14-y period during routine anesthetic events in clinically healthy animals, and TT4 and FT4 concentrations were measured using commercially available immunoassays. The RI established for TT4 and FT4 were 5.1 to 14.9 ug/dL and 0.48 to 1.17 ng/dL for cynomolgus macaques, and 3.9 to 14.7 ug/dL and 0.36 to 1.12 ng/dL for rhesus macaques. Significant differences in thyroid hormone concentrations were found between Indian and Chinese origin rhesus, and between Mauritian and other origin cynomolgus. In addition, juvenile and subadult rhesus exhibited significantly higher FT4 and TT4 concentrations than did older animals. Individual RI were established for subgroups with adequately different thyroid hormone concentrations. These results will allow a more thorough diagnostic evaluation of cynomolgus and rhesus macaques with clinical signs consistent with thyroid disease and will ultimately be a refinement in NHP medicine.

Previous exposure to dengue virus is associated with increased Zika virus burden at the maternal-fetal interface in rhesus macaques.

Concerns have arisen that pre-existing immunity to dengue virus (DENV) could enhance Zika virus (ZIKV) disease, due to the homology between ZIKV and DENV and the observation of antibody-dependent enhancement (ADE) among DENV serotypes. To date, no study has examined the impact of pre-existing DENV immunity on ZIKV pathogenesis during pregnancy in a translational non-human primate model. Here we show that macaques with a prior DENV-2 exposure had a higher burden of ZIKV vRNA in maternal-fetal interface tissues as compared to DENV-naive macaques. However, pre-existing DENV immunity had no detectable impact on ZIKV replication kinetics in maternal plasma, and all pregnancies progressed to term without adverse outcomes or gross fetal abnormalities detectable at delivery. Understanding the risks of ADE to pregnant women worldwide is critical as vaccines against DENV and ZIKV are developed and licensed and as DENV and ZIKV continue to circulate.

African-Lineage Zika Virus Replication Dynamics and Maternal-Fetal Interface Infection in Pregnant Rhesus Macaques.

Following the Zika virus (ZIKV) outbreak in the Americas, ZIKV was causally associated with microcephaly and a range of neurological and developmental symptoms, termed congenital Zika syndrome (CZS). The viruses responsible for this outbreak belonged to the Asian lineage of ZIKV. However, in vitro and in vivo studies assessing the pathogenesis of African-lineage ZIKV demonstrated that African-lineage isolates often replicated to high titers and caused more-severe pathology than Asian-lineage isolates. To date, the pathogenesis of African-lineage ZIKV in a translational model, particularly during pregnancy, has not been rigorously characterized. Here, we infected four pregnant rhesus macaques with a low-passage-number strain of African-lineage ZIKV and compared its pathogenesis to those for a cohort of four pregnant rhesus macaques infected with an Asian-lineage isolate and a cohort of mock-inoculated controls. The viral replication kinetics for the two experimental groups were not significantly different, and both groups developed robust neutralizing antibody titers above levels considered to be protective. There was no evidence of significant fetal head growth restriction or gross fetal harm at delivery (1 to 1.5 weeks prior to full term) in either group. However, a significantly higher burden of ZIKV viral RNA (vRNA) was found in the maternal-fetal interface tissues of the macaques exposed to an African-lineage isolate. Our findings suggest that ZIKV of any genetic lineage poses a threat to pregnant individuals and their infants. IMPORTANCE ZIKV was first identified in 1947 in Africa, but most of our knowledge of ZIKV is based on studies of the distinct Asian genetic lineage, which caused the outbreak in the Americas in 2015 to 2016. In its most recent update, the WHO stated that improved understanding of African-lineage ZIKV pathogenesis during pregnancy must be a priority. The recent detection of African-lineage isolates in Brazil underscores the need to understand the impact of these viruses. Here, we provide the first comprehensive assessment of African-lineage ZIKV infection during pregnancy in a translational nonhuman primate model. We show that African-lineage isolates replicate with kinetics similar to those of Asian-lineage isolates and can infect the placenta. However, there was no evidence of more-severe outcomes with African-lineage isolates. Our results highlight both the threat that African-lineage ZIKV poses to pregnant individuals and their infants and the need for epidemiological and translational in vivo studies with African-lineage ZIKV.

Cervical cancer incidence stratified by age in women with HIV compared with the general population in the United States, 2002-2016.

OBJECTIVE: Recommendations for the age of initiating screening for cervical cancer in women with HIV (WWH) in the United States have not changed since 1995 when all women (regardless of immune status) were screened for cervical cancer from the age of onset of sexual activity, which often occurs in adolescence. By 2009, recognizing the lack of benefit as well as harms in screening young women, guidelines were revised to initiate cervical cancer screening for the general population at age 21 years. By comparing cervical cancer incidence in young WWH to that of the general population, we assessed the potential for increasing the recommended age of initiating cervical cancer screening in WWH. DESIGN: We compared age-specific invasive cervical cancer (ICC) rates among WWH to the general population in the United States HIV/AIDS Cancer Match Study. METHODS: We estimated standardized incidence ratios as the observed number of cervical cancer cases among WWH divided by the expected number, standardized to the general population by age, race/ethnicity, registry, and calendar year. RESULTS: ICC rates among WWH were elevated across all age groups between ages 25 and 54 years (SIR = 3.80; 95% CI 3.48--4.15) but there were zero cases among ages less than 25 years. CONCLUSION: The absence of ICC among WWH less than 25 years supports initiating cervical cancer screening at age 21 years, rather than adolescence, to prevent cancers in WWH at ages with higher risk of ICC.