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Purpose The causes for the survival disparity among Black women with epithelial ovarian cancer (EOC) are likely multi-factorial. Here we describe the African American Cancer Epidemiology Study (AACES), the largest cohort of Black women with EOC. Methods AACES phase 2 (enrolled 2020 onward) is a multi-site, population-based study focused on overall survival (OS) of EOC. Rapid case ascertainment is used in ongoing patient recruitment in eight U.S. states, both northern and southern. Data collection is composed of a survey, biospecimens, and medical record abstraction. Results characterizing the survival experience of the phase 1 study population (enrolled 2010–2015) are presented. Results Thus far, ~ 650 patients with EOC have been enrolled in the AACES. The five-year OS of AACES participants approximates those of Black women in the Surveillance Epidemiology and End Results (SEER) registry who survive at least 10-month past diagnosis and is worse compared to white women in SEER, 49 vs. 60%, respectively. A high proportion of women in AACES have low levels of household income (45% Conclusion AACES is well positioned to evaluate the contribution of social determinants of health to the poor survival of Black women with EOC and advance understanding of the multi-factorial causes of the ovarian cancer survival disparity in Black women.

Obesity disproportionately affects African American (AA) women and has been shown to increase ovarian cancer risk, with some suggestions that the association may differ by race.We evaluated body mass index (BMI) and invasive epithelial ovarian cancer (EOC) risk in a pooled study of case-control and nested case-control studies including AA and White women. We evaluated both young adult and recent BMI (within the last 5 years). Associations were estimated using multi-level and multinomial logistic regression models.The sample included 1078 AA cases, 2582 AA controls, 3240 White cases and 9851 White controls. We observed a higher risk for the non-high-grade serous (NHGS) histotypes for AA women with obesity (ORObesity contributes to NHGS EOC risk in AA and White women, but risk across racial groups studied differs by HT use and histotype.

Chlamydia is the most frequently reported sexually transmitted infection. COVID-19 exacerbated the challenges in treating and preventing new Chlamydia trachomatis (CT) infections. This study examined the impact of COVID-19 on treating CT-positive patients discharged from a safety-net women's emergency unit.This was a preretrospective and postretrospective cohort study. Chlamydia trachomatis -positive female patients seen in the women's emergency unit were evaluated. Patients discharged in 2019, the "pre-COVID-19" group, and those discharged in 2020, the "COVID-19" group, were compared. The primary outcome was CT treatment within 30 days, and secondary outcomes included prescription dispensation, repeat tests taken, and expedited partner treatment. A subgroup of patients discharged before treatment who entered a nurse-led follow-up program was also evaluated.Of the 1357 cases included, there were no differences in successful 30-day treatment (709 of 789 [89.9%] vs. 568 of 511 [89.9%], P = 0.969) or repeat positive CT test (74 of 333 [22.2%] vs. 46 of 211 [21.8%]), P = 0.36) between pre-COVID-19 and COVID-19. However, the patients who picked up their prescription (196 of 249 [78.7%] vs. 180 of 206 [87.4%], P = 0.021) and those who were prescribed expedited partner therapy (156 of 674 [23.1%] vs. 292 of 460 [63.5%], Plt; 0.001) increased. Findings in the subgroup of patients who entered the follow-up program were consistent with those in the full cohort.The COVID-19 pandemic did not change treatment patterns of CT-positive patients in this safety-net women's emergency unit. However, patients were more likely to pick up their medications during COVID-19. Despite the perseverance of these programs through the pandemic, most patients are discharged before positive results, and a fair amount remain untreated.

The seventh multi-stakeholder Paediatric Strategy Forum focused on chimeric antigen receptor (CAR) T-cells for children and adolescents with cancer. The development of CAR T-cells for patients with haematological malignancies, especially B-cell precursor acute lymphoblastic leukaemia (BCP-ALL), has been spectacular. However, currently, there are scientific, clinical and logistical challenges for use of CAR T-cells in BCP-ALL and other paediatric malignancies, particularly in acute myeloid leukaemia (AML), lymphomas and solid tumours. The aims of the Forum were to summarise the current landscape of CAR T-cell therapy development in paediatrics, too identify current challenges and future directions, with consideration of other immune effector modalities and ascertain the best strategies to accelerate their development and availability to children. Although the effect is of limited duration in about half of the patients, anti-CD19 CAR T-cells produce high response rates in relapsed/refractory BCP-ALL and this has highlighted previously unknown mechanisms of relapse. CAR T-cell treatment as first- or second-line therapy could also potentially benefit patients whose disease has high-risk features associated with relapse and failure of conventional therapies. Identifying patients with very early and early relapse in whom CAR T-cell therapy may replace haematopoietic stem cell transplantation and be definitive therapy versus those in whom it provides a more effective bridge to haematopoietic stem cell transplantation is a very high priority. Development of approaches to improve persistence, either by improving T cell fitness or using more humanised/fully humanised products and co-targeting of multiple antigens to prevent antigen escape, could potentially further optimise therapy. Many differences exist between paediatric B-cell non-Hodgkin lymphomas (B-NHL) and BCP-ALL. In view of the very small patient numbers with relapsed lymphoma, careful prioritisation is needed to evaluate CAR T-cells in children with Burkitt lymphoma, primary mediastinal B cell lymphoma and other NHL subtypes. Combination trials of alternative targets to CD19 (CD20 or CD22) should also be explored as a priority to improve efficacy in this population. Development of CD30 CAR T-cell immunotherapy strategies in patients with relapsed/refractory Hodgkin lymphoma will likely be most efficiently accomplished by joint paediatric and adult trials. CAR T-cell approaches are early in development for AML and T-ALL, given the unique challenges of successful immunotherapy actualisation in these diseases. At this time, CD33 and CD123 appear to be the most universal targets in AML and CD7 in T-ALL. The results of ongoing or planned first-in-human studies are required to facilitate further understanding. There are promising early results in solid tumours, particularly with GD2 targeting cell therapies in neuroblastoma and central nervous system gliomas that represent significant unmet clinical needs. Further understanding of biology is critical to success. The comparative benefits of autologous versus allogeneic CAR T-cells, T-cells engineered with T cell receptors T-cells engineered with T cell receptor fusion constructs, CAR Natural Killer (NK)-cell products, bispecific T-cell engager antibodies and antibody-drug conjugates require evaluation in paediatric malignancies. Early and proactive academia and multi-company engagement are mandatory to advance cellular immunotherapies in paediatric oncology. Regulatory advice should be sought very early in the design and preparation of clinical trials of innovative medicines, for which regulatory approval may ultimately be sought. Aligning strategic, scientific, regulatory, health technology and funding requirements from the inception of a clinical trial is especially important as these are very expensive therapies. The model for drug development for cell therapy in paediatric oncology could also involve a ‘later stage handoff’ to industry after early development in academic hands. Finally, and very importantly, strategies must evolve to ensure appropriate ease of access for children who need and could potentially benefit from these therapies.

BackgroundDeprivation and segregation indices are often examined as possible explanations for observed health disparities in population-based studies. In this study we assessed the role of recognized deprivation and segregation indices specifically as they affect survival in a cohort of self-identified Black women diagnosed with ovarian cancer who enrolled in the African American Cancer Epidemiology Study (AACES).MethodsMediation analysis was used to examine the direct and indirect effects between deprivation or segregation and overall survival, via a Bayesian structural equation model with Gibbs variable selection.ResultsThe results suggest that high SES -related indices have an association with increased survival, ranging from 25%-56%. In contrast, ICE-race does not have a significant impact on overall survival. In many cases, the indirect effects have very wide credible intervals, consequently the total effect is not well estimated despite the estimation of the direct effect.ConclusionsOur results show that black women living in higher SES neighborhoods are associated with increased survival with ovarian cancer, using area-level economic indices such as Yost or ICE-income. In addition, the KOLAK urbanization index has a similar impact, and the highlights importance of area-level deprivation and segregation as potentially modifiable social factors in ovarian cancer survival.

Lay abstract This study describes treatment patterns and outcomes in newly diagnosed multiple myeloma (NDMM) patients in Spain who were not candidates for transplant. The study looked at two patient groups: patients diagnosed between 1 January 2012 and 31 December 2013 and those diagnosed between 1 April 2016 and 31 March 2017. Among the 113 patients considered, the most common first-line therapies were proteasome inhibitor (PI) + alkylator combinations (49%) and PI-based regimens without an alkylator (30%). We saw increased use of PI with immunomodulators (which arm the immune system to battle disease) and decreased use of PI-based regimens without an alkylator or immunomodulator. First-line use of oral regimens was low but increased over time. The median length of first-line treatment for both groups combined was 6.9 months. Finding low use of first-line oral regimens and maintenance therapy and a short duration of first-line treatment, our study highlights the unmet needs that exist in NDMM patients who are not transplant candidates in Spain. Aim: To describe treatment patterns and outcomes in nontransplant newly diagnosed multiple myeloma (NDMM) patients in Spain. Methods: This retrospective study included two cohorts of NDMM patients diagnosed between 1 January 2012 to 31 December 2013 and 1 April 2016 to 31 March 2017. Results: Among 113 patients, proteasome inhibitor (PI) + alkylator combinations (49%) and PI-based regimens without an alkylator (30%) were the most common first-line (1L) therapies. Use of PI + immunomodulatory drug-based regimens increased between the cohorts; PI-based regimens without an alkylator/immunomodulatory drug decreased. Use of 1L oral regimens was low but increased over time; use of maintenance therapy was low across both periods. Median 1L duration of treatment was 6.9 months. Conclusion: Short 1L duration of treatment and low use of 1L oral regimens and maintenance therapy highlight unmet needs in NDMM.

Introduction: The needs of medically-underserved populations (MUPs) are consistently outpacing the number of physicians caring for them. Medical students’ motivations toward working with MUPs consistently decline as they progress through medical school. Given the shortage of doctors caring for MUPs, the objective of our study was to further investigate factors that influence medical students’ motivation to work with MUPs while they progress through their education. By identifying these elements, we hope to recommend identified factors within medical education that support the development of more physicians who care for MUPs. Methods: This cross-sectional study is an assessment of medical students at the University of Texas at Southwestern Medical School (UTSW). The study utilized the Medical Student Attitudes Toward the Underserved (MSATU), a validated survey that assesses medical student motivations toward the provision of medical care to MUPs. Surveys were administered at three time points selected to represent key transition points in medical education. Results: There was no significant difference between MSATU scores among the three time points. MSATU scores were higher among students who identified as female, had higher empathy, had higher value placed on teamwork, and had higher community-centeredness. MSATU scores were also higher among students planning to specialize in primary care compared to students planning to specialize in a non-primary care field (P=.239). Conclusion: This study identifies factors associated with high MSATU scores within UTSW medical education, including female identification, higher empathy score, higher emphasis on teamwork, higher community-centeredness, and plans to practice primary care. Additionally, the results support maintenance of MSATU scores across all three time points. Future research should examine individual-level data to determine whether individual students are maintaining their MSATU scores or if individual fluctuations are neutralized by group changes.

In contrast to nearly all other tissues, the anatomy of cell differentiation in the bone marrow remains unknown. This is owing to a lack of strategies for examining myelopoiesis—the differentiation of myeloid progenitors into a large variety of innate immune cells—in situ in the bone marrow. Such strategies are required to understand differentiation and lineage-commitment decisions, and to define how spatial organizing cues inform tissue function. Here we develop approaches for imaging myelopoiesis in mice, and generate atlases showing the differentiation of granulocytes, monocytes and dendritic cells. The generation of granulocytes and dendritic cells–monocytes localizes to different blood-vessel structures known as sinusoids, and displays lineage-specific spatial and clonal architectures. Acute systemic infection with Listeria monocytogenes induces lineage-specific progenitor clusters to undergo increased self-renewal of progenitors, but the different lineages remain spatially separated. Monocyte–dendritic cell progenitors (MDPs) map with nonclassical monocytes and conventional dendritic cells; these localize to a subset of blood vessels expressing a major regulator of myelopoiesis, colony-stimulating factor 1 (CSF1, also known as M-CSF)1. Specific deletion of Csf1 in endothelium disrupts the architecture around MDPs and their localization to sinusoids. Subsequently, there are fewer MDPs and their ability to differentiate is reduced, leading to a loss of nonclassical monocytes and dendritic cells during both homeostasis and infection. These data indicate that local cues produced by distinct blood vessels are responsible for the spatial organization of definitive blood cell differentiation. A combination of fluorescent antibodies is used to build visual maps of all myeloid cells in the bone marrow, providing new insight into how the bone marrow microenvironment regulates cell-fate decisions.

In New York City in the late 1970s, the Black community created hip-hop, a significant cultural phenomenon, which has since spread around the world. Our research is centered on the revolutionary hip-hop fashion movement in Black history as it relates to Black millennials’ experiences of fashioning their bodies. We examine the perception of Black millennials who are attending or have attended historically Black colleges and universities (HBCU) and their knowledge and perceptions of prominent Black-owned, urban fashion brands that emerged in the 1980s and 1990s. Additionally, we seek to understand how or if these brands influence Black millennial consumers and their stylistic choices today. We used a qualitative approach and conducted 14 in-depth, semistructured interviews. Based on analysis of the data, we identified four themes: awareness of urban styles; ambiguous perceptions; 1980s and 1990s urban style influence; and awareness of cultural appropriation. We offer implications to the apparel industry.

Aim: To understand physician visit patterns among patients with stage IV (including nonmetastatic [M0] and metastatic [M1] disease) urothelial carcinoma (UC) and understand factors associated with a timely referral to a medical oncologist and systemic treatment. Patients & methods: Retrospective analysis of Surveillance, Epidemiology and End Results-Medicare data. Results: First physician encounter was with a urologist (M0: 69%; M1: 53%) or primary care physician ([PCP]; M0: 19%, M1: 25%) for the majority of patients around UC diagnosis. After the index urologist encounter, most patients had a subsequent medical oncologist visit at a median of 52 days (M0: 69.5 days, M1: 33 days). In an adjusted model, older age, index PCP visit, higher comorbidities and M0 disease were negatively associated with a medical oncologist referral. Among those referred to a medical oncologist, older age, Hispanic or non-Hispanic Black race and not being married were negatively associated with subsequent chemotherapy receipt (p < 0.05). Conclusion: Many patients with advanced UC encounter multiple specialists during their disease course. Older patients or those with a first UC-related encounter with a PCP are less likely to be referred to medical oncology. Once referred to medical oncology, social determinants, including race and marital status, are relevant predictors of receiving chemotherapy.

Background In a randomized study, glasdegib (a hedgehog inhibitor) plus low‐dose cytarabine (LDAC) significantly prolonged survival in comparison with LDAC in patients with acute myeloid leukemia (AML). A quality‐adjusted time without symptoms of disease progression or toxicity (Q‐TWiST) approach was used to evaluate comparative quality‐adjusted survival. Methods Overall survival was partitioned into the following: time with any treatment‐emergent grade 3 or higher adverse events (TOX); time without symptoms of disease progression or toxicity (TWiST); and time after treatment discontinuation due to insufficient clinical response, relapse, or death time after progression (REL). Q‐TWiST was calculated by multiplying the restricted mean time in each state by respective utilities and then summing up the utility‐adjusted time. Results At 20 months of follow‐up, the survival probabilities for the glasdegib‐LDAC arm and the LDAC arm were 28.2% and 7.9%, respectively. Glasdegib‐LDAC patients (n = 78), in comparison with LDAC patients (n = 38), had significantly longer mean TWiST (+3.4 months; 95% confidence interval [CI], 1.8‐5.2 months) and TOX (+0.8 months; 95% CI, 0.1‐1.6 months) and longer but nonsignificant REL (+0.3 months; 95% CI, −1.9 to 2.3 months). Q‐TWiST was 4.0 months (95% CI, 2.1‐5.8 months) longer with glasdegib plus LDAC, and this translated into a 75% relative improvement in quality‐adjusted survival with respect to LDAC. Results were robust to the length of follow‐up (6‐24 months) and remained significant when all adverse events, regardless of grade, were included. Conclusions These results suggest that most of the survival benefit from glasdegib plus LDAC versus LDAC alone is TWiST, and this represents added time in relatively “good” health. These results support the clinical value of glasdegib plus LDAC as initial therapy for AML in patients for whom intensive chemotherapy is not an option., This analysis suggests that most of the survival benefit from glasdegib plus low‐dose cytarabine (LDAC) in comparison with LDAC alone is time without symptoms of disease progression or toxicity, which represents added time in relatively “good” health. These results support the clinical value of glasdegib plus LDAC as an initial therapy for acute myeloid leukemia in patients for whom intensive chemotherapy is not an option.

Courtney Johnson,1 Jennifer Stephens,1 Christopher Walker,2 Joseph C Cappelleri,3 Ahmed Shelbaya4 1Pharmerit International, Real World Evidence and Data Analytics, Bethesda, MD, USA; 2Pfizer Ltd., Global Medical Affairs, Tadworth, Surrey, England; 3Pfizer Inc., Statistics, Groton, CT, USA; 4Pfizer Inc., Health Economics and Outcomes Research, New York, NY, USACorrespondence: Jennifer StephensPharmerit International, 4350 East West Highway, Suite 1100, Bethesda, MD, USATel +1 240-821-1290Email jstephens@pharmerit.comObjective: This study describes treatment patterns, healthcare resource utilization (HCRU), and costs associated with persistence, switching, and dosing of branded celecoxib in osteoarthritis (OA) patients.Methods: This retrospective claims database analysis used MarketScan® Commercial Claims and Encounters (MarketScan) data from 2009 to 2013. Included patients were adult (≥ 18 years), incident celecoxib users with ≥ 1 OA claim. The treatment switch analysis analyzed outcomes in patients persistent on celecoxib versus switched to a generic nonsteroidal anti-inflammatory drug (NSAID). The dosing analysis stratified patients as under-dose (< 200 mg per day) and standard dose (≥ 200 mg per day). HCRU, costs, and treatment duration were compared in persistent versus switched and standard dose versus under-dose patients using descriptive, multivariate logistic regression, and Kaplan–Meier analysis.Results: A total of 65,530 patients met the inclusion criteria. During follow-up, 83% discontinued celecoxib without switching, 10% were persistent, and 5% switched to a generic NSAID. Ninety percent received a standard dose of celecoxib. Switched (versus persistent) patients had significantly higher all-cause hospital admissions, length of stay, emergency room (ER) visits, and office visits per person year (PPY), all P < 0.001; and under-dosed (versus standard dose) patients had significantly higher hospital admissions (P< 0.001), length of stay (P< 0.001), and ER visits (P= 0.021) PPY. Persistent versus switched patients had lower mean total all-cause costs PPY ($20,378 vs $23,949, P< 0.001). Standard dose versus under-dose patients had lower mean total all-cause costs ($23,680 vs $26,955 PPY, P< 0.001), and not statistically significant higher mean total OA-related costs ($5698 vs $5524 PPY, P=0.441).Conclusion: Patients that switched from branded celecoxib to a generic NSAID or received an under-dose of branded celecoxib had higher average overall HCRU and costs. OA-related inpatient and outpatient cost savings may offset the higher drug cost of celecoxib for persistent patients.Keywords: generic, healthcare resource use, Celebrex, NSAIDS, switching, discontinuation

We report a design and implementation of proton deflectometry with an in situ reference x-ray image of a mesh to precisely measure non-uniform magnetic fields in expanding plasmas at the OMEGA and OMEGA EP laser facilities. The technique has been developed with proton and x-ray sources generated from both directly driven capsule implosions and short pulse laser–solid interactions. The accuracy of the measurement depends on the contrast of both the proton and x-ray images. We present numerical and analytic studies to optimize the image contrast using a variety of mesh materials and grid spacings. Our results show clear enhancement of the image contrast by factors of four to six using a high Z mesh with large grid spacing. This leads to further improvement in the accuracy of the magnetic field measurement using this technique in comparison with its first demonstration at the OMEGA laser facility [Rev. Sci. Instrum. 93, 023502 (2022)RSINAK0034-674810.1063/5.0064263].

In the United States, racial/ethnic and sexual youth and young adults (YYA) of color are disproportionately affected by HIV. Subsequently, YYA experience HIV stigma and engage in increased risk behaviors and reduced HIV testing. HIV communication has been identified as a potential buffer to HIV stigma, resulting in health-seeking behaviors, such as HIV testing. In this study, we respond to a meaningful gap in the literature by examining different types of HIV communication and their impact on HIV stigma and HIV testing in a diverse sample of YYA. We analyzed secondary data from the Kaiser Family Foundation National Survey of Teens and Young Adults on HIV/AIDS. A 40-question, web-based survey was conducted with 1437 youth (ages 15–24). Recruitment included a dual sampling method from households with: (1) listed phone numbers, (2) unlisted phone numbers, (3) telephones, (4) no telephone, and (5) only cell phone access. The purpose of the survey was to establish participants’ HIV knowledge, communication, experiences, and testing behaviors. Findings suggested an association between intimate-partner HIV communication, increased HIV testing, and reduced HIV stigma. We also identified differentials in HIV testing and stigma based on gender, income, age, and sexual minority status, explained by HIV communication. Further research is needed that examines ways to use intimate-partner HIV communication to reduce stigma and increase HIV testing among YYA of different sociodemographic characteristics and sexual orientations.

The early stages of the virus-cell interaction have long evaded observation by existing microscopy methods due to the rapid diffusion of virions in the extracellular space and the large three-dimensional cellular structures involved. Here we present an active-feedback single-particle tracking method with simultaneous volumetric imaging of the live cell environment called 3D-TrIm to address this knowledge gap. 3D-TrIm captures the extracellular phase of the infectious cycle in what we believe is unprecedented detail. We report what are, to our knowledge, previously unobserved phenomena in the early stages of the virus-cell interaction, including skimming contact events at the millisecond timescale, orders of magnitude change in diffusion coefficient upon binding and cylindrical and linear diffusion modes along cellular protrusions. Finally, we demonstrate how this method can move single-particle tracking from simple monolayer culture toward more tissue-like conditions by tracking single virions in tightly packed epithelial cells. This multiresolution method presents opportunities for capturing fast, three-dimensional processes in biological systems.

The seventh multi-stakeholder Paediatric Strategy Forum focused on chimeric antigen receptor (CAR) T-cells for children and adolescents with cancer. The development of CAR T-cells for patients with haematological malignancies, especially B-cell precursor acute lymphoblastic leukaemia (BCP-ALL), has been spectacular. However, currently, there are scientific, clinical and logistical challenges for use of CAR T-cells in BCP-ALL and other paediatric malignancies, particularly in acute myeloid leukaemia (AML), lymphomas and solid tumours. The aims of the Forum were to summarise the current landscape of CAR T-cell therapy development in paediatrics, too identify current challenges and future directions, with consideration of other immune effector modalities and ascertain the best strategies to accelerate their development and availability to children. Although the effect is of limited duration in about half of the patients, anti-CD19 CAR T cells produce high response rates in relapsed/refractory BCP-ALL and this has highlighted previously unknown mechanisms of relapse. CAR T-cell treatment as first-or second-line therapy could also potentially benefit patients whose disease has high-risk features associated with relapse and failure of conventional therapies. Identifying patients with very early and early relapse in whom CAR T-cell therapy may replace haematopoietic stem cell transplanta-tion and be definitive therapy versus those in whom it provides a more effective bridge to hae-matopoietic stem cell transplantation is a very high priority. Development of approaches to improve persistence, either by improving T cell fitness or using more humanised/fully huma-nised products and co-targeting of multiple antigens to prevent antigen escape, could potentially further optimise therapy. Many differences exist between paediatric B-cell non-Hodgkin lymphomas (B-NHL) and BCP-ALL. In view of the very small patient numbers with relapsed lymphoma, careful prior-itisation is needed to evaluate CAR T-cells in children with Burkitt lymphoma, primary medi-astinal B cell lymphoma and other NHL subtypes. Combination trials of alternative targets to CD19 (CD20 or CD22) should also be explored as a priority to improve efficacy in this pop-ulation. Development of CD30 CAR T-cell immunotherapy strategies in patients with relapsed/refractory Hodgkin lymphoma will likely be most efficiently accomplished by joint paediatric and adult trials.CAR T-cell approaches are early in development for AML and T-ALL, given the unique challenges of successful immunotherapy actualisation in these diseases. At this time, CD33 and CD123 appear to be the most universal targets in AML and CD7 in T-ALL. The results of ongoing or planned first-in-human studies are required to facilitate further understanding. There are promising early results in solid tumours, particularly with GD2 targeting cell ther-apies in neuroblastoma and central nervous system gliomas that represent significant unmet clinical needs. Further understanding of biology is critical to success.The comparative benefits of autologous versus allogeneic CAR T-cells, T-cells engineered with T cell receptors T-cells engineered with T cell receptor fusion constructs, CAR Natural Killer (NK)-cell products, bispecific T-cell engager antibodies and antibody-drug conjugates require evaluation in paediatric malignancies.Early and proactive academia and multi-company engagement are mandatory to advance cellular immunotherapies in paediatric oncology. Regulatory advice should be sought very early in the design and preparation of clinical trials of innovative medicines, for which regu-latory approval may ultimately be sought. Aligning strategic, scientific, regulatory, health technology and funding requirements from the inception of a clinical trial is especially impor-tant as these are very expensive therapies.The model for drug development for cell therapy in paediatric oncology could also involve a 'later stage handoff' to industry after early development in academic hands. Finally, and very importantly, strategies must evolve to ensure appropriate ease of access for children who need and could potentially benefit from these therapies. 2021 The Author(s). Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

PURPOSE: Women with endometriosis have a 2 to 3-fold greater risk of endometrioid and clear cell ovarian cancer than other women, based on estimates from studies predominantly of White women. Fibroids have not been consistently associated with ovarian cancer risk but are the most common indication for hysterectomies in the U.S. Hysterectomy has been associated with lower ovarian cancer risk in subgroups of women including those with fibroids; thus fibroids may indirectly impact ovarian cancer risk. We evaluated the association of endometriosis and fibroids with ovarian cancer risk among Black and White women, taking into consideration the impact of hysterectomy. METHODS: We used data from six studies in the Ovarian Cancer in Women of African Ancestry (OCWAA) consortium. Participants included 2,995 Black women and 5,281 White women. Logistic regression was used to calculate odds ratios (ORs) and 95% confidence intervals (CIs) for the association between endometriosis and fibroids with ovarian cancer risk, overall, by race, and stratified by histotype. We also assessed effect modification by hysterectomy. RESULTS: Overall the prevalences of endometriosis and fibroids were 6.4% and 43.2% among Black women and 7.0% and 21.5% among White women, respectively. Endometriosis was associated with an increased risk of endometrioid and clear cell ovarian cancer in Black and White women. Among Black women the association was strongest for endometrioid tumors (OR=7.06; 95% CI=3.86-12.91) compared to White women (OR=2.17; 95% CI=1.36-3.45) with a significant difference by race (phetereogeneity=0.003). When stratified by hysterectomy the association between endometriosis and ovarian cancer risk in White women was stronger in those who did not report a hysterectomy. However, in Black women, the elevated risk of ovarian cancer among women with endometriosis was present among those with and without hysterectomy. Fibroids were associated with a slightly elevated risk of ovarian cancer in Black (OR=1.34; 95% CI=1.11-1.62) and White women (OR=1.22; 95% CI=1.05-1.41). For both groups, the association was present only in those who did not report a hysterectomy. Black women who had a history of fibroids and no hysterectomy had a 53% greater odds of ovarian cancer (95% CI=1.23-1.89) compared to those without fibroids, while there was no association with fibroids in the hysterectomy group (OR=0.92, 95% CI=0.62-1.36) (pinteraction=0.05). A similar pattern was observed among White women, but the interaction was not significant (pinteraction=0.21). CONCLUSION: Both Black and White women with endometriosis had a higher risk of ovarian cancer, and hysterectomy modified this association only among White women. Fibroids were associated with modestly increased risk of ovarian cancer among Black and White women, with hysterectomy modifying the risk in both groups. Further research is needed to understanding how racial differences in diagnoses of these conditions, and differential access to care and treatment options, impact or modify ovarian cancer risk. Citation Format: Holly Harris, Lauren Peres, Courtney Johnson, Kristin Guertin, Alicia Beeghly-Fadiel, Elisa Bandera, Traci Bethea, Charlotte Joslin, Anna Wu, Patricia Moorman, Heather Ochs-Balcom, Jessica Petrick, Veronica Setiawan, Lynn Rosenberg, Joellen Schildkraut, Evan Myers. Racial differences in the association of endometriosis and fibroids with risk of ovarian cancer [abstract]. In: Proceedings of the 15th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2022 Sep 16-19; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2022;31(1 Suppl):Abstract nr C105.

The early stages of the virus-cell interaction have long evaded observation by existing microscopy methods due to the rapid diffusion of virions in the extracellular space and the large 3D cellular structures involved. Here we present an active-feedback single-particle tracking method with simultaneous volumetric imaging of the live cell environment to address this knowledge gap to present unprecedented detail to the extracellular phase of the infectious cycle. We report previously unobserved phenomena in the early stages of the virus-cell interaction, including skimming contact events at the millisecond timescale, orders of magnitude change in diffusion coefficient upon binding, and cylindrical and linear diffusion modes along cellular protrusions. Finally, we demonstrate how this new method can move single-particle tracking from simple monolayer culture towards more tissue-like conditions by tracking single virions in tightly packed epithelial cells. This multi-resolution method presents new opportunities for capturing fast, 3D processes in biological systems.One-Sentence SummaryActive-feedback 3D single-particle tracking enables an unprecedented look at the early stages of virus-cell interactions.

To determine predictors of obstructive sleep apnea (OSA) in underweight children and to describe the demographic, clinical, and polysomnographic characteristics of an ethnically diverse population of underweight children with OSA.Case-control study.University of Texas Southwestern Medical Center and Children's Medical Center of Dallas.Underweight children aged 2 to 18 years who underwent a polysomnogram for suspected OSA between January 2014 and December 2020 were included. Underweight was defined as body mass index5th percentile per Centers for Disease Control and Prevention guidelines. Children with apnea-hypopnea index1.0 served as a control group. Univariate and multiple logistic regression analysis was used to determine the predictors of OSA. Significance was set atAn overall 124 children met inclusion criteria: mean age, 6.4 years; 50% female; 44% Hispanic, 31% African American, and 18% Caucasian. A total of 83 children had OSA (apnea-hypopnea index ≥1.0). Height was negatively correlated with OSA (odds ratio, 0.94; 95% CI, 0.88-0.99;Underweight children with OSA, as compared with those without OSA, are more likely to have decreased height, tonsillar hypertrophy, and allergic rhinitis. There are no predictors of severe OSA in underweight children. We recommend polysomnography for the diagnosis of OSA in symptomatic underweight children with large tonsils, especially when they have a history of allergies.

Aim: To describe treatment patterns and outcomes of patients with unresectable stage III and metastatic/stage IV melanoma. Materials & methods: An observational retrospective chart review of patients diagnosed with advanced melanoma before 1 November 2015 who initiated a new line of therapy (LOT) from 1 January 2015 to 31 May 2016. Results: Among 487 patients, ipilimumab monotherapy (27.5%) was the most common first line of therapy (1LOT) in 2015, surpassed by nivolumab monotherapy (21.5%) in 2016. 12-month survival was ≥80.1%; proportions were highest forpatients treated with nivolumab + ipilimumab (86.6%). All treatments relatively well tolerated in real-world setting and adverse events were consistent with the previously reported safety profiles. Conclusion: This study provides important insights into real-world advanced melanoma treatment patterns and demonstrates encouraging treatment safety and patient survival data.

Background: Early antibiotic switch and early discharge protocols have not been widely studied in Latin America. Our objective was to describe real-world treatment patterns, resource use, and estimate opportunities for early switch from intravenous to oral antibiotics and early discharge for patients hospitalized with methicillin-resistant Staphylococcus aureus complicated skin and soft-tissue infections. Materials/methods: This retrospective medical chart review recruited 72 physicians from Brazil to collect data from patients hospitalized with documented methicillin-resistant Staphylococcus aureus complicated skin and soft tissue infections between May 2013 and May 2015, and discharged alive by June 2015. Data collected included clinical characteristics and outcomes, hospital length of stay, methicillin-resistant Staphylococcus aureus-targeted intravenous and oral antibiotic use, and early switch and early discharge eligibility using literature-based and expert-validated criteria. Results: A total of 199 patient charts were reviewed, of which 196 (98.5%) were prescribed methicillin-resistant Staphylococcus aureus -active therapy. Only four patients were switched from intravenous to oral antibiotics while hospitalized. The mean length of methicillin-resistant Staphylococcus aureus-active treatment was 14.7 (standard deviation, 10.1) days, with 14.6 (standard deviation, 10.1) total days of intravenous therapy. The mean length of hospital stay was 22.2 (standard deviation, 23.0) days. The most frequent initial methicillin-resistant Staphylococcus aureus-active therapies were intravenous vancomycin (58.2%), intravenous clindamycin (19.9%), and intravenous daptomycin (6.6%). Thirty-one patients (15.6%) were discharged with methicillin-resistant Staphylococcus aureus -active antibiotics of which 80.6% received oral antibiotics. Sixty-two patients (31.2%) met early switch criteria and potentially could have discontinued intravenous therapy 6.8 (standard deviation, 7.8) days sooner, and 65 patients (32.7%) met early discharge criteria and potentially could have been discharged 5.3 (standard deviation, 7.0) days sooner. Conclusions: Only 2% of patients were switched from intravenous to oral antibiotics in our study while almost one-third were early switch eligible. Additionally, one-third of hospitalized patients with methicillin-resistant Staphylococcus aureus complicated skin and soft tissue infections were early discharge eligible indicating opportunity for reducing intravenous therapy and days of hospital stay. These results provide insight into possible benefits of implementation of early switch/early discharge protocols in Brazil. Keywords: IV-to-PO switch, Length of stay, Clinical criteria, Antibiotic therapy, Economics

Hematopoiesis in the bone marrow (BM) is the primary source of immune cells. Hematopoiesis is regulated by a diverse cellular microenvironment that supports stepwise differentiation of multipotent stem cells and progenitors into mature blood cells. Blood cell production is not static and the bone marrow has evolved to sense and respond to infection by rapidly generating immune cells that are quickly released into the circulation to replenish those that are consumed in the periphery. Unfortunately, infection also has deleterious effects injuring hematopoietic stem cells (HSC), inefficient hematopoiesis, and remodeling and destruction of the microenvironment. Despite its central role in immunity, the role of the microenvironment in the response to infection has not been systematically investigated. Here we summarize the key experimental evidence demonstrating a critical role of the bone marrow microenvironment in orchestrating the bone marrow response to infection and discuss areas of future research.

BACKGROUND: Urothelial carcinoma (UC) is generally diagnosed early and may incur significant lifetime costs. This study estimated, from the payer’s perspective, the lifetime costs among patients diagnosed with UC according to stage at diagnosis. METHODS: This retrospective analysis of the linked Surveillance, Epidemiology, and End Results (SEER)-Medicare database identified patients ≥66 years with newly diagnosed UC from 2004–2013. Patients were followed from UC diagnosis to death or last follow-up to estimate lifetime costs. Costs were allocated to 3 phases: diagnosis (≤3 months after diagnosis), terminal (≤3 months before death), and continuation (months between diagnosis and terminal phases). Survival-adjusted lifetime costs (total and major UC-related) were estimated for patients with UC based on stage at diagnosis (stages 0 through IV) and in a subgroup of patients receiving ≥1 systemic line of chemotherapy (LOC). RESULTS: The sample included 15,588 patients: 3,446 stage 0 (8% ≥1 LOC; median [IQR] follow-up in months: 44 [23–71]); 3,902 stage I (12% ≥1 LOC; 33 [15–62]); 4,301 stage II (26% ≥1 LOC; 17 [7–39]); 1,612 stage III (25% ≥1 LOC; 17 [7–42]); and 2,327 stage IV (33% ≥1 LOC; 8 [3–18]). Median age was 78 years and 72% were male. Mean lifetime costs were lowest for stage IV patients (stage 0, $151,626; stage 1, $150,123; stage II, $149,728; stage III, $190,996; stage IV, $117,503). Hospitalizations not involving a cystectomy contributed about half of lifetime costs across all stages. Cystectomy contributed 2–13% of the total lifetime UC costs ($3,356 stage 0; $7,011 stage I; $11,855 stage II; $25,509 stage III; $11,693 stage IV). UC-related office visits contributed 8–15% of lifetime costs ($11,717 stage 0; $14,611 stage I; $19,882 stage II; $21,480 stage III; $17,820 stage IV). CONCLUSION: UC continues to be a costly cancer with stage III patients having highest lifetime costs. Hospitalizations drive most of the lifetime costs across all stages; most of these hospitalizations did not involve costs related to cystectomy. Treatment plans requiring shorter and fewer hospitalizations may lessen the economic burden of UC.

SummaryIn contrast to virtually all other tissues in the body the anatomy of differentiation in the bone marrow remains unknown. This is due to the lack of strategies to examine blood cell production in situ, which are required to better understand differentiation, lineage commitment decisions, and to define how spatial organizing cues inform tissue function. Here we developed imaging approaches to map all myeloid cells in whole bones and generated 3D atlases of granulocyte and monocyte/dendritic cell differentiation during homeostasis. We found that myeloid progenitors leave the hematopoietic stem cell niche during differentiation. Granulocyte and monocyte dendritic cell progenitors (MDP) do not interact, instead they localize to different sinusoids where they give rise to clusters of immature cells. MDP cluster with Ly6Clomonocytes and conventional dendritic cells; these localize to a unique subset of colony stimulating factor 1 (CSF1, the major regulator of monopoiesis1) -expressing sinusoids. Csf1 deletion in the vasculature disrupted the MDP clusters and their interaction with sinusoids, leading to reduced MDP numbers and differentiation ability, with subsequent loss of peripheral Ly6Clomonocytes and dendritic cells. These data indicate that there is a specific spatial organization of definitive hematopoiesis and that local cues produced by distinct blood vessels are responsible for this organization. These maps provide a blueprint for in situ analyses of hematopoiesis in blood disorders.

Objectives While evidence has mounted regarding the short-term effectiveness of pharmacotherapy for opioid use disorder (OUD), little is known about longer-term psychosocial, economic, and health outcomes. We report herein 12-month outcomes for an observational study enrolling participants who had previously taken part in a long-acting buprenorphine subcutaneous injection (BUP-XR) trial for moderate to severe OUD. Methods The RECOVER (Remission from Chronic Opioid Use: Studying Environmental and SocioEconomic Factors on Recovery; NCT03604861) study enrolled participants from 35 US community-based sites. Self-reported sustained opioid abstinence over 12 months and self-reported past-week abstinence at 3-, 6-, 9-, and 12-month visits were assessed. Multiple regression models assessed the association of BUP-XR duration with abstinence, controlling for potential confounders. Withdrawal, pain, health-related quality of life, depression, and employment at RECOVER baseline and 12-month visits were also compared to values collected before treatment in the BUP-XR trial. Results Of 533 RECOVER participants, 425 completed the 12-month visit (average age 42 years; 66% male); 50.8% self-reported sustained 12-month and 68.0% past-week opioid abstinence. In multiple regressions, participants receiving 12-month versus ≤2-month BUP-XR treatment duration had significantly higher likelihood of sustained opioid abstinence (75.3% vs 24.1%; P = 0.001), with similar results for past-week self-reported abstinence over time. During RECOVER, participants had fewer withdrawal symptoms, lower pain, positive health-related quality of life, minimal depression, and higher employment versus pre-trial visit. Conclusions RECOVER participants reported positive outcomes over the 12-month observational period, including high opioid abstinence and stable or improved humanistic outcomes. These findings provide insights into the long-term impact of pharmacotherapy in OUD recovery.

Knowledge of the anatomy of each tissue and the relationships between progenitors and daughter cells is necessary to understand physiology and pathology. The anatomy of hematopoiesis in the marrow remains largely unknown. Here we identify strategies to image all steps of blood cell production in the mouse sternum using confocal microscopy. We show that long-distance migration of multipotent progenitors, lineage-committed progenitor recruitment to vessels, and generation of lineage-specific oligoclonal structures that are the main production sites for immature cells are key features of the anatomy of blood production. This structural organization is extremely durable and resilient to insults as it was maintained after hemorrhage, Listeria monocytogenes infection, and aging (80-weeks). Importantly, this anatomy is also enabled with local plasticity as production sites for each blood lineage selectively expand/contract in respond to insults followed by a return to homeostasis. We used immunophenotyping to identify fifty-six surface markers that can be combined to image any populations of interest. For example, we found that ESAM is selectively expressed in 100% of LT-HSC, 90% of ST-HSC, 70% of MPP2 and MPP3, 30% of MPP4, 10% of CMP, and 90% of MkP and megakaryocytes but absent in more mature cells. Transplantation experiments revealed that all functional LT- and ST-HSC, MPP2, MPP3 and CMP were contained -exclusively- in the ESAM positive fraction (p100 μm, no different from random simulations, n=41 LT-HSC from 5 sternum sections of 4 wild-type mice) and are clonally unrelated between them. Multipotent and oligopotent progenitors reside near sinusoids (mean distance =9.7 μm) but this association is not different from that observed for random cells. In contrast, as progenitors become lineage-restricted, they localize to arterioles (for lymphoid progenitors) or sinusoids (all other progenitors) where they enter oligoclonal structures that are the main production sites for immature cells in each lineage. Each production site has distinct architectures: lymphoid sites are characterized by tight clusters of PreProB cells surrounding CLP; erythroid sites are characterized by strings of 4-21 CFU-E decorating the surface of sinusoids with early erythroblasts differentiating orthogonally to the vessel surface; in megakaryocyte sites one or two megakaryocyte progenitors produce megakaryocytes that decorate blood vessels over large (>200μm 3) marrow regions. We previously showed that production sites for neutrophils contain 1 or 2 granulocyte progenitors tightly clustered with preneutrophils and that sites for monocytes/dendritic cells contain loose clusters of dendritic cells surrounding monocyte dendritic cell progenitors (Zhang Nature 2021). This spatial architecture is durable and resilient and is maintained after acute challenge via phlebotomy, L. monocytogenes infection, or physiological aging (80-week-old mice). However, we also observed plasticity of production sites. Two days after phlebotomy we found increases in erythroid site numbers (368 vs 945 per mm 3, p In summary, we have developed strategies that allow imaging of differentiation in situ and defined a complex - but durable and plastic- anatomy for the hematopoietic tissue. Disclosures No relevant conflicts of interest to declare.

Background: Black patients can face a higher incidence and poorer prognosis from cutaneous T-cell lymphoma (CTCL) compared to their white counterparts yet race is not a known factor in the treatment of CTCL. The significance of race, particularly in the treatment of early-stage CTCL using extracorporeal photopheresis (ECP), is not well understood. Objective: To characterize race-based and stage- based differences in ECP utilization and response among adults with mycosis fungoides and Sezary syndrome. Methods: A 10-year retrospective chart review was performed at a single tertiary referral center institution. Results: Among total 42 qualifying CTCL patients that received, 57.1% were female, 47.6% identified as black, and 54.7% presented with early-stage CTCL (Stage IA–IIA). There were no race-based differences in the number of systemic therapies trialed before ECP (p=0.8), use of ECP as 1st-line treatment (p=0.5), number of ECP treatments (p=0.4965), or use of concomitant medications (e.g. interferon, oral retinoids). White patients began ECP sooner than black patients following CTCL diagnosis (median 16 vs 4 months; p=0.08). Black patients were significantly more likely to face progressive disease following ECP (p=0.04) and had a shorter duration of response (16.1 vs 36.5 months; p=0.0455). Limitations: This was a retrospective study. Conclusion: There are race-based differences in ECP use and disease progression among adults with CTCL. Future research may investigate the source of these disparities, be they attributable to biologic differences in disease or differential treatment prescription.

Using two visual priming experiments, the present study investigates whether presenting facilitative semantic (i.e. colour) and morphosyntactic (i.e. grammatical gender) information in a prime image prior to reading a target sentence facilitates naming of a sentence-final target image among L1 German and L1 English-L2 German speakers. In Experiment 1, L1 and L2 German speakers used both semantic and gender cues to predict the sentence-final target image. In Experiment 2, a new group of L2 German speakers used gender cues to predict, but this effect was stronger when gender information was provided via a gender-marked indefinite article and adjective in the prime, than when the prime contained only the gender-marked article. These results suggest that if L2 speakers are able to overcome unstable and often inaccurate L2 gender assignment, they can use gender cues in a native-like manner for prediction, but that multiple gender-marked cues may be necessary for such prediction to occur.