Translating research into practice: Protocol for a community-engaged, stepped wedge randomized trial to reduce disparities in breast cancer treatment through a regional patient navigation collaborative

BACKGROUND: Racial and socioeconomic disparities in breast cancer mortality persist. In Boston, MA, Black, Non-Hispanic women and Medicaid-insured individuals are 2-3 times more likely to have delays in treatment compared to White or privately insured women. While evidence-based care coordination strategies for reducing delays exist, they are not systematically implemented across healthcare settings. METHODS: Translating Research Into Practice (TRIP) utilizes community engaged research methods to address breast cancer care delivery disparities. Four Massachusetts Clinical and Translational Science Institute (CTSI) hubs collaborated with the Boston Breast Cancer Equity Coalition (The Coalition) to implement an evidence-based care coordination intervention for Boston residents at risk for delays in breast cancer care. The Coalition used a community-driven process to define the problem of care delivery disparities, identify the target population, and develop a rigorous pragmatic approach. We chose a cluster-randomized, stepped-wedge hybrid type I effectiveness-implementation study design. The intervention implements three evidence-based strategies: patient navigation services, a shared patient registry for use across academic medical centers, and a web-based social determinants of health platform to identify and address barriers to care. Primary clinical outcomes include time to first treatment and receipt of guideline-concordant treatment, which are captured through electronic health records abstraction. We will use mixed methods to collect the secondary implementation outcomes of acceptability, adoption/penetration, fidelity, sustainability and cost. CONCLUSION: TRIP utilizes an innovative community-driven research strategy, focused on interdisciplinary collaborations, to design and implement a translational science study that aims to more efficiently integrate proven health services interventions into clinical practice

The Innate Mononuclear Phagocyte Network Depletes B Lymphocytes through Fc Receptor–dependent Mechanisms during Anti-CD20 Antibody Immunotherapy

Anti-CD20 antibody immunotherapy effectively treats non-Hodgkin's lymphoma and autoimmune disease. However, the cellular and molecular pathways for B cell depletion remain undefined because human mechanistic studies are limited. Proposed mechanisms include antibody-, effector cell–, and complement-dependent cytotoxicity, the disruption of CD20 signaling pathways, and the induction of apoptosis. To identify the mechanisms for B cell depletion in vivo, a new mouse model for anti-CD20 immunotherapy was developed using a panel of twelve mouse anti–mouse CD20 monoclonal antibodies representing all four immunoglobulin G isotypes. Anti-CD20 antibodies rapidly depleted the vast majority of circulating and tissue B cells in an isotype-restricted manner that was completely dependent on effector cell Fc receptor expression. B cell depletion used both FcγRI- and FcγRIII-dependent pathways, whereas B cells were not eliminated in FcR common γ chain–deficient mice. Monocytes were the dominant effector cells for B cell depletion, with no demonstrable role for T or natural killer cells. Although most anti-CD20 antibodies activated complement in vitro, B cell depletion was completely effective in mice with genetic deficiencies in C3, C4, or C1q complement components. That the innate monocyte network depletes B cells through FcγR-dependent pathways during anti-CD20 immunotherapy has important clinical implications for anti-CD20 and other antibody-based therapies

RE: How the Coronavirus Disease-2019 May Improve Care: Rethinking Cervical Cancer Prevention

Feldman and Haas have written a timely piece on the potential to enhance cancer prevention and cancer care delivery in the COVID-19 era. Using cervical cancer prevention as a use case, the commentary describes clinical care provided via virtual platforms and in nontraditional settings, such as the patient’s home, as areas needing creative approaches to ensure care is provided safely and efficiently. As we consider factors that are relevant to delivering effective cancer prevention and cancer care post-COVID, we suggest that addressing social determinants of health, an often forgotten dimension of lived experience, should be prioritized as a strategy to enhance the equity of care provision. Social determinants of health, including food and housing insecurity have been shown to impact outcomes of patients with cancer, through a number of mechanisms including delays and incomplete care

Density matrix algorithm for the calculation of dynamical properties of low dimensional systems

I extend the scope of the density matrix renormalization group technique developed by White to the calculation of dynamical correlation functions. As an application and performance evaluation I calculate the spin dynamics of the 1D Heisenberg chain.Comment: 4 pages + 4 figures in one Latex + 4 postscript file

Pharmacotherapy and pregnancy: Highlights from the first International Conference for Individualized Pharmacotherapy in Pregnancy

Data are sparse on the effects of medication use during pregnancy. Half of the world's population is women. The majority of women become pregnant, and many of those women take some kind of medication during their pregnancy, even if only for a short time. The majority of drugs have not been rigorously studied in pregnant women to determine the most effective dose with the least potential for adverse effects. Instead, women are given “cookie‐cutter” therapy, using doses extrapolated from nonpregnant women, men, or pregnant animals. This can lead to problems. Instead, individualization of pharmacotherapy in pregnancy promises to take individual women and determine the optimal dose and drug for them to maximize the effect of the drug while attempting to minimize the side effects to them and their unborn babies. Because this field of study is underrepresented, we held a conference to bring together researchers and experts to discuss current knowledge, issues, and challenges surrounding individualized pharmacotherapy in pregnancy. Speakers came from the NIH, the Food and Drug Administration (FDA), and various research centers in the United States and Canada. Below are the summaries of the discussions at the conference. Full notes from the panel discussions are available from the authors on request

The nuclear structural protein NuMA is a negative regulator of 53BP1 in DNA double-strand break repair

P53-binding protein 1 (53BP1) mediates DNA repair pathway choice and promotes checkpoint activation. Chromatin marks induced by DNA double-strand breaks and recognized by 53BP1 enable focal accumulation of this multifunctional repair factor at damaged chromatin. Here, we unveil an additional level of regulation of 53BP1 outside repair foci. 53BP1 movements are constrained throughout the nucleoplasm and increase in response to DNA damage. 53BP1 interacts with the structural protein NuMA, which controls 53BP1 diffusion. This interaction, and colocalization between the two proteins in vitro and in breast tissues, is reduced after DNA damage. In cell lines and breast carcinoma NuMA prevents 53BP1 accumulation at DNA breaks, and high NuMA expression predicts better patient outcomes. Manipulating NuMA expression alters PARP inhibitor sensitivity of BRCA1-null cells, end-joining activity, and immunoglobulin class switching that rely on 53BP1. We propose a mechanism involving the sequestration of 53BP1 by NuMA in the absence of DNA damage. Such a mechanism may have evolved to disable repair functions and may be a decisive factor for tumor responses to genotoxic treatments

Multilevel factors associated with long-term adherence to screening mammography in older women in the U.S.

In the U.S., guidelines recommend that women continue mammography screening until at least age 74, but recent evidence suggests declining screening rates in older women. We estimated adherence to screening mammography and multilevel factors associated with adherence in a longitudinal cohort of older women. Women aged 66–75 years receiving screening mammography within the Breast Cancer Surveillance Consortium were linked to Medicare claims (2005–2010). Claims data identified baseline adherence, defined as receiving subsequent mammography within approximately 2 years, and length of time adherent to guidelines. Characteristics associated with adherence were investigated using logistic and Cox proportional hazards regression models. Analyses were stratified by age to investigate variation in relationships between patient factors and adherence. Among 49,775 women, 89% were adherent at baseline. Among women 66–70 years, those with less than a high school education were more likely to be non-adherent at baseline (odds ratio [OR] 1.96; 95% confidence interval [CI] 1.65–2.33) and remain adherent for less time (hazard ratio [HR] 1.41; 95% CI 1.11–1.80) compared to women with a college degree. Women with ≥1 versus no Charlson co-morbidities were more likely to be non-adherent at baseline (OR 1.46; 95% CI 1.31–1.62) and remain adherent for less time (HR 1.44; 95% CI 1.24–1.66). Women aged 71–75 had lower adherence overall, but factors associated with non-adherence were similar. In summary, adherence to guidelines is high among Medicare-enrolled women in the U.S. receiving screening mammography. Efforts are needed to ensure that vulnerable populations attain these same high levels of adherence

Pharmacotherapy and Pregnancy: Highlights from the Third International Conference for Individualized Pharmacotherapy in Pregnancy

To address provider struggles to provide evidence-based, rational drug therapy to pregnant women, this third Conference was convened to highlight the current progress and research in the field. Speakers from academic centers, industry, and governmental institutions spoke about: the Food and Drug Administration’s role in pregnancy pharmacology and the new labeling initiative; drug registries in pregnancy; the pharmacist’s role in medication use in pregnancy; therapeutic areas such as preterm labor, gestational diabetes, nausea and vomiting in pregnancy, and hypertension; breast-feeding and medications; ethical challenges for consent in pregnancy drug studies; the potential for cord blood banks; and concerns about the fetus when studying drugs in pregnancy. The Conference highlighted several areas of collaboration within the current Obstetrics Pharmacology Research Units Network and hoped to educate providers, researchers, and agencies with the common goal to improve the ability to safely and effectively use individualized pharmacotherapy in pregnancy

Presence of cerebral microbleeds is associated with worse executive function in pediatric brain tumor survivors.

BackgroundA specific form of small-vessel vasculopathy-cerebral microbleeds (CMBs)-has been linked to various types of dementia in adults. We assessed the incidence of CMBs and their association with neurocognitive function in pediatric brain tumor survivors.MethodsIn a multi-institutional cohort of 149 pediatric brain tumor patients who received cranial radiation therapy (CRT) between 1987 and 2014 at age <21 years and 16 patients who did not receive CRT, we determined the presence of CMBs on brain MRIs. Neurocognitive function was assessed using a computerized testing program (CogState). We used survival analysis to determine cumulative incidence of CMBs and Poisson regression to examine risk factors for CMBs. Linear regression models were used to assess effect of CMBs on neurocognitive function.ResultsThe cumulative incidence of CMBs was 48.8% (95% CI: 38.3-60.5) at 5 years. Children who had whole brain irradiation developed CMBs at a rate 4 times greater than those treated with focal irradiation (P < .001). In multivariable analysis, children with CMBs performed worse on the Groton Maze Learning test (GML) compared with those without CMBs (Z-score -1.9; 95% CI: -2.7, -1.1; P < .001), indicating worse executive function when CMBs are present. CMBs in the frontal lobe were associated with worse performance on the GML (Z-score -2.4; 95% CI: -2.9, -1.8; P < .001). Presence of CMBs in the temporal lobes affected verbal memory (Z-score -2.0; 95% CI: -3.3, -0.7; P = .005).ConclusionCMBs are common and associated with neurocognitive dysfunction in pediatric brain tumor survivors treated with radiation

Planetary Candidates Observed by Kepler, III: Analysis of the First 16 Months of Data

New transiting planet candidates are identified in sixteen months (May 2009 - September 2010) of data from the Kepler spacecraft. Nearly five thousand periodic transit-like signals are vetted against astrophysical and instrumental false positives yielding 1,091 viable new planet candidates, bringing the total count up to over 2,300. Improved vetting metrics are employed, contributing to higher catalog reliability. Most notable is the noise-weighted robust averaging of multi-quarter photo-center offsets derived from difference image analysis which identifies likely background eclipsing binaries. Twenty-two months of photometry are used for the purpose of characterizing each of the new candidates. Ephemerides (transit epoch, T_0, and orbital period, P) are tabulated as well as the products of light curve modeling: reduced radius (Rp/R*), reduced semi-major axis (d/R*), and impact parameter (b). The largest fractional increases are seen for the smallest planet candidates (197% for candidates smaller than 2Re compared to 52% for candidates larger than 2Re) and those at longer orbital periods (123% for candidates outside of 50-day orbits versus 85% for candidates inside of 50-day orbits). The gains are larger than expected from increasing the observing window from thirteen months (Quarter 1-- Quarter 5) to sixteen months (Quarter 1 -- Quarter 6). This demonstrates the benefit of continued development of pipeline analysis software. The fraction of all host stars with multiple candidates has grown from 17% to 20%, and the paucity of short-period giant planets in multiple systems is still evident. The progression toward smaller planets at longer orbital periods with each new catalog release suggests that Earth-size planets in the Habitable Zone are forthcoming if, indeed, such planets are abundant.Comment: Submitted to ApJS. Machine-readable tables are available at http://kepler.nasa.gov, http://archive.stsci.edu/kepler/results.html, and the NASA Exoplanet Archiv