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We demonstrate an automated two‐step tumor segmentation method leveraging color information from brightfield images of fresh core needle biopsies of breast tissue. Three different color spaces (HSV, CIELAB, YCbCr) were explored for the segmentation task. By leveraging white‐light and green‐light images, we identified two different types of color transformations that could separate adipose from benign and tumor or cancerous tissue. We leveraged these two distinct color transformation methods in a two‐step process where adipose tissue segmentation was followed by benign tissue segmentation thereby isolating the malignant region of the biopsy. Our tumor segmentation algorithm and imaging probe could highlight suspicious regions on unprocessed biopsy tissue to guide selection of areas most similar to malignant tissues for tissue pathology whether it be formalin fixed or frozen sections, expedite tissue selection for molecular testing, detect positive tumor margins, or serve an alternative to tissue pathology, in countries where these services are lacking. [ABSTRACT FROM AUTHOR]

We performed a scoping review of literature on schools' transfer of rights practices under the Individuals with Disabilities Education Act (IDEA) with respect to students with intellectual and developmental disabilities. The review found only limited empirical evidence of how IDEA transfer of rights policies are implemented in schools and affect students and parents. We found a substantial disconnect between this limited empirical evidence and generalizations about school practice made in recent literature that is not empirically based. In addition, we found some misunderstanding of relevant federal policy and little attention to variation in states' policies and schools' practices. Further research is needed to understand the intersection of relevant public policy, school practice, and student postsecondary education, employment, and independent living outcomes. [ABSTRACT FROM AUTHOR]

This randomized controlled trial tested the Vermont Family Based Approach (VFBA) in primary care pediatrics. The VFBA is a model of healthcare delivery that shifts the focus from the individual to the family, emphasizes emotional and behavioral health, and uses evidence-based health promotion/prevention along with the treatment of emotional and behavioral problems. Participants were 81 families of 3–15-year-olds. For children, the VFBA was associated with greater reductions than the Control condition on the Child Behavior Checklist Emotionally Reactive, Withdrawn, Sleep Problems, Aggressive Behavior and Total Problems scales. For parents, the VFBA was associated with greater reductions than the Control condition on the Adult Self-Report Anxious/Depressed, Rule-Breaking Behavior, Internalizing Problems and Total Problems scales. The VFBA was also associated with greater improvement than the Control condition in the parents' health-related quality of life, as indicated by all scales of the Medical Outcomes Study Health Survey. [ABSTRACT FROM AUTHOR]

This article summarizes data collected from key informants in Iowa, Maryland, and Oklahoma regarding efforts to support integrated employment for people with intellectual and developmental disabilities (IDD). We highlight features that contribute to the effectiveness of collaborative structures that have resulted in each state's success in achieving integrated employment outcomes for individuals with IDD across three state systems: IDD, vocational rehabilitation, and education. We present these features using the seven elements of the High-Performing States Employment Model. These elements have been found to be important in achieving higher rates of competitive integrated employment outcomes for people with IDD. [ABSTRACT FROM AUTHOR]

Ductal carcinoma in-situ (DCIS) accounts for 20–25% of all new breast cancer diagnoses. DCIS has an uncertain risk of progression to invasive breast cancer and a lack of predictive biomarkers may result in relatively high levels (~ 75%) of overtreatment. To identify unique prognostic biomarkers of invasive progression, crystallographic and chemical features of DCIS microcalcifications have been explored. Samples from patients with at least 5-years of follow up and no known recurrence (174 calcifications in 67 patients) or ipsilateral invasive breast cancer recurrence (179 microcalcifications in 57 patients) were studied. Significant differences were noted between the two groups including whitlockite relative mass, hydroxyapatite and whitlockite crystal maturity and, elementally, sodium to calcium ion ratio. A preliminary predictive model for DCIS to invasive cancer progression was developed from these parameters with an AUC of 0.797. These results provide insights into the differing DCIS tissue microenvironments, and how these impact microcalcification formation. [ABSTRACT FROM AUTHOR]

Background: Gastroschisis mortality in sub-Saharan Africa (SSA) remains high at 59–100%. Silo inaccessibility contributes to this disparity. Standard of care (SOC) silos cost $240, while median monthly incomes in SSA are < $200. Our multidisciplinary American and Ugandan team designed and bench-tested a low-cost (LC) silo that costs < $2 and is constructed from locally available materials. Here we describe in vivo LC silo testing. Methods: A piglet gastroschisis model was achieved by eviscerating intestines through a midline incision. Eight piglets were randomized to LC or SOC silos. Bowel was placed into the LC or SOC silo, maintained for 1-h, and reduced. Procedure times for placement, intestinal reduction, and silo removal were recorded. Tissue injury of the abdominal wall and intestine was assessed. Bacterial and fungal growth on silos was also compared. Results: There were no gross injuries to abdominal wall or intestine in either group or difference in minor bleeding. Times for silo application, bowel reduction, and silo removal between groups were not statistically or clinically different, indicating similar ease of use. Microbiologic analysis revealed growth on all samples, but density was below the standard peritoneal inoculum of 105 CFU/g for both silos. There was no significant difference in bacterial or fungal growth between LC and SOC silos. Conclusion: LC silos designed for manufacturing and clinical use in SSA demonstrated similar ease of use, absence of tissue injury, and acceptable microbiology profile, similar to SOC silos. The findings will allow our team to proceed with a pilot study in Uganda. [ABSTRACT FROM AUTHOR]

This work looks at how the infrastructure or conventions of practice and social arrangements govern local classroom literacy practices and how marginalized students resist the infrastructure and expose institutional change-making possibilities. Drawing from a longitudinal study, we analyzed five days of lessons that constituted a project in order to attend to aspects of instruction and activity that were indicative of the infrastructure and whether, and if so, how, students used language, body, silence, etc., to disrupt these guiding practices. The questions that guide this work are the following: What does student resistance reveal about the institutional infrastructure in this classroom? How did youth exploit the infrastructure's fissures and what does it reveal about racial wisdom? Our findings demonstrate how students navigated, negotiated, and addressed the institutional complexities that shaped this assignment and offered limited ways to navigate it. This work offers a broader understanding of what students' enactment of resistance disrupts and provides a clearer understanding of student racial wisdom. [ABSTRACT FROM AUTHOR]

Premise: In the absence of hawkmoth pollinators, chasmogamous (CH) flowers of Ruellia humilis self‐pollinate by two secondary mechanisms. Other floral visitors might exert selection on CH floral traits to restore outcrossing, but at the same time preferential predation of CH seeds generates selection to increase the allocation of resources to cleistogamous (CL) flowers. Methods: To assess the potential for an evolutionary response to these competing selection pressures, we estimated additive genetic variances (σA2 ${\sigma }_{{\rm{A}}}^{2}$) and covariances for 14 reproductive traits and three fitness components in a Missouri population lacking hawkmoth pollinators. Results: We found significant σA2 ${\sigma }_{{\rm{A}}}^{2}$ for all 11 floral traits and two measures of resource allocation to CL flowers, indicating the potential for a short‐term response to selection on most reproductive traits. Selection generated by seed predators is predicted to increase the percentage of CL flowers by 0.24% per generation, and mean stigma–anther separation is predicted to decrease as a correlated response, increasing the fraction of plants that engage in prior selfing. However, the initial response to this selection is opposed by strong directional dominance. Conclusions: The predicted evolutionary decrease in the number of CH flowers available for potential outcrossing, combined with the apparent preclusion of potential diurnal pollinators by the pollen‐harvesting activities of sweat bees, suggest that 100% cleistogamy is the likely outcome of evolution in the absence of hawkmoths. However, rare mutations with large effects, such as delaying budbreak until after sunrise, could provide pathways for the restoration of outcrossing that are not reachable by gradual quantitative‐genetic evolution. [ABSTRACT FROM AUTHOR]

Background. Randomized studies of neoadjuvant (NA) trastuzumab and pertuzumab combined with chemotherapy for HER2-positive breast cancers (BC) have reported pathological complete response (pCR) rates of 39 to 61%. This study aimed to determine the real-world efficacy and toxicity of NA trastuzumab and pertuzumab combined with chemotherapy in a UK tertiary referral cancer centre. Methods. HER2-positive early BC patients given neoadjuvant chemotherapy with trastuzumab and pertuzumab between October 2016 and February 2018 at our tertiary referral cancer centre were identified via pharmacy records. Clinico-pathological information, treatment regimens, treatment-emergent toxicities, operative details, and pathological responses and outcomes were recorded. Results. 78 female patients were identified; 2 had bilateral diseases and 48 of 78 (62%) were node positive at presentation. 55 of 80 (71%) tumours were ER-positive. PCR occurred in 37 of 78 (46.3%; 95% CI: 35.3–57.2%) patients. 14 of 23 (60.8%) patients with ER-negative tumours achieved pCR; 23 of 55 (41.8%) were ER-positive and 6 of 19 (31.6%) were ER-positive and PgR-positive. No cardiac toxicity was documented. Diarrhoea occurred in 53 of 72 (74%) patients. Grade 3–4 toxicity occurred in ≥2% patients. These were diarrhoea, fatigue, and infection. The Median follow up period was 45.2 months (95% CI 43.8–46.3) with 71 of 78 (91.0%) remaining disease-free and 72 of 78 (92.3%) alive. Estimated OS at 2 years 86% (95% CI: 75–99%). Conclusion. This data confirms the efficacy of neoadjuvant chemotherapy combined with dual HER2 directed therapy. While no cardiac toxicity was observed, diarrhoea occurred frequently. The low pCR rate observed in ER and PgR-positive BCs warrants further investigation and consideration of strategies to increase the pCR rate. [ABSTRACT FROM AUTHOR]

There is conflicting evidence on the role of lipid biomarkers in breast cancer (BC), and no study to our knowledge has examined this association among African women. We estimated odds ratios (ORs) and 95% confidence intervals (95% CI) for the association of lipid biomarkers—total cholesterol, high-density lipoprotein (HDL), low-density lipoprotein (LDL), and triglycerides—with odds of BC overall and by subtype (Luminal A, Luminal B, HER2-enriched and triple-negative or TNBC) for 296 newly diagnosed BC cases and 116 healthy controls in Nigeria. Each unit standard deviation (SD) increase in triglycerides was associated with 39% increased odds of BC in fully adjusted models (aOR: 1.39; 95% CI: 1.03, 1.86). Among post-menopausal women, higher total cholesterol (aOR: 1.65; 95% CI: 1.06, 2.57), LDL cholesterol (aOR: 1.59; 95% CI: 1.04, 2.41), and triglycerides (aOR: 1.91; 95% CI: 1.21, 3.01) were associated with increased odds of BC. Additionally, each unit SD increase in LDL was associated with 64% increased odds of Luminal B BC (aOR 1.64; 95% CI: 1.06, 2.55). Clinically low HDL was associated with 2.7 times increased odds of TNBC (aOR 2.67; 95% CI: 1.10, 6.49). Among post-menopausal women, higher LDL cholesterol and triglycerides were significantly associated with increased odds of Luminal B BC and HER2 BC, respectively. In conclusion, low HDL and high LDL are associated with increased odds of TN and Luminal B BC, respectively, among African women. Future prospective studies can definitively characterize this association and inform clinical approaches targeting HDL as a BC prevention strategy. [ABSTRACT FROM AUTHOR]

Recent national and state-level policy changes have created an imperative for service providers to transform from sheltered work to competitive integrated employment. The current study sought to understand the impact of participation in a 1-year, comprehensive technical assistance pilot designed to support service providers to transform away from sheltered workshops towards encouraging competitive integrated employment and delivering job development supports. Findings showed competitive integrated employment is attainable if given the appropriate organizational emphasis and when effective job development practices are implemented to a strategically identified group. Implications highlight the values of slowly preparing individuals for competitive integrated employment; facilitating an active, person-centered job placement process; engaging key stakeholders in job development; and focusing on individual job placement in the context of organizational transformation. [ABSTRACT FROM AUTHOR]

This study sought to assess the impact of COVID-19 on placental vasculature in the context of maternal symptomatology – comparing asymptomatic to symptomatic pregnant patients – and disease severity – comparing pregnant patients with mild, moderate, severe, and critical COVID-19 infection. PCR-confirmed COVID-19 positive pregnant patients in a single health system who delivered between 3/2020-5/2021 included. All patients had positive COVID test and delivered during the study period. Primary outcome was incidence of any vascular malperfusion on placental pathology. Secondary outcomes were FVM and MVM on placental pathology. Placental pathology compared between symptomatic (sCOVID) and asymptomatic (aCOVID) patients. Secondary analysis of symptomatic patients, comparing placental pathology between mild disease(mCOVID) and worse disease(moderate, severe, or critical-defined by 2020 NIH guidelines) (dCOVID), also performed. Of 112 patients, 53 (47%) had symptoms. Twenty-seven (24.1%) patients had evidence of vascular malperfusion; 26 (23.2%) had MVM. When comparing aCOVID and sCOVID patients, no difference in rate of vascular malperfusion identified, nor any differences in rates of FVM or MVM. Among sCOVID patients (n = 53), 39 (74%) had mCOVID and 14 (26%) had dCOVID (moderate n = 4, severe n = 9, critical n = 1). Patients with dCOVID had earlier median delivery GA (37.4wks vs 39.2wks, p = .03). No difference in latency from diagnosis to delivery seen between mCOVID and dCOVID groups (4.4 vs 3.0wks, p = .96). Twelve (30.8%) patients had vascular malperfusion on pathology, all had mCOVID (p = .02). Eleven (28.2%) mCOVID patients had MVM; no dCOVID patients had evidence of vascular malperfusion (p = .03). No difference in FVM was found between cohorts. Symptomatic COVID-19 infection did not impact placental vasculature differently than asymptomatic infection, even when stratifying by trimester of infection. Among pregnant patients with symptomatic COVID-19, mild disease was associated with placental vascular changes on the maternal side while severe disease was not. Further studies are needed to understand the implications of these findings. [ABSTRACT FROM AUTHOR]

Collaborative design (co-design) involving practitioners and researchers is emerging as a productive context for addressing theoretical as well as practical issues of teaching and learning. Co-design affords learning opportunities for all participants, although the focus has typically been on teachers. In this study, the Interconnected Interactive Model of Professional Growth (IIMPG) serves as a conceptual tool for tracing professional growth pathways of teachers and researchers in co-design contexts. The IIMPG is illustrated through a case study of a teacher and a researcher during a multi-year co-design project. Interactional analyses of their co-design work indicated change in the roles of the teacher and the researcher, knowledge of science inquiry as text-based modeling, and strategies for supporting students in engaging in it. Four years later, the teacher and researcher collaborated in retrospective reflection on their co-design work. Analyses revealed increased awareness of the underlying principles governing the multiple components of the design and how these supported conceptual coherence and interconnected knowledge for students. The multiple lenses and timescales enabled new insights on when, how, and why people learn during collaborative design. The IIMPG served as a generative tool for capturing professional growth pathways for teachers and researchers over iterative co-design cycles. [ABSTRACT FROM AUTHOR]

Most tissue collections of neoplasms are composed of formalin-fixed and paraffin-embedded (FFPE) excised tumor samples used for routine diagnostics. DNA sequencing is becoming increasingly important in cancer research and clinical management; however it is difficult to accurately sequence DNA from FFPE samples. We developed and validated a new bioinformatic pipeline to use existing variant-calling strategies to robustly identify somatic single nucleotide variants (SNVs) from whole exome sequencing using small amounts of DNA extracted from archival FFPE samples of breast cancers. We optimized this strategy using 28 pairs of technical replicates. After optimization, the mean similarity between replicates increased 5-fold, reaching 88% (range 0–100%), with a mean of 21.4 SNVs (range 1–68) per sample, representing a markedly superior performance to existing tools. We found that the SNV-identification accuracy declined when there was less than 40 ng of DNA available and that insertion–deletion variant calls are less reliable than single base substitutions. As the first application of the new algorithm, we compared samples of ductal carcinoma in situ of the breast to their adjacent invasive ductal carcinoma samples. We observed an increased number of mutations (paired-samples sign test, P  < 0.05), and a higher genetic divergence in the invasive samples (paired-samples sign test, P  < 0.01). Our method provides a significant improvement in detecting SNVs in FFPE samples over previous approaches. [ABSTRACT FROM AUTHOR]

Background: The association between obesity and breast cancer (BC) has been extensively studied among US, European and Asian study populations, with often conflicting evidence. However, despite the increasing prevalence of obesity and associated conditions in Africa, the continent with the highest age-standardized BC mortality rate globally, few studies have evaluated this association, and none has examined in relation to molecular subtypes among African women. The current analysis examines the association between body composition, defined by body mass index (BMI), height, and weight, and BC by molecular subtype among African women.Methods: We estimated odds ratios (ORs) and 95% confidence intervals (95% CI) for the association between measures of body composition and BC and molecular subtypes among 419 histologically confirmed cases of BC and 286 healthy controls from the Mechanisms for Established and Novel Risk Factors for Breast Cancer in Women of Nigerian Descent (MEND) case-control study.Results: Higher BMI (aOR: 0.79; 95% CI: 0.67, 0.95) and weight (aOR: 0.83; 95% CI: 0.69, 0.98) were associated with reduced odds of BC in adjusted models, while height was associated with non-statistically significant increased odds of BC (aOR: 1.07, 95% CI: 0.90, 1.28). In pre/peri-menopausal, but not post-menopausal women, both higher BMI and weight were significantly associated with reduced odds of BC. Further, higher BMI was associated with reduced odds of Luminal A, Luminal B, and HER2-enriched BC among pre/peri-menopausal women, and reduced odds of triple-negative BC among post-menopausal women.Conclusions: Higher BMI and weight were associated with reduced odds of BC overall and by molecular subtype among West African women. Larger studies of women of African descent are needed to definitively characterize these associations and inform cancer prevention strategies. [ABSTRACT FROM AUTHOR]

Purpose of Reveiw: To compile knowledge of expected intravascular imaging findings in coronary venous and arterial bypass grafts, both at baseline and in diseased states in order to improve understanding of the pathology demonstrated in failing grafts. Also, to learn how intravascular imaging could be used to guide necessary graft interventions and to consider whether imaging practices in grafts could become formalized or potentially influence outcomes of graft interventions, which are notoriously poor. Recent Findings: Disease in saphenous vein grafts has features overlapping with pathology in native vessels, but can also involve unique findings which have been described in studies and can be delineated well with intravascular imaging. The latter has also been used successfully to examine findings in internal mammary as well as radial artery grafts, particularly in the peri-operative period. Previously reported cases, as well as a case example here, show the feasibility and potential utility of these imaging modalities within grafts to guide coronary intervention. Summary: Intravascular imaging within bypass grafts is feasible and expected findings can be recognized and understood with review of existing data and with clinical experience gained in individual operator practice. Future directions could explore guidelines for imaging-guided intervention within bypass grafts and could examine whether outcomes could be improved with intravascular imaging guidance. [ABSTRACT FROM AUTHOR]

The prognostic value of cytonuclear grade in ductal carcinoma in situ (DCIS) is debated, partly due to high interobserver variability and the use of multiple guidelines. The aim of this study was to evaluate interobserver agreement in grading DCIS between Dutch, British, and American pathologists. Haematoxylin and eosin‐stained slides of 425 women with primary DCIS were independently reviewed by nine breast pathologists based in the Netherlands, the UK, and the USA. Chance‐corrected kappa (κma) for association between pathologists was calculated based on a generalised linear mixed model using the ordinal package in R. Overall κma for grade of DCIS (low, intermediate, or high) was estimated to be 0.50 (95% confidence interval [CI] 0.44–0.56), indicating a moderate association between pathologists. When the model was adjusted for national guidelines, the association for grade did not change (κma = 0.53; 95% CI 0.48–0.57); subgroup analysis for pathologists using the UK pathology guidelines only had significantly higher association (κma = 0.58; 95% CI 0.56–0.61). To assess if concordance of grading relates to the expression of the oestrogen receptor (ER) and HER2, archived immunohistochemistry was analysed on a subgroup (n = 106). This showed that non‐high grade according to the majority opinion was associated with ER positivity and HER2 negativity (100 and 89% of non‐high grade cases, respectively). In conclusion, DCIS grade showed only moderate association using whole slide images scored by nine breast pathologists. As therapeutic decisions and inclusion in ongoing clinical trials are guided by DCIS grade, there is a pressing need to reduce interobserver variability in grading. ER and HER2 might be supportive to prevent the accidental and unwanted inclusion of high‐grade DCIS in such trials. [ABSTRACT FROM AUTHOR]

Background: Nigeria reports the highest age-standardized mortality rate for breast cancer (BC) among African countries and disproportionately high rates of high-grade cancer. Histological grade is a strong predictor of mortality, and evidence suggests that educational attainment influences cancer outcomes. Objective: We characterize the association between educational trends across the lifecourse and BC grade at diagnosis. Methods: Data on 224 BC patients enrolled in the Mechanisms for Established and Novel Risk Factors for Breast Cancer in Nigerian Women (MEND) study was analyzed. Participant and parental (mother and father) education was categorized as low (primary school or less) or high (secondary school or greater). Accordingly, the educational trend across the life-course was determined for each participant relative to each parent: stable high, increasing, decreasing, or stable low. BC grade was classified as high (grade 3) or low (grades 1–2). Findings: About 34% of participants, 71% of fathers, and 85% of mothers had low education. Approximately one-third of participants were diagnosed with high-grade BC. Participants with low-grade BC were more likely to have highly educated fathers (p = 0.04). After adjusting for age, comorbidities, marital status and mammogram screening, participants with highly educated fathers were 60% less likely to have high-grade BC (aOR 0.41; 95% CI 0.20 to 0.84) compared to those with less-educated fathers. Stable high life-course education relative to father was also associated with a significantly lower likelihood of having high-grade BC (aOR 0.36; 95% CI 0.15 to 0.87) compared to stable low life-course education. No significant associations were observed for the participant’s education, mother’s education, or life-course education relative to mother. Conclusions: Early-life socioeconomic status (SES) may influence BC grade. This deserves further study to inform policies that may be useful in reducing high-grade BC in Nigeria. [ABSTRACT FROM AUTHOR]

Intra-tumoral heterogeneity (ITH) could represent clonal evolution where subclones with greater fitness confer more malignant phenotypes and invasion constitutes an evolutionary bottleneck. Alternatively, ITH could represent branching evolution with invasion of multiple subclones. The two models respectively predict a hierarchy of subclones arranged by phenotype, or multiple subclones with shared phenotypes. We delineate these modes of invasion by merging ancestral, topographic, and phenotypic information from 12 human colorectal tumors (11 carcinomas, 1 adenoma) obtained through saturation microdissection of 325 small tumor regions. The majority of subclones (29/46, 60%) share superficial and invasive phenotypes. Of 11 carcinomas, 9 show evidence of multiclonal invasion, and invasive and metastatic subclones arise early along the ancestral trees. Early multiclonal invasion in the majority of these tumors indicates the expansion of co-evolving subclones with similar malignant potential in absence of late bottlenecks and suggests that barriers to invasion are minimal during colorectal cancer growth. Invasion is a critical step in tumor development. Here, in colorectal cancer, the authors show that multiclonal invasion of the muscularis mucosae is pervasive, suggesting that invasive capacity is not a significant bottleneck in the evolution of the disease. [ABSTRACT FROM AUTHOR]

Objectives: This study assessed the prevalence, general interest, and barriers to implementing global health curricula in pathology residency programs.Methods: We conducted a survey of 166 US pathology residency programs.Results: Thirty-two (195) of 166 programs responded. Of these, 13% have a formalized global health program (n = 4), and the majority indicated at least some general interest in global health among trainees (88%, n = 28) and faculty (94%, n = 30), albeit at a low to moderate level. Funding limitations, regulatory constraints, and insufficient knowledge of global health were frequently cited barriers to developing a global health program.Conclusions: Few US pathology departments incorporate global health education into postgraduate training. The importance of pathology in global health has been underappreciated, despite its critical role in the delivery of health care in resource-limited settings. One solution is for pathology departments to expand global health educational opportunities for trainees. [ABSTRACT FROM AUTHOR]

While the benefits of community life engagement (CLE) for individuals with intellectual and developmental disability (IDD) are clear, high-quality day services and supports remain largely undefined. This study interviewed "experts" in the field of CLE in order to seek agreement about what constitutes "best practices" for day services and supports that lead to CLE. Using a semistructured interview protocol, we asked 13 experts in the field, representing diverse standpoints, about their delivery and utilization of supports. Four overarching themes emerged: (Guidepost 1) Individualize supports for each person; (Guidepost 2) Promote community membership and contribution; (Guidepost 3) Use human and social capital to decrease dependence on paid supports; and (Guidepost 4) Ensure that supports are outcome-oriented and regularly monitored. Recommendations are offered for the field. [ABSTRACT FROM AUTHOR]

Introduction: Breast cancer is a major cause of morbidity and mortality for women in Sub-Saharan Africa and for black American women. There is evidence that the pathologic characteristics of breast cancers in both African women and black American women may differ from their counterparts of European ancestry. However, despite the great burden of disease, data on pathologic features of breast carcinoma in Sub-Saharan Africa is limited and often contradictory. This lack of information makes it difficult to prioritize resource use in efforts to improve breast cancer outcomes in the region. Methods: We examined consecutive cases of breast cancer in Tanzanian women (n = 83), black American women (n = 120), and white American women (n = 120). Each case was assessed for tumor type, grade, mitotic count, ER and HER2 status, and tumor infiltrating lymphocyte involvement. Results: The Tanzanian subjects were younger and had higher stage tumors than the subjects in either American group. Breast cancers in the Tanzanian and black American groups were more likely to be high grade (p = 0.008), to have a high mitotic rate (p<0.0001), and to be ER-negative (p<0.001) than the tumors in the white American group. Higher levels of tumor infiltrating lymphocyte involvement were seen among Tanzanian and black American subjects compared to white American subjects (p = 0.0001). Among all subjects, tumor infiltrating lymphocyte levels were higher in tumors with a high mitotic rate. Among Tanzanian and black American subjects, tumor infiltrating lymphocyte levels were higher in ER-negative tumors. These findings have implications for treatment priorities for breast cancer in Tanzania and other Sub-Saharan African countries. [ABSTRACT FROM AUTHOR]

In this article, we provide a brief summary of work by us and others to discover the molecular underpinnings of early conduction system development and function. We focus on how the multifunctional protein Tbx3 contributes to acquisition and homeostasis of the tissue-specific properties of the sinoatrial and atrioventricular nodes. We also provide unpublished, preliminary findings supporting the role of Tbx3-regulated alternative RNA processing in the developing conduction system. [ABSTRACT FROM AUTHOR]

Zika virus (ZIKV) is a newly-identified infectious cause of congenital disease. Transplacental transfer of maternal IgG to the fetus plays an important role in preventing many neonatal infections. However, antibody transfer may also have negative consequences, such as mediating enhancement of flavivirus infections in early life, or trafficking of virus immune complexes to the fetal compartment. ZIKV infection produces placental pathology which could lead to impaired IgG transfer efficiency as occurs in other maternal infections, such as HIV-1 and malaria. In this study, we asked whether ZIKV infection during pregnancy impairs transplacental transfer of IgG. We enrolled pregnant women with fever or rash in a prospective cohort in Vitoria, Brazil during the recent ZIKV epidemic. ZIKV and dengue virus (DENV)-specific IgG, ZIKV and DENV neutralizing antibodies, and routine vaccine antigen-specific IgG were measured in maternal samples collected around delivery and 20 paired cord blood samples. We concluded that 8 of these mothers were infected with ZIKV during pregnancy and 12 were ZIKV-uninfected. The magnitude of flavivirus-specific IgG, neutralizing antibody, and vaccine-elicited IgG were highly correlated between maternal plasma and infant cord blood in both ZIKV-infected and -uninfected mother-infant pairs. Moreover, there was no difference in the magnitude of plasma flavivirus-specific IgG levels between mothers and infants regardless of ZIKV infection status. Our data suggests that maternal ZIKV infection during pregnancy does not impair the efficiency of placental transfer of flavivirus-specific, functional, and vaccine-elicited IgG. These findings have implications for the neonatal outomes of maternal ZIKV infection and optimal administration of antibody-based ZIKV vaccines and therapeutics. [ABSTRACT FROM AUTHOR]

Introduction: Use of a microcatheter is essential for chronic total occlusion (CTO) percutaneous coronary intervention (PCI). Several microcatheters have recently been introduced in clinical practice aiming to improve deliverability and resistance to deformation. Areas covered: We review the technical characteristics of several new microcatheters (Mamba, Mamba Flex, Teleport Control, Teleport, Nhancer Rx, Sasuke, and ReCross) and compare them with existing microcatheters. Expert opinion: The recently developed microcatheters offer additional options for guidewire support during CTO PCI. Accumulation of clinical experience and performance of comparative effectiveness studies are needed for better understanding the role of these devices in contemporary CTO PCI. [ABSTRACT FROM AUTHOR]

Purpose: The purpose of the study was to define quantitative measures of intra-tumor heterogeneity in breast cancer based on histopathology data gathered from multiple samples on individual patients and determine their association with distant recurrence-free survival (DRFS).Methods: We collected data from 971 invasive breast cancers, from 1st January 2000 to 23rd March 2014, that underwent repeat tumor sampling at our institution. We defined and calculated 31 measures of intra-tumor heterogeneity including ER, PR, and HER2 immunohistochemistry (IHC), proliferation, EGFR IHC, grade, and histology. For each heterogeneity measure, Cox proportional hazards models were used to determine whether patients with heterogeneous disease had different distant recurrence-free survival (DRFS) than those with homogeneous disease.Results: The presence of heterogeneity in ER percentage staining was prognostic of reduced DRFS with a hazard ratio of 4.26 (95% CI 2.22-8.18, p < 0.00002). It remained significant after controlling for the ER status itself (p < 0.00062) and for patients that had chemotherapy (p < 0.00032). Most of the heterogeneity measures did not show any association with DRFS despite the considerable sample size.Conclusions: Intra-tumor heterogeneity of ER receptor status may be a predictor of patient DRFS. Histopathologic data from multiple tissue samples may offer a view of tumor heterogeneity and assess recurrence risk. [ABSTRACT FROM AUTHOR]

Retinal ganglion cell (RGC) degeneration drives vision loss in blinding conditions. RGC death is often triggered by axon degeneration in the optic nerve. Here, we study the contributions of dynamic and homeostatic Ca2+ levels to RGC death from axon injury. We find that axonal Ca2+ elevations from optic nerve injury do not propagate over distance or reach RGC somas, and acute and chronic Ca2+ dynamics do not affect RGC survival. Instead, we discover that baseline Ca2+ levels vary widely between RGCs and predict their survival after axon injury, and that lowering these levels reduces RGC survival. Further, we find that well-surviving RGC types have higher baseline Ca2+ levels than poorly surviving types. Finally, we observe considerable variation in the baseline Ca2+ levels of different RGCs of the same type, which are predictive of within-type differences in survival. [Display omitted] • Retinal ganglion cells (RGCs) have differential resting Ca2+ levels • Ca2+ elevations from axon injury do not propagate from the optic nerve to the retina • RGCs with high resting Ca2+ levels survive at higher rates than those with low Ca2+ • Reducing intracellular Ca2+ reduces RGC survival after optic nerve crush Elevations in homeostatic neuronal Ca2+ are generally associated with neurodegeneration. McCracken et al. demonstrate that Ca2+ levels are diverse across the retinal ganglion cell (RGC) population and that RGCs with higher resting Ca2+ levels are more likely to survive degeneration induced by optic nerve crush both within and across RGC types. [ABSTRACT FROM AUTHOR]

BACKGROUND: Federal legislation has called for the phasing out of sheltered workshops and the transition to integrated employment, causing providers to struggle with how to adapt their model towards providing community integration services. OBJECTIVE: Our purpose was to identify the essential characteristics of successful organizational transformation for providers serving individuals with intellectual and developmental disabilities. METHODS: A Delphi panel consisting of 36 experts in the field of organizational transformation underwent an iterative process to respond to previously identified characteristics of successful organizational transformation, develop new characteristics, and then rank the final characteristics in order of importance. RESULTS: The identified essential characteristics to successful organizational transformation in ranked order were: clear and consistent goals; an agency culture that values inclusion; an active, person-centered job placement process; a strong internal and external communication plan; reallocated and restructured resources; an ongoing investment in professional staff development; a focus on customer engagement; effective employment performance measurement, quality assurance, and program oversight; a holistic approach; and multiple and diverse community partnerships. CONCLUSIONS:The Delphi panel confirmed the six characteristics identified in previous research, and added four newcharacteristics that reflected recent changes in the field of employment and the understanding of what creates lasting organizational change. [ABSTRACT FROM AUTHOR]

Background: Metaplastic breast cancer (MBC) is characterized by chemoresistance and hematogenous spread. We sought to identify factors associated with improved MBC outcomes and increased likelihood of MBC diagnosis.Methods: Women ≥ 18 years of age with stage I-III MBC and non-MBC diagnosed between 2010 and 2014 were identified in the National Cancer Data Base. Kaplan-Meier and multivariate Cox proportional hazards models were used to estimate associations with overall survival (OS). Multivariate logistic regression identified factors associated with MBC diagnosis.Results: Overall, 2451 MBC and 568,057 non-MBC patients were included; 70.3% of MBC vs. 11.3% of non-MBC patients were triple negative (p < 0.001). Five-year OS was reduced among MBC vs. non-MBC patients for the entire cohort (72.7 vs. 87.5%) and among triple-negative patients (71.1 vs. 77.8%; both p < 0.001). In MBC, triple-negative (vs. luminal) subtype was not associated with worse OS (hazard ratio [HR] 1.16, 95% confidence interval [CI] 0.88-1.54, p = 0.28). Compared with non-MBC patients, MBC patients were more likely to receive mastectomy (59.0 vs. 44.9%), chemotherapy (74.1 vs. 43.1%), and axillary lymph node dissection (ALND; 35.2 vs. 32.2%, all p ≤ 0.001). MBC patients more frequently had negative ALND (pN0) than non-MBC patients (20.0 vs. 10.6%, p < 0.001). Among MBC patients, chemotherapy (HR 0.69, 95% CI 0.53-0.89, p = 0.004) and radiotherapy (HR 0.52, 95% CI 0.39-0.69, p < 0.001) were associated with improved survival, while ALND was associated with decreased survival (HR 1.37, 95% CI 1.06-1.77, p = 0.02).Conclusions: MBC patients had worse survival than non-MBC patients, independent of receptor status, suggesting that MBC may confer an additional survival disadvantage. Multimodal therapy was associated with improved outcomes, but ALND was not and may be overutilized in MBC. [ABSTRACT FROM AUTHOR]

KCNH2 encodes the Kv11.1 a-subunit that underlies the rapidly activating delayedrectifier K+ current in the heart. Loss-of-function KCNH2 mutations cause long QT syndrome type 2 (LQT2), and most LQT2-linked missense mutations inhibit the trafficking of Kv11.1 channel protein to the cell surface membrane. Several trafficking-deficient LQT2 mutations (e.g., G601S) generate Kv11.1 proteins that are sequestered in a microtubule-dependent quality control (QC) compartment in the transitional endoplasmic reticulum (ER). We tested the hypothesis that the QC mechanisms that regulate LQT2-linked Kv11.1 protein trafficking are mutation-specific. Confocal imaging analyses of HEK293 cells stably expressing the trafficking-deficient LQT2 mutation F805C showed that, unlike G601S-Kv11.1 protein, F805C-Kv11.1 protein was concentrated in several transitional ER subcompartments. The microtubule depolymerizing drug nocodazole differentially affected G601S- and F805C-Kv11.1 protein immunostaining. Nocodazole caused G601S-Kv11.1 protein to distribute into peripheral reticular structures, and it increased the diffuse immunostaining of F805CKv11.1 protein around the transitional ER subcompartments. Proteasome inhibition also affected the immunostaining of G601S- and F805C-Kv11.1 protein differently. Incubating cells in MG132 minimally impacted G601S-Kv11.1 immunostaining, but it dramatically increased the diffuse immunostaining of F805C-Kv11.1 protein in the transitional ER. Similar results were seen after incubating cells in the proteasome inhibitor lactacystin. Differences in the cellular distribution of G601S-Kv11.1 and F805CKv11.1 protein persisted in transfected human inducible pluripotent stem cell derived cardiomyocytes. These are the first data to visually demonstrate mutation-specific differences in the trafficking-deficient LQT2 phenotype, and this study has identified a novel way to categorize trafficking-deficient LQT2 mutations based on differences in intracellular retention. [ABSTRACT FROM AUTHOR]

Abstract: Gender nonconforming youth are at risk for body dissatisfaction and disordered eating. Currently, only a small body of literature addresses this high‐risk group. The five cases in this series highlight important themes for this patient population from an interdisciplinary perspective. Identified themes include increased risk for self‐harm/suicide, complex psychiatric, and medical implications of delay to treatment for either gender dysphoria or disordered eating, and the importance of collaborative management to maximize care and facilitate healthy development to adulthood. The purpose of this case series is to expand the interdisciplinary discussion regarding the breadth of presentation and management considerations for gender nonconforming adolescents with disordered eating. An interdisciplinary approach to care might enhance access to comprehensive, collaborative treatment for disordered eating, and gender dysphoria in this unique population. [ABSTRACT FROM AUTHOR]

This paper presents the procedures and results of a qualitative study that was part of a larger study comparing two methods of accessing a self-management training for amputees: e-learning and a virtual world. Interviews were conducted in Second Life (SL) with fourteen subjects who completed the training in the virtual world and six subjects who completed e-learning training. Interpretative Phenomenological Analysis (IPA) was used for qualitative data analysis, leading to the identification of 14 themes within five major categories. An overarching theme of the SL experience resulting from analysis was that of an expanded sense of possibilities. [ABSTRACT FROM AUTHOR]