Sex, Gender, and Women's Heart Health: How Women's Heart Programs Address the Knowledge Gap.

This article aims to bridge existing knowledge gaps that impact clinical cardiovascular care and outcomes for women in Canada. The authors discuss various aspects of women's heart health, emphasizing the efficacy of multidisciplinary care in promoting women's well-being. The article also identifies the impact of national women's heart health campaigns and the value of peer support in improving outcomes. The article addresses the particular risks that women face, such as pregnancy-related complications and hormone replacement therapy, all of which are associated with cardiovascular events, and highlights the differences in ischemic symptoms between men and women. Despite improvements in acute event outcomes, challenges persist in accessing timely ambulatory care, particularly for women. Canada has responded to these challenges by introducing Women Heart Programs, which offer tailored programs, support groups, and specialized testing. However, these programs remain few in number and are found only in urban settings. Overall, this review identifies sex and gender factors related to women's heart health, underscoring the importance of specialized programs and multidisciplinary care in improving women's cardiovascular health.

Cet article vise à répondre aux incertitudes actuelles qui se répercutent sur les soins cardiovasculaires et les issues cliniques chez les femmes au Canada. Les auteurs abordent différents aspects de la santé cardiaque des femmes, mettant l'accent sur l'efficacité des soins multidisciplinaires pour améliorer le bien-être des femmes. L'article présente également l'effet des campagnes nationales sur la santé cardiaque des femmes et l'importance de l'entraide entre collègues pour améliorer les résultats. L'article traite des risques particuliers touchant les femmes, comme les complications liées à la grossesse et l'hormonothérapie substitutive, qui sont toutes associées à des événements cardiovasculaires, et il souligne les différences entre les hommes et les femmes pour ce qui est des symptômes ischémiques. Bien que des améliorations aient été observées quant à l'issue des événements aigus, des difficultés persistent sur le plan de l'accès rapide à des soins ambulatoires, surtout pour les femmes. Le Canada a répondu à ces difficultés en créant des programmes pour la santé cardiaque des femmes, qui offrent des services adaptés, des groupes de soutien et des analyses spécialisées. Cependant, ils sont encore peu nombreux et accessibles seulement en milieu urbain. Dans l'ensemble, cette analyse définit les facteurs liés au sexe et au genre qui interviennent dans la santé cardiaque des femmes, soulignant l'importance de mettre en place des programmes spécialisés et des soins multidisciplinaires pour améliorer la santé cardiovasculaire des femmes.

A key role for platelet GPVI in neutrophil recruitment, migration, and NETosis in the early stages of acute lung injury.

Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) are associated with high morbidity and mortality. Excessive neutrophil infiltration into the pulmonary airspace is the main cause for the acute inflammation and lung injury. Platelets have been implicated in the pathogenesis of ALI/ARDS, but the underlying mechanisms are not fully understood. Here, we show that the immunoreceptor tyrosine-based activation motif-coupled immunoglobulin-like platelet receptor, glycoprotein VI (GPVI), plays a key role in the early phase of pulmonary thrombo-inflammation in a model of lipopolysaccharide (LPS)-induced ALI in mice. In wild-type (WT) control mice, intranasal LPS application triggered severe pulmonary and blood neutrophilia, hypothermia, and increased blood lactate levels. In contrast, GPVI-deficient mice as well as anti-GPVI-treated WT mice were markedly protected from pulmonary and systemic compromises and showed no increased pulmonary bleeding. High-resolution multicolor microscopy of lung sections and intravital confocal microcopy of the ventilated lung revealed that anti-GPVI treatment resulted in less stable platelet interactions with neutrophils and overall reduced platelet-neutrophil complex (PNC) formation. Anti-GPVI treatment also reduced neutrophil crawling and adhesion on endothelial cells, resulting in reduced neutrophil transmigration and alveolar infiltrates. Remarkably, neutrophil activation was also diminished in anti-GPVI-treated animals, associated with strongly reduced formation of PNC clusters and neutrophil extracellular traps (NETs) compared with that in control mice. These results establish GPVI as a key mediator of neutrophil recruitment, PNC formation, and NET formation (ie, NETosis) in experimental ALI. Thus, GPVI inhibition might be a promising strategy to reduce the acute pulmonary inflammation that causes ALI/ARDS.

Mixed-Methods Evaluation of a Patient Behaviour Risk Screening, Communication and Care Planning Intervention for Hospital Settings.

Workplace violence is a common safety concern for hospital staff. The Behaviour Safety Risk Communication and Care Planning program identifies, manages and cares for patients at risk of exhibiting unsafe behaviours. This paper reports on a mixed-methods evaluation consisting of staff surveys, focus groups and open forums, screening audits, patient interviews and assessment of effectiveness measures at five hospital sites. Staff perceptions about safety risk imposed by a patient's behaviour significantly improved after this program was implemented. Opportunities exist to improve staff adherence to screening processes and communication with patients. This study provides insight for teams implementing similar interventions.

Developing and Implementing a Patient Behaviour Risk Screening, Communication and Care Planning Intervention for Hospital Settings.

Workplace violence prevention of patient behaviours is a primary safety focus in hospital settings. In response to provincial mandates, a multi-site tertiary care hospital system developed the Behaviour Safety Risk Communication and Care Planning Program. Components include patient risk screening, communication tools and care plans that outline mitigation strategies. The program has been implemented at six sites using the following strategies: educational and planning meetings, formation of steering committees, identification of champions, educational materials/training, facilitation and consultation, and audit and feedback. Our paper can guide program development and implementation in similar contexts.

Upper limb robotic assessment: Pilot study comparing velocity dependent resistance in individuals with acquired brain injury to healthy controls.

INTRODUCTION: Assessment of velocity dependent resistance (VDR) can provide insights into spasticity in individuals with upper motor neuron syndrome. This study investigates the relationship between Modified Ashworth scores and a biomechanical based representation of VDR using a rehabilitation robot. Comparisons in VDR are made for the upper limb (UL) between individuals with acquired brain injury and healthy controls for the para-sagittal plane. METHODS: The system manipulates the individual's limb through five flexion and extension motions at increasing speeds to obtain force profiles at different velocities. An approximation of VDR is calculated and analyzed statistically against clinical scales and tested for interactions. RESULTS: All individuals (aged 18-65), including healthy controls exhibited VDR greater than 0 (P < 0.05). MAS scores were found to be related to VDR (P < 0.05) with an interaction found between MAS Bicep and Tricep scores (P < 0.01). Considering this interaction, evidence of differences in VDR were found between several neighboring assessment score combinations. CONCLUSION: The robot can detect and quantify VDR that captures information relevant to UL spasticity. Results suggests a better categorization of VDR is possible and supports further development of rehabilitation robotics for assisting spasticity assessment.

High-Sensitivity Cardiac Troponin-Optimizing the Diagnosis of Acute Myocardial Infarction/Injury in Women (CODE-MI): Rationale and design for a multicenter, stepped-wedge, cluster-randomized trial.

Despite evidence that high-sensitivity cardiac troponin (hs-cTn) levels in women are lower than in men, a single threshold based on the 99th percentile upper reference limit of the overall reference population is commonly used to diagnose myocardial infarction in clinical practice. This trial aims to determine whether the use of a lower female-specific hs-cTn threshold would improve the diagnosis, treatment, and outcomes of women presenting to the emergency department with symptoms suggestive of myocardial ischemia. METHODS/DESIGN: CODE-MI (hs-cTn-Optimizing the Diagnosis of Acute Myocardial Infarction/Injury in Women) is a multicenter, stepped-wedge, cluster-randomized trial of 30 secondary and tertiary care hospitals across 8 Canadian provinces, with the unit of randomization being the hospital. All adults (≥20 years of age) presenting to the emergency department with symptoms suggestive of myocardial ischemia and at least 1 hs-cTn test are eligible for inclusion. Over five, 5-month intervals, hospitals will be randomized to implement lower female hs-cTn thresholds according to the assay being used at each site. Men will continue to be assessed using the overall thresholds throughout. Women with a peak hs-cTn value between the female-specific and the overall thresholds will form our primary cohort. The primary outcome, a 1-year composite of all-cause mortality or readmission for nonfatal myocardial infarction, incident heart failure, or emergent/urgent coronary revascularization, will be compared before and after the implementation of female thresholds using mixed-effects logistic regression models. The cohort and outcomes will be obtained from routinely collected administrative data. The trial is designed to detect a 20% relative risk difference in the primary outcome, or a 2.2% absolute difference, with 82% power. CONCLUSIONS: This pragmatic trial will assess whether adopting lower female hs-cTn thresholds leads to appropriate assessment of women with symptoms suggestive of myocardial infarction, thereby improving treatment and outcomes.

Interrater Reliability of Three Versions of the Chedoke Arm and Hand Activity Inventory.

Purpose: The purpose of this study was to estimate the interrater reliability of three shortened versions of the Chedoke Arm and Hand Activity Inventory (CAHAI-7, CAHAI-8, CAHAI-9) when used with persons with acquired brain injury (ABI). The CAHAI is an assessment of upper limb function with high reliability in the stroke and ABI populations. In the stroke population, three shortened versions of the measure have established reliability. Clinicians report time constraints as a barrier to using standardized assessments; thus, establishing the reliability of the shortened versions of the CAHAI in the ABI population may increase the use of this measure. Method: This was an observational, parameter estimation study. The participants were recruited from an in-patient ABI rehabilitation programme. The administration of the CAHAI to six persons with ABI was video recorded, and the video recordings were assessed by six clinicians to estimate interrater reliability. A Latin square design was used to balance the order in which the raters evaluated the videos. A repeated-measures analysis of variance was performed, and the variance components were used to calculate an intra-class correlation coefficient (ICC) and standard error of measurement (SEM) with 95% confidence limits (CLs) for each of the shortened versions. Results: Interrater reliability was high for all three versions: CAHAI-7, ICC=0.96 (95% CL: 0.89, 0.99; SEM 2.65); CAHAI-8, ICC=0.96 (95% CL: 0.90, 0.99; SEM 2.72); and CAHAI-9, ICC=0.95 (95% CL: 0.85, 0.99; SEM 3.49). Conclusions: These results suggest that the three shortened versions of the CAHAI demonstrate high reliability in the ABI population. These versions may be particularly useful when time constraints or patient tolerance are an issue.

Objectif : évaluer la fiabilité interévaluateurs de trois versions abrégées du Chedoke Arm and Hand Activity Inventory (CAHAI-7, CAHAI-8, CAHAI-9) auprès des personnes atteintes d'un traumatisme crânien (TC). L'inventaire CAHAI, qui évalue la fonction des membres supérieurs, présente une forte fiabilité auprès des populations d'accidents vasculaires cérébraux (AVC) et de TC. Au sein de la population d'AVC, trois versions abrégées de la mesure ont une fiabilité démontrée. Les cliniciens déclarent le manque de temps comme un obstacle à l'utilisation d'évaluations standardisées. Ainsi, si la fiabilité des versions abrégées de l'inventaire CAHAI est établie au sein de la population de TC, cette mesure pourrait être utilisée davantage. Méthodologie : dans cette étude observationnelle d'évaluation des paramètres, les participants ont été recrutés dans un programme de réadaptation des TC pour patients hospitalisés. L'exécution de l'inventaire CAHAI auprès de six personnes ayant un TC a été vidéo-enregistrée, et six cliniciens ont évalué les vidéos pour déterminer la fiabilité interévaluateurs. Les chercheurs ont utilisé le modèle du carré latin pour équilibrer l'ordre dans lequel les évaluateurs ont évalué les vidéos. Ils ont procédé à une analyse répétée de la variance et ont utilisé les éléments de variance pour calculer le coefficient de corrélation intraclasse (CCI) et la mesure d'écart-type (MÉT) aux limites de confiance (LC) à 95 % pour chacune des versions abrégées. Résultats : les trois versions de l'inventaire ont une fiabilité interévaluateurs élevée : CAHAI-7 : CCI=0,96 (LC à 95 % : 0,89, 0,99; MÉT : 2,65); CAHAI-8 : CCI=0,96 (LC à 95 % : 0,90, 0,99; MÉT : 2,72); CAHAI-9 : CCI=0,95 (LC à 95 % : 0,85, 0,99; MÉT : 3,49). Conclusions : selon ces résultats, les trois versions abrégées de l'inventaire CAHAI sont très fiables auprès de la population TC. Elles peuvent être particulièrement utiles lorsque le manque de temps ou la tolérance des patients représentent un enjeu.

Transverse forces versus modified ashworth scale for upper limb flexion/extension in para-sagittal plane.

Spasticity is a common impairment following an upper motor neuron lesion in conditions such as stroke and brain injury. A clinical issue is how to best quantify and measure spasticity. Recently, research has been performed to develop new methods of spasticity quantification using various systems. This paper follows up on previous work taking a closer look at the role of transversal forces obtained via rehabilitation robot for motions in the para-sagittal plane. Results from 45 healthy individuals and 40 individuals with acquired brain injury demonstrate that although the passive upper motions are vertical, horizontal forces into and away from the individual's body demonstrate a relationship with the Modified Ashworth Scale. This finding leads the way to new avenues of spasticity quantification and monitoring.

Inter-rater reliability of the Chedoke Arm and Hand Activity Inventory.

BACKGROUND: The Chedoke Arm and Hand Activity Inventory (CAHAI) is an assessment of upper limb function designed for use in the stroke population. The CAHAI has strong reliability and validity in this population; however, it is unknown whether this measure can be used with other clinical populations such as acquired brain injury (ABI). PURPOSE: The purpose of this study was to estimate the inter-rater reliability of the CAHAI when used with persons with ABI. METHODS: The research design was an observational parameter estimation study. The administration of the CAHAI was videotaped for 6 persons with ABI. To estimate inter-rater reliability each video was assessed independently by 6 clinicians yielding a total of 36 assessments. A Latin square design was used to balance the order raters evaluated the videos. Shrout and Fleiss Type 2,1 intra class correlation coefficients (ICC) and standard error of measurement (SEM) were calculated to estimate inter-rater reliability of the CAHAI. RESULTS: Inter-rater reliability was high ICC = 0.96 (95% CL: 0.88, 0.99) and the SEM was 3.35 (95% CL: 2.63, 4.63) CAHAI points. CONCLUSIONS: These results suggest that the CAHAI, although designed for use in the stroke population, can be used reliably in the ABI population.

Association between change in cervical length and spontaneous preterm birth in twin pregnancies.

BACKGROUND: There is a lack of consensus on the optimal transvaginal cervical length for determining risk for spontaneous preterm birth in twin pregnancies. Change in transvaginal cervical length over time may reflect early activation of the parturition process, as has been demonstrated in singleton pregnancies. The association between change in transvaginal cervical length and the risk for spontaneous preterm birth has not yet been described in the population of women with diamniotic twin pregnancies. OBJECTIVE: Our primary objective is to determine whether rate of change in transvaginal cervical length in the midtrimester is associated with spontaneous preterm birth in twin gestations. Our secondary objective is to describe parameters for identifying patients at increased risk for spontaneous preterm birth based on change in transvaginal cervical length over time. STUDY DESIGN: This is a retrospective cohort of serial transvaginal cervical length performed for twin pregnancies at a single institution from 2008 through 2015. Women with diamniotic twin pregnancies who had transvaginal cervical length measurements at 18 and 22 weeks' gestation and outcome data available were included. Logistic regression was used to determine the relationship between the rate of change in transvaginal cervical length and the risk for the primary outcome of spontaneous preterm birth <35 weeks as well as spontaneous preterm birth <32 weeks. RESULTS: In all, 527 subjects met inclusion criteria for this study. The average rate of change in transvaginal cervical length for patients with spontaneous preterm birth <35 weeks was -0.21 cm/wk (SD 0.27) vs -0.10 cm/wk (SD 0.24) for patients who delivered ≥35 weeks (P < .01). The rate of change in transvaginal cervical length was associated with spontaneous preterm birth <35 weeks when controlling for initial transvaginal cervical length and other important risk factors for spontaneous preterm birth. Results for spontaneous preterm birth <32 weeks were similar. This association remained significant when the rate of weekly change was treated as a dichotomous variable based on an apparent inflection point in the risk for spontaneous preterm birth: women with rapid change in transvaginal cervical length, ≥-0.2 cm/wk, had 3.45 times the odds of spontaneous preterm birth as those with less rapid change (95% confidence interval, 2.15-5.52) when controlling for initial transvaginal cervical length. CONCLUSION: Change in transvaginal cervical length in the midtrimester is associated with spontaneous preterm birth, and therefore protocols for serial transvaginal cervical length measurement can provide the clinician with information to identify at-risk patients. A decrease of ≥0.2 cm/wk of transvaginal cervical length identifies patients at increased risk for spontaneous preterm birth <35 weeks.

A comparison of prevaginal and postvaginal manipulation fetal fibronectin.

BACKGROUND: Fetal fibronectin (fFN) is used as a biomarker for preterm delivery. Currently, its use is discouraged if there has been vaginal manipulation in the previous 24 hours. OBJECTIVE: Our objective is to determine if there are differences between fFN results before and after vaginal manipulation in the form of sterile vaginal exam or transvaginal ultrasound. STUDY DESIGN: This was a prospective observational cohort study at a single center of women between 22-33 6/7 weeks at risk for preterm delivery due to: (1) a history of preterm delivery, short cervix, or multifetal gestation; or (2) symptoms of preterm labor. We excluded women with vaginal bleeding or infection, placenta previa, ruptured membranes, cervical dilation >3 cm, or any form of vaginal manipulation in the previous 24 hours. Specimen A was collected prior to planned vaginal exam or transvaginal ultrasound and specimen B was collected within 4 hours. The agreement between specimens A and B was assessed using descriptive statistics. Test characteristics of specimens A and B using the outcome of preterm delivery (<37 weeks) were calculated. RESULTS: In all, 310 specimen pairs from 237 women were collected. Specimen A was positive in 37 (12%) instances and negative in 273 (88%) while specimen B was positive in 39 (13%) and negative in 271 (87%). There were discordant results in 26 specimen pairs. Of these, 14 (5%) negative specimen A results subsequently became positive for specimen B, and 12 (32%) positive specimen A results became negative for specimen B. Overall, there was a 92% agreement between specimens A and B (confidence interval, 88-94%). The specificity of specimens A and B for preterm birth was 90% vs 89%, respectively, with a negative predictive value of 87% for both. The false-negative rate was 12.8% for specimen A and 13.3% for specimen B. CONCLUSION: There is a moderately high degree of agreement between prevaginal and postvaginal manipulation fFN results. Their test characteristics for evaluating preterm birth are similar with strong specificity and negative predictive values, and their false-negative rates are not clinically different. Consideration should be made to the utilization of postvaginal manipulation fFN when a prevaginal manipulation specimen is not available.

Aberrant lymphatic drainage and risk for melanoma recurrence after negative sentinel node biopsy in middle-aged and older men.

BACKGROUND: Aberrant lymphatic drainage is believed to contribute to the high recurrence rate of head and neck melanomas. The purpose of this study was to identify the clinical significance of unexpected lymphatic drainage patterns. METHODS: A single institution retrospective analysis was performed of middle-aged and older men (mean age, 66.2 years; range, 41-87 years) who underwent successful lymphoscintigraphy with sentinel lymph node biopsy (SLNB) from 1997 through 2012. Node status, distribution, and recurrence were assessed comparing patients with expected and unexpected drainage patterns. RESULTS: Sixty-six patients were identified with 55.8 months median follow-up (range, 5.6-206.1 months). Unexpected sentinel lymph node drainage was associated with multiple basin drainage (p < .01) and greater recurrence after negative SLNB (p = .03). Both groups had similar anatomic distribution, sentinel lymph node sampling, histopathologic characteristics, follow-up, and survival. CONCLUSION: Lymphatic drainage differing from expected patterns is associated with greater recurrence after negative SLNB in middle-aged and older men. © 2015 Wiley Periodicals, Inc. Head Neck 38: E754-E760, 2016.

Robotic pilot study for analysing spasticity: clinical data versus healthy controls.

BACKGROUND: Spasticity is a motor disorder that causes significant disability and impairs function. There are no definitive parameters that assess spasticity and there is no universally accepted definition. Spasticity evaluation is important in determining stages of recovery. It can determine treatment effectiveness as well as how treatment should proceed. This paper presents a novel cross sectional robotic pilot study for the primary purpose of assessment. The system collects force and position data to quantify spasticity through similar motions of the Modified Ashworth Scale (MAS) assessment in the Sagittal plane. Validity of the system is determined based on its ability to measure velocity dependent resistance. METHODS: Forty individuals with Acquired Brain Injury (ABI) and 45 healthy individuals participated in a robotic pilot study. A linear regression model was applied to determine the effect an ABI has on force data obtained through the robotic system in an effort to validate it. Parameters from the model were compared for both groups. Two techniques were performed in an attempt to classify between healthy and patients. Dynamic Time Warping (DTW) with k-nearest neighbour (KNN) classification is compared to a time-series algorithm using position and force data in a linear discriminant analysis (LDA). RESULTS: The system is capable of detecting a velocity dependent resistance (p<0.05). Differences were found between healthy individuals and those with MAS 0 who are considered to be healthy. DTW with KNN is shown to improve classification between healthy and patients by approximately 20 % compared to that of an LDA. CONCLUSIONS: Quantitative methods of spasticity evaluation demonstrate that differences can be observed between healthy individuals and those with MAS of 0 who are often clinically considered to be healthy. Exploiting the time-series nature of the collected data demonstrates that position and force together are an accurate predictor of patient health.

Tuberculin skin test reversion following isoniazid preventive therapy reflects diversity of immune response to primary Mycobacterium tuberculosis infection.

RATIONALE: Healthy household contacts (HHC) of individuals with Tuberculosis (TB) with Tuberculin Skin Test (TST) conversions are considered to harbor latent Mycobacterium tuberculosis (Mtb), and at risk for TB. The immunologic, clinical, and public health implications of TST reversions that occur following Isoniazid preventive therapy (IPT) remain controversial. OBJECTIVES: To measure frequency of TST reversion following IPT, and variation in interferon-gamma (IFN-γ) responses to Mtb, in healthy Ugandan TB HHC with primary Mtb infection evidenced by TST conversion. METHODS: Prospective cohort study of healthy, HIV-uninfected, TST-negative TB HHC with TST conversions. Repeat TST was performed 12 months following conversion (3 months following completion of 9 month IPT course) to assess for stable conversion vs. reversion. Whole blood IFN-γ responses to Mtb antigen 85B (MtbA85B) and whole Mtb bacilli (wMtb) were measured in a subset (n = 27 and n = 42, respectively) at enrollment and TST conversion, prior to initiation of IPT. RESULTS: Of 122 subjects, TST reversion was noted in 25 (20.5%). There were no significant differences in demographic, clinical, or exposure variables between reverters and stable converters. At conversion, reverters had significantly smaller TST compared to stable converters (13.7 mm vs 16.4 mm, respectively; p = 0.003). At enrollment, there were no significant differences in IFN-γ responses to MtbA85B or wMTB between groups. At conversion, stable converters demonstrated significant increases in IFN-γ responses to Ag85B and wMtb compared to enrollment (p = 0.001, p<0.001, respectively), while there were no significant changes among reverters. CONCLUSIONS: TST reversion following IPT is common following primary Mtb infection and associated with unique patterns of Mtb-induced IFN-γ production. We have demonstrated that immune responses to primary Mtb infection are heterogeneous, and submit that prospective longitudinal studies of cell mediated immune responses to Mtb infection be prioritized to identify immune phenotypes protective against development of TB disease.

Clinical evaluation of a novel intraoperative handheld gamma camera for sentinel lymph node biopsy.

OBJECTIVE: Preoperative lymphoscintigraphy (PLS) combined with intraoperative gamma probe (GP) localization is standard procedure for localizing the sentinel lymph nodes (SLN) in melanoma and breast cancer. In this study, we evaluated the ability of a novel intraoperative handheld gamma camera (IHGC) to image SLNs during surgery. METHODS: The IHGC is a small-field-of-view camera optimized for real-time imaging of lymphatic drainage patterns. Unlike conventional cameras, the IHGC can acquire useful images in a few seconds in a free-running fashion and be moved manually around the patient to find a suitable view of the node. Thirty-nine melanoma and eleven breast cancer patients underwent a modified SLN biopsy protocol in which nodes localized with the GP were imaged with the IHGC. The IHGC was also used to localize additional nodes that could not be found with the GP. RESULTS: The removal of 104 radioactive SLNs was confirmed ex vivo by GP counting. In vivo, the relative node detection sensitivity was 88.5 (82.3, 94.6)% for the IHGC (used in conjunction with the GP) and 94.2 (89.7, 98.7)% for the GP alone, a difference not found to be statistically significant (McNemar test, p = 0.24). CONCLUSION: Small radioactive SLNs can be visualized intraoperatively using the IHGC with exposure time of 20 s or less, with no significant difference in node detection sensitivity compared to a GP. The IHGC is a useful complement to the GP, especially for SLNs that are difficult to locate with the GP alone.

Mycobacterium tuberculosis specific CD8(+) T cells rapidly decline with antituberculosis treatment.

RATIONALE: Biomarkers associated with response to therapy in tuberculosis could have broad clinical utility. We postulated that the frequency of Mycobacterium tuberculosis (Mtb) specific CD8(+) T cells, by virtue of detecting intracellular infection, could be a surrogate marker of response to therapy and would decrease during effective antituberculosis treatment. OBJECTIVES: We sought to determine the relationship of Mtb specific CD4(+) T cells and CD8(+) T cells with duration of antituberculosis treatment. MATERIALS AND METHODS: We performed a prospective cohort study, enrolling between June 2008 and August 2010, of HIV-uninfected Ugandan adults (n = 50) with acid-fast bacillus smear-positive, culture confirmed pulmonary TB at the onset of antituberculosis treatment and the Mtb specific CD4(+) and CD8(+) T cell responses to ESAT-6 and CFP-10 were measured by IFN-γ ELISPOT at enrollment, week 8 and 24. RESULTS: There was a significant difference in the Mtb specific CD8(+) T response, but not the CD4(+) T cell response, over 24 weeks of antituberculosis treatment (p<0.0001), with an early difference observed at 8 weeks of therapy (p = 0.023). At 24 weeks, the estimated Mtb specific CD8(+) T cell response decreased by 58%. In contrast, there was no significant difference in the Mtb specific CD4(+) T cell during the treatment. The Mtb specific CD4(+) T cell response, but not the CD8(+) response, was negatively impacted by the body mass index. CONCLUSIONS: Our data provide evidence that the Mtb specific CD8(+) T cell response declines with antituberculosis treatment and could be a surrogate marker of response to therapy. Additional research is needed to determine if the Mtb specific CD8(+) T cell response can detect early treatment failure, relapse, or to predict disease progression.

Using the Science of Psychology to Target Perpetrators of Racism and Race-Based Discrimination For Intervention Efforts: Preventing Another Trayvon Martin Tragedy.

Psychological science offers a variety of methods to both understand and intervene when acts of potential racial or ethnic racism, bias or prejudice occur. The Trayvon Martin killing is a reminder of how vulnerable African American men and boys, especially young African American men, are to becoming victims of social inequities in our society. We examine several historical events of racial bias (the Los Angeles civil disturbance after the Rodney King verdict, the federal government's launch of a "War on Drugs" and the killing of Trayvon Martin) to illustrate the ways in which behaviors of racism and race-based discrimination can be viewed from a psychological science lens in the hopes of eliminating and preventing these behaviors. If society is to help end the genocide of African American men and boys then we must broaden our focus from simply understanding instances of victimization to a larger concern with determining how policies, laws, and societal norms serve as the foundation for maintaining implicit biases that are at the root of race-based discrimination, prejudice, bias and inequity. In our call to action, we highlight the contributions that psychologists, particularly racial and ethnic minority professionals, can make to reduce the negative impact of racial and ethnic bias through their volunteer/pro bono clinical efforts.

Systemic immune activation and microbial translocation in dual HIV/tuberculosis-infected subjects.

BACKGROUND: Systemic immune activation is a strong predictor of progression of human immunodeficiency virus type 1 (HIV-1) disease and a prominent feature of infection with Mycobacterium tuberculosis. OBJECTIVE: To understand the role of systemic immune activation and microbial translocation in HIV/tuberculosis dually infected patients over the full spectrum of HIV-1 immunodeficiency, we studied circulating sCD14 and lipopolysaccharide (LPS) and their relationship to HIV-1 activity. METHODS: Two cohorts of HIV/tuberculosis subjects defined by CD4 T-cell count at time of diagnosis of tuberculosis were studied: those with low (<350/µL) and those with high (≥ 350/µL) CD4 T-cell count. Circulating soluble CD14 (sCD14) and LPS were assessed. RESULTS: Levels of sCD14 were higher in HIV/tuberculosis with high (≥ 350/µL) as compared to low CD4 T-cell count (P < .001). Whereas sCD14 levels remained elevated in HIV/tuberculosis subjects with lower CD4 T-cell counts despite treatment of tuberculosis, in HIV/tuberculosis patients with higher CD4 T-cell count (≥ 350/µL), levels declined regardless of whether highly active antiretroviral therapy (HAART) was included with the anti-tuberculosis regimen. Circulating LPS levels in HIV/tuberculosis patients with CD4 T-cell count ≥ 350/µL were unaffected by treatment of tuberculosis with or without HAART. CONCLUSION: During HIV/tuberculosis, systemic immune activation is dissociated from microbial translocation. Changes in circulating sCD14 and LPS are dependent on CD4 T-cell count.

Altered local and systemic immune profiles underlie lymph node metastasis in breast cancer patients.

Cancer-mediated immune dysfunction contributes to tumor progression and correlates with patient outcome. Metastasis to tumor draining lymph nodes (TDLNs) is an important step in breast cancer progression and is used to predict patient outcome and survival. Although lymph nodes are important immune organs, the role of immune cells in TDLNs has not been thoroughly investigated. We hypothesized that the host immune response in node negative (NN) patients is more intact and thereby can resist tumor invasion compared to node positive (NP) patients. As such, lymph node metastasis requires breakdown of the host immune response in addition to escape of cancer cells from the tumor. To investigate the immunological differences between NN and NP breast cancer patients, we purified and profiled immune cells from the three major compartments where cancer and immune cells interact: tumor, TDLNs and peripheral blood. Significant down-regulation of genes associated with immune-related pathways and up-regulation of genes associated with tumor-promoting pathways was consistently observed in NP patients' TDLNs compared to NN patients. Importantly, these signatures were seen even in NP patients' tumor-free TDLNs, suggesting that such immune changes are not driven solely by local tumor invasion. Furthermore, similar patterns were also observed in NP patients' tumor and blood immune cells, suggesting that immunological differences between NN and NP patients are systemic. Together, these findings suggest that alterations in overall immune function may underlie risk for LN metastasis in breast cancer patients.

PRC2/EED-EZH2 complex is up-regulated in breast cancer lymph node metastasis compared to primary tumor and correlates with tumor proliferation in situ.

BACKGROUND: Lymph node metastasis is a key event in the progression of breast cancer. Therefore it is important to understand the underlying mechanisms which facilitate regional lymph node metastatic progression. METHODOLOGY/PRINCIPAL FINDINGS: We performed gene expression profiling of purified tumor cells from human breast tumor and lymph node metastasis. By microarray network analysis, we found an increased expression of polycomb repression complex 2 (PRC2) core subunits EED and EZH2 in lymph node metastatic tumor cells over primary tumor cells which were validated through real-time PCR. Additionally, immunohistochemical (IHC) staining and quantitative image analysis of whole tissue sections showed a significant increase of EZH2 expressing tumor cells in lymph nodes over paired primary breast tumors, which strongly correlated with tumor cell proliferation in situ. We further explored the mechanisms of PRC2 gene up-regulation in metastatic tumor cells and found up-regulation of E2F genes, MYC targets and down-regulation of tumor suppressor gene E-cadherin targets in lymph node metastasis through GSEA analyses. Using IHC, the expression of potential EZH2 target, E-cadherin was examined in paired primary/lymph node samples and was found to be significantly decreased in lymph node metastases over paired primary tumors. CONCLUSIONS/SIGNIFICANCE: This study identified an over expression of the epigenetic silencing complex PRC2/EED-EZH2 in breast cancer lymph node metastasis as compared to primary tumor and its positive association with tumor cell proliferation in situ. Concurrently, PRC2 target protein E-cadherin was significant decreased in lymph node metastases, suggesting PRC2 promotes epithelial mesenchymal transition (EMT) in lymph node metastatic process through repression of E-cadherin. These results indicate that epigenetic regulation mediated by PRC2 proteins may provide additional advantage for the outgrowth of metastatic tumor cells in lymph nodes. This opens up epigenetic drug development possibilities for the treatment and prevention of lymph node metastasis in breast cancer.