Why Are Outcomes Different for Registry Patients Enrolled Prospectively and Retrospectively? Insights from the Global Anticoagulant Registry in the FIELD-Atrial Fibrillation (GARFIELD-AF).

Background: Retrospective and prospective observational studies are designed to reflect real-world evidence on clinical practice, but can yield conflicting results. The GARFIELD-AF Registry includes both methods of enrolment and allows analysis of differences in patient characteristics and outcomes that may result. Methods and Results: Patients with atrial fibrillation (AF) and ≥1 risk factor for stroke at diagnosis of AF were recruited either retrospectively (n = 5069) or prospectively (n = 5501) from 19 countries and then followed prospectively. The retrospectively enrolled cohort comprised patients with established AF (for a least 6, and up to 24 months before enrolment), who were identified retrospectively (and baseline and partial follow-up data were collected from the emedical records) and then followed prospectively between 0-18 months (such that the total time of follow-up was 24 months; data collection Dec-2009 and Oct-2010). In the prospectively enrolled cohort, patients with newly diagnosed AF (≤6 weeks after diagnosis) were recruited between Mar-2010 and Oct-2011 and were followed for 24 months after enrolment. Differences between the cohorts were observed in clinical characteristics, including type of AF, stroke prevention strategies, and event rates. More patients in the retrospectively identified cohort received vitamin K antagonists (62.1% vs. 53.2%) and fewer received non-vitamin K oral anticoagulants (1.8% vs . 4.2%). All-cause mortality rates per 100 person-years during the prospective follow-up (starting the first study visit up to 1 year) were significantly lower in the retrospective than prospectively identified cohort (3.04 [95% CI 2.51 to 3.67] vs . 4.05 [95% CI 3.53 to 4.63]; p = 0.016). Conclusions: Interpretations of data from registries that aim to evaluate the characteristics and outcomes of patients with AF must take account of differences in registry design and the impact of recall bias and survivorship bias that is incurred with retrospective enrolment. Clinical Trial Registration: - URL: http://www.clinicaltrials.gov . Unique identifier for GARFIELD-AF (NCT01090362)

Improved risk stratification of patients with atrial fibrillation: an integrated GARFIELD-AF tool for the prediction of mortality, stroke and bleed in patients with and without anticoagulation.

OBJECTIVES: To provide an accurate, web-based tool for stratifying patients with atrial fibrillation to facilitate decisions on the potential benefits/risks of anticoagulation, based on mortality, stroke and bleeding risks. DESIGN: The new tool was developed, using stepwise regression, for all and then applied to lower risk patients. C-statistics were compared with CHA2DS2-VASc using 30-fold cross-validation to control for overfitting. External validation was undertaken in an independent dataset, Outcome Registry for Better Informed Treatment of Atrial Fibrillation (ORBIT-AF). PARTICIPANTS: Data from 39 898 patients enrolled in the prospective GARFIELD-AF registry provided the basis for deriving and validating an integrated risk tool to predict stroke risk, mortality and bleeding risk. RESULTS: The discriminatory value of the GARFIELD-AF risk model was superior to CHA2DS2-VASc for patients with or without anticoagulation. C-statistics (95% CI) for all-cause mortality, ischaemic stroke/systemic embolism and haemorrhagic stroke/major bleeding (treated patients) were: 0.77 (0.76 to 0.78), 0.69 (0.67 to 0.71) and 0.66 (0.62 to 0.69), respectively, for the GARFIELD-AF risk models, and 0.66 (0.64-0.67), 0.64 (0.61-0.66) and 0.64 (0.61-0.68), respectively, for CHA2DS2-VASc (or HAS-BLED for bleeding). In very low to low risk patients (CHA2DS2-VASc 0 or 1 (men) and 1 or 2 (women)), the CHA2DS2-VASc and HAS-BLED (for bleeding) scores offered weak discriminatory value for mortality, stroke/systemic embolism and major bleeding. C-statistics for the GARFIELD-AF risk tool were 0.69 (0.64 to 0.75), 0.65 (0.56 to 0.73) and 0.60 (0.47 to 0.73) for each end point, respectively, versus 0.50 (0.45 to 0.55), 0.59 (0.50 to 0.67) and 0.55 (0.53 to 0.56) for CHA2DS2-VASc (or HAS-BLED for bleeding). Upon validation in the ORBIT-AF population, C-statistics showed that the GARFIELD-AF risk tool was effective for predicting 1-year all-cause mortality using the full and simplified model for all-cause mortality: C-statistics 0.75 (0.73 to 0.77) and 0.75 (0.73 to 0.77), respectively, and for predicting for any stroke or systemic embolism over 1 year, C-statistics 0.68 (0.62 to 0.74). CONCLUSIONS: Performance of the GARFIELD-AF risk tool was superior to CHA2DS2-VASc in predicting stroke and mortality and superior to HAS-BLED for bleeding, overall and in lower risk patients. The GARFIELD-AF tool has the potential for incorporation in routine electronic systems, and for the first time, permits simultaneous evaluation of ischaemic stroke, mortality and bleeding risks. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier for GARFIELD-AF (NCT01090362) and for ORBIT-AF (NCT01165710)

Two-year outcomes of patients with newly diagnosed atrial fibrillation: results from GARFIELD-AF.

AIMS: The relationship between outcomes and time after diagnosis for patients with non-valvular atrial fibrillation (NVAF) is poorly defined, especially beyond the first year. METHODS AND RESULTS: GARFIELD-AF is an ongoing, global observational study of adults with newly diagnosed NVAF. Two-year outcomes of 17 162 patients prospectively enrolled in GARFIELD-AF were analysed in light of baseline characteristics, risk profiles for stroke/systemic embolism (SE), and antithrombotic therapy. The mean (standard deviation) age was 69.8 (11.4) years, 43.8% were women, and the mean CHA2DS2-VASc score was 3.3 (1.6); 60.8% of patients were prescribed anticoagulant therapy with/without antiplatelet (AP) therapy, 27.4% AP monotherapy, and 11.8% no antithrombotic therapy. At 2-year follow-up, all-cause mortality, stroke/SE, and major bleeding had occurred at a rate (95% confidence interval) of 3.83 (3.62; 4.05), 1.25 (1.13; 1.38), and 0.70 (0.62; 0.81) per 100 person-years, respectively. Rates for all three major events were highest during the first 4 months. Congestive heart failure, acute coronary syndromes, sudden/unwitnessed death, malignancy, respiratory failure, and infection/sepsis accounted for 65% of all known causes of death and strokes for <10%. Anticoagulant treatment was associated with a 35% lower risk of death. CONCLUSION: The most frequent of the three major outcome measures was death, whose most common causes are not known to be significantly influenced by anticoagulation. This suggests that a more comprehensive approach to the management of NVAF may be needed to improve outcome. This could include, in addition to anticoagulation, interventions targeting modifiable, cause-specific risk factors for death. CLINICAL TRIAL REGISTRATION: http://www.clinicaltrials.gov. Unique identifier: NCT01090362

Risk profiles and one-year outcomes of patients with newly diagnosed atrial fibrillation in India: Insights from the GARFIELD-AF Registry.

BACKGROUND: The Global Anticoagulant Registry in the FIELD-Atrial Fibrillation (GARFIELD-AF) is an ongoing prospective noninterventional registry, which is providing important information on the baseline characteristics, treatment patterns, and 1-year outcomes in patients with newly diagnosed non-valvular atrial fibrillation (NVAF). This report describes data from Indian patients recruited in this registry. METHODS AND RESULTS: A total of 52,014 patients with newly diagnosed AF were enrolled globally; of these, 1388 patients were recruited from 26 sites within India (2012-2016). In India, the mean age was 65.8 years at diagnosis of NVAF. Hypertension was the most prevalent risk factor for AF, present in 68.5% of patients from India and in 76.3% of patients globally (P < 0.001). Diabetes and coronary artery disease (CAD) were prevalent in 36.2% and 28.1% of patients as compared with global prevalence of 22.2% and 21.6%, respectively (P < 0.001 for both). Antiplatelet therapy was the most common antithrombotic treatment in India. With increasing stroke risk, however, patients were more likely to receive oral anticoagulant therapy [mainly vitamin K antagonist (VKA)], but average international normalized ratio (INR) was lower among Indian patients [median INR value 1.6 (interquartile range {IQR}: 1.3-2.3) versus 2.3 (IQR 1.8-2.8) (P < 0.001)]. Compared with other countries, patients from India had markedly higher rates of all-cause mortality [7.68 per 100 person-years (95% confidence interval 6.32-9.35) vs 4.34 (4.16-4.53), P < 0.0001], while rates of stroke/systemic embolism and major bleeding were lower after 1 year of follow-up. CONCLUSION: Compared to previously published registries from India, the GARFIELD-AF registry describes clinical profiles and outcomes in Indian patients with AF of a different etiology. The registry data show that compared to the rest of the world, Indian AF patients are younger in age and have more diabetes and CAD. Patients with a higher stroke risk are more likely to receive anticoagulation therapy with VKA but are underdosed compared with the global average in the GARFIELD-AF. CLINICAL TRIAL REGISTRATION-URL: http://www.clinicaltrials.gov. Unique identifier: NCT01090362

ESTs in Plants: Where Are We Heading?

Expressed sequence tags (ESTs) are the most important resources for transcriptome exploration. Next-generation sequencing technologies have been generating gigabytes of genetic codes representing genes, partial and whole genomes most of which are EST datasets. Niche of EST in plants for breeding, regulation of gene expression through miRNA studies, and their application for adapting to climatic changes are discussed. Some of the recent tools for analysis of EST exclusive to plants are listed out. Systems biology though in its infancy in plants has influenced EST mapping for unraveling gene regulatory circuits, which is illustrated with a few significant examples. This review throws a glance at the evolving role of ESTs in plants

Assessing the Reach, Scope and Outcomes of Government Action on Women’s Health and Human Rights: A Protocol for the Development of an International Women’s Rights Dataset

Background: The UN Convention on the Elimination of all Forms of Discrimination Against Women (CEDAW) represents an international commitment to equality in the enjoyment of human rights. International human rights scholars posit that, in facilitating constructive dialogues between states and human rights experts, the near-universally ratified Convention is a powerful tool for achieving global health goals, such as the Sustainable Development Goals (SDGs). Yet, the performance of such rights-based approaches in achieving gender equality, and empowering all women, has not been systematically measured and evaluated on a global scale. This study seeks to address the urgent need to support data-driven analyses to hold governments to account through the development of a global dataset measuring state action on women’s health and human rights. Methods: Standard systematic review methods will be used to review CEDAW periodic review reports produced by United Nations (UN) Member States, civil society organisations and the CEDAW Committee. Global participation with the review mechanism, the scope of health inequities covered by Committee recommendations, the nature of reported government action and the extent of implementation of each program will be extracted from each report. Only data from the two most recent reporting cycles will be analysed. Descriptive statistics will be used to analyse quantitative data, and all qualitative data will be analysed using policy mapping techniques. Discussion: Using these data, the study will navigate the nature and the extent of state action to address these issues including by increasing women’s leadership and participation, data collection, strengthening health systems, governance and coordination and establishing new human rights infrastructure. It will use the diversity of health and human rights issues affecting women to reframe traditional conceptualisations of global women’s health which have largely focussed on sexual and reproductive health, to the exclusion of other aspects of women’s lives through the life course. In addition, the study will aid the development of authoritative guidance on how each of these areas of state action and inaction contribute to health inequities, and a framework for designing interventions to address discrimination against women as it relates to health

Structure-based virtual screening of novel, high-affinity BRD4 inhibitors

Bromodomains (BRDs) are a diverse family of evolutionarily conserved protein-interaction modules. Among various members of the bromodomain and extra terminal domain family, BRD4 is found to be an important target for many diseases such as cancer, acute myeloid leukemia, multiple myeloma, Burkitt's lymphoma, etc. Therefore, in this study an attempt has been made to screen compounds from NCI Diversity, Drug Bank and Toslab Databases targeting the K<SUB>ac</SUB> binding site of BRD4 using molecular docking, molecular dynamics simulations, MM-PB/GBSA binding free energy calculations and steered molecular dynamics simulations. Using virtual screening and docking, we have identified 11 inhibitors. These new inhibitors exhibit binding energy values higher than that of the (+)JQ1 inhibitor which is effective against BRD4. However, due to the toxicity of (+)JQ1, the designing of new inhibitors becomes significantly important. Thus, these new 11 ligands were systematically analyzed using other computational investigations. Results reveal that the compounds ZINC01411240, ZINC19632618 and ZINC04818522 could be potential drug candidates for targeting BRD4. It can also be seen from the results that there is a linear relationship between the results obtained from the SMD simulation and free energy obtained from the MM-PBSA/GBSA approach. This study clearly illustrates that the steered molecular dynamics can be effectively used for the design of new inhibitors

HIV seroconversion among Baltimore City residents tested at a mobile van programme

BackgroundMany individuals with HIV in the USA are unaware of their diagnosis, and therefore cannot be engaged in treatment services, have worse clinical outcomes and are more likely to transmit HIV to others. Mobile van testing may increase HIV testing and diagnosis. Our objective was to characterise risk factors for HIV seroconversion among individuals using mobile van testing.MethodsA case cohort study (n=543) was conducted within an HIV surveillance dataset of mobile van testing users with at least two HIV tests between September 2004 and August 2009 in Baltimore, Maryland. A subcohort (n=423) was randomly selected; all additional cases were added from the parent cohort. Cases (n=122 total, two from random subcohort) had documented seroconversion at the follow-up visit. A unique aspect of the analysis was use of Department of Corrections data to document incarceration between the times of initial and subsequent testing. Multivariate Cox proportional hazards models were used to compare HIV transmission risk factors between individuals who seroconverted and those who did not.ResultsOne hundred and twenty-two HIV seroconversions occurred among 8756 individuals (1.4%), a rate higher than that in Baltimore City Health Department's STD Clinic clients (1%). Increased HIV seroconversion risk was associated with men who have sex with men (MSM) (HR 32.76, 95% CI 5.62 to 191.12), sex with an HIV positive partner (HR 70.2, 95% CI 9.58 to 514.89), and intravenous drug use (IDU) (HR 5.65, 95% CI 2.41 to 13.23).ConclusionsHIV testing is a crucial first step in the HIV care continuum and an important HIV prevention tool. This study confirmed the need to reach high-risk populations (MSM, sex with HIV-positive individuals, individuals with IDU) and to increase comprehensive prevention services so that high-risk individuals stay HIV uninfected. HIV testing in mobile vans may be an effective outreach strategy for identifying infection in certain populations at high risk for HIV

Inhibition of Tissue Matrix Metalloproteinases Interferes with Mycobacterium tuberculosis-Induced Granuloma Formation and Reduces Bacterial Load in a Human Lung Tissue Model

Granulomas are hallmarks of pulmonary tuberculosis (TB) and traditionally viewed as host-protective structures. However, recent evidence suggest that Mycobacterium tuberculosis (Mtb) uses its virulence factors to stimulate the formation of granuloma. In the present study, we investigated the contribution of matrix metalloproteinases (MMPs), host enzymes that cause degradation of the extracellular matrix, to granuloma formation and bacterial load in Mtb-infected tissue. To this end, we used our lung tissue model for TB, which is based on human lung-derived cells and primary human monocyte-derived macrophages. Global inhibition of MMPs in the Mtb-infected tissue model reduced both granuloma formation and bacterial load. The infection caused upregulation of a set of MMPs (MMP1, 3, 9, and 12), and this finding could be validated in lung biopsies from patients with non-cavitary TB. Data from this study indicate that MMP activation contributes to early TB granuloma formation, suggesting that host-directed, MMP-targeted intervention could be considered as adjunct therapy to TB treatment.Funding Agencies|Swedish Research Council [2014-02289, 2015-02593]; Swedish Heart. Lung Foundation [20130685, 20150709]</p