Machine learning-based prediction of adverse events following an acute coronary syndrome (PRAISE): a modelling study of pooled datasets.

BACKGROUND: The accuracy of current prediction tools for ischaemic and bleeding events after an acute coronary syndrome (ACS) remains insufficient for individualised patient management strategies. We developed a machine learning-based risk stratification model to predict all-cause death, recurrent acute myocardial infarction, and major bleeding after ACS. METHODS: Different machine learning models for the prediction of 1-year post-discharge all-cause death, myocardial infarction, and major bleeding (defined as Bleeding Academic Research Consortium type 3 or 5) were trained on a cohort of 19 826 adult patients with ACS (split into a training cohort [80%] and internal validation cohort [20%]) from the BleeMACS and RENAMI registries, which included patients across several continents. 25 clinical features routinely assessed at discharge were used to inform the models. The best-performing model for each study outcome (the PRAISE score) was tested in an external validation cohort of 3444 patients with ACS pooled from a randomised controlled trial and three prospective registries. Model performance was assessed according to a range of learning metrics including area under the receiver operating characteristic curve (AUC). FINDINGS: The PRAISE score showed an AUC of 0·82 (95% CI 0·78-0·85) in the internal validation cohort and 0·92 (0·90-0·93) in the external validation cohort for 1-year all-cause death; an AUC of 0·74 (0·70-0·78) in the internal validation cohort and 0·81 (0·76-0·85) in the external validation cohort for 1-year myocardial infarction; and an AUC of 0·70 (0·66-0·75) in the internal validation cohort and 0·86 (0·82-0·89) in the external validation cohort for 1-year major bleeding. INTERPRETATION: A machine learning-based approach for the identification of predictors of events after an ACS is feasible and effective. The PRAISE score showed accurate discriminative capabilities for the prediction of all-cause death, myocardial infarction, and major bleeding, and might be useful to guide clinical decision making. FUNDING: None.

Recommendations for Structure and Content for a School-Based Adolescent Immunization Curriculum.

Despite high utilization of childhood vaccinations, adolescent immunization coverage rates lag behind recommended coverage levels. The four vaccines recommended for adolescents ages 11 to 18 years are tetanus, diphtheria, and pertussis vaccine; human papillomavirus vaccine; meningococcal conjugate vaccine; and an annual influenza vaccine. The Healthy People 2020 goal is 80% coverage for each recommended immunization, but coverage rates in Georgia among adolescents fall below those goals for all but the tetanus, diphtheria, and pertussis vaccine. We developed a multicomponent intervention that included a school-based, teacher-delivered educational curriculum to increase adolescent vaccination coverage rates in Richmond County, Georgia. We facilitated focus group discussions with middle- and high school science teachers who delivered the immunization curriculum in two consecutive school years. The objective of the focus group was to understand teachers' perspectives about the curriculum impact and to synthesize recommendations for optimal dissemination of the curriculum content, structure, and packaging. Teachers provided recommendations for curriculum fit within existing classes, timing of delivery, and dosage of delivery and recommended creating a flexible tool kit, such as a downloadable online package. Teachers also recommended increasing emphasis on disease transmission and symptoms to keep students engaged. These findings can be applied to the development of an online, cost-effective tool kit geared toward teaching adolescents about the immune system and adolescent vaccinations.

Assessment of Arbovirus Surveillance 13 Years after Introduction of West Nile Virus, United States.

Before 1999, the United States had no appropriated funding for arboviral surveillance, and many states conducted no such surveillance. After emergence of West Nile virus (WNV), federal funding was distributed to state and selected local health departments to build WNV surveillance systems. The Council of State and Territorial Epidemiologists conducted assessments of surveillance capacity of resulting systems in 2004 and in 2012; the assessment in 2012 was conducted after a 61% decrease in federal funding. In 2004, nearly all states and assessed local health departments had well-developed animal, mosquito, and human surveillance systems to monitor WNV activity and anticipate outbreaks. In 2012, many health departments had decreased mosquito surveillance and laboratory testing capacity and had no systematic disease-based surveillance for other arboviruses. Arboviral surveillance in many states might no longer be sufficient to rapidly detect and provide information needed to fully respond to WNV outbreaks and other arboviral threats (e.g., dengue, chikungunya).

School-Located Vaccination Clinics for Adolescents: Correlates of Acceptance Among Parents.

Four vaccines are recommended by The Advisory Committee for Immunization Practices for adolescents: tetanus, diphtheria, acellular pertussis vaccine (Tdap), meningococcal conjugate vaccine (MCV4), human papillomavirus vaccine (HPV), and annual seasonal influenza vaccine. However, coverage among adolescents is suboptimal. School-located vaccination clinics (SLVCs) offer vaccines to students at school, increasing access. This study seeks to determine the relationship between attitudes of parents of middle- and high-school students and acceptance of SLVCs for all four adolescent recommended vaccines. We conducted a telephone and web-based survey among parents of students enrolled in six middle and five high schools in Georgia. Analyses were conducted to examine associations between parental attitudes and willingness to allow their child to be vaccinated at school. Tdap and influenza vaccine had the highest rates of parental SLVC acceptance while HPV vaccine had the lowest. Parents who accepted SLVCs had higher perceived severity of influenza, meningococcal, and HPV illnesses compared to parents who did not accept SLVC. Intention to vaccinate was associated with SLVC acceptance for Tdap [Adjusted OR (AOR) 7.38; 95% confidence interval (CI) 2.44-22.31], MCV4 (AOR 2.97; 95% CI 1.67-5.28), and HPV vaccines (AOR 7.61; 95% CI 3.43-16.89). Social norms were associated with acceptance of SLVCs for influenza vaccine (AOR 1.44; 95% CI 1.12-1.84). These findings suggest parents of adolescents are generally supportive of SLVCs for recommended adolescent vaccines. Perceived severity of illness and intention to get their adolescent vaccinated were the most consistent correlates of parental SLVC acceptance for all vaccines. Future SLVC planning should focus on perceptions of disease severity and benefits of vaccination.

Quantitative patterns of stylistic influence in the evolution of literature.

Literature is a form of expression whose temporal structure, both in content and style, provides a historical record of the evolution of culture. In this work we take on a quantitative analysis of literary style and conduct the first large-scale temporal stylometric study of literature by using the vast holdings in the Project Gutenberg Digital Library corpus. We find temporal stylistic localization among authors through the analysis of the similarity structure in feature vectors derived from content-free word usage, nonhomogeneous decay rates of stylistic influence, and an accelerating rate of decay of influence among modern authors. Within a given time period we also find evidence for stylistic coherence with a given literary topic, such that writers in different fields adopt different literary styles. This study gives quantitative support to the notion of a literary "style of a time" with a strong trend toward increasingly contemporaneous stylistic influence.

Assessing providers' vaccination behaviors during routine immunization in India.

Progress has been made toward improving routine immunization coverage in India, but universal coverage has not been achieved. Little is known about how providers' vaccination behaviors affect coverage rates. The purpose of this study was to identify provider behaviors that served as barriers to vaccination that could lead to missed opportunities to vaccinate. We conducted a study of health-care providers' vaccination behaviors during clinic visits for children <3 years of age. Information on provider behaviors was collected through parent report and direct observation. Compared with illness visits, parents were eight times more likely to report vaccination status was verified (p < 0.001) and three times more likely to report receiving counseling on immunization (p = 0.022) during vaccination visits. Training of all vaccination practitioners should focus on behaviors such as the necessity of verifying vaccination status regardless of visit type, stressing the importance of counseling parents on immunization and emphasizing what is a valid contraindication to vaccination.

Microbial origins of chronic diseases.

Chronic diseases such as cardiovascular disease and cancer are among the leading causes of death worldwide and have been on the rise over the past decade. Associations between microbial agents and development of chronic diseases have been made in the past, and new connections are currently being assessed. Investigators are examining the relationship between infectious agents and chronic disease using new technologies with more rigor and specificity. This review examines microbial agents' links to and associations with cardiovascular diseases, cancer, neurodegenerative diseases, renal diseases, psychiatric disorders, and obesity and addresses the important role of the human microbiome in maintenance of health and its potential role in chronic diseases. These associations and relationships will impact future research priorities, surveillance approaches, treatment strategies, and prevention programs for chronic diseases.

CDC Grand Rounds: discovering new diseases via enhanced partnership between public health and pathology experts.

Despite advances in public health, medicine, and technology, infectious diseases remain a major source of illness and death worldwide. In the United States alone, unexplained deaths resulting from infectious disease agents have an estimated annual incidence of 0.5 per 100,000 persons aged 1-49 years. Emerging and newly recognized infections, such as hantavirus pulmonary syndrome and West Nile encephalitis, often are associated with life-threatening illnesses and death. Other infectious diseases once thought to be on the decline, such as pertussis, again are becoming major public health threats. Animals increasingly are being recognized as potential vectors for infectious diseases affecting humans; approximately 75% of recently emerging human infectious diseases are of animal origin. Increasing global interconnectivity necessitates more rapid identification of infectious disease agents to prevent, treat, and control diseases.

National capacity for surveillance, prevention, and control of West Nile virus and other arbovirus infections--United States, 2004 and 2012.

In the first 5 years after its introduction in the United States in 1999, West Nile virus (WNV) spread to the 48 contiguous states, resulting in 667 reported deaths. To establish detection and response capacity, WNV surveillance and prevention was supported through CDC Epidemiology and Laboratory Capacity (ELC) cooperative agreements with all 50 states and six large cities/counties. In 2005, the Council of State and Territorial Epidemiologists (CSTE) conducted an assessment of ELC recipients and determined that, since 1999, all had developed WNV surveillance and control programs, resulting in a national arboviral surveillance infrastructure. From 2004 to 2012, ELC funding for WNV surveillance decreased by 61%. In 2012, the United States had its most severe WNV season since 2003, prompting a follow-up assessment of the capacity of ELC-supported WNV programs. Since the first assessment, 22% of jurisdictions had stopped conducting active human surveillance, 13% had stopped mosquito surveillance, 70% had reduced mosquito trapping and testing, and 64% had eliminated avian mortality surveillance. Reduction in early detection capacity compromises local and national ability to rapidly detect changes in WNV and other arboviral activity and to initiate prevention measures. Each jurisdiction is encouraged to review its current surveillance systems in light of the local threat of WNV and emerging arboviruses (e.g., dengue and chikungunya) and ensure it is able to rapidly detect and respond to critical changes in arbovirus activity.

Development, theoretical framework, and evaluation of a parent and teacher-delivered intervention on adolescent vaccination.

The Advisory Committee on Immunization Practices recommended immunization schedule for adolescents includes three vaccines (tetanus, diphtheria, and acellular pertussis [Tdap]; human papillomavirus [HPV] vaccine; and meningococcal conjugate vaccine [MCV4]) and an annual influenza vaccination. Given the increasing number of recommended vaccines for adolescents and health and economic costs associated with nonvaccination, it is imperative that effective strategies for increasing vaccination rates among adolescents are developed. This article describes the development, theoretical framework, and initial first-year evaluation of an intervention designed to promote vaccine acceptance among a middle and high school-based sample of adolescents and their parents in eastern Georgia. Adolescents, parents, and teachers were active participants in the development of the intervention. The intervention, which consisted of a brochure for parents and a teacher-delivered curriculum for adolescents, was guided by constructs from the health belief model and theory of reasoned action. Evaluation results indicated that our intervention development methods were successful in creating a brochure that met cultural relevance and the literacy needs of parents. We also demonstrated an increase in student knowledge of and positive attitudes toward vaccines. To our knowledge, this study is the first to extensively engage middle and high school students, parents, and teachers in the design and implementation of key theory-based educational components of a school-based, teacher-delivered adolescent vaccination intervention.

Lung Metastasectomy: Where Do We Stand? Results from an Italian Multicentric Prospective Database.

Background/Objectives: The surgical resection of pulmonary metastases is considered a therapeutic option in selected cases. In light of this, we present the results from a national multicenter prospective registry of lung metastasectomy. Methods: This retrospective analysis involves data collected prospectively and consecutively in a national multicentric Italian database, including patients who underwent lung metastasectomy. The primary endpoints were the analysis of morbidity and overall survival (OS), with secondary endpoints focusing on the analysis of potential risk factors affecting both morbidity and OS. Results: A total 470 lung procedures were performed (4 pneumonectomies, 46 lobectomies/bilobectomies, 13 segmentectomies and 407 wedge resections) on 461 patients (258 men and 203 women, mean age of 63.1 years). The majority of patients had metastases from colorectal cancer (45.8%). In most cases (63.6%), patients had only one lung metastasis. A minimally invasive approach was chosen in 143 cases (30.4%). The mean operative time was 118 min, with no reported deaths. Morbidity most frequently consisted of prolonged air leaking and bleeding, but no re-intervention was required. Statistical analysis revealed that morbidity was significantly affected by operative time and pulmonary comorbidities, while OS was significantly affected by disease-free interval (DFI) > 24 months (p = 0.005), epithelial histology (p = 0.001) and colorectal histology (p = 0.004) during univariate analysis. No significant correlation was found between OS and age, gender, surgical approach, surgical extent, surgical device, the number of resected metastases, lesion diameter, the site of lesions and nodal involvement. Multivariate analysis of OS confirmed that only epithelial histology and DFI were risk-factors, with p-values of 0.041 and 0.031, respectively. Conclusions: Lung metastasectomy appears to be a safe procedure, with acceptable morbidity, even with a minimally invasive approach. However, it remains a local treatment of a systemic disease. Therefore, careful attention should be paid to selecting patients who could truly benefit from surgical intervention.

Progress in global surveillance and response capacity 10 years after severe acute respiratory syndrome.

Ten years have elapsed since the World Health Organization issued its first global alert for an unexplained illness named severe acute respiratory syndrome (SARS). The anniversary provides an opportunity to reflect on the international response to this new global microbial threat. While global surveillance and response capacity for public health threats have been strengthened, critical gaps remain. Of 194 World Health Organization member states that signed on to the International Health Regulations (2005), <20% had achieved compliance with the core capacities required by the deadline in June 2012. Lessons learned from the global SARS outbreak highlight the need to avoid complacency, strengthen efforts to improve global capacity to address the next pandemic using all available 21st century tools, and support research to develop new treatment options, countermeasures, and insights while striving to address the global inequities that are the root cause of many of these challenges.

Understanding reasons for participating in a school-based influenza vaccination program and decision-making dynamics among adolescents and parents.

Influenza remains a significant cause of morbidity and mortality in the United States. Vaccinating school-aged children has been demonstrated to be beneficial to the child and in reducing viral transmission to vulnerable groups such as the elderly. This qualitative study sought to identify reasons parents and students participated in a school-based influenza vaccination clinic and to characterize the decision-making process for vaccination. Eight focus groups were conducted with parents and students. Parents and students who participated in the influenza vaccination clinic stated the educational brochure mailed to their home influenced participation in the program. Parents of non-participating students mentioned barriers, such as the lengthy and complicated consent process and suspicions about the vaccine clinic, as contributing to their decision not to vaccinate their child. Vaccinated students reported initiating influenza vaccine discussion with their parents. Parental attitudes and the educational material influenced parents' decision to allow their child to receive influenza vaccine. This novel study explored reasons for participating in a school-based vaccination clinic and the decision-making process between parents and child(ren). Persons running future school-based vaccination clinics may consider hosting an 'information session with a question and answer session' to address parental concerns and assist with the consent process.

Quantification of artistic style through sparse coding analysis in the drawings of Pieter Bruegel the Elder.

Recently, statistical techniques have been used to assist art historians in the analysis of works of art. We present a novel technique for the quantification of artistic style that utilizes a sparse coding model. Originally developed in vision research, sparse coding models can be trained to represent any image space by maximizing the kurtosis of a representation of an arbitrarily selected image from that space. We apply such an analysis to successfully distinguish a set of authentic drawings by Pieter Bruegel the Elder from another set of well-known Bruegel imitations. We show that our approach, which involves a direct comparison based on a single relevant statistic, offers a natural and potentially more germane alternative to wavelet-based classification techniques that rely on more complicated statistical frameworks. Specifically, we show that our model provides a method capable of discriminating between authentic and imitation Bruegel drawings that numerically outperforms well-known existing approaches. Finally, we discuss the applications and constraints of our technique.

Attitudes and practices of auxiliary nurse midwives and accredited social health activists in Uttar Pradesh and Bihar regarding polio immunization in India.

Although India was removed from the list of polio endemic countries in January 2012, maintaining the focus on polio vaccination is critically important to prevent reintroduction of the virus. In 2009-2010, we conducted a study to assess the attitudes and practices of frontline health workers in India regarding polio immunization in Uttar Pradesh and Bihar. More than 95% of auxiliary nurse midwives (ANMs) and accredited social health activists (ASHAs) agreed that polio supplementary immunization campaigns helped in increasing acceptance of all vaccines. The majority of ANMs (60-70%) and ASHAs (56-71%) believed that polio immunization activities benefitted or greatly benefitted other activities they were carrying out. Less than 5% of ANMs and ASHAs felt they were very likely to face resistance when promoting or administering polio vaccine. This study provides information that may be useful for programs in other countries for polio eradication and in India for measles elimination.

EZH2-Mediated H3K27me3 Targets Transcriptional Circuits of Neuronal Differentiation.

The Polycomb Repressive Complex 2 (PRC2) plays important roles in the epigenetic regulation of cellular development and differentiation through H3K27me3-dependent transcriptional repression. Aberrant PRC2 activity has been associated with cancer and neurodevelopmental disorders, particularly with respect to the malfunction of sits catalytic subunit EZH2. Here, we investigated the role of the EZH2-mediated H3K27me3 apposition in neuronal differentiation. We made use of a transgenic mouse model harboring Ezh2 conditional KO alleles to derive embryonic stem cells and differentiate them into glutamatergic neurons. Time course transcriptomics and epigenomic analyses of H3K27me3 in absence of EZH2 revealed a significant dysregulation of molecular networks affecting the glutamatergic differentiation trajectory that resulted in: (i) the deregulation of transcriptional circuitries related to neuronal differentiation and synaptic plasticity, in particular LTD, as a direct effect of EZH2 loss and (ii) the appearance of a GABAergic gene expression signature during glutamatergic neuron differentiation. These results expand the knowledge about the molecular pathways targeted by Polycomb during glutamatergic neuron differentiation.

hOA-DN30: a highly effective humanized single-arm MET antibody inducing remission of 'MET-addicted' cancers.

BACKGROUND: The tyrosine kinase receptor encoded by the MET oncogene is a major player in cancer. When MET is responsible for the onset and progression of the transformed phenotype (MET-addicted cancers), an efficient block of its oncogenic activation results in potent tumor growth inhibition. METHODS: Here we describe a molecular engineered MET antibody (hOA-DN30) and validate its pharmacological activity in MET-addicted cancer models in vitro and in vivo. Pharmacokinetics and safety profile in non-human primates have also been assessed. RESULTS: hOA-DN30 efficiently impaired MET activation and the intracellular signalling cascade by dose and time dependent removal of the receptor from the cell surface (shedding). In vitro, the antibody suppressed cell growth by blocking cell proliferation and by concomitantly inducing cell death in multiple MET-addicted human tumor cell lines. In mice xenografts, hOA-DN30 induced an impressive reduction of tumor masses, with a wide therapeutic window. Moreover, the antibody showed high therapeutic efficacy against patient-derived xenografts generated from MET-addicted gastric tumors, leading to complete tumor regression and long-lasting effects after treatment discontinuation. Finally, hOA-DN30 showed a highly favorable pharmacokinetic profile and substantial tolerability in Cynomolgus monkeys. CONCLUSIONS: hOA-DN30 unique ability to simultaneously erase cell surface MET and release the 'decoy' receptor extracellular region results in a paramount MET blocking action. Its remarkable efficacy in a large number of pre-clinical models, as well as its pharmacological features and safety profile in non-human primates, strongly envisage a successful clinical application of this novel single-arm MET therapeutic antibody for the therapy of MET-addicted cancers.

Advances in detecting and responding to threats from bioterrorism and emerging infectious disease.

Much progress has been made in recent years to strengthen local, state, national and international capacities to detect and respond to bioterrorism events and naturally occurring outbreaks of disease. New tools and systems are available to estimate the potential impact of a biological event and predict resource needs for effective response, enable earlier detection of an attack or outbreak, enhance diagnostic capacity and facilitate rapid intervention to mitigate the impact of an event on a community. These advances have required new approaches to preparedness, planning and surveillance, as well as new partnerships and collaborations across a range of disciplines. We examine some of these developments, discuss potential uses and limitations of these approaches, and identify priorities for the future.