Many Routes to an Antibody Heavy-Chain CDR3: Necessary, Yet Insufficient, for Specific Binding

DOE PAGES

D'Angelo, Sara; Ferrara, Fortunato; Naranjo, Leslie; ...

2018-03-08

Because of its great potential for diversity, the immunoglobulin heavy-chain complementarity-determining region 3 (HCDR3) is taken as an antibody molecule’s most important component in conferring binding activity and specificity. For this reason, HCDR3s have been used as unique identifiers to investigate adaptive immune responses in vivo and to characterize in vitro selection outputs where display systems were employed. Here, we show that many different HCDR3s can be identified within a target-specific antibody population after in vitro selection. For each identified HCDR3, a number of different antibodies bearing differences elsewhere can be found. In such selected populations, all antibodies with themore » same HCDR3 recognize the target, albeit at different affinities. In contrast, within unselected populations, the majority of antibodies with the same HCDR3 sequence do not bind the target. In one HCDR3 examined in depth, all target-specific antibodies were derived from the same VDJ rearrangement, while non-binding antibodies with the same HCDR3 were derived from many different V and D gene rearrangements. Careful examination of previously published in vivo datasets reveals that HCDR3s shared between, and within, different individuals can also originate from rearrangements of different V and D genes, with up to 26 different rearrangements yielding the same identical HCDR3 sequence. On the basis of these observations, we conclude that the same HCDR3 can be generated by many different rearrangements, but that specific target binding is an outcome of unique rearrangements and VL pairing: the HCDR3 is necessary, albeit insufficient, for specific antibody binding.« less

Many Routes to an Antibody Heavy-Chain CDR3: Necessary, Yet Insufficient, for Specific Binding

DOE Office of Scientific and Technical Information (OSTI.GOV)

D'Angelo, Sara; Ferrara, Fortunato; Naranjo, Leslie

Because of its great potential for diversity, the immunoglobulin heavy-chain complementarity-determining region 3 (HCDR3) is taken as an antibody molecule’s most important component in conferring binding activity and specificity. For this reason, HCDR3s have been used as unique identifiers to investigate adaptive immune responses in vivo and to characterize in vitro selection outputs where display systems were employed. Here, we show that many different HCDR3s can be identified within a target-specific antibody population after in vitro selection. For each identified HCDR3, a number of different antibodies bearing differences elsewhere can be found. In such selected populations, all antibodies with themore » same HCDR3 recognize the target, albeit at different affinities. In contrast, within unselected populations, the majority of antibodies with the same HCDR3 sequence do not bind the target. In one HCDR3 examined in depth, all target-specific antibodies were derived from the same VDJ rearrangement, while non-binding antibodies with the same HCDR3 were derived from many different V and D gene rearrangements. Careful examination of previously published in vivo datasets reveals that HCDR3s shared between, and within, different individuals can also originate from rearrangements of different V and D genes, with up to 26 different rearrangements yielding the same identical HCDR3 sequence. On the basis of these observations, we conclude that the same HCDR3 can be generated by many different rearrangements, but that specific target binding is an outcome of unique rearrangements and VL pairing: the HCDR3 is necessary, albeit insufficient, for specific antibody binding.« less

Detecting population recovery using gametic disequilibrium-based effective population size estimates

Treesearch

David A. Tallmon; Robin S. Waples; Dave Gregovich; Michael K. Schwartz

2012-01-01

Recovering populations often must meet specific growth rate or abundance targets before their legal status can be changed from endangered or threatened. While the efficacy, power, and performance of population metrics to infer trends in declining populations has received considerable attention, how these same metrics perform when populations are increasing is less...

Social identity and support for counteracting tobacco company marketing that targets vulnerable populations.

PubMed

Baig, Sabeeh A; Pepper, Jessica K; Morgan, Jennifer C; Brewer, Noel T

2017-06-01

Tobacco companies use advertising to target vulnerable populations, including youth, racial/ethnic minorities, and sexual minorities. We sought to examine how personal identity affects support for population-specific anti-smoking advertisements that could serve as countermeasures to industry marketing practices. In 2014-2015, we surveyed probability phone samples of adults and adolescents (n = 6,139) and an online convenience sample of adults (n = 4,137) in the United States. We experimentally varied the description of tobacco industry marketing practices (no description, general, or specific to a target group). The four prevention target groups were teens; African Americans; Latinos; and gays, lesbians, and bisexuals (GLBs). Participants were either members or non-members of their prevention target group. Support was highest for anti-smoking advertisements targeting teens, moderate for Latinos and African Americans, and lowest for GLBs. In-group members expressed higher support than out-group members when anti-smoking advertisements targeted African Americans, Latinos, and GLBs (all p < 0.05). However, when teens were the target prevention group, in-group members expressed lower support than out-group members (p < 0.05). The description of industry marketing practices did not have an effect. Results were similar across the phone and online studies. Our findings suggest that the public strongly supports advertisements to prevent smoking among teens, but support for similar efforts among other vulnerable populations is comparatively low. Anti-smoking campaigns for vulnerable populations may benefit from a greater understanding of the role of social identity in shaping public support for such campaigns. Copyright © 2017 Elsevier Ltd. All rights reserved.

Target specific oral anticoagulants in the management of thromboembolic disease in the elderly.

PubMed

Maddula, Surekha; Ansell, Jack

2013-08-01

The elderly population represents a population at highest risk of thromboembolism, but also the most vulnerable to hemorrhage. In the community setting there is a general tendency to under- treat this patient group. Specific consideration must be taken with elderly patients because they have reduced renal function, co-morbidities and risk of falls, altered pharmacodynamics, and challenges with adherence. Vitamin K antagonists, most often warfarin, have been the first line choice of therapy for long-term anticoagulation and enjoyed an unopposed position in the market for the last 70 years. Recently several new oral anticoagulants have been developed and found to be equally effective as warfarin in phase III studies and may provide an optimal treatment option in the elderly population. In this review we explore the target-specific oral anticoagulants and the pharmacological differences between them with a focus on the elderly population in whom these new drugs would constitute a possible alternative to warfarin therapy.

Population-specific life histories contribute to metapopulation viability

USGS Publications Warehouse

Halsey, Samniqueka J.; Bell, Timothy J.; McEachern, A. Kathryn; Pavlovic, Noel B.

2016-01-01

Restoration efforts can be improved by understanding how variations in life-history traits occur within populations of the same species living in different environments. This can be done by first understanding the demographic responses of natural occurring populations. Population viability analysis continues to be useful to species management and conservation with sensitivity analysis aiding in the understanding of population dynamics. In this study, using life-table response experiments and elasticity analyses, we investigated how population-specific life-history demographic responses contributed to the metapopulation viability of the Federally threatened Pitcher's thistle (Cirsium pitcheri). Specifically, we tested the following hypotheses: (1) Subpopulations occupying different environments within a metapopulation have independent demographic responses and (2) advancing succession results in a shift from a demographic response focused on growth and fecundity to one dominated by stasis. Our results showed that reintroductions had a positive contribution to the metapopulation growth rate as compared to native populations which had a negative contribution. We found no difference in succession on the contribution to metapopulation viability. In addition, we identified distinct population-specific contributions to metapopulation viability and were able to associate specific life-history demographic responses. For example, the positive impact of Miller High Dunes population on the metapopulation growth rate resulted from high growth contributions, whereas increased time of plant in stasis for the State Park Big Blowout population resulted in negative contributions. A greater understanding of how separate populations respond in their corresponding environment may ultimately lead to more effective management strategies aimed at reducing extinction risk. We propose the continued use of sensitivity analyses to evaluate population-specific demographic influences on metapopulation viability. In understanding the underlying causes of the projected extinction probabilities of each population and identifying broad-scale contributions of different populations to the metapopulation, the process of pinpointing target populations is simplified. More detailed analyses can then be applied to the target populations to increase population viability and consequently metapopulation viability. Based on our research, we suggest that the best approach to improve the overall metapopulation viability is to manage the contributions to population growth for each population separately.

Bioassay and biomolecular identification, sorting, and collection methods using magnetic microspheres

DOEpatents

Kraus, Jr., Robert H.; Zhou, Feng [Los Alamos, NM; Nolan, John P [Santa Fe, NM

2007-06-19

The present invention is directed to processes of separating, analyzing and/or collecting selected species within a target sample by use of magnetic microspheres including magnetic particles, the magnetic microspheres adapted for attachment to a receptor agent that can subsequently bind to selected species within the target sample. The magnetic microspheres can be sorted into a number of distinct populations, each population with a specific range of magnetic moments and different receptor agents can be attached to each distinct population of magnetic microsphere.

Culturally Grounded Prevention for Minority Youth Populations: A Systematic Review of the Literature

PubMed Central

Lauricella, Michela; Valdez, Jessica K.; Okamoto, Scott K.; Helm, Susana; Zaremba, Colleen

2016-01-01

Contemporary prevention science has focused on the application of cultural adaptations of evidence-based prevention programs for minority youth populations. Far less is known about culturally grounded methods that are intended to organically develop prevention programs within specific populations and communities. This article systematically reviews recent literature on culturally grounded interventions used to prevent health disparities in ethnic minority youth populations. In this review, we assessed 31 peer-reviewed articles published in 2003 or later that fit inclusionary criteria pertaining to the development and evaluation of culturally grounded prevention programs. The evaluated studies indicated different approaches toward cultural grounding, as well as specific populations, geographic regions, and health issues that have been targeted. Specifically, the findings indicated that most of the studies focused on the development and evaluation of culturally grounded HIV/STI and substance abuse prevention programs for Mexican American, African American, and American Indian/Alaska Native youth residing in the South or Southwestern U.S. These studies largely relied on community-based participatory or qualitative research methods to develop programs from the “ground up.” This review has implications for the development of future culturally grounded and culturally adapted prevention programs targeting underserved minority youth populations and geographic regions. Specifically, it identifies populations and regions where culturally grounded prevention efforts are underdeveloped or non-existent, providing some scientific direction for the future development of these types of programs. PMID:26733384

Culturally Grounded Prevention for Minority Youth Populations: A Systematic Review of the Literature.

PubMed

Lauricella, Michela; Valdez, Jessica K; Okamoto, Scott K; Helm, Susana; Zaremba, Colleen

2016-02-01

Contemporary prevention science has focused on the application of cultural adaptations of evidence-based prevention programs for minority youth populations. Far less is known about culturally grounded methods that are intended to organically develop prevention programs within specific populations and communities. This article systematically reviews recent literature on culturally grounded interventions used to prevent health disparities in ethnic minority youth populations. In this review, we assessed 31 peer-reviewed articles published in 2003 or later that fit inclusionary criteria pertaining to the development and evaluation of culturally grounded prevention programs. The evaluated studies indicated different approaches toward cultural grounding, as well as specific populations, geographic regions, and health issues that have been targeted. Specifically, the findings indicated that most of the studies focused on the development and evaluation of culturally grounded HIV/STI and substance abuse prevention programs for Mexican-American, African American, and American Indian/Alaska Native youth residing in the South or Southwestern US. These studies largely relied on community-based participatory or qualitative research methods to develop programs from the "ground up." This review has implications for the development of future culturally grounded and culturally adapted prevention programs targeting underserved minority youth populations and geographic regions. Specifically, it identifies populations and regions where culturally grounded prevention efforts are underdeveloped or non-existent, providing some scientific direction for the future development of these types of programs.

Sequence-specific antimicrobials using efficiently delivered RNA-guided nucleases.

PubMed

Citorik, Robert J; Mimee, Mark; Lu, Timothy K

2014-11-01

Current antibiotics tend to be broad spectrum, leading to indiscriminate killing of commensal bacteria and accelerated evolution of drug resistance. Here, we use CRISPR-Cas technology to create antimicrobials whose spectrum of activity is chosen by design. RNA-guided nucleases (RGNs) targeting specific DNA sequences are delivered efficiently to microbial populations using bacteriophage or bacteria carrying plasmids transmissible by conjugation. The DNA targets of RGNs can be undesirable genes or polymorphisms, including antibiotic resistance and virulence determinants in carbapenem-resistant Enterobacteriaceae and enterohemorrhagic Escherichia coli. Delivery of RGNs significantly improves survival in a Galleria mellonella infection model. We also show that RGNs enable modulation of complex bacterial populations by selective knockdown of targeted strains based on genetic signatures. RGNs constitute a class of highly discriminatory, customizable antimicrobials that enact selective pressure at the DNA level to reduce the prevalence of undesired genes, minimize off-target effects and enable programmable remodeling of microbiota.

Huntingtin Haplotypes Provide Prioritized Target Panels for Allele-specific Silencing in Huntington Disease Patients of European Ancestry

PubMed Central

Kay, Chris; Collins, Jennifer A; Skotte, Niels H; Southwell, Amber L; Warby, Simon C; Caron, Nicholas S; Doty, Crystal N; Nguyen, Betty; Griguoli, Annamaria; Ross, Colin J; Squitieri, Ferdinando; Hayden, Michael R

2015-01-01

Huntington disease (HD) is a dominant neurodegenerative disorder caused by a CAG repeat expansion in the Huntingtin gene (HTT). Heterozygous polymorphisms in cis with the mutation allow for allele-specific suppression of the pathogenic HTT transcript as a therapeutic strategy. To prioritize target selection, precise heterozygosity estimates are needed across diverse HD patient populations. Here we present the first comprehensive investigation of all common target alleles across the HTT gene, using 738 reference haplotypes from the 1000 Genomes Project and 2364 haplotypes from HD patients and relatives in Canada, Sweden, France, and Italy. The most common HD haplotypes (A1, A2, and A3a) define mutually exclusive sets of polymorphisms for allele-specific therapy in the greatest number of patients. Across all four populations, a maximum of 80% are treatable using these three target haplotypes. We identify a novel deletion found exclusively on the A1 haplotype, enabling potent and selective silencing of mutant HTT in approximately 40% of the patients. Antisense oligonucleotides complementary to the deletion reduce mutant A1 HTT mRNA by 78% in patient cells while sparing wild-type HTT expression. By suppressing specific haplotypes on which expanded CAG occurs, we demonstrate a rational approach to the development of allele-specific therapy for a monogenic disorder. PMID:26201449

Cell-mediated immunity to herpes simplex virus: recognition of type-specific and type-common surface antigens by cytotoxic T cell populations.

PubMed Central

Eberle, R; Russell, R G; Rouse, B T

1981-01-01

In this communication, we examine the specificity of anti-herpes simplex virus (HSV) cytotoxic T lymphocytes (CTL). Serological studies of the two related HSV serotypes (HSV-1 and HSV-2) have revealed both type-specific and cross-reactive antigenic determinants in the viral envelope and on the surface of infected cells. By analysis of cytotoxicity of CTL, generated in vitro by restimulation of splenocytes from mice primed with one or the other HSV serotype, the recognition of both type-specific and cross-reactive determinants on infected target cells by anti-HSV CTL was detectable. Thus, effector cells generated by priming and restimulating with the same virus recognized both type-specific and cross-reactive determinants on target cells infected with the homologous virus, but only cross-reactive determinants on target cells infected with the heterologous HSV serotype. CTL generated by restimulation with the heterologous virus were capable of recognizing only the cross-reactive determinants on either HSV-1- or HSV-2-infected target cells. These results indicate that two subpopulations of CTL exist in a population of anti-HSV immune spleen cells--those which recognize type-specific determinants and those specific for cross-reactive antigenic determinants present on the surface of HSV infected cells. The type-specific subset of anti-HSV CTL was shown to recognize the gC glycoprotein of HSV-1 infected target cells. In addition to the gC glycoprotein, at least one other type-specific surface antigen was also recognized by anti-HSV CTL in addition to the cross-reactive determinants recognized by anti-HSV CTL. PMID:6277790

Identifying members of the domain Archaea with rRNA-targeted oligonucleotide probes.

PubMed

Burggraf, S; Mayer, T; Amann, R; Schadhauser, S; Woese, C R; Stetter, K O

1994-09-01

Two 16S rRNA-targeted oligonucleotide probes were designed for the archaeal kingdoms Euryachaeota and Crenarchaeota. Probe specificities were evaluated by nonradioactive dot blot hybridization against selected reference organisms. The successful application of fluorescent-probe derivatives for whole-cell hybridization required organism-specific optimizations of fixation and hybridization conditions to assure probe penetration and morphological integrity of the cells. The probes allowed preliminary grouping of three new hyperthermophilic isolates. Together with other group-specific rRNA-targeted oligonucleotide probes, these probes will facilitate rapid in situ monitoring of the populations present in hydrothermal systems and support cultivation attempts.

Accuracy and precision of as-received implant torque wrenches.

PubMed

Britton-Vidal, Eduardo; Baker, Philip; Mettenburg, Donald; Pannu, Darshanjit S; Looney, Stephen W; Londono, Jimmy; Rueggeberg, Frederick A

2014-10-01

Previous implant torque evaluation did not determine if the target value fell within a confidence interval for the population mean of the test groups, disallowing determination of whether a specific type of wrench met a standardized goal value. The purpose of this study was to measure both the accuracy and precision of 2 different configurations (spring style and peak break) of as-received implant torque wrenches and compare the measured values to manufacturer-stated values. Ten wrenches from 4 manufacturers, representing a variety of torque-limiting mechanisms and specificity of use (with either a specific brand or universally with any brand of implant product). Drivers were placed into the wrench, and tightening torque was applied to reach predetermined values using a NIST-calibrated digital torque wrench. Five replications of measurement were made for each wrench and averaged to provide a single value from that instrument. The target torque value for each wrench brand was compared to the 95% confidence interval for the true population mean of measured values to see if it fell within the measured range. Only 1 wrench brand (Nobel Biocare) demonstrated the target torque value falling within the 95% confidence interval for the true population mean. For others, the targeted torque value fell above the 95% confidence interval (Straumann and Imtec) or below (Salvin Torq). Neither type of torque-limiting mechanism nor designation of a wrench to be used as a dedicated brand-only product or to be used as a universal product on many brands affected the ability of a wrench to deliver torque values where the true population mean included the target torque level. Copyright © 2014 Editorial Council for the Journal of Prosthetic Dentistry. Published by Elsevier Inc. All rights reserved.

Controlling range expansion in habitat networks by adaptively targeting source populations.

PubMed

Hock, Karlo; Wolff, Nicholas H; Beeden, Roger; Hoey, Jessica; Condie, Scott A; Anthony, Kenneth R N; Possingham, Hugh P; Mumby, Peter J

2016-08-01

Controlling the spread of invasive species, pests, and pathogens is often logistically limited to interventions that target specific locations at specific periods. However, in complex, highly connected systems, such as marine environments connected by ocean currents, populations spread dynamically in both space and time via transient connectivity links. This results in nondeterministic future distributions of species in which local populations emerge dynamically and concurrently over a large area. The challenge, therefore, is to choose intervention locations that will maximize the effectiveness of the control efforts. We propose a novel method to manage dynamic species invasions and outbreaks that identifies the intervention locations most likely to curtail population expansion by selectively targeting local populations most likely to expand their future range. Critically, at any point during the development of the invasion or outbreak, the method identifies the local intervention that maximizes the long-term benefit across the ecosystem by restricting species' potential to spread. In so doing, the method adaptively selects the intervention targets under dynamically changing circumstances. To illustrate the effectiveness of the method we applied it to controlling the spread of crown-of-thorns starfish (Acanthaster sp.) outbreaks across Australia's Great Barrier Reef. Application of our method resulted in an 18-fold relative improvement in management outcomes compared with a random targeting of reefs in putative starfish control scenarios. Although we focused on applying the method to reducing the spread of an unwanted species, it can also be used to facilitate the spread of desirable species through connectivity networks. For example, the method could be used to select those fragments of habitat most likely to rebuild a population if they were sufficiently well protected. © 2016 Society for Conservation Biology.

Comparative Analysis of State Fish Consumption Advisories Targeting Sensitive Populations

PubMed Central

Scherer, Alison C.; Tsuchiya, Ami; Younglove, Lisa R.; Burbacher, Thomas M.; Faustman, Elaine M.

2008-01-01

Objective Fish consumption advisories are issued to warn the public of possible toxicological threats from consuming certain fish species. Although developing fetuses and children are particularly susceptible to toxicants in fish, fish also contain valuable nutrients. Hence, formulating advice for sensitive populations poses challenges. We conducted a comparative analysis of advisory Web sites issued by states to assess health messages that sensitive populations might access. Data sources We evaluated state advisories accessed via the National Listing of Fish Advisories issued by the U.S. Environmental Protection Agency. Data extraction We created criteria to evaluate advisory attributes such as risk and benefit message clarity. Data synthesis All 48 state advisories issued at the time of this analysis targeted children, 90% (43) targeted pregnant women, and 58% (28) targeted women of childbearing age. Only six advisories addressed single contaminants, while the remainder based advice on 2–12 contaminants. Results revealed that advisories associated a dozen contaminants with specific adverse health effects. Beneficial health effects of any kind were specifically associated only with omega-3 fatty acids found in fish. Conclusions These findings highlight the complexity of assessing and communicating information about multiple contaminant exposure from fish consumption. Communication regarding potential health benefits conferred by specific fish nutrients was minimal and focused primarily on omega-3 fatty acids. This overview suggests some lessons learned and highlights a lack of both clarity and consistency in providing the breadth of information that sensitive populations such as pregnant women need to make public health decisions about fish consumption during pregnancy. PMID:19079708

Fluorescent CSC models evidence that targeted nanomedicines improve treatment sensitivity of breast and colon cancer stem cells.

PubMed

Gener, Petra; Gouveia, Luis Pleno; Sabat, Guillem Romero; de Sousa Rafael, Diana Fernandes; Fort, Núria Bergadà; Arranja, Alexandra; Fernández, Yolanda; Prieto, Rafael Miñana; Ortega, Joan Sayos; Arango, Diego; Abasolo, Ibane; Videira, Mafalda; Schwartz, Simo

2015-11-01

To be able to study the efficacy of targeted nanomedicines in marginal population of highly aggressive cancer stem cells (CSC), we have developed a novel in vitro fluorescent CSC model that allows us to visualize these cells in heterogeneous population and to monitor CSC biological performance after therapy. In this model tdTomato reporter gene is driven by CSC specific (ALDH1A1) promoter and contrary to other similar models, CSC differentiation and un-differentiation processes are not restrained and longitudinal studies are feasible. We used this model for preclinical validation of poly[(d,l-lactide-co-glycolide)-co-PEG] (PLGA-co-PEG) micelles loaded with paclitaxel. Further, active targeting against CD44 and EGFR receptors was validated in breast and colon cancer cell lines. Accordingly, specific active targeting toward surface receptors enhances the performance of nanomedicines and sensitizes CSC to paclitaxel based chemotherapy. Many current cancer therapies fail because of the failure to target cancer stem cells. This surviving population soon proliferates and differentiates into more cancer cells. In this interesting article, the authors designed an in vitro cancer stem cell model to study the effects of active targeting using antibody-labeled micelles containing chemotherapeutic agent. This new model should allow future testing of various drug/carrier platforms before the clinical phase. Copyright © 2015 Elsevier Inc. All rights reserved.

Identification of cells initiating human melanomas

PubMed Central

Schatton, Tobias; Murphy, George F.; Frank, Natasha Y.; Yamaura, Kazuhiro; Waaga-Gasser, Ana Maria; Gasser, Martin; Zhan, Qian; Jordan, Stefan; Duncan, Lyn M.; Weishaupt, Carsten; Fuhlbrigge, Robert C.; Kupper, Thomas S.; Sayegh, Mohamed H.; Frank, Markus H.

2012-01-01

Tumour-initiating cells capable of self-renewal and differentiation, which are responsible for tumour growth, have been identified in human haematological malignancies1,2 and solid cancers3–6. If such minority populations are associated with tumour progression in human patients, specific targeting of tumour-initiating cells could be a strategy to eradicate cancers currently resistant to systemic therapy. Here we identify a subpopulation enriched for human malignant-melanoma-initiating cells (MMIC) defined by expression of the chemoresistance mediator ABCB5 (refs 7, 8) and show that specific targeting of this tumorigenic minority population inhibits tumour growth. ABCB5+ tumour cells detected in human melanoma patients show a primitive molecular phenotype and correlate with clinical melanoma progression. In serial human-to-mouse xenotransplantation experiments, ABCB5+ melanoma cells possess greater tumorigenic capacity than ABCB5− bulk populations and re-establish clinical tumour heterogeneity. In vivo genetic lineage tracking demonstrates a specific capacity of ABCB5+ sub-populations for self-renewal and differentiation, because ABCB5+ cancer cells generate both ABCB5+ and ABCB5− progeny, whereas ABCB5− tumour populations give rise, at lower rates, exclusively to ABCB5− cells. In an initial proof-of-principle analysis, designed to test the hypothesis that MMIC are also required for growth of established tumours, systemic administration of a monoclonal antibody directed at ABCB5, shown to be capable of inducing antibody-dependent cell-mediated cytotoxicity in ABCB5+ MMIC, exerted tumour-inhibitory effects. Identification of tumour-initiating cells with enhanced abundance in more advanced disease but susceptibility to specific targeting through a defining chemoresistance determinant has important implications for cancer therapy. PMID:18202660

A method for evaluating cognitively informed micro-targeted campaign strategies: An agent-based model proof of principle

PubMed Central

Pilditch, Toby D.

2018-01-01

In political campaigns, perceived candidate credibility influences the persuasiveness of messages. In campaigns aiming to influence people’s beliefs, micro-targeted campaigns (MTCs) that target specific voters using their psychological profile have become increasingly prevalent. It remains open how effective MTCs are, notably in comparison to population-targeted campaign strategies. Using an agent-based model, the paper applies recent insights from cognitive models of persuasion, extending them to the societal level in a novel framework for exploring political campaigning. The paper provides an initial treatment of the complex dynamics of population level political campaigning in a psychologically informed manner. Model simulations show that MTCs can take advantage of the psychology of the electorate by targeting voters favourable disposed towards the candidate. Relative to broad campaigning, MTCs allow for efficient and adaptive management of complex campaigns. Findings show that disliked MTC candidates can beat liked population-targeting candidates, pointing to societal questions concerning campaign regulations. PMID:29634722

A method for evaluating cognitively informed micro-targeted campaign strategies: An agent-based model proof of principle.

PubMed

Madsen, Jens Koed; Pilditch, Toby D

2018-01-01

In political campaigns, perceived candidate credibility influences the persuasiveness of messages. In campaigns aiming to influence people's beliefs, micro-targeted campaigns (MTCs) that target specific voters using their psychological profile have become increasingly prevalent. It remains open how effective MTCs are, notably in comparison to population-targeted campaign strategies. Using an agent-based model, the paper applies recent insights from cognitive models of persuasion, extending them to the societal level in a novel framework for exploring political campaigning. The paper provides an initial treatment of the complex dynamics of population level political campaigning in a psychologically informed manner. Model simulations show that MTCs can take advantage of the psychology of the electorate by targeting voters favourable disposed towards the candidate. Relative to broad campaigning, MTCs allow for efficient and adaptive management of complex campaigns. Findings show that disliked MTC candidates can beat liked population-targeting candidates, pointing to societal questions concerning campaign regulations.

Guidelines for integrating population education into primary education and literacy programmes.

PubMed

1989-01-01

In recent seminars and workshops in the Asia and Pacific region the integration of population education into primary schools and literacy programs were the main topics. In most of the countries in this area separate courses in population education appear to be unfeasible for primary and secondary schools. In the nonformal area experience has indicated that population education acquires more meaning and relevance if it is integrated into an ongoing development program. The integration approach requires knowledge of the contents of the accommodating subjects or programs and knowledge of the contents of the accommodating subjects or programs and knowledge of the contents of population education. Guidelines suggested include the following steps in developing an integrated curriculum and instructional materials. First determine the needs, characteristics and other background information needed on the target group. Next prioritize the problems and needs of the target group, and formulate educational objectives from the identified needs and problems. Next determine and sequence the curriculum contents and then determine specific population education objectives and contents for integration, and what specific materials have to be developed. Then identify the specific type of format of materials to be developed, and write the first draft of the material. Also prepare illustrations and other art and graphic materials. Then the draft material should be reviewed and translated into the language of the target audience if needed. The materials should then be pretested, or field tested, using a sample of the intended users. To make sure the materials are reaching the target groups and being used effectively, a user's guide should be prepared and teachers and facilitators, as well as supervisors, should be prepared on the use of the material. In addition, a distribution and utilization plan should be prepared. Nonformal education materials can be distributed through libraries, reading center, residences of village leaders, neighborhood stores, and direct mail. The material distribution and utilization should be monitored and evaluated.

Evaluating a Culturally Tailored HIV Risk Reduction Intervention Among Latina Immigrants in the Farmworker Community.

PubMed

Sanchez, Mariana; Rojas, Patria; Li, Tan; Ravelo, Gira; Cyrus, Elena; Wang, Weize; Kanamori, Mariano; Peragallo, Nilda P; De La Rosa, Mario R

2016-09-01

Latina immigrants in the farmworker community are a vulnerable and understudied population at risk of acquiring HIV. Employing a CBPR framework, this pilot study was the first to evaluate the efficacy of SEPA, a CDC evidenced-based and culturally tailored HIV risk reduction intervention on a cohort of N = 110 predominantly undocumented Latina immigrants in a farmworker community. Findings revealed SEPA was effective in increasing HIV knowledge and decreasing HIV risk behaviors. However, no changes in self-efficacy were found in the present sample. We posit specific socio-cultural and structural barriers specific to the farmworker community not targeted in the original intervention may have hindered the program's capacity to influence changes in self-efficacy among this less acculturated population. Possible socio-cultural adaptations of the intervention to the target population and policy implications are discussed.

Addressing population health and health inequalities: the role of fundamental causes.

PubMed

Cerdá, Magdalena; Tracy, Melissa; Ahern, Jennifer; Galea, Sandro

2014-09-01

As a case study of the impact of universal versus targeted interventions on population health and health inequalities, we used simulations to examine (1) whether universal or targeted manipulations of collective efficacy better reduced population-level rates and racial/ethnic inequalities in violent victimization; and (2) whether experiments reduced disparities without addressing fundamental causes. We applied agent-based simulation techniques to the specific example of an intervention on neighborhood collective efficacy to reduce population-level rates and racial/ethnic inequalities in violent victimization. The agent population consisted of 4000 individuals aged 18 years and older with sociodemographic characteristics assigned to match distributions of the adult population in New York City according to the 2000 U.S. Census. Universal experiments reduced rates of victimization more than targeted experiments. However, neither experiment reduced inequalities. To reduce inequalities, it was necessary to eliminate racial/ethnic residential segregation. These simulations support the use of universal intervention but suggest that it is not possible to address inequalities in health without first addressing fundamental causes.

Identification of cells initiating human melanomas.

PubMed

Schatton, Tobias; Murphy, George F; Frank, Natasha Y; Yamaura, Kazuhiro; Waaga-Gasser, Ana Maria; Gasser, Martin; Zhan, Qian; Jordan, Stefan; Duncan, Lyn M; Weishaupt, Carsten; Fuhlbrigge, Robert C; Kupper, Thomas S; Sayegh, Mohamed H; Frank, Markus H

2008-01-17

Tumour-initiating cells capable of self-renewal and differentiation, which are responsible for tumour growth, have been identified in human haematological malignancies and solid cancers. If such minority populations are associated with tumour progression in human patients, specific targeting of tumour-initiating cells could be a strategy to eradicate cancers currently resistant to systemic therapy. Here we identify a subpopulation enriched for human malignant-melanoma-initiating cells (MMIC) defined by expression of the chemoresistance mediator ABCB5 (refs 7, 8) and show that specific targeting of this tumorigenic minority population inhibits tumour growth. ABCB5+ tumour cells detected in human melanoma patients show a primitive molecular phenotype and correlate with clinical melanoma progression. In serial human-to-mouse xenotransplantation experiments, ABCB5+ melanoma cells possess greater tumorigenic capacity than ABCB5- bulk populations and re-establish clinical tumour heterogeneity. In vivo genetic lineage tracking demonstrates a specific capacity of ABCB5+ subpopulations for self-renewal and differentiation, because ABCB5+ cancer cells generate both ABCB5+ and ABCB5- progeny, whereas ABCB5- tumour populations give rise, at lower rates, exclusively to ABCB5- cells. In an initial proof-of-principle analysis, designed to test the hypothesis that MMIC are also required for growth of established tumours, systemic administration of a monoclonal antibody directed at ABCB5, shown to be capable of inducing antibody-dependent cell-mediated cytotoxicity in ABCB5+ MMIC, exerted tumour-inhibitory effects. Identification of tumour-initiating cells with enhanced abundance in more advanced disease but susceptibility to specific targeting through a defining chemoresistance determinant has important implications for cancer therapy.

12 CFR 1805.802 - Assistance Agreement; sanctions.

Code of Federal Regulations, 2010 CFR

2010-01-01

... internal controls; and/or (4) Achieve specific lending, investment, and development service objectives... TREASURY COMMUNITY DEVELOPMENT FINANCIAL INSTITUTIONS PROGRAM Terms and Conditions of Assistance § 1805.802... Investment Area(s) includes an Indian Reservation or Targeted Population(s) includes an Indian Tribe, the...

Assessing sufficiency of thermal riverscapes for resilient salmon and steelhead populations

EPA Science Inventory

Resilient salmon populations require river networks that provide water temperature regimes sufficient to support a diversity of salmonid life histories across space and time. Efforts to protect, enhance and restore watershed thermal regimes for salmon may target specific location...

Molecular profiling of childhood cancer: Biomarkers and novel therapies.

PubMed

Saletta, Federica; Wadham, Carol; Ziegler, David S; Marshall, Glenn M; Haber, Michelle; McCowage, Geoffrey; Norris, Murray D; Byrne, Jennifer A

2014-06-01

Technological advances including high-throughput sequencing have identified numerous tumor-specific genetic changes in pediatric and adolescent cancers that can be exploited as targets for novel therapies. This review provides a detailed overview of recent advances in the application of target-specific therapies for childhood cancers, either as single agents or in combination with other therapies. The review summarizes preclinical evidence on which clinical trials are based, early phase clinical trial results, and the incorporation of predictive biomarkers into clinical practice, according to cancer type. There is growing evidence that molecularly targeted therapies can valuably add to the arsenal available for treating childhood cancers, particularly when used in combination with other therapies. Nonetheless the introduction of molecularly targeted agents into practice remains challenging, due to the use of unselected populations in some clinical trials, inadequate methods to evaluate efficacy, and the need for improved preclinical models to both evaluate dosing and safety of combination therapies. The increasing recognition of the heterogeneity of molecular causes of cancer favors the continued development of molecularly targeted agents, and their transfer to pediatric and adolescent populations.

The Influence on Population Weight Gain and Obesity of the Macronutrient Composition and Energy Density of the Food Supply.

PubMed

Crino, Michelle; Sacks, Gary; Vandevijvere, Stefanie; Swinburn, Boyd; Neal, Bruce

2015-03-01

Rates of overweight and obesity have increased dramatically in all regions of the world over the last few decades. Almost all of the world's population now has ubiquitous access to low-cost, but highly-processed, energy-dense, nutrient-poor food products. These changes in the food supply, rather than decreases in physical activity, are most likely the primary driver of population weight gain and obesity. To-date, the majority of prevention efforts focus on personalised approaches targeting individuals. Population-wide food supply interventions addressing sodium and trans fat reduction have proven highly effective and comparable efforts are now required to target obesity. The evidence suggests that strategies focusing upon reducing the energy density and portion size of foods will be more effective than those targeting specific macronutrients. Government leadership, clearly specified targets, accountability and transparency will be the key to achieving the food supply changes required to address the global obesity epidemic.

Performance Characteristics of qPCR Assays Targeting Human- and Ruminant-Associated Bacteroidetes for Microbial Source Tracking across Sixteen Countries on Six Continents

PubMed Central

2013-01-01

Numerous quantitative PCR assays for microbial fecal source tracking (MST) have been developed and evaluated in recent years. Widespread application has been hindered by a lack of knowledge regarding the geographical stability and hence applicability of such methods beyond the regional level. This study assessed the performance of five previously reported quantitative PCR assays targeting human-, cattle-, or ruminant-associated Bacteroidetes populations on 280 human and animal fecal samples from 16 countries across six continents. The tested cattle-associated markers were shown to be ruminant-associated. The quantitative distributions of marker concentrations in target and nontarget samples proved to be essential for the assessment of assay performance and were used to establish a new metric for quantitative source-specificity. In general, this study demonstrates that stable target populations required for marker-based MST occur around the globe. Ruminant-associated marker concentrations were strongly correlated with total intestinal Bacteroidetes populations and with each other, indicating that the detected ruminant-associated populations seem to be part of the intestinal core microbiome of ruminants worldwide. Consequently tested ruminant-targeted assays appear to be suitable quantitative MST tools beyond the regional level while the targeted human-associated populations seem to be less prevalent and stable, suggesting potential for improvements in human-targeted methods. PMID:23755882

Molecular beacon-enabled purification of living cells by targeting cell type-specific mRNAs.

PubMed

Wile, Brian M; Ban, Kiwon; Yoon, Young-Sup; Bao, Gang

2014-10-01

Molecular beacons (MBs) are dual-labeled oligonucleotides that fluoresce only in the presence of complementary mRNA. The use of MBs to target specific mRNAs allows sorting of specific cells from a mixed cell population. In contrast to existing approaches that are limited by available surface markers or selectable metabolic characteristics, the MB-based method enables the isolation of a wide variety of cells. For example, the ability to purify specific cell types derived from pluripotent stem cells (PSCs) is important for basic research and therapeutics. In addition to providing a general protocol for MB design, validation and nucleofection into cells, we describe how to isolate a specific cell population from differentiating PSCs. By using this protocol, we have successfully isolated cardiomyocytes differentiated from mouse or human PSCs (hPSCs) with ∼ 97% purity, as confirmed by electrophysiology and immunocytochemistry. After designing MBs, their ordering and validation requires 2 weeks, and the isolation process requires 3 h.

USE OF EXPERT RATINGS AS SAMPLING STRATA FOR A MORE COST-EFFECTIVE PROBABILITY SAMPLE OF A RARE POPULATION

PubMed Central

McCaffrey, Daniel; Perlman, Judith; Marshall, Grant N.; Hambarsoomians, Katrin

2010-01-01

We consider situations in which externally observable characteristics allow experts to quickly categorize individual households as likely or unlikely to contain a member of a rare target population. This classification can form the basis of disproportionate stratified sampling such that households classified as “unlikely” are sampled at a lower rate than those classified as “likely,” thereby reducing screening costs. Design weights account for this approach and allow unbiased estimates for the target population. We demonstrate that with sensitivity and specificity of expert classification at least 70%, and ideally at least 80%, our approach can economically increase effective sample size for a rare population. We develop heuristics for implementing this approach and demonstrate that sensitivity drives design effects and screening costs whereas specificity only drives the latter. We demonstrate that the potential gains from this approach increase as the target population becomes rarer. We further show that for most applications, unlikely strata should be sampled at 1/6 to ½ the rate of likely strata. This approach was applied to a survey of Cambodian immigrants in which the 82% of households rated “unlikely” were sampled at ¼ the rate as “likely” households, reducing screening from 9.4 to 4.0 approaches per complete. Sensitivity and specificity were 86% and 91% respectively. Weighted estimation had a design effect of 1.26 so screening costs per effective sample size were reduced 47%. We also note that in this instance, expert classification appeared to be uncorrelated with survey outcomes of interest among eligibles. PMID:20936050

Teaching about the Big Three-O (300 Million) Using the Internet

ERIC Educational Resources Information Center

Risinger, C. Frederick

2006-01-01

Most researchers and the Census Bureau expect the U.S. population to hit the 300 million mark sometime in October. This will make the United States the world's third most populous nation--behind China and India. In this article, the author found several websites dealing with the specific 300 million target, population growth in general, and…

How does the size and shape of local populations in China compare to general anthropometric surveys currently used for product design?

PubMed

Daniell, Nathan; Fraysse, François; Paul, Gunther

2012-01-01

Anthropometry has long been used for a range of ergonomic applications & product design. Although products are often designed for specific cohorts, anthropometric data are typically sourced from large scale surveys representative of the general population. Additionally, few data are available for emerging markets like China and India. This study measured 80 Chinese males that were representative of a specific cohort targeted for the design of a new product. Thirteen anthropometric measurements were recorded and compared to two large databases that represented a general population, a Chinese database and a Western database. Substantial differences were identified between the Chinese males measured in this study and both databases. The subjects were substantially taller, heavier and broader than subjects in the older Chinese database. However, they were still substantially smaller, lighter and thinner than Western males. Data from current Western anthropometric surveys are unlikely to accurately represent the target population for product designers and manufacturers in emerging markets like China.

The waiting time problem in a model hominin population.

PubMed

Sanford, John; Brewer, Wesley; Smith, Franzine; Baumgardner, John

2015-09-17

Functional information is normally communicated using specific, context-dependent strings of symbolic characters. This is true within the human realm (texts and computer programs), and also within the biological realm (nucleic acids and proteins). In biology, strings of nucleotides encode much of the information within living cells. How do such information-bearing nucleotide strings arise and become established? This paper uses comprehensive numerical simulation to understand what types of nucleotide strings can realistically be established via the mutation/selection process, given a reasonable timeframe. The program Mendel's Accountant realistically simulates the mutation/selection process, and was modified so that a starting string of nucleotides could be specified, and a corresponding target string of nucleotides could be specified. We simulated a classic pre-human hominin population of at least 10,000 individuals, with a generation time of 20 years, and with very strong selection (50% selective elimination). Random point mutations were generated within the starting string. Whenever an instance of the target string arose, all individuals carrying the target string were assigned a specified reproductive advantage. When natural selection had successfully amplified an instance of the target string to the point of fixation, the experiment was halted, and the waiting time statistics were tabulated. Using this methodology we tested the effect of mutation rate, string length, fitness benefit, and population size on waiting time to fixation. Biologically realistic numerical simulations revealed that a population of this type required inordinately long waiting times to establish even the shortest nucleotide strings. To establish a string of two nucleotides required on average 84 million years. To establish a string of five nucleotides required on average 2 billion years. We found that waiting times were reduced by higher mutation rates, stronger fitness benefits, and larger population sizes. However, even using the most generous feasible parameters settings, the waiting time required to establish any specific nucleotide string within this type of population was consistently prohibitive. We show that the waiting time problem is a significant constraint on the macroevolution of the classic hominin population. Routine establishment of specific beneficial strings of two or more nucleotides becomes very problematic.

The Ability of Narrative Communication to Address Health-related Social Norms

PubMed Central

Moran, Meghan Bridgid; Murphy, Sheila T.; Frank, Lauren; Baezconde-Garbanati, Lourdes

2013-01-01

Social norms are an important predictor of health behavior and have been targeted by a variety of health communication campaigns. However, these campaigns often encounter challenges related to the socially specific context in which norms exist: specifically, the extent to which the target population identifies with the reference group presented in the ad and the extent to which the target population believes the campaign's message. We argue that because of its capacity to effect identification among viewers, narrative communication is particularly appropriate for impacting social norms and, consequently, behavioral intention. This manuscript presents the results of a randomized trial testing the effectiveness of two films – one narrative, one non-narrative – in changing perceived social norms and behavioral intention regarding Pap testing to detect cervical cancer. Results of the study indicate that the narrative film was in fact more effective at producing positive changes in perceived norm and intention. PMID:24179677

Genotyping by Sequencing Using Specific Allelic Capture to Build a High-Density Genetic Map of Durum Wheat

PubMed Central

Holtz, Yan; Ardisson, Morgane; Ranwez, Vincent; Besnard, Alban; Leroy, Philippe; Poux, Gérard; Roumet, Pierre; Viader, Véronique; Santoni, Sylvain; David, Jacques

2016-01-01

Targeted sequence capture is a promising technology which helps reduce costs for sequencing and genotyping numerous genomic regions in large sets of individuals. Bait sequences are designed to capture specific alleles previously discovered in parents or reference populations. We studied a set of 135 RILs originating from a cross between an emmer cultivar (Dic2) and a recent durum elite cultivar (Silur). Six thousand sequence baits were designed to target Dic2 vs. Silur polymorphisms discovered in a previous RNAseq study. These baits were exposed to genomic DNA of the RIL population. Eighty percent of the targeted SNPs were recovered, 65% of which were of high quality and coverage. The final high density genetic map consisted of more than 3,000 markers, whose genetic and physical mapping were consistent with those obtained with large arrays. PMID:27171472

The PEPvIII-KLH (CDX-110) vaccine in glioblastoma multiforme patients.

PubMed

Heimberger, Amy B; Sampson, John H

2009-08-01

Conventional therapies for glioblastoma multiforme (GBM) fail to target tumor cells exclusively, resulting in non-specific toxicity. Immune targeting of tumor-specific mutations may allow for more precise eradication of neoplastic cells. EGFR variant III (EGFRvIII) is a tumor-specific mutation that is widely expressed in GBM and other neoplasms and its expression enhances tumorigenicity. This in-frame deletion mutation splits a codon, resulting in a novel glycine at the fusion junction producing a tumor-specific epitope target for cellular or humoral immunotherapy. We have previously shown that vaccination with a peptide that spans the EGFRvIII fusion junction (PEPvIII-KLH/CDX-110) is an efficacious immunotherapy in syngeneic murine models. In this review, we summarize our results in GBM patients targeting this mutation in multiple, multi-institutional Phase II immunotherapy trials. These trials demonstrated that a selected population of GBM patients who received vaccines targeting EGFRvIII had an unexpectedly long survival time. Further therapeutic strategies and potential pitfalls of using this approach are discussed.

Direct profiling of environmental microbial populations by thermal dissociation analysis of native rRNAs hybridized to oligonucleotide microarrays

NASA Technical Reports Server (NTRS)

El Fantroussi, Said; Urakawa, Hidetoshi; Bernhard, Anne E.; Kelly, John J.; Noble, Peter A.; Smidt, H.; Yershov, G. M.; Stahl, David A.

2003-01-01

Oligonucleotide microarrays were used to profile directly extracted rRNA from environmental microbial populations without PCR amplification. In our initial inspection of two distinct estuarine study sites, the hybridization patterns were reproducible and varied between estuarine sediments of differing salinities. The determination of a thermal dissociation curve (i.e., melting profile) for each probe-target duplex provided information on hybridization specificity, which is essential for confirming adequate discrimination between target and nontarget sequences.

Biological control agents elevate hantavirus by subsidizing deer mouse populations.

PubMed

Pearson, Dean E; Callaway, Ragan M

2006-04-01

Biological control of exotic invasive plants using exotic insects is practiced under the assumption that biological control agents are safe if they do not directly attack non-target species. We tested this assumption by evaluating the potential for two host-specific biological control agents (Urophora spp.), widely established in North America for spotted knapweed (Centaurea maculosa) control, to indirectly elevate Sin Nombre hantavirus by providing food subsidies to populations of deer mice (Peromyscus maniculatus), the primary reservoir for the virus. We show that seropositive deer mice (mice testing positive for hantavirus) were over three times more abundant in the presence of the biocontrol food subsidy. Elevating densities of seropositive mice may increase risk of hantavirus infection in humans and significantly alter hantavirus ecology. Host specificity alone does not ensure safe biological control. To minimize indirect risks to non-target species, biological control agents must suppress pest populations enough to reduce their own numbers.

Targeting Neurotrophins to Specific Populations of Neurons: NGF, BDNF, and NT-3 and Their Relevance for Treatment of Spinal Cord Injury

PubMed Central

Keefe, Kathleen M.; Sheikh, Imran S.; Smith, George M.

2017-01-01

Neurotrophins are a family of proteins that regulate neuronal survival, synaptic function, and neurotransmitter release, and elicit the plasticity and growth of axons within the adult central and peripheral nervous system. Since the 1950s, these factors have been extensively studied in traumatic injury models. Here we review several members of the classical family of neurotrophins, the receptors they bind to, and their contribution to axonal regeneration and sprouting of sensory and motor pathways after spinal cord injury (SCI). We focus on nerve growth factor (NGF), brain derived neurotrophic factor (BDNF), and neurotrophin-3 (NT-3), and their effects on populations of neurons within diverse spinal tracts. Understanding the cellular targets of neurotrophins and the responsiveness of specific neuronal populations will allow for the most efficient treatment strategies in the injured spinal cord. PMID:28273811

Targeting Neurotrophins to Specific Populations of Neurons: NGF, BDNF, and NT-3 and Their Relevance for Treatment of Spinal Cord Injury.

PubMed

Keefe, Kathleen M; Sheikh, Imran S; Smith, George M

2017-03-03

Neurotrophins are a family of proteins that regulate neuronal survival, synaptic function, and neurotransmitter release, and elicit the plasticity and growth of axons within the adult central and peripheral nervous system. Since the 1950s, these factors have been extensively studied in traumatic injury models. Here we review several members of the classical family of neurotrophins, the receptors they bind to, and their contribution to axonal regeneration and sprouting of sensory and motor pathways after spinal cord injury (SCI). We focus on nerve growth factor (NGF), brain derived neurotrophic factor (BDNF), and neurotrophin-3 (NT-3), and their effects on populations of neurons within diverse spinal tracts. Understanding the cellular targets of neurotrophins and the responsiveness of specific neuronal populations will allow for the most efficient treatment strategies in the injured spinal cord.

COMPARATIVE DIVERSITY OF FECAL BACTERIA IN AGRICULTURALLY SIGNIFICANT ANIMALS TO IDENTIFY ALTERNATIVE TARGETS FOR MICROBIAL SOURCE TRACKING

EPA Science Inventory

Animals of agricultural significance contribute a large percentage of fecal pollution to waterways via runoff contamination. The premise of microbial source tracking is to utilize fecal bacteria to identify target populations which are directly correlated to specific animal feces...

Targeting and tailoring physical activity information using print and information technologies.

PubMed

Napolitano, Melissa A; Marcus, Bess H

2002-07-01

With the large numbers of physically inactive individuals, it is important that interventions reach a broad spectrum of the population. This paper focuses on targeting and tailoring physical activity information, and the use of mediated interventions, specifically those using print, and other information technologies for promoting physical activity.

Group Cognitive Behavior Therapy Program with Troubled Adolescents: A Learning Experience

ERIC Educational Resources Information Center

Edelman, Sarah; Clin, Louise Remond M.

2005-01-01

Group CBT programs are widely used for assisting teenagers with anxiety, depression and other psychological problems. The majority of reported programs have targeted school or clinical populations however few have specifically targeted adolescents from highly troubled and disadvantaged backgrounds. This paper describes a group CBT program that was…

Caveolin1 Identifies a Specific Subpopulation of Cerebral Cortex Callosal Projection Neurons (CPN) Including Dual Projecting Cortical Callosal/Frontal Projection Neurons (CPN/FPN)

PubMed Central

2018-01-01

Abstract The neocortex is composed of many distinct subtypes of neurons that must form precise subtype-specific connections to enable the cortex to perform complex functions. Callosal projection neurons (CPN) are the broad population of commissural neurons that connect the cerebral hemispheres via the corpus callosum (CC). Currently, how the remarkable diversity of CPN subtypes and connectivity is specified, and how they differentiate to form highly precise and specific circuits, are largely unknown. We identify in mouse that the lipid-bound scaffolding domain protein Caveolin 1 (CAV1) is specifically expressed by a unique subpopulation of Layer V CPN that maintain dual ipsilateral frontal projections to premotor cortex. CAV1 is expressed by over 80% of these dual projecting callosal/frontal projection neurons (CPN/FPN), with expression peaking early postnatally as axonal and dendritic targets are being reached and refined. CAV1 is localized to the soma and dendrites of CPN/FPN, a unique population of neurons that shares information both between hemispheres and with premotor cortex, suggesting function during postmitotic development and refinement of these neurons, rather than in their specification. Consistent with this, we find that Cav1 function is not necessary for the early specification of CPN/FPN, or for projecting to their dual axonal targets. CPN subtype-specific expression of Cav1 identifies and characterizes a first molecular component that distinguishes this functionally unique projection neuron population, a population that expands in primates, and is prototypical of additional dual and higher-order projection neuron subtypes. PMID:29379878

The developing cancer stem-cell model: clinical challenges and opportunities.

PubMed

Vermeulen, Louis; de Sousa e Melo, Felipe; Richel, Dick J; Medema, Jan Paul

2012-02-01

During the past decade, a stem-cell-like subset of cancer cells has been identified in many malignancies. These cells, referred to as cancer stem cells (CSCs), are of particular interest because they are believed to be the clonogenic core of the tumour and therefore represent the cell population that drives growth and progression. Many efforts have been made to design therapies that specifically target the CSC population, since this was predicted to be the crucial population to eliminate. However, recent insights have complicated the initial elegant model, by showing a dominant role for the tumour microenvironment in determining CSC characteristics within a malignancy. This is particularly important since dedifferentiation of non-tumorigenic tumour cells towards CSCs can occur, and therefore the CSC population in a neoplasm is expected to vary over time. Moreover, evidence suggests that not all tumours are driven by rare CSCs, but might instead contain a large population of tumorigenic cells. Even though these results suggest that specific targeting of the CSC population might not be a useful therapeutic strategy, research into the hierarchical cellular organisation of malignancies has provided many important new insights in the biology of tumours. In this Personal View, we highlight how the CSC concept is developing and influences our thinking on future treatment for solid tumours, and recommend ways to design clinical trials to assess drugs that target malignant disease in a rational fashion. Copyright © 2012 Elsevier Ltd. All rights reserved.

Development of germ-line-specific CRISPR-Cas9 systems to improve the production of heritable gene modifications in Arabidopsis

PubMed Central

Mao, Yanfei; Zhang, Zhengjing; Feng, Zhengyan; Wei, Pengliang; Zhang, Hui; Botella, José Ramón; Zhu, Jian-Kang

2017-01-01

Summary The Streptococcus-derived CRISPR/Cas9 system is being widely used to perform targeted gene modifications in plants. This customized endonuclease system has two components, the single-guide RNA (sgRNA) for target DNA recognition and the CRISPR-associated protein 9 (Cas9) for DNA cleavage. Ubiquitously expressed CRISPR/Cas9 systems (UC) generate targeted gene modifications with high efficiency but only those produced in reproductive cells are transmitted to the next generation. We report the design and characterization of a germ-line-specific Cas9 system (GSC) for Arabidopsis gene modification in male gametocytes, constructed using a SPOROCYTELESS (SPL) genomic expression cassette. Four loci in two endogenous genes were targeted by both systems for comparative analysis. Mutations generated by the GSC system were rare in T1 plants but were abundant (30%) in the T2 generation. The vast majority (70%) of the T2 mutant population generated using the UC system were chimeras while the newly developed GSC system produced only 29% chimeras, with 70% of the T2 mutants being heterozygous. Analysis of two loci in the T2 population showed that the abundance of heritable gene mutations was 37% higher in the GSC system compared to the UC system and the level of polymorphism of the mutations was also dramatically increased with the GSC system. Two additional systems based on germ-line-specific promoters (pDD45-GT and pLAT52-GT) were also tested, and one of them was capable of generating heritable homozygous T1 mutant plants. Our results suggest that future application of the described GSC system will facilitate the screening for targeted gene modifications, especially lethal mutations in the T2 population. PMID:26360626

Psychometric Needs Assessment. Theory and Practice.

ERIC Educational Resources Information Center

Scissons, Edward H.

The Psychometric Needs Assessment (PNA) model was designed to provide a means of describing a target population and various sub-populations contained therein. The specific purpose of such description is to provide a guide to determination of the continuing educational programming needs of professionals. Major attributes of the PNA model are the…

Targeted marketing and public health.

PubMed

Grier, Sonya A; Kumanyika, Shiriki

2010-01-01

Targeted marketing techniques, which identify consumers who share common needs or characteristics and position products or services to appeal to and reach these consumers, are now the core of all marketing and facilitate its effectiveness. However, targeted marketing, particularly of products with proven or potential adverse effects (e.g., tobacco, alcohol, entertainment violence, or unhealthful foods) to consumer segments defined as vulnerable raises complex concerns for public health. It is critical that practitioners, academics, and policy makers in marketing, public health, and other fields recognize and understand targeted marketing as a specific contextual influence on the health of children and adolescents and, for different reasons, ethnic minority populations and other populations who may benefit from public health protections. For beneficial products, such understanding can foster more socially productive targeting. For potentially harmful products, understanding the nature and scope of targeted marketing influences will support identification and implementation of corrective policies.

Meditations on birth weight: is it better to reduce the variance or increase the mean?

PubMed

Haig, David

2003-07-01

A conceptual model is presented here in which the birth weight distribution is decomposed into a distribution of target weights and a distribution of perturbations from the target. The target weight is the adaptive goal of fetal development. In the simplest model, perinatal mortality is independent of variation in target weight and determined solely by the magnitude of the perturbation of birth weight from the target. In this model, mortality risk is concentrated in the tails of the birth weight distribution. A difference between populations in their distributions of target weights will be associated with a corresponding shift in their curves of weight-specific risk, without any difference between the populations in overall risk. In this model, risk would be reduced by decreasing the variance of the distribution of perturbations. The model is discussed in the context of the so-called "paradoxes of low birth weight."

Interruption of the Sequential Release of Small and Large Molecules from Tumor Cells by Low Temperature During Cytolysis Mediated by Immune T-Cells or Complement

PubMed Central

Martz, Eric; Burakoff, Steven J.; Benacerraf, Baruj

1974-01-01

Specific lysis of tumor cells by thymus-derived lymphocytes from alloimmunized mice (T-effector specific lysis) was studied with target cells labeled with isotopes attached to both small (14C-labeled nicotinamide) and large (51Cr-labeled) molecules. The results confirm and extend previous reports that target cells release small molecules considerably earlier than large molecules during T-effector specific lysis. After interruption of T-effector specific lysis by specific antibody and complement directed against the killer cells, or by ethylenediaminetetraacetic acid, release of both isotopes continued, eventually reaching identical levels of specific release, the value of which represents the fraction of the target cell population which had been committed to die at the time these treatments were applied. On the other hand, release of both isotopes during T-effector specific lysis stops immediately when the cultures are cooled to 0°. Thus, while ethylenediaminetetraacetic acid or specific complement-mediated lysis of the killer cells merely prevents the initiation of any new damage to target cells, cooling to 0° also stops the lytic process in already-damaged target cells. The colloid osmotic phase of target cell lysis induced by specific antibody and complement was similarly stopped at 0° in tumor cells, but not in erythrocytes. Thus, in tumor target cells, both T-effector specific lysis and complement cause a sequential release of progressively larger molecules which can be immediately stopped at any point by cooling to 0°. PMID:4359327

RchyOptimyx: Cellular Hierarchy Optimization for Flow Cytometry

PubMed Central

Aghaeepour, Nima; Jalali, Adrin; O’Neill, Kieran; Chattopadhyay, Pratip K.; Roederer, Mario; Hoos, Holger H.; Brinkman, Ryan R.

2013-01-01

Analysis of high-dimensional flow cytometry datasets can reveal novel cell populations with poorly understood biology. Following discovery, characterization of these populations in terms of the critical markers involved is an important step, as this can help to both better understand the biology of these populations and aid in designing simpler marker panels to identify them on simpler instruments and with fewer reagents (i.e., in resource poor or highly regulated clinical settings). However, current tools to design panels based on the biological characteristics of the target cell populations work exclusively based on technical parameters (e.g., instrument configurations, spectral overlap, and reagent availability). To address this shortcoming, we developed RchyOptimyx (cellular hieraRCHY OPTIMization), a computational tool that constructs cellular hierarchies by combining automated gating with dynamic programming and graph theory to provide the best gating strategies to identify a target population to a desired level of purity or correlation with a clinical outcome, using the simplest possible marker panels. RchyOptimyx can assess and graphically present the trade-offs between marker choice and population specificity in high-dimensional flow or mass cytometry datasets. We present three proof-of-concept use cases for RchyOptimyx that involve 1) designing a panel of surface markers for identification of rare populations that are primarily characterized using their intracellular signature; 2) simplifying the gating strategy for identification of a target cell population; 3) identification of a non-redundant marker set to identify a target cell population. PMID:23044634

GENERATION OF CYTOTOXIC LYMPHOCYTES IN MIXED LYMPHOCYTE REACTIONS

PubMed Central

Forman, James; Möller, Göran

1973-01-01

Generation of cytotoxic effector cells by a unidirectional mixed lymphocyte reaction (MLR) in the mouse H-2 system was studied using labeled YAC (H-2a) leukemia cells as targets. The responding effector cell displayed a specific cytotoxic effect against target cells of the same H-2 genotype as the stimulating cell population. Killing of syngeneic H-2 cells was not observed, even when the labeled target cells were "innocent bystanders" in cultures where specific target cells were reintroduced. Similar results were found with spleen cells taken from mice sensitized in vivo 7 days earlier. The effector cell was not an adherent cell and was not activated by supernatants from MLR. The supernatants were not cytotoxic by themselves. When concanavalin A or phytohemagglutinin was added to the cytotoxic test system, target and effector cells were agglutinated. Under these conditions, killing of H-2a target cells was observed in mixed cultures where H-2a lymphocytes were also the effector cells. These findings indicate that specifically activated, probably thymus-derived lymphocytes, can kill nonspecifically once they have been activated and providing there is close contact between effector and target cells. Thus, specificity of T cell killing appears to be restricted to recognition and subsequent binding to the targets, the actual effector phase being nonspecific. PMID:4269560

The Resolved Stellar Populations Early Release Science Program

NASA Astrophysics Data System (ADS)

Gilbert, Karoline; Weisz, Daniel; Resolved Stellar Populations ERS Program Team

2018-06-01

The Resolved Stellar Populations Early Release Science Program (PI D. Weisz) will observe Local Group targets covering a range of stellar density and star formation histories, including a globular cluster, and ultra-faint dwarf galaxy, and a star-forming dwarf galaxy. Using observations of these diverse targets we will explore a broad science program: we will measure star formation histories, the sub-solar stellar initial mass function, and proper motions, perform studies of evolved stars, and map extinction in the target fields. Our observations will be of high archival value for other science such as calibrating stellar evolution models, studying variable stars, and searching for metal-poor stars. We will determine optimal observational setups and develop data reduction techniques that will be common to JWST studies of resolved stellar populations. We will also design, test, and release point spread function (PSF) fitting software specific to NIRCam and NIRISS, required for the crowded stellar regime. Prior to the Cycle 2 Call for Proposals, we will release PSF fitting software, matched HST and JWST catalogs, and clear documentation and step-by-step tutorials (such as Jupyter notebooks) for reducing crowded stellar field data and producing resolved stellar photometry catalogs, as well as for specific resolved stellar photometry science applications.

Cambodian Inclusive Education for Vulnerable Populations: Toward an Ecological Perspective Policy

ERIC Educational Resources Information Center

Hackett, Jacob D.; Hudson, Roxanne F.; West, Elizabeth A.; Brown, Sharan E.

2016-01-01

Cambodia is a dynamic country in transition and its population is committed to improve an economic, social, and educational system (Chandler, 2008). An imperial legacy and traumatic history involving a genocide specifically targeted at Cambodian intellectual elite continue to affect Cambodian schools with the most impact being felt by vulnerable…

Adapting the ALP Model for Student and Institutional Needs

ERIC Educational Resources Information Center

Sides, Meredith

2016-01-01

With the increasing adoption of accelerated models of learning comes the necessary step of adapting these models to fit the unique needs of the student population at each individual institution. One such college adapted the ALP (Accelerated Learning Program) model and made specific changes to the target population, structure and scheduling, and…

The PEP-3-KLH (CDX-110) vaccine in glioblastoma multiforme patients

PubMed Central

Heimberger, Amy B.; Sampson, John H

2009-01-01

Conventional therapies for glioblastoma multiforme (GBM) fail to target tumor cells exclusively resulting in non-specific toxicity. Immune targeting of tumor-specific mutations may allow for more precise eradication of neoplastic cells. The epidermal growth factor receptor variant III (EGFRvIII) is a tumor-specific mutation that is widely expressed on GBM and other neoplasms and its expression enhances tumorigenicity. This in-frame deletion mutation splits a codon resulting in a novel glycine at the fusion junction producing a tumor-specific epitope target for cellular or humoral immunotherapy. We have previously shown that vaccination with a peptide that spans the EGFRvIII fusion junction (PEPvIII-KLH/CDX-110) is an efficacious immunotherapy in syngeneic murine models. In this review, we summarize our results in GBM patients targeting this mutation in multiple, multi-institutional Phase II immunotherapy trials. These trials demonstrated that a selected population of GBM patients who received the vaccines targeting EGFRvIII had an unexpectedly long survival time. Further therapeutic strategies and potential pitfalls using this approach are discussed. PMID:19591631

23 CFR 1345.3 - Definitions.

Code of Federal Regulations, 2010 CFR

2010-04-01

..., the District of Columbia, Puerto Rico, the Virgin Islands, Guam, American Samoa or the Commonwealth of... fiscal year beginning after September 30, 2003. Targeted population means a specific group of people...

Quantitative Tracking of Combinatorially Engineered Populations with Multiplexed Binary Assemblies.

PubMed

Zeitoun, Ramsey I; Pines, Gur; Grau, Willliam C; Gill, Ryan T

2017-04-21

Advances in synthetic biology and genomics have enabled full-scale genome engineering efforts on laboratory time scales. However, the absence of sufficient approaches for mapping engineered genomes at system-wide scales onto performance has limited the adoption of more sophisticated algorithms for engineering complex biological systems. Here we report on the development and application of a robust approach to quantitatively map combinatorially engineered populations at scales up to several dozen target sites. This approach works by assembling genome engineered sites with cell-specific barcodes into a format compatible with high-throughput sequencing technologies. This approach, called barcoded-TRACE (bTRACE) was applied to assess E. coli populations engineered by recursive multiplex recombineering across both 6-target sites and 31-target sites. The 31-target library was then tracked throughout growth selections in the presence and absence of isopentenol (a potential next-generation biofuel). We also use the resolution of bTRACE to compare the influence of technical and biological noise on genome engineering efforts.

Targeting cancer stem cell-specific markers and/or associated signaling pathways for overcoming cancer drug resistance.

PubMed

Ranji, Peyman; Salmani Kesejini, Tayyebali; Saeedikhoo, Sara; Alizadeh, Ali Mohammad

2016-10-01

Cancer stem cells (CSCs) are a small subpopulation of tumor cells with capabilities of self-renewal, dedifferentiation, tumorigenicity, and inherent chemo-and-radio therapy resistance. Tumor resistance is believed to be caused by CSCs that are intrinsically challenging to common treatments. A number of CSC markers including CD44, CD133, receptor tyrosine kinase, aldehyde dehydrogenases, epithelial cell adhesion molecule/epithelial specific antigen, and ATP-binding cassette subfamily G member 2 have been proved as the useful targets for defining CSC population in solid tumors. Furthermore, targeting CSC markers through new therapeutic strategies will ultimately improve treatments and overcome cancer drug resistance. Therefore, the identification of novel strategies to increase sensitivity of CSC markers has major clinical implications. This review will focus on the innovative treatment methods such as nano-, immuno-, gene-, and chemotherapy approaches for targeting CSC-specific markers and/or their associated signaling pathways.

Population-specific plasma proteomes of marine and freshwater three-spined sticklebacks (Gasterosteus aculeatus).

PubMed

Kültz, Dietmar; Li, Johnathon; Zhang, Xuezhen; Villarreal, Fernando; Pham, Tuan; Paguio, Darlene

2015-12-01

Molecular phenotypes that distinguish resident marine (Bodega Harbor) from landlocked freshwater (FW, Lake Solano) three-spined sticklebacks were revealed by label-free quantitative proteomics. Secreted plasma proteins involved in lipid transport, blood coagulation, proteolysis, plasminogen-activating cascades, extracellular stimulus responses, and immunity are most abundant in this species. Globulins and albumins are much less abundant than in mammalian plasma. Unbiased quantitative proteome profiling identified 45 highly population-specific plasma proteins. Population-specific abundance differences were validated by targeted proteomics based on data-independent acquisition. Gene ontology enrichment analyses and known functions of population-specific plasma proteins indicate enrichment of processes controlling cell adhesion, tissue remodeling, proteolytic processing, and defense signaling in marine sticklebacks. Moreover, fetuin B and leukocyte cell derived chemotaxin 2 are much more abundant in marine fish. These proteins promote bone morphogenesis and likely contribute to population-specific body armor differences. Plasma proteins enriched in FW fish promote translation, heme biosynthesis, and lipid transport, suggesting a greater presence of plasma microparticles. Many prominent population-specific plasma proteins (e.g. apoptosis-associated speck-like protein containing a CARD) lack any homolog of known function or adequate functional characterization. Their functional characterization and the identification of population-specific environmental contexts and selective pressures that cause plasma proteome diversification are future directions emerging from this study. © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Microselection – affinity selecting antibodies against a single rare cell in a heterogeneous population

PubMed Central

Sørensen, Morten Dræby; Agerholm, Inge Errebo; Christensen, Britta; Kølvraa, Steen; Kristensen, Peter

2010-01-01

Abstract Rare cells not normally present in the peripheral bloodstream, such as circulating tumour cells, have potential applications for development of non-invasive methods for diagnostics or follow up. Obtaining these cells however require some means of discrimination, achievable by cell type specific antibodies. Here we have generated a microselection method allowing antibody selection, by phage display, targeting a single cell in a heterogeneous population. One K562 cell (female origin) was positioned on glass slide among millions of lymphocytes from male donor, identifying the K562 cell by FISH (XX). Several single cell selections were performed on such individual slides. The phage particles bound to the target cell is protected by a minute disc, while inactivating all remaining phage by UV-irradiation; leaving only the phage bound to the target cell viable. We hereby retrieved up to eight antibodies per single cell selection, including three highly K562 cell type specific. PMID:20726925

Considering the needs of English language learner populations: an examination of the population validity of reading intervention research.

PubMed

Moore, Brooke A; Klingner, Janette K

2014-01-01

This article synthesizes reading intervention research studies intended for use with struggling or at-risk students to determine which studies adequately address population validity, particularly in regard to the diverse reading needs of English language learners. An extensive search of the professional literature between 2001 and 2010 yielded a total of 67 reading intervention studies targeting at-risk elementary students. Findings revealed that many current research studies fail to adequately describe the sample, including the accessible and target populations, and to disaggregate their findings based on demographic characteristics. When population validity issues are not addressed, researchers cannot generalize findings to other populations of students, and it becomes unclear what intervention strategies work, especially with English language learner student populations. However, 25 studies did specifically recognize and address the needs of English language learners, indicating more researchers are taking into consideration the diverse needs of other struggling student populations. © Hammill Institute on Disabilities 2012.

Therapeutic Effectiveness of Anticancer Phytochemicals on Cancer Stem Cells

PubMed Central

Oh, Jisun; Hlatky, Lynn; Jeong, Yong-Seob; Kim, Dohoon

2016-01-01

Understanding how to target cancer stem cells (CSCs) may provide helpful insights for the development of therapeutic or preventive strategies against cancers. Dietary phytochemicals with anticancer properties are promising candidates and have selective impact on CSCs. This review summarizes the influence of phytochemicals on heterogeneous cancer cell populations as well as on specific targeting of CSCs. PMID:27376325

A Study of the Impacts of Navigational Links, Task Complexity, and Experience with the Older User on Website Usability in a Community College Domain

ERIC Educational Resources Information Center

Garrett, Robin Eileen

2014-01-01

Community colleges serve a diverse population of learners including many older students counting on the community college for enhanced skills or personal enrichment. Many of these colleges target this population with programs designed specifically to meet the needs and goals of the older adult but may not consider this population when designing a…

Modeling health gains and cost savings for ten dietary salt reduction targets.

PubMed

Wilson, Nick; Nghiem, Nhung; Eyles, Helen; Mhurchu, Cliona Ni; Shields, Emma; Cobiac, Linda J; Cleghorn, Christine L; Blakely, Tony

2016-04-26

Dietary salt reduction is included in the top five priority actions for non-communicable disease control internationally. We therefore aimed to identify health gain and cost impacts of achieving a national target for sodium reduction, along with component targets in different food groups. We used an established dietary sodium intervention model to study 10 interventions to achieve sodium reduction targets. The 2011 New Zealand (NZ) adult population (2.3 million aged 35+ years) was simulated over the remainder of their lifetime in a Markov model with a 3 % discount rate. Achieving an overall 35 % reduction in dietary salt intake via implementation of mandatory maximum levels of sodium in packaged foods along with reduced sodium from fast foods/restaurant food and discretionary intake (the "full target"), was estimated to gain 235,000 QALYs over the lifetime of the cohort (95 % uncertainty interval [UI]: 176,000 to 298,000). For specific target components the range was from 122,000 QALYs gained (for the packaged foods target) down to the snack foods target (6100 QALYs; and representing a 34-48 % sodium reduction in such products). All ten target interventions studied were cost-saving, with the greatest costs saved for the mandatory "full target" at NZ$1260 million (US$820 million). There were relatively greater health gains per adult for men and for Māori (indigenous population). This work provides modeling-level evidence that achieving dietary sodium reduction targets (including specific food category targets) could generate large health gains and cost savings for a national health sector. Demographic groups with the highest cardiovascular disease rates stand to gain most, assisting in reducing health inequalities between sex and ethnic groups.

Evidence for label-retaining tumour-initiating cells in human glioblastoma

PubMed Central

Deleyrolle, Loic P.; Harding, Angus; Cato, Kathleen; Siebzehnrubl, Florian A.; Rahman, Maryam; Azari, Hassan; Olson, Sarah; Gabrielli, Brian; Osborne, Geoffrey; Vescovi, Angelo

2011-01-01

Individual tumour cells display diverse functional behaviours in terms of proliferation rate, cell–cell interactions, metastatic potential and sensitivity to therapy. Moreover, sequencing studies have demonstrated surprising levels of genetic diversity between individual patient tumours of the same type. Tumour heterogeneity presents a significant therapeutic challenge as diverse cell types within a tumour can respond differently to therapies, and inter-patient heterogeneity may prevent the development of general treatments for cancer. One strategy that may help overcome tumour heterogeneity is the identification of tumour sub-populations that drive specific disease pathologies for the development of therapies targeting these clinically relevant sub-populations. Here, we have identified a dye-retaining brain tumour population that displays all the hallmarks of a tumour-initiating sub-population. Using a limiting dilution transplantation assay in immunocompromised mice, label-retaining brain tumour cells display elevated tumour-initiation properties relative to the bulk population. Importantly, tumours generated from these label-retaining cells exhibit all the pathological features of the primary disease. Together, these findings confirm dye-retaining brain tumour cells exhibit tumour-initiation ability and are therefore viable targets for the development of therapeutics targeting this sub-population. PMID:21515906

Host specificity of microsporidia pathogenic to the gypsy moth, Lymantria dispar (L.): Field studies in Slovakia

Treesearch

Leellen F. Solter; Daniela K. Pilarska; Michael L. McManus; Milan Zubrik; Jan Patocka; Wei-Fone Huang; Julius Novotny

2010-01-01

Several species of microsporidia are important chronic pathogens of Lymantria dispar in Europe but have never been recovered from North American gypsy moth populations. The major issue for their introduction into North American L. dispar populations is concern about their safety to native non-target insects. In this study, we...

A novel method for evaluating antibody-dependent cell-mediated cytotoxicity by flowcytometry using cryopreserved human peripheral blood mononuclear cells

PubMed Central

Yamashita, Makiko; Kitano, Shigehisa; Aikawa, Hiroaki; Kuchiba, Aya; Hayashi, Mitsuhiro; Yamamoto, Noboru; Tamura, Kenji; Hamada, Akinobu

2016-01-01

Analyzing the cytotoxic functions of effector cells, such as NK cells against target cancer cells, is thought to be necessary for predicting the clinical efficacy of antibody-dependent cellular cytotoxicity (ADCC) -dependent antibody therapy. The 51Cr release assay has long been the most widely used method for quantification of ADCC activity. However, the reproducibilities of these release assays are not adequate, and they do not allow evaluation of the lysis susceptibilities of distinct cell types within the target cell population. In this study, we established a novel method for evaluating cytotoxicity, which involves the detection and quantification of dead target cells using flowcytometry. CFSE (carboxyfluorescein succinimidyl ester) was used as a dye to specifically stain and thereby label the target cell population, allowing living and dead cells, as well as both target and effector cells, to be quantitatively distinguished. Furthermore, with our new approach, ADCC activity was more reproducibly, sensitively, and specifically detectable, not only in freshly isolated but also in frozen human peripheral blood mononuclear cells (PBMCs), than with the calcein-AM release assay. This assay, validated herein, is expected to become a standard assay for evaluating ADCC activity which will ultimately contribute the clinical development of ADCC dependent-antibody therapies. PMID:26813960

A novel method for evaluating antibody-dependent cell-mediated cytotoxicity by flowcytometry using cryopreserved human peripheral blood mononuclear cells.

PubMed

Yamashita, Makiko; Kitano, Shigehisa; Aikawa, Hiroaki; Kuchiba, Aya; Hayashi, Mitsuhiro; Yamamoto, Noboru; Tamura, Kenji; Hamada, Akinobu

2016-01-27

Analyzing the cytotoxic functions of effector cells, such as NK cells against target cancer cells, is thought to be necessary for predicting the clinical efficacy of antibody-dependent cellular cytotoxicity (ADCC) -dependent antibody therapy. The (51)Cr release assay has long been the most widely used method for quantification of ADCC activity. However, the reproducibilities of these release assays are not adequate, and they do not allow evaluation of the lysis susceptibilities of distinct cell types within the target cell population. In this study, we established a novel method for evaluating cytotoxicity, which involves the detection and quantification of dead target cells using flowcytometry. CFSE (carboxyfluorescein succinimidyl ester) was used as a dye to specifically stain and thereby label the target cell population, allowing living and dead cells, as well as both target and effector cells, to be quantitatively distinguished. Furthermore, with our new approach, ADCC activity was more reproducibly, sensitively, and specifically detectable, not only in freshly isolated but also in frozen human peripheral blood mononuclear cells (PBMCs), than with the calcein-AM release assay. This assay, validated herein, is expected to become a standard assay for evaluating ADCC activity which will ultimately contribute the clinical development of ADCC dependent-antibody therapies.

Development and evaluation of a university campus-based food safety media campaign for young adults.

PubMed

Abbot, Jaclyn Maurer; Policastro, Peggy; Bruhn, Christine; Schaffner, Donald W; Byrd-Bredbenner, Carol

2012-06-01

Food safety information campaigns are more likely to be most effective if the messages are tailored to the needs of a specific audience. Designing effective campaigns involves careful study of the target population and working with them using a community-based participatory research model. Thus, the development of the campaign materials for a university campus-based food safety media campaign for young adults followed intense efforts of working with the target audience to gather the baseline data needed to characterize this audience, to identify the most salient messages for college students, and to create materials and events that would resonate with them. This campaign was implemented and evaluated on eight university campuses in the United States. The results indicate that the campaign significantly increased self-ratings of food safety knowledge and skill, actual food safety knowledge, food safety self-efficacy, stage of change for safe food handling, and reported hand washing behaviors of a geographically and racially diverse group of college students. The positive study outcomes support the value of engaging in these research and development efforts and reflect the usefulness of the audience-specific materials and activities developed for the campaign. The findings also demonstrate the versatility and utility of the materials on different campuses. Developing health media campaigns specifically for unique populations is key to ensuring health messages reach the target audience and, even more importantly, appeal to them. The detailed overview of the development of a food safety media campaign aimed at young adults presented in this article illustrates how health professionals can work with their target population to develop a focused, effective health promotion campaign.

Development of a real-time PCR assay for monitoring anaerobic fungal and cellulolytic bacterial populations within the rumen.

PubMed

Denman, Stuart E; McSweeney, Christopher S

2006-12-01

Traditional methods for enumerating and identifying microbial populations within the rumen can be time consuming and cumbersome. Methods that involve culturing and microscopy can also be inconclusive, particularly when studying anaerobic rumen fungi. A real-time PCR SYBR Green assay, using PCR primers to target total rumen fungi and the cellulolytic bacteria Ruminococcus flavefaciens and Fibrobacter succinogenes, is described, including design and validation. The DNA and crude protein contents with respect to the fungal biomass of both polycentric and monocentric fungal isolates were investigated across the fungal growth stages to aid in standard curve generation. The primer sets used were found to be target specific with no detectable cross-reactivity. Subsequently, the real-time PCR assay was employed in a study to detect these populations within cattle rumen. The anaerobic fungal target was observed to increase 3.6-fold from 0 to 12 h after feeding. The results also indicated a 5.4-fold increase in F. succinogenes target between 0 and 12 h after feeding, whereas R. flavefaciens was observed to maintain more or less consistent levels. This is the first report of a real-time PCR assay to estimate the rumen anaerobic fungal population.

Personalized gene silencing therapeutics for Huntington disease.

PubMed

Kay, C; Skotte, N H; Southwell, A L; Hayden, M R

2014-07-01

Gene silencing offers a novel therapeutic strategy for dominant genetic disorders. In specific diseases, selective silencing of only one copy of a gene may be advantageous over non-selective silencing of both copies. Huntington disease (HD) is an autosomal dominant disorder caused by an expanded CAG trinucleotide repeat in the Huntingtin gene (HTT). Silencing both expanded and normal copies of HTT may be therapeutically beneficial, but preservation of normal HTT expression is preferred. Allele-specific methods can selectively silence the mutant HTT transcript by targeting either the expanded CAG repeat or single nucleotide polymorphisms (SNPs) in linkage disequilibrium with the expansion. Both approaches require personalized treatment strategies based on patient genotypes. We compare the prospect of safe treatment of HD by CAG- and SNP-specific silencing approaches and review HD population genetics used to guide target identification in the patient population. Clinical implementation of allele-specific HTT silencing faces challenges common to personalized genetic medicine, requiring novel solutions from clinical scientists and regulatory authorities. © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Modelling the dynamics of feral alfalfa populations and its management implications.

PubMed

Bagavathiannan, Muthukumar V; Begg, Graham S; Gulden, Robert H; Van Acker, Rene C

2012-01-01

Feral populations of cultivated crops can pose challenges to novel trait confinement within agricultural landscapes. Simulation models can be helpful in investigating the underlying dynamics of feral populations and determining suitable management options. We developed a stage-structured matrix population model for roadside feral alfalfa populations occurring in southern Manitoba, Canada. The model accounted for the existence of density-dependence and recruitment subsidy in feral populations. We used the model to investigate the long-term dynamics of feral alfalfa populations, and to evaluate the effectiveness of simulated management strategies such as herbicide application and mowing in controlling feral alfalfa. Results suggest that alfalfa populations occurring in roadside habitats can be persistent and less likely to go extinct under current roadverge management scenarios. Management attempts focused on controlling adult plants alone can be counterproductive due to the presence of density-dependent effects. Targeted herbicide application, which can achieve complete control of seedlings, rosettes and established plants, will be an effective strategy, but the seedbank population may contribute to new recruits. In regions where roadside mowing is regularly practiced, devising a timely mowing strategy (early- to mid-August for southern Manitoba), one that can totally prevent seed production, will be a feasible option for managing feral alfalfa populations. Feral alfalfa populations can be persistent in roadside habitats. Timely mowing or regular targeted herbicide application will be effective in managing feral alfalfa populations and limit feral-population-mediated gene flow in alfalfa. However, in the context of novel trait confinement, the extent to which feral alfalfa populations need to be managed will be dictated by the tolerance levels established by specific production systems for specific traits. The modelling framework outlined in this paper could be applied to other perennial herbaceous plants with similar life-history characteristics.

Population studies of Glossina pallidipes in Ethiopia: emphasis on cuticular hydrocarbons and wing morphometric analysis.

PubMed

Getahun, M N; Cecchi, G; Seyoum, E

2014-10-01

Tsetse flies, like many insects, use pheromones for inter- and intra-specific communication. Several of their pheromones are cuticular hydrocarbons (CHCs) that are perceived by contact at close range. We hypothesized that for a successful implementation of the Sterile Insect Technique (SIT), along with proper identification of target area and target species, the target tsetse populations and the sterile flies must chemically communicate with each other. To study the population structuring of Glossina pallidipes in Ethiopia, CHCs were extracted and analyzed from three tsetse belts. As a comparative approach, wing morphometric analysis was performed. The analysis of the relative abundance of CHCs revealed that populations of G. pallidipes from the Rift Valley tsetse belt showed a distinct clustering compared to populations from the other two belts. The spatial pattern of CHC differences was complemented by the wing morphometric analysis. Our data suggest that CHCs of known biological and ecological role, when combined with wing morphometric data, will provide an alternative means for the study of population structuring of Glossina populations. This could aid the planning of area wide control strategies using SIT, which is dependent on sexual competence. Copyright © 2014 International Atomic Energy Agency 2014. Published by Elsevier B.V. All rights reserved.

Development of germ-line-specific CRISPR-Cas9 systems to improve the production of heritable gene modifications in Arabidopsis.

PubMed

Mao, Yanfei; Zhang, Zhengjing; Feng, Zhengyan; Wei, Pengliang; Zhang, Hui; Botella, José Ramón; Zhu, Jian-Kang

2016-02-01

The Streptococcus-derived CRISPR/Cas9 system is being widely used to perform targeted gene modifications in plants. This customized endonuclease system has two components, the single-guide RNA (sgRNA) for target DNA recognition and the CRISPR-associated protein 9 (Cas9) for DNA cleavage. Ubiquitously expressed CRISPR/Cas9 systems (UC) generate targeted gene modifications with high efficiency but only those produced in reproductive cells are transmitted to the next generation. We report the design and characterization of a germ-line-specific Cas9 system (GSC) for Arabidopsis gene modification in male gametocytes, constructed using a SPOROCYTELESS (SPL) genomic expression cassette. Four loci in two endogenous genes were targeted by both systems for comparative analysis. Mutations generated by the GSC system were rare in T1 plants but were abundant (30%) in the T2 generation. The vast majority (70%) of the T2 mutant population generated using the UC system were chimeras while the newly developed GSC system produced only 29% chimeras, with 70% of the T2 mutants being heterozygous. Analysis of two loci in the T2 population showed that the abundance of heritable gene mutations was 37% higher in the GSC system compared to the UC system and the level of polymorphism of the mutations was also dramatically increased with the GSC system. Two additional systems based on germ-line-specific promoters (pDD45-GT and pLAT52-GT) were also tested, and one of them was capable of generating heritable homozygous T1 mutant plants. Our results suggest that future application of the described GSC system will facilitate the screening for targeted gene modifications, especially lethal mutations in the T2 population. © 2015 Society for Experimental Biology, Association of Applied Biologists and John Wiley & Sons Ltd.

Targeting of MPEG-protected polyamino acid carrier to human E-selectin in vitro.

PubMed

Kang, H W; Weissleder, R; Bogdanov, A

2002-01-01

Targeted diagnostic agents are expected to have a significant impact in molecular imaging of cell-surface associated markers of proliferation, inflammation and angiogenesis. In this communication, we describe a new class of targeted polyamino acid-based protected graft copolymers (PGC) of poly-(L-lysine) and methyl poly-(ethylene glycol) (PGC) covalently conjugated with a monoclonal antibody fragment, F(ab')(2). We utilized targeted PGC conjugates as carriers of near-infrared indocyanine fluorophores (Cy5.5) for optical imaging of endothelial cell populations expressing IL-1 beta inducible proinflammatory marker E-selectin. We compared two conjugation chemistries, involving either introduction of sulfhydryl group to F(ab')(2), or via direct attachment of the antibody fragment directly to the chemically activated PGC. Both PGC-based targeted agents demonstrated high binding specificity (20-30 fold over non-specific uptake) and were utilized for imaging E-selectin expression on human endothelial cells activated with IL-1 beta.

Questionable Specificity of Genetic Total Faecal Pollution Markers for Integrated Water Quality Monitoring and Source Tracking

NASA Astrophysics Data System (ADS)

Vierheilig, Julia; Reischer, Georg H.; Farnleitner, Andreas H.

2010-05-01

Characterisation of microbial faecal hazards in water is a fundamental aspect for target-orientated water resources management to achieve appropriate water quality for various purposes like water supply or agriculture and thus to minimize related health risks. Nowadays the management of water resources increasingly demands detailed knowledge on the extent and the origin of microbial pollution. Cultivation of standard faecal indicator bacteria, which has been used for over a century to test the microbiological water quality, cannot sufficiently meet these challenges. The abundant intestinal bacterial populations are very promising alternative targets for modern faecal indication systems. Numerous assays for the detection of genetic markers targeting source-specific populations of the phylum Bacteroidetes have been developed in recent years. In some cases markers for total faecal pollution were also proposed in order to relate source-specific marker concentrations to general faecal pollution levels. However, microbial populations in intestinal and non-intestinal systems exhibit a dazzling array of diversity and molecular analysis of microbial faecal pollution has been based on a fragmentary puzzle of very limited sequence information. The aim of this study was to test the available qPCR-based methods detecting genetic Bacteroidetes markers for total faecal pollution in terms of their value and specificity as indicators of faecal pollution. We applied the AllBac (Layton et al., 2006) the BacUni (Kildare et al., 2007) and the Bacteroidetes (Dick and Field, 2004) assays on soil DNA samples. Samples were collected in well characterised karst spring catchments in Austria's Eastern Calcareous Alps. They were at various levels of altitude between 800 and 1800 meters above sea level and from several different habitats (woodland, alpine pastures, krummholz). In addition we tried to choose sampling sites representing a presumptive gradient of faecal pollution levels. For example sites with obvious faecal influence (e.g. right next to a cowpat) were included as well as more pristine sites without faecal influence from large animals (e.g. fenced areas). Surprisingly, results from investigations with the AllBac assay showed concentrations of the total faecal marker in soil in the range of 106 to 109 Marker Equivalents per g of soil, which is equal or only slightly lower than the concentrations of this particular marker in faeces or raw sewage. Preliminary results from the other tested assays seem to confirm that the targeted markers are also highly abundant in soils. In addition, the markers were present in comparable concentrations in soils from pristine locations as well as in soils under the potential influence of faeces giving a strong indication that these methods also target non-intestinal, autochthonous soil populations. In contrast, source-specific markers (ruminant-specific BacR and human-specific BacH, Reischer et al., 2007, 2006) could only be detected in 30 to 50% of the soil samples at concentrations close to the detection limit, which is at least four orders of magnitude lower than in faecal samples of the respective target sources, ruminant animals and humans. The achieved results call the applicability of the proposed qPCR-based assays for total faecal pollution into question. In fact the assays do not seem to be specific for intestinal Bacteroidetes populations at all and the respective marker concentration levels in pristine soils negate their applicability in the investigated areas. This study also emphasizes the need to test the specificity and sensitivity of qPCR-based assays for total faecal pollution on the local level and especially against non-intestinal environmental samples, which might contribute to marker levels in the aquatic compartment. In conclusion there is a strong demand for marker-based detection techniques for total faecal pollution in water quality monitoring and risk assessment but currently none of the tested assays seems to meet the methodical requirements.

Molecular Diversity of Bacteroidales in Fecal and Environmental Samples and Swine-Associated Subpopulations

PubMed Central

Lamendella, Regina; Li, Kent C.; Oerther, Daniel

2013-01-01

Several swine-specific microbial source tracking methods are based on PCR assays targeting Bacteroidales 16S rRNA gene sequences. The limited application of these assays can be explained by the poor understanding of their molecular diversity in fecal sources and environmental waters. In order to address this, we studied the diversity of 9,340 partial (>600 bp in length) Bacteroidales 16S rRNA gene sequences from 13 fecal sources and nine feces-contaminated watersheds. The compositions of major Bacteroidales populations were analyzed to determine which host and environmental sequences were contributing to each group. This information allowed us to identify populations which were both exclusive to swine fecal sources and detected in swine-contaminated waters. Phylogenetic and diversity analyses revealed that some markers previously believed to be highly specific to swine populations are shared by multiple hosts, potentially explaining the cross-amplification signals obtained with nontargeted hosts. These data suggest that while many Bacteroidales populations are cosmopolitan, others exhibit a preferential host distribution and may be able to survive different environmental conditions. This study further demonstrates the importance of elucidating the diversity patterns of targeted bacterial groups to develop more inclusive fecal source tracking applications. PMID:23160126

The genomic landscape of rapid repeated evolutionary ...

EPA Pesticide Factsheets

Atlantic killifish populations have rapidly adapted to normally lethal levels of pollution in four urban estuaries. Through analysis of 384 whole killifish genome sequences and comparative transcriptomics in four pairs of sensitive and tolerant populations, we identify the aryl hydrocarbon receptor–based signaling pathway as a shared target of selection. This suggests evolutionary constraint on adaptive solutions to complex toxicant mixtures at each site. However, distinct molecular variants apparently contribute to adaptive pathway modification among tolerant populations. Selection also targets other toxicity-mediatinggenes and genes of connected signaling pathways; this indicates complex tolerance phenotypes and potentially compensatory adaptations. Molecular changes are consistent with selection on standing genetic variation. In killifish, high nucleotide diversityhas likely been a crucial substrate for selective sweeps to propel rapid adaptation. This manuscript describes genomic evaluations that contribute to our understanding of the ecological and evolutionary risks associated with chronic contaminant exposures to wildlife populations. Here, we assessed genetic patterns associated with long-term response to an important class of highly toxic environmental pollutants. Specifically, chemical-specific tolerance has rapidly and repeatedly evolved in an estuarine fish species resident to estuaries of the Atlantic U.S. coast. We used laboratory studies to ch

Osteoporosis in older persons: current pharmacotherapy and future directions.

PubMed

Duque, Gustavo

2013-10-01

Osteopororic fractures are highly prevalent in older persons having catastrophic consequences in their quality of life and increasing disability and mortality in this population. The mechanisms of osteoporosis in older persons are unique in terms of cellular changes and response to osteoporosis treatment. Therefore, specifically targeted treatments are required in this particular population. This paper provides an overview on the particular mechanisms of osteoporosis in older persons and the current and future therapeutic strategies to improve bone mass and prevent fractures in this population. Osteoporosis in older persons (especially in the old-old) has a unique pathophysiology that predisposes them to fractures thus having catastrophic consequences. Identification of patients at risk followed by therapies targeted to their cellular changes is pivotal to close the care gap observed in osteoporosis, predominantly in the older population. The treatment of osteoporosis has evolved from daily to yearly dosing thus facilitating compliance and effectiveness. It is expected that future biologically targeted treatments will have a similar separate dosing regime with better anti-fracture efficacy and lower incidence of side effects.

Evidence of weak genetic structure and recent gene flow between Bactrocera dorsalis s.s. and B. papayae, across Southern Thailand and West Malaysia, supporting a single target pest for SIT applications

PubMed Central

2014-01-01

Background Bactrocera dorsalis s.s. (Hendel) and B. papayae Drew & Hancock, are invasive pests belonging to the B. dorsalis complex. Their species status, based on morphology, is sometimes arguable. Consequently, the existence of cryptic species and/or population isolation may decrease the effectiveness of the sterile insect technique (SIT) due to an unknown degree of sexual isolation between released sterile flies and wild counterparts. To evaluate the genetic relationship and current demography in wild populations for guiding the application of area-wide integrated pest management using SIT, seven microsatellite-derived markers from B. dorsalis s.s. and another five from B. papayae were used for surveying intra- and inter-specific variation, population structure, and recent migration among sympatric and allopatric populations of the two morphological forms across Southern Thailand and West Malaysia. Results Basic genetic variations were not significantly different among forms, populations, and geographical areas (P > 0.05). Nonetheless, two sets of microsatellite markers showed significantly different levels of polymorphisms. Genetic differentiation between intra- and inter-specific differences was significant, but low. Seventeen populations revealed three hypothetical genetic clusters (K = 3) regardless of forms and geographical areas. The genetic structure of sympatric populations slightly changed during the different years of collection. Recent gene flow (m ≥ 0.10) was frequently detected whether samples were sympatric or allopatric. Ninety-five of 379 individuals distributed across the given area were designated as recent migrants or of admixed ancestry. As a consequence of substantial migration, no significant correlation between genetic and geographic distances was detected (R2 = 0.056, P = 0.650). Conclusions According to the 12 microsatellite variations, weak population structure and recent gene flow suggest that there is no status for cryptic species between B. dorsalis s.s. and B. papayae forms in Southern Thailand and West Malaysia. Both forms can be treated as a single target pest for the SIT program in an area-wide sense. Additionally, the result of species identification based on molecular data and morphological character are not congruent. The use of independent, multiple approaches in the characterization of the target population may ensure the effectiveness and feasibility of SIT-based control in the target area. PMID:24929425

Evidence of weak genetic structure and recent gene flow between Bactrocera dorsalis s.s. and B. papayae, across Southern Thailand and West Malaysia, supporting a single target pest for SIT applications.

PubMed

Aketarawong, Nidchaya; Isasawin, Siriwan; Thanaphum, Sujinda

2014-06-14

Bactrocera dorsalis s.s. (Hendel) and B. papayae Drew & Hancock, are invasive pests belonging to the B. dorsalis complex. Their species status, based on morphology, is sometimes arguable. Consequently, the existence of cryptic species and/or population isolation may decrease the effectiveness of the sterile insect technique (SIT) due to an unknown degree of sexual isolation between released sterile flies and wild counterparts. To evaluate the genetic relationship and current demography in wild populations for guiding the application of area-wide integrated pest management using SIT, seven microsatellite-derived markers from B. dorsalis s.s. and another five from B. papayae were used for surveying intra- and inter-specific variation, population structure, and recent migration among sympatric and allopatric populations of the two morphological forms across Southern Thailand and West Malaysia. Basic genetic variations were not significantly different among forms, populations, and geographical areas (P > 0.05). Nonetheless, two sets of microsatellite markers showed significantly different levels of polymorphisms. Genetic differentiation between intra- and inter-specific differences was significant, but low. Seventeen populations revealed three hypothetical genetic clusters (K = 3) regardless of forms and geographical areas. The genetic structure of sympatric populations slightly changed during the different years of collection. Recent gene flow (m ≥ 0.10) was frequently detected whether samples were sympatric or allopatric. Ninety-five of 379 individuals distributed across the given area were designated as recent migrants or of admixed ancestry. As a consequence of substantial migration, no significant correlation between genetic and geographic distances was detected (R2 = 0.056, P = 0.650). According to the 12 microsatellite variations, weak population structure and recent gene flow suggest that there is no status for cryptic species between B. dorsalis s.s. and B. papayae forms in Southern Thailand and West Malaysia. Both forms can be treated as a single target pest for the SIT program in an area-wide sense. Additionally, the result of species identification based on molecular data and morphological character are not congruent. The use of independent, multiple approaches in the characterization of the target population may ensure the effectiveness and feasibility of SIT-based control in the target area.

Electrochemical branched-DNA assay for polymerase chain reaction-free detection and quantification of oncogenes in messenger RNA.

PubMed

Lee, Ai-Cheng; Dai, Ziyu; Chen, Baowei; Wu, Hong; Wang, Jun; Zhang, Aiguo; Zhang, Lurong; Lim, Tit-Meng; Lin, Yuehe

2008-12-15

We describe a novel electrochemical branched-DNA (bDNA) assay for polymerase chain reaction (PCR)-free detection and quantification of p185 BCR-ABL leukemia fusion transcripts in the population of messenger ribonucleic acid (mRNA) extracted from cell lines. The bDNA amplifier carrying high loading of alkaline phosphatase (ALP) tracers was used to amplify the target signal. The targets were captured on microplate well surfaces through cooperative sandwich hybridization prior to the labeling of bDNA. The activity of captured ALP was monitored by square-wave voltammetric (SWV) analysis of the electroactive enzymatic product in the presence of 1-naphthyl phosphate. The voltammetric characteristics of substrate and enzymatic product as well as the parameters of SWV analysis were systematically optimized. A detection limit of 1 fM (1 x 10(-19) mol of target transcripts in 100 microL) and a 3-order-wide dynamic range of target concentration were achieved by the electrochemical bDNA assay. Such limit corresponded to approximately 17 fg of the p185 BCR-ABL fusion transcripts. The specificity and sensitivity of assay enabled direct detection of target transcripts in as little as 4.6 ng of mRNA population without PCR amplification. In combination with the use of a well-quantified standard, the electrochemical bDNA assay was capable of direct use for a PCR-free quantitative analysis of target transcripts in mRNA population. A mean transcript copy number of 62,900/ng of mRNA was determined, which was at least 50-fold higher than that of real-time quantitative PCR (qPCR). The finding was consistent with the underestimation of targets by qPCR reported earlier. In addition, the unique design based on bDNA technology increases the assay specificity as only the p185 BCR-ABL fusion transcripts will respond to the detection. The approach thus provides a simple, sensitive, accurate, and quantitative tool alternative to the qPCR for early disease diagnosis.

The use of the sexual function questionnaire as a screening tool for women with sexual dysfunction.

PubMed

Quirk, Frances; Haughie, Scott; Symonds, Tara

2005-07-01

To determine if the validated Sexual Function Questionnaire (SFQ), developed to assess efficacy in female sexual dysfunction (FSD) clinical trials, may also have utility in identifying target populations for such studies. Data from five clinical trials and two general population surveys were used to analyze the utility of the SFQ as a tool to discriminate between the presence of specific components of FSD (i.e., hypoactive sexual desire disorder, female sexual arousal disorder, female orgasmic disorder, and dyspareunia). Sensitivity/specificity analysis and logistic regression analysis, using data from all five clinical studies and the general population surveys, confirmed that the SFQ domains have utility in detecting the presence of specific components of FSD and provide scores indicative of the presence of a specific sexual disorder. The SFQ is a valuable new tool for detecting the presence of FSD and identifying the specific components of sexual functions affected (desire, arousal, orgasm, or dyspareunia).

Could Killing Bacterial Subpopulations Hit Tuberculosis out of the Park?

PubMed

Baranowski, Catherine; Rubin, Eric J

2016-07-14

One hurdle to treating tuberculosis could be that it is so difficult to kill nonreplicating subpopulations of the causative pathogens. This work describes two new cephalosporin derivatives that specifically target this population of Mycobacterium tuberculosis.

The need to increase awareness of the risk factors of COPD.

PubMed

Roche, Nicolas

2016-07-01

COPD is a heterogeneous disease responsible for a major burden on public and individual health. A wide variety of intrinsic and environmental risk factors are involved, and exert their influence at various time points during the life span of individuals. Knowledge of these factors is of utmost importance to develop appropriate screening and prevention programs, and may help improving the pathophysiological knowledge of the disease. Accordingly, there are multiple targets of information and education on risk factors for COPD, including the general population and patients, workers and employers, doctors and other healthcare professionals, researchers, policy-makers, payers, etc. Gender and socioeconomic factors need to be specifically considered. Importantly, it is likely that increasing the specific knowledge of COPD risk factors among the above-mentioned targets cannot not be obtained without increasing the general knowledge of COPD in the population, which at present is dramatically low.

Injury risk functions based on population-based finite element model responses: Application to femurs under dynamic three-point bending.

PubMed

Park, Gwansik; Forman, Jason; Kim, Taewung; Panzer, Matthew B; Crandall, Jeff R

2018-02-28

The goal of this study was to explore a framework for developing injury risk functions (IRFs) in a bottom-up approach based on responses of parametrically variable finite element (FE) models representing exemplar populations. First, a parametric femur modeling tool was developed and validated using a subject-specific (SS)-FE modeling approach. Second, principal component analysis and regression were used to identify parametric geometric descriptors of the human femur and the distribution of those factors for 3 target occupant sizes (5th, 50th, and 95th percentile males). Third, distributions of material parameters of cortical bone were obtained from the literature for 3 target occupant ages (25, 50, and 75 years) using regression analysis. A Monte Carlo method was then implemented to generate populations of FE models of the femur for target occupants, using a parametric femur modeling tool. Simulations were conducted with each of these models under 3-point dynamic bending. Finally, model-based IRFs were developed using logistic regression analysis, based on the moment at fracture observed in the FE simulation. In total, 100 femur FE models incorporating the variation in the population of interest were generated, and 500,000 moments at fracture were observed (applying 5,000 ultimate strains for each synthesized 100 femur FE models) for each target occupant characteristics. Using the proposed framework on this study, the model-based IRFs for 3 target male occupant sizes (5th, 50th, and 95th percentiles) and ages (25, 50, and 75 years) were developed. The model-based IRF was located in the 95% confidence interval of the test-based IRF for the range of 15 to 70% injury risks. The 95% confidence interval of the developed IRF was almost in line with the mean curve due to a large number of data points. The framework proposed in this study would be beneficial for developing the IRFs in a bottom-up manner, whose range of variabilities is informed by the population-based FE model responses. Specifically, this method mitigates the uncertainties in applying empirical scaling and may improve IRF fidelity when a limited number of experimental specimens are available.

Using formative research to lay the foundation for community level HIV prevention efforts: an example from the AIDS Community Demonstration Projects.

PubMed Central

Higgins, D L; O'Reilly, K; Tashima, N; Crain, C; Beeker, C; Goldbaum, G; Elifson, C S; Galavotti, C; Guenther-Grey, C

1996-01-01

The AIDS Community Demonstration Projects provided community-level HIV prevention interventions to historically hard-to-reach groups at high risk for HIV infection. The projects operated under a common research protocol which encompassed formative research, intervention delivery, process evaluation, and outcome evaluation. A formative research process specifically focusing on intervention development was devised to assist project staff in identifying, prioritizing, accessing, and understanding the intervention target groups. This process was central to the creation of interventions that were acceptable and unique to the target populations. Intended to be rapid, the process took 6 months to complete. Drawn from the disciplines of anthropology, community psychology, sociology, and public health, the formative research process followed distinct steps which included (a) defining the populations at high-risk for HIV; (b) gathering information about these populations through interviews with persons who were outside of, but who had contact with, the target groups (such as staff from the health department and alcohol and drug treatment facilities, as well as persons who interacted in an informal manner with the target groups, such as clerks in neighborhood grocery stores and bartenders); (c) interviewing people with access to the target populations (gatekeepers), and conducting observations in areas where these high-risk groups were reported to gather (from previous interviews); (d) interviewing members of these groups at high risk for HIV infection or transmission; and (e) systematically integrating information throughout the process. Semistructured interview schedules were used for all data collection in this process. This standardized systematic method yielded valuable information about the focal groups in each demonstration project site. The method, if adopted by others, would assist community intervention specialists in developing interventions that are culturally appropriate and meaningful to their respective target populations. PMID:8862154

A survey of the population genetic variation in the human kinome.

PubMed

Zhang, Wei; Catenacci, Daniel V T; Duan, Shiwei; Ratain, Mark J

2009-08-01

Protein kinases are key regulators of various biological processes, such as control of cell growth, metabolism, differentiation and apoptosis. Therefore, protein kinases have been an important class of targets for anticancer drugs. Health-related disparities such as differential drug response have been observed between human populations. A survey of the human kinases and their ligand genes for those containing population-specific genetic variants could provide new insights into the mechanisms of these health disparities and suggest novel targets for ethnicity-specific personalized medicine. Using the International HapMap Project genotypic data on single-nucleotide polymorphisms (SNPs), the protein kinase complement of the human genome (kinome) and some experimentally verified ligand genes were scanned for the existence of population-specific SNPs (eSNPs). In general, protein kinases were found to contain a much higher proportion of eSNPs than the whole genome background, indicating a stronger pressure for adaptation in individual populations. In contrast, the proportion of ligand genes containing eSNPs was not different from that of the whole genome background. Although with some important limitations, our results suggest that human kinases are more likely to be under recent positive selection than ligands. Our findings suggest that the health-related disparities associated with kinase signaling pathways are more likely to be driven by the genetic variation in the kinase genes than their cognate ligands. Illustrating the role of molecular evolution in the genetic variation of the human kinome could provide a promising route to understand the ethnic differences in cancer and facilitate the realization of ethnicity-based individualized medicine.

Novel fusion proteins for the antigen-specific staining and elimination of B cell receptor-positive cell populations demonstrated by a tetanus toxoid fragment C (TTC) model antigen.

PubMed

Klose, Diana; Saunders, Ute; Barth, Stefan; Fischer, Rainer; Jacobi, Annett Marita; Nachreiner, Thomas

2016-02-17

In an earlier study we developed a unique strategy allowing us to specifically eliminate antigen-specific murine B cells via their distinct B cell receptors using a new class of fusion proteins. In the present work we elaborated our idea to demonstrate the feasibility of specifically addressing and eliminating human memory B cells. The present study reveals efficient adaptation of the general approach to selectively target and eradicate human memory B cells. In order to demonstrate the feasibility we engineered a fusion protein following the principle of recombinant immunotoxins by combining a model antigen (tetanus toxoid fragment C, TTC) for B cell receptor targeting and a truncated version of Pseudomonas aeruginosa exotoxin A (ETA') to induce apoptosis after cellular uptake. The TTC-ETA' fusion protein not only selectively bound to a TTC-reactive murine B cell hybridoma cell line in vitro but also to freshly isolated human memory B cells from immunized donors ex vivo. Specific toxicity was confirmed on an antigen-specific population of human CD27(+) memory B cells. This protein engineering strategy can be used as a generalized platform approach for the construction of therapeutic fusion proteins with disease-relevant antigens as B cell receptor-binding domains, offering a promising approach for the specific depletion of autoreactive B-lymphocytes in B cell-driven autoimmune diseases.

Get Tested Why Not? A novel approach to internet-based chlamydia and gonorrhea testing in Canada.

PubMed

Mann, Tara A; Uddin, Zhaida; Hendriks, Andrew M; Bouchard, Christiane J; Etches, Vera G

2013-03-07

The objective of the Get Tested Why Not campaign is to increase access to chlamydia and gonorrhea testing and sexual health information, with specific focus on youth. Individuals between the ages of 15-29 are most affected by chlamydia and gonorrhea infections in Ottawa and were identified as the target population. Youth from the target population were engaged in the development and launch of the campaign. Development of the campaign began in 2009 and led to a launch on March 21, 2011. Social media promotion as well as traditional advertising approaches developed awareness of the campaign within the target population. The campaign consists of a bilingual, youth-friendly website and texting service. After assessing appropriateness of testing, clients can download a requisition form for urine-based chlamydia and gonorrhea testing and submit a sample at one of 26 laboratories across Ottawa. During year 1 of the campaign, there were 13,385 website hits and 104 specimens submitted for chlamydia and gonorrhea testing. The majority (57.6%, n=60) of requisitions were submitted by members of the target population (age 15-29). Of the requisitions submitted, 95 (91.3%) were negative, 4 (3.9%) were positive and 5 (4.8%) were cancelled due to lab errors. The campaign is reaching the target population and has demonstrated a positive impact on knowledge and intended behaviours of users. The use of technology has expanded testing options, thereby potentially broadening Ottawa Public Health's reach to clients who may be less likely to test through traditional testing approaches.

Task-phase-specific dynamics of basal forebrain neuronal ensembles

PubMed Central

Tingley, David; Alexander, Andrew S.; Kolbu, Sean; de Sa, Virginia R.; Chiba, Andrea A.; Nitz, Douglas A.

2014-01-01

Cortically projecting basal forebrain neurons play a critical role in learning and attention, and their degeneration accompanies age-related impairments in cognition. Despite the impressive anatomical and cell-type complexity of this system, currently available data suggest that basal forebrain neurons lack complexity in their response fields, with activity primarily reflecting only macro-level brain states such as sleep and wake, onset of relevant stimuli and/or reward obtainment. The current study examined the spiking activity of basal forebrain neuron populations across multiple phases of a selective attention task, addressing, in particular, the issue of complexity in ensemble firing patterns across time. Clustering techniques applied to the full population revealed a large number of distinct categories of task-phase-specific activity patterns. Unique population firing-rate vectors defined each task phase and most categories of task-phase-specific firing had counterparts with opposing firing patterns. An analogous set of task-phase-specific firing patterns was also observed in a population of posterior parietal cortex neurons. Thus, consistent with the known anatomical complexity, basal forebrain population dynamics are capable of differentially modulating their cortical targets according to the unique sets of environmental stimuli, motor requirements, and cognitive processes associated with different task phases. PMID:25309352

City-specific vehicle emission control strategies to achieve stringent emission reduction targets in China's Yangtze River Delta region.

PubMed

Zhang, Shaojun; Wu, Ye; Zhao, Bin; Wu, Xiaomeng; Shu, Jiawei; Hao, Jiming

2017-01-01

The Yangtze River Delta (YRD) region is one of the most prosperous and densely populated regions in China and is facing tremendous pressure to mitigate vehicle emissions and improve air quality. Our assessment has revealed that mitigating vehicle emissions of NOx would be more difficult than reducing the emissions of other major vehicular pollutants (e.g., CO, HC and PM 2.5 ) in the YRD region. Even in Shanghai, where the emission control implemented are more stringent than in Jiangsu and Zhejiang, we observed little to no reduction in NOx emissions from 2000 to 2010. Emission-reduction targets for HC, NOx and PM 2.5 are determined using a response surface modeling tool for better air quality. We design city-specific emission control strategies for three vehicle-populated cities in the YRD region: Shanghai and Nanjing and Wuxi in Jiangsu. Our results indicate that even if stringent emission control consisting of the Euro 6/VI standards, the limitation of vehicle population and usage, and the scrappage of older vehicles is applied, Nanjing and Wuxi will not be able to meet the NOx emissions target by 2020. Therefore, additional control measures are proposed for Nanjing and Wuxi to further mitigate NOx emissions from heavy-duty diesel vehicles. Copyright © 2016. Published by Elsevier B.V.

Health disparities and direct-to-consumer prescription drug advertising: a content analysis of targeted magazine genres, 1992-2002.

PubMed

Mastin, Teresa; Andsager, Julie L; Choi, Jounghwa; Lee, Kyungjin

2007-01-01

Health disparities exist in the United States based on race, gender, and socioeconomic status. One way to alleviate some of the disparities regarding certain diseases or conditions is to increase awareness among populations most affected. Physicians have suggested that direct-to-consumer advertising (DTCA) of prescription drugs could play a role in awareness. Social identity theory suggests that individuals are likely to attend messages if they can identify, often based on race or gender, with people portrayed in the messages. This study analyzed DTCA in 11 years of Black, women's, news, and entertainment magazines to determine whether models in the ads targeted specific populations. Black magazines were more likely to contain ads featuring Black models only than were other genres, which had more DTCA picturing White models only. Health conditions the drugs were intended for varied by genre and over time, with STD drugs appearing primarily in Black magazines, and DTCA for heart disease not published in Black magazines, despite cardiovascular diseases being the No. 1 cause of death for Blacks (and Whites). Women's magazines featured DTCA for a wide variety of drugs, reinforcing their roles as caretakers, with proportionally few ads for women's health. Implications for targeted use of magazine genres as a means of providing health information to specific populations are discussed.

Serving some and serving all: how providers navigate the challenges of providing racially targeted health services.

PubMed

Zhou, Amy

2017-10-01

Racially targeted healthcare provides racial minorities with culturally and linguistically appropriate health services. This mandate, however, can conflict with the professional obligation of healthcare providers to serve patients based on their health needs. The dilemma between serving a particular population and serving all is heightened when the patients seeking care are racially diverse. This study examines how providers in a multi-racial context decide whom to include or exclude from health programs. This study draws on 12 months of ethnographic fieldwork at an Asian-specific HIV organization. Fieldwork included participant observation of HIV support groups, community outreach programs, and substance abuse recovery groups, as well as interviews with providers and clients. Providers managed the dilemma in different ways. While some programs in the organization focused on an Asian clientele, others de-emphasized race and served a predominantly Latino and African American clientele. Organizational structures shaped whether services were delivered according to racial categories. When funders examined client documents, providers prioritized finding Asian clients so that their documents reflected program goals to serve the Asian population. In contrast, when funders used qualitative methods, providers could construct an image of a program that targets Asians during evaluations while they included other racial minorities in their everyday practice. Program services were organized more broadly by health needs. Even within racially targeted programs, the meaning of race fluctuates and is contested. Patients' health needs cross cut racial boundaries, and in some circumstances, the boundaries of inclusion can expand beyond specific racial categories to include racial minorities and underserved populations more generally.

Translational Approaches Targeting Reconsolidation

PubMed Central

Kroes, Marijn C.W.; LeDoux, Joseph E.; Phelps, Elizabeth A.

2017-01-01

Maladaptive learned responses and memories contribute to psychiatric disorders that constitute a significant socio-economic burden. Primary treatment methods teach patients to inhibit maladaptive responses, but do not get rid of the memory itself, which explains why many patients experience a return of symptoms even after initially successful treatment. This highlights the need to discover more persistent and robust techniques to diminish maladaptive learned behaviours. One potentially promising approach is to alter the original memory, as opposed to inhibiting it, by targeting memory reconsolidation. Recent research shows that reactivating an old memory results in a period of memory flexibility and requires restorage, or reconsolidation, for the memory to persist. This reconsolidation period allows a window for modification of a specific old memory. Renewal of memory flexibility following reactivation holds great clinical potential as it enables targeting reconsolidation and changing of specific learned responses and memories that contribute to maladaptive mental states and behaviours. Here, we will review translational research on non-human animals, healthy human subjects, and clinical populations aimed at altering memories by targeting reconsolidation using biological treatments (electrical stimulation, noradrenergic antagonists) or behavioural interference (reactivation–extinction paradigm). Both approaches have been used successfully to modify aversive and appetitive memories, yet effectiveness in treating clinical populations has been limited. We will discuss that memory flexibility depends on the type of memory tested and the brain regions that underlie specific types of memory. Further, when and how we can most effectively reactivate a memory and induce flexibility is largely unclear. Finally, the development of drugs that can target reconsolidation and are safe for use in humans would optimize cross-species translations. Increasing the understanding of the mechanism and limitations of memory flexibility upon reactivation should help optimize efficacy of treatments for psychiatric patients. PMID:27240676

Surgical treatment of Parkinson’s disease: Past, present, and future

PubMed Central

Duker, Andrew P.; Espay, Alberto J.

2013-01-01

Advances in functional neurosurgery have expanded the treatment of Parkinson’s disease (PD), from early lesional procedures to targeted electrical stimulation of specific nodes in the basal ganglia circuitry. Deep brain stimulation (DBS), applied to selected patients with Parkinson’s disease (PD) and difficult-to-manage motor fluctuations, yields substantial reductions in off time and dyskinesia. Outcomes for DBS targeting the two major studied targets in PD, the subthalamic nucleus (STN) and the internal segment of the globus pallidus (GPi), appear to be broadly similar and the choice is best made based on individual patient factors and surgeon preference. Emerging concepts in DBS include examination of new targets, such as the potential efficacy of pedunculopontine nucleus (PPN) stimulation for treatment of freezing and falls, the utilization of pathologic oscillations in the beta band to construct an adaptive “closed-loop” DBS, and new technologies, including segmented electrodes to steer current toward specific neural populations. PMID:23896506

HLA-targeted flow cytometric sorting of blood cells allows separation of pure and viable microchimeric cell populations.

PubMed

Drabbels, Jos J M; van de Keur, Carin; Kemps, Berit M; Mulder, Arend; Scherjon, Sicco A; Claas, Frans H J; Eikmans, Michael

2011-11-10

Microchimerism is defined by the presence of low levels of nonhost cells in a person. We developed a reliable method for separating viable microchimeric cells from the host environment. For flow cytometric cell sorting, HLA antigens were targeted with human monoclonal HLA antibodies (mAbs). Optimal separation of microchimeric cells (present at a proportion as low as 0.01% in artificial mixtures) was obtained with 2 different HLA mAbs, one targeting the chimeric cells and the other the background cells. To verify purity of separated cell populations, flow-sorted fractions of 1000 cells were processed for DNA analysis by HLA-allele-specific and Y-chromosome-directed real-time quantitative PCR assays. After sorting, PCR signals of chimeric DNA markers in the positive fractions were significantly enhanced compared with those in the presort samples, and they were similar to those in 100% chimeric control samples. Next, we demonstrate applicability of HLA-targeted FACS sorting after pregnancy by separating chimeric maternal cells from child umbilical cord mononuclear cells. Targeting allelic differences with anti-HLA mAbs with FACS sorting allows maximal enrichment of viable microchimeric cells from a background cell population. The current methodology enables reliable microchimeric cell detection and separation in clinical specimens.

Deregulation upon DNA damage revealed by joint analysis of context-specific perturbation data

PubMed Central

2011-01-01

Background Deregulation between two different cell populations manifests itself in changing gene expression patterns and changing regulatory interactions. Accumulating knowledge about biological networks creates an opportunity to study these changes in their cellular context. Results We analyze re-wiring of regulatory networks based on cell population-specific perturbation data and knowledge about signaling pathways and their target genes. We quantify deregulation by merging regulatory signal from the two cell populations into one score. This joint approach, called JODA, proves advantageous over separate analysis of the cell populations and analysis without incorporation of knowledge. JODA is implemented and freely available in a Bioconductor package 'joda'. Conclusions Using JODA, we show wide-spread re-wiring of gene regulatory networks upon neocarzinostatin-induced DNA damage in Human cells. We recover 645 deregulated genes in thirteen functional clusters performing the rich program of response to damage. We find that the clusters contain many previously characterized neocarzinostatin target genes. We investigate connectivity between those genes, explaining their cooperation in performing the common functions. We review genes with the most extreme deregulation scores, reporting their involvement in response to DNA damage. Finally, we investigate the indirect impact of the ATM pathway on the deregulated genes, and build a hypothetical hierarchy of direct regulation. These results prove that JODA is a step forward to a systems level, mechanistic understanding of changes in gene regulation between different cell populations. PMID:21693013

Deregulation upon DNA damage revealed by joint analysis of context-specific perturbation data.

PubMed

Szczurek, Ewa; Markowetz, Florian; Gat-Viks, Irit; Biecek, Przemysław; Tiuryn, Jerzy; Vingron, Martin

2011-06-21

Deregulation between two different cell populations manifests itself in changing gene expression patterns and changing regulatory interactions. Accumulating knowledge about biological networks creates an opportunity to study these changes in their cellular context. We analyze re-wiring of regulatory networks based on cell population-specific perturbation data and knowledge about signaling pathways and their target genes. We quantify deregulation by merging regulatory signal from the two cell populations into one score. This joint approach, called JODA, proves advantageous over separate analysis of the cell populations and analysis without incorporation of knowledge. JODA is implemented and freely available in a Bioconductor package 'joda'. Using JODA, we show wide-spread re-wiring of gene regulatory networks upon neocarzinostatin-induced DNA damage in Human cells. We recover 645 deregulated genes in thirteen functional clusters performing the rich program of response to damage. We find that the clusters contain many previously characterized neocarzinostatin target genes. We investigate connectivity between those genes, explaining their cooperation in performing the common functions. We review genes with the most extreme deregulation scores, reporting their involvement in response to DNA damage. Finally, we investigate the indirect impact of the ATM pathway on the deregulated genes, and build a hypothetical hierarchy of direct regulation. These results prove that JODA is a step forward to a systems level, mechanistic understanding of changes in gene regulation between different cell populations.

HLA-B*27 subtype specificity determines targeting and viral evolution of a hepatitis C virus-specific CD8+ T cell epitope.

PubMed

Nitschke, Katja; Barriga, Alejandro; Schmidt, Julia; Timm, Jörg; Viazov, Sergei; Kuntzen, Thomas; Kim, Arthur Y; Lauer, Georg M; Allen, Todd M; Gaudieri, Silvana; Rauch, Andri; Lange, Christian M; Sarrazin, Christoph; Eiermann, Thomas; Sidney, John; Sette, Alessandro; Thimme, Robert; López, Daniel; Neumann-Haefelin, Christoph

2014-01-01

HLA-B*27 is associated with spontaneous HCV genotype 1 clearance. HLA-B*27-restricted CD8+ T cells target three NS5B epitopes. Two of these epitopes are dominantly targeted in the majority of HLA-B*27+ patients. In chronic infection, viral escape occurs consistently in these two epitopes. The third epitope (NS5B2820) was dominantly targeted in an acutely infected patient. This was in contrast, however, to the lack of recognition and viral escape in the large majority of HLA-B*27+ patients. Here, we set out to determine the host factors contributing to selective targeting of this epitope. Four-digit HLA class I typing and viral sequence analyses were performed in 78 HLA-B*27+ patients with chronic HCV genotype 1 infection. CD8+ T cell analyses were performed in a subset of patients. In addition, HLA/peptide affinity was compared for HLA-B*27:02 and 05. The NS5B2820 epitope is only restricted by the HLA-B*27 subtype HLA-B*27:02 (that is frequent in Mediterranean populations), but not by the prototype HLA-B*27 subtype B*27:05. Indeed, the epitope is very dominant in HLA-B*27:02+ patients and is associated with viral escape mutations at the anchor position for HLA-binding in 12 out of 13 HLA-B*27:02+ chronically infected patients. The NS5B2820 epitope is immunodominant in the context of HLA-B*27:02, but is not restricted by other HLA-B*27 subtypes. This finding suggests an important role of HLA subtypes in the restriction of HCV-specific CD8+ responses. With minor HLA subtypes covering up to 39% of specific populations, these findings may have important implications for the selection of epitopes for global vaccines. Copyright © 2013 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

Mesenchymal Stem Cells for Vascular Target Discovery in Breast Cancer-Associated Angiogenesis

DTIC Science & Technology

2004-09-01

Matrigel plug and sorted by flow cytometry . Sorting of these retrieved cells based on co-expression of the GFP marker and cell- surface endothelial...express the green fluorescent protein (GFP) and clonal MSC populations can be isolated and phenotypically and genotypically analyzed by flow cytometry ...monoclonal populations of these GFP+ murine MSCs and conducted flow cytometry analysis to determine their phenotype. Specifically, we determined if

Population pharmacokinetics and dosing simulations of imipenem in serious bacteraemia in immunocompromised patients with febrile neutropenia.

PubMed

Jaruratanasirikul, Sutep; Wongpoowarak, Wibul; Jullangkoon, Monchana; Samaeng, Maseetoh

2015-02-01

The aims of this study were to i) reveal the population pharmacokinetics; and ii) assess the probability of target attainment (PTA) and cumulative fraction of response (CFR) (defined as the expected population PTA for a specific drug dose and a specific population of microorganisms) of imipenem in febrile neutropenic patients with bacteraemia. Ten patients were randomised into two groups: Group I received a 0.5-h infusion of 0.5 g of imipenem every 6 h (q6h) for 8 doses; and Group II received a 4-h infusion of 0.5 g q6h for 8 doses. A Monte Carlo simulation was performed to determine the PTA. The volume of distribution and total clearance of imipenem were 20.78 ± 1.35 l and 23.19 ± 1.34 l/h, respectively. Only a 4-h infusion of 1 g q6h regimen achieved a PTA >93% for 80% T>MIC for a MIC of 2 μg/ml. A 4-h infusion of all simulated regimens and a 0.5-h infusion of 0.5 g q6h and 1 g q6h achieved targets (CFR ≥ 90%) against Escherichia coli and Klebsiella spp. However, against Pseudomonas aeruginosa and Acinetobacter spp., no regimens achieved their targets. In conclusion, the results indicate that a higher than manufacturer's dosage recommendation is required to maximize the activity of imipenem. Copyright © 2014 Japanese Pharmacological Society. Production and hosting by Elsevier B.V. All rights reserved.

16S rRNA beacons for bacterial monitoring during human space missions.

PubMed

Larios-Sanz, Maia; Kourentzi, Katerina D; Warmflash, David; Jones, Jeffrey; Pierson, Duane L; Willson, Richard C; Fox, George E

2007-04-01

Microorganisms are unavoidable in space environments and their presence has, at times, been a source of problems. Concerns about disease during human space missions are particularly important considering the significant changes the immune system incurs during spaceflight and the history of microbial contamination aboard the Mir space station. Additionally, these contaminants may have adverse effects on instrumentation and life-support systems. A sensitive, highly specific system to detect, characterize, and monitor these microbial populations is essential. Herein we describe a monitoring approach that uses 16S rRNA targeted molecular beacons to successfully detect several specific bacterial groupings. This methodology will greatly simplify in-flight monitoring by minimizing sample handling and processing. We also address and provide solutions to target accessibility problems encountered in hybridizations that target 16S rRNA.

Neuronal and Cardiovascular Potassium Channels as Therapeutic Drug Targets

PubMed Central

Humphries, Edward S. A.

2015-01-01

Potassium (K+) channels, with their diversity, often tissue-defined distribution, and critical role in controlling cellular excitability, have long held promise of being important drug targets for the treatment of dysrhythmias in the heart and abnormal neuronal activity within the brain. With the exception of drugs that target one particular class, ATP-sensitive K+ (KATP) channels, very few selective K+ channel activators or inhibitors are currently licensed for clinical use in cardiovascular and neurological disease. Here we review what a range of human genetic disorders have told us about the role of specific K+ channel subunits, explore the potential of activators and inhibitors of specific channel populations as a therapeutic strategy, and discuss possible reasons for the difficulty in designing clinically relevant K+ channel modulators. PMID:26303307

Skin cancer interventions across the cancer control continuum: A review of experimental evidence (1/1/2000-6/30/2015) and future research directions.

PubMed

Geller, Alan C; Dickerman, Barbra A; Taber, Jennifer M; Dwyer, Laura A; Hartman, Anne M; Perna, Frank M

2018-06-01

While the general efficacy of skin cancer interventions have been reviewed, employing the cancer control continuum would be useful to identify research gaps at specific cancer control points. We characterized the intervention evidence base for specific behavioral targets (e.g., tanning, sun protection, screening) and clinically related targets (e.g., sunburn, skin exams, cancers) at each point in the cancer control continuum. The review included articles published from 1/1/2000-6/30/15 that had an experimental design and targeted behavioral intervention in skin cancer (e.g., specific behaviors or clinically related targets). The search yielded 86 articles, including seven dissemination studies. Of the 79 non-dissemination studies, 57 exclusively targeted primary prevention behaviors, five exclusively targeted screening, 10 targeted both detection and prevention, and eight addressed cancer survivorship. Among prevention studies (n=67), 29 (43%) targeted children and 38 (57%) targeted adults. Of the 15 screening studies, nine targeted high-risk groups (e.g., men aged ≥50 years) and six targeted the general population. Although research has focused on skin cancer prevention, empirically validated interventions are still needed for youth engaged in indoor tanning and for behavioral interventions to pursue change in clinically relevant targets. Research must also address detection among those at highest risk for skin cancer, amelioration of emotional distress attendant to diagnosis and treatment, and survivorship concerns. We discuss essential qualities and opportunities for intervention development and translational research to inform the field. Copyright © 2018 Elsevier Inc. All rights reserved.

Genomic Alterations in Advanced Esophageal Cancer May Lead to Subtype-Specific Therapies

PubMed Central

Forde, Patrick M.

2013-01-01

The development of targeted agents for metastatic esophageal or gastroesophageal junction (GEJ) tumors has been limited when compared with that for other common tumors. To date, the anti-human epidermal growth factor receptor-2 (HER-2) antibody, trastuzumab, in combination with chemotherapy, is the only approved novel agent for these cancers, and its use is limited to the small population of patients whose tumors overexpress HER-2. Despite recent progress in the field, median overall survival remains only 8–12 months for patients with stage IV esophageal or GEJ cancer. In this article, we examine the molecular aberrations thought to drive the development and spread of esophageal cancer and identify promising targets for specific tumor inhibition. Data from clinical studies of targeted agents are reviewed, including epidermal growth factor receptor antibodies, tyrosine kinase inhibitors, HER-2, and vascular endothelial growth factor-directed therapy. Current and future targets include MET, fibroblast growth factor receptor, and immune-based therapies. Evidence from trials to date suggests that molecularly unselected patient cohorts derive minimal benefit from most target-specific agents, suggesting that future collaborative investigation should focus on preselected molecular subgroups of patients with this challenging heterogeneous disease. PMID:23853247

The Role of Special Operations Forces in Counter-Narcotic Operations

DTIC Science & Technology

1990-06-01

and Colombia . The thesis describes the present structure of US Army Special Operations Forces and their capabilites. It recommends missions for each...target countries of Colombia , Peru and Bolivia. The area known as the Andean Ridge will be the specific target area for this thesis. In examining...organization, recognized that pre- conditions exist in Colombia for their initial success. They must retain support of the local population to maintain control

The representation of vulnerable populations in quality improvement studies.

PubMed

Rolnitsky, Asaph; Kirtsman, Maksim; Goldberg, Hanna R; Dunn, Michael; Bell, Chaim M

2018-05-01

A mapping review to quantify representation of vulnerable populations, who suffer from disparity and often inequitable healthcare, in quality improvement (QI) research. Studies published in 2004-2014 inclusive from Medline, Embase and Cochrane databases for English language research with the terms 'quality improvement' or 'quality control' or 'QI' and 'plan-do-study-act' or 'PDSA' in the years 2004-2014 inclusively. Published clinical research that was a QI-themed, as identified by its declared search terms, MESH terms, abstract or title. Three reviewers identified the eligible studies independently. Excluded were publications that were not trials, evaluations or analyses. Of 2039 results, 1660 were eligible for inclusion. There were 586 (33.5%) publications that targeted a specific vulnerable population: children (184, 10.54%), mental health patients (125, 7.16%), the elderly (100, 5.73%), women (57, 3.27%), the poor (30, 1.72%), rural residents (29, 1.66%), visible minorities (27, 1.55%), the terminally ill (17, 0.97%), adolescents (16, 0.92%) and prisoners (1 study). Seventy-four articles targeted two or more vulnerable populations, and 11 targeted three population categories. On average, there were 158 QI research studies published per year, increasing from 69 in 2004 to 396 in 2014 (R2 = 0.7, P < 0.001). The relative representation of vulnerable populations had a mean of 33.58% and was stable over the time period (standard deviation (SD) = 5.9%, R2 = 0.001). Seven countries contributed to over 85% of the publications targeting vulnerable populations, with the USA contributing 62% of the studies. Over 11 years, there has been a marked increase in QI publications. Roughly one-third of all published QI research is on vulnerable populations, a stable proportion over time. Nevertheless, some vulnerable populations are under-represented. Increased education, resources and attention are encouraged to improve the health of vulnerable populations through focused QI initiatives.

Which population groups should be targeted for cardiovascular prevention? A modelling study based on the Norwegian Hordaland Health Study (HUSK).

PubMed

Brekke, Mette; Rekdal, Magne; Straand, Jørund

2007-06-01

To assess level of cardiovascular risk factors in a non-selected, middle-aged population. To estimate the proportion target for risk intervention according to present guidelines and according to different cut-off levels for two risk algorithms. Population survey, modelling study. The Norwegian Hordaland Health Study (HUSK) 1997-99. A total of 22 289 persons born in 1950-57. Own and relatives' cardiovascular morbidity, antihypertensive and lipid-lowering treatment, smoking, blood pressure, cholesterol. Framingham and Systematic Coronary Risk Evaluation (SCORE) algorithms. The European guidelines on CVD prevention in clinical practice were applied to estimate size of risk groups. Some 9.7% of men and 7.6% of women had CVD, diabetes mellitus, a high level of one specific risk factor, or received lipid-lowering or antihypertensive treatment. Applying a SCORE (60 years) cut-off level at 5% to the rest of the population selected 52.4% of men and 0.8% of women into a primary prevention group, while a cut-off level at 8% included 22.0% and 0.06% respectively. A cut-off level for the Framingham score (60 years) of 20% selected 43.6% of men and 4.7% of women, while a cut-off level of 25% selected 25.6% of men and 1.8% of women. The findings illustrate how choices regarding risk estimation highly affect the size of the target population. Modelling studies are important when preparing guidelines, to address implications for resource allocation and risk of medicalization. The population share to be targeted for primary prevention ought to be estimated, including the impact of various cut-off points for risk algorithms on the size of the risk population.

Using qualitative methods to develop a contextually tailored instrument: Lessons learned.

PubMed

Lee, Haeok; Kiang, Peter; Kim, Minjin; Semino-Asaro, Semira; Colten, Mary Ellen; Tang, Shirley S; Chea, Phala; Peou, Sonith; Grigg-Saito, Dorcas C

2015-01-01

To develop a population-specific instrument to inform hepatitis B virus (HBV) and human papilloma virus (HPV) prevention education and intervention based on data and evidence obtained from the targeted population of Khmer mothers reflecting their socio-cultural and health behaviors. The principles of community-based participatory research (CBPR) guided the development of a standardized survey interview. Four stages of development and testing of the survey instrument took place in order to inform the quantitative health survey used to collect data in stage five of the project. This article reports only on Stages 1-4. This process created a new quantitative measure of HBV and HPV prevention behavior based on the revised Network Episode Model and informed by the targeted population. The CBPR method facilitated the application and translation of abstract theoretical ideas of HBV and HPV prevention behavior into culturally-relevant words and expressions of Cambodian Americans (CAs). The design of an instrument development process that accounts for distinctive socio-cultural backgrounds of CA refugee/immigrant women provides a model for use in developing future health surveys that are intended to aid minority-serving health care professionals and researchers as well as targeted minority populations.

Using qualitative methods to develop a contextually tailored instrument: Lessons learned

PubMed Central

Lee, Haeok; Kiang, Peter; Kim, Minjin; Semino-Asaro, Semira; Colten, Mary Ellen; Tang, Shirley S.; Chea, Phala; Peou, Sonith; Grigg-Saito, Dorcas C.

2015-01-01

Objective: To develop a population-specific instrument to inform hepatitis B virus (HBV) and human papilloma virus (HPV) prevention education and intervention based on data and evidence obtained from the targeted population of Khmer mothers reflecting their socio-cultural and health behaviors. Methods: The principles of community-based participatory research (CBPR) guided the development of a standardized survey interview. Four stages of development and testing of the survey instrument took place in order to inform the quantitative health survey used to collect data in stage five of the project. This article reports only on Stages 1-4. Results: This process created a new quantitative measure of HBV and HPV prevention behavior based on the revised Network Episode Model and informed by the targeted population. The CBPR method facilitated the application and translation of abstract theoretical ideas of HBV and HPV prevention behavior into culturally-relevant words and expressions of Cambodian Americans (CAs). Conclusions: The design of an instrument development process that accounts for distinctive socio-cultural backgrounds of CA refugee/immigrant women provides a model for use in developing future health surveys that are intended to aid minority-serving health care professionals and researchers as well as targeted minority populations. PMID:27981114

An optimal stratified Simon two-stage design.

PubMed

Parashar, Deepak; Bowden, Jack; Starr, Colin; Wernisch, Lorenz; Mander, Adrian

2016-07-01

In Phase II oncology trials, therapies are increasingly being evaluated for their effectiveness in specific populations of interest. Such targeted trials require designs that allow for stratification based on the participants' molecular characterisation. A targeted design proposed by Jones and Holmgren (JH) Jones CL, Holmgren E: 'An adaptive Simon two-stage design for phase 2 studies of targeted therapies', Contemporary Clinical Trials 28 (2007) 654-661.determines whether a drug only has activity in a disease sub-population or in the wider disease population. Their adaptive design uses results from a single interim analysis to decide whether to enrich the study population with a subgroup or not; it is based on two parallel Simon two-stage designs. We study the JH design in detail and extend it by providing a few alternative ways to control the familywise error rate, in the weak sense as well as the strong sense. We also introduce a novel optimal design by minimising the expected sample size. Our extended design contributes to the much needed framework for conducting Phase II trials in stratified medicine. © 2016 The Authors Pharmaceutical Statistics Published by John Wiley & Sons Ltd. © 2016 The Authors Pharmaceutical Statistics Published by John Wiley & Sons Ltd.

Cancer stem cells and personalized cancer nanomedicine.

PubMed

Gener, Petra; Rafael, Diana Fernandes de Sousa; Fernández, Yolanda; Ortega, Joan Sayós; Arango, Diego; Abasolo, Ibane; Videira, Mafalda; Schwartz, Simo

2016-02-01

Despite the progress in cancer treatment over the past years advanced cancer is still an incurable disease. Special attention is pointed toward cancer stem cell (CSC)-targeted therapies, because this minor cell population is responsible for the treatment resistance, metastatic growth and tumor recurrence. The recently described CSC dynamic phenotype and interconversion model of cancer growth hamper even more the possible success of current cancer treatments in advanced cancer stages. Accordingly, CSCs can be generated through dedifferentiation processes from non-CSCs, in particular, when CSC populations are depleted after treatment. In this context, the use of targeted CSC nanomedicines should be considered as a promising tool to increase CSC sensitivity and efficacy of specific anti-CSC therapies.

Undoing an epidemiological paradox: the tobacco industry's targeting of US Immigrants.

PubMed

Acevedo-Garcia, Dolores; Barbeau, Elizabeth; Bishop, Jennifer Anne; Pan, Jocelyn; Emmons, Karen M

2004-12-01

We sought to ascertain whether the tobacco industry has conceptualized the US immigrant population as a separate market. We conducted a content analysis of major tobacco industry documents. The tobacco industry has engaged in 3 distinct marketing strategies aimed at US immigrants: geographically based marketing directed toward immigrant communities, segmentation based on immigrants' assimilation status, and coordinated marketing focusing on US immigrant groups and their countries of origin. Public health researchers should investigate further the tobacco industry's characterization of the assimilated and non-assimilated immigrant markets, and its specific strategies for targeting these groups, in order to develop informed national and international tobacco control countermarketing strategies designed to protect immigrant populations and their countries of origin.

Influence of behavior and mating success on brood-specific contribution to fish recruitment in ponds.

PubMed

Parkos, Joseph J; Wahl, David H; Philipp, David P

2011-10-01

One source of uncertainty in predicting the response of populations to exploitation is individual differences within a population in both vulnerability to capture and contribution to population renewal. For species with parental care, individuals engaged in nesting behavior are often targeted for exploitation, but predicting outcomes of this nonrandom vulnerability will depend in part on an understanding of how parental traits are related to potential for brood contribution to the population. Variation in brood-specific contribution to recruitment of largemouth bass (Micropterus salmoides), a fish species with extended parental care, was quantified to determine if differences in mating success, parental care behaviors, and timing of reproduction influenced offspring recruitment. Dependence of these relationships on brood predation was tested in communities that differed in the presence of bluegill, Lepomis macrochirus, an important nest predator. Daily snorkel surveys were conducted in experimental ponds during spring to monitor male spawning and parental care behaviors in populations of largemouth bass. Tissue samples collected from larvae in nests were used to develop brood-specific DNA fingerprints for determining nest origins of fall recruits. Largemouth bass spawning period in bluegill ponds was longer and more variable in duration, with lower, more variable mating success, than in ponds without bluegill. In all populations, only one or two broods provided the majority of recruits, and these were broods produced during the earliest days of spawning by the oldest, largest males. In bluegill ponds, brood contribution from earliest nests also increased with brood size. Earliest nesters were the oldest males, and recruits from these nests were often above average in body size. Offspring needed to be guarded to at least swim-up larval stage to contribute any recruits. Termination of parental protection before offspring were free swimming mainly occurred with broods guarded by smaller males in ponds with brood predators. These age- and size-specific differences in timing of spawning and duration of parental care are consistent with influences of residual reproductive value and energetic constraints on reproductive behavior. Furthermore, these patterns of individual contribution to recruitment imply that fisheries that selectively target either nesting individuals or larger, older males could potentially decrease recruitment at the population scale.

Calcium and vitamin D disparities are related to gender, age, race, household income level, and weight classification but not vegetarian status in the United States: Analysis of the NHANES 2001-2008 data set.

PubMed

Wallace, Taylor C; Reider, Carroll; Fulgoni, Victor L

2013-01-01

Adequate calcium and vitamin D intakes are critical during all life cycle stages. This study aimed to characterize usual intakes of calcium and vitamin D from food and dietary supplements in specific subpopulations of Americans so that fortification/enrichment and supplementation efforts may be targeted toward populations who are truly in need. The National Cancer Institute method was used to estimate usual intakes of calcium and vitamin D by source and compared usual intakes to the established Dietary Reference Intakes for U.S. residents aged ≥4 years using National Health and Nutrition Examination Survey 2001-2002, 2003-2004, 2005-2006, and 2007-2008 data sets. These results showed for the first time that low-income, overweight, and/or obese minority populations may be at greater risk of calcium and vitamin D insufficiency. Children aged 4-8 years were more likely to obtain recommended dairy intakes compared with older children and adults of all ages. Food intakes of calcium decreased with age in adults. Adults who used supplemental calcium showed a lower prevalence of insufficiency. Calcium and vitamin D intakes from food and dietary supplements were not related to vegetarian status. Excessive intakes of calcium and vitamin D above the tolerable upper intake level were low among all studied populations and "overnutrification" was not widely present across these analyses. Age- and gender-specific supplementation and modest use of fortification with calcium and vitamin D may be warranted for targeting certain subpopulations, particularly older adults, teenagers, minorities, and those who are low income and overweight and/or obese. This study aimed to characterize usual intakes of calcium and vitamin D from food and dietary supplements in specific subpopulations of Americans so that fortification/enrichment and supplementation efforts may be better targeted. Low-income, overweight, and/or obese minority populations may be at a greater risk of calcium and vitamin D insufficiency.

Imaging Metastasis Using an Integrin-Targeting Chain-Shaped Nanoparticle

PubMed Central

Peiris, Pubudu M.; Toy, Randall; Doolittle, Elizabeth; Pansky, Jenna; Abramowski, Aaron; Tam, Morgan; Vicente, Peter; Tran, Emily; Hayden, Elliott; Camann, Andrew; Mayer, Aaron; Erokwu, Bernadette O.; Berman, Zachary; Wilson, David; Baskaran, Harihara; Flask, Chris A.; Keri, Ruth A.; Karathanasis, Efstathios

2012-01-01

While the enhanced permeability and retention effect may promote the preferential accumulation of nanoparticles into well-vascularized primary tumors, it is ineffective in the case of metastases hidden within a large population of normal cells. Due to their small size, high dispersion to organs, and low vascularization, metastatic tumors are less accessible to targeted nanoparticles. To tackle these challenges, we designed a nanoparticle for vascular targeting based on an αvβ3 integrin-targeted nanochain particle composed of four iron oxide nanospheres chemically linked in a linear assembly. The chain-shaped nanoparticles enabled enhanced ‘sensing’ of the tumor-associated remodeling of the vascular bed offering increased likelihood of specific recognition of metastatic tumors. Compared to spherical nanoparticles, the chain-shaped nanoparticles resulted in superior targeting of αvβ3 integrin due to geometrically enhanced multivalent docking. We performed multimodal in vivo imaging (Fluorescence Molecular Tomography and Magnetic Resonance Imaging) in a non-invasive and quantitative manner, which showed that the nanoparticles targeted metastases in the liver and lungs with high specificity in a highly aggressive breast tumor model in mice. PMID:23005348

Using GIS Mapping to Target Public Health Interventions: Examining Birth Outcomes Across GIS Techniques.

PubMed

MacQuillan, E L; Curtis, A B; Baker, K M; Paul, R; Back, Y O

2017-08-01

With advances in spatial analysis techniques, there has been a trend in recent public health research to assess the contribution of area-level factors to health disparity for a number of outcomes, including births. Although it is widely accepted that health disparity is best addressed by targeted, evidence-based and data-driven community efforts, and despite national and local focus in the U.S. to reduce infant mortality and improve maternal-child health, there is little work exploring how choice of scale and specific GIS visualization technique may alter the perception of analyses focused on health disparity in birth outcomes. Retrospective cohort study. Spatial analysis of individual-level vital records data for low birthweight and preterm births born to black women from 2007 to 2012 in one mid-sized Midwest city using different geographic information systems (GIS) visualization techniques [geocoded address records were aggregated at two levels of scale and additionally mapped using kernel density estimation (KDE)]. GIS analyses in this study support our hypothesis that choice of geographic scale (neighborhood or census tract) for aggregated birth data can alter programmatic decision-making. Results indicate that the relative merits of aggregated visualization or the use of KDE technique depend on the scale of intervention. The KDE map proved useful in targeting specific areas for interventions in cities with smaller populations and larger census tracts, where they allow for greater specificity in identifying intervention areas. When public health programmers seek to inform intervention placement in highly populated areas, however, aggregated data at the census tract level may be preferred, since it requires lower investments in terms of time and cartographic skill and, unlike neighborhood, census tracts are standardized in that they become smaller as the population density of an area increases.

Role of lymphocyte-specific protein tyrosine kinase (LCK) in the expansion of glioma-initiating cells by fractionated radiation

DOE Office of Scientific and Technical Information (OSTI.GOV)

Kim, Rae-Kwon; Yoon, Chang-Hwan; Hyun, Kyung-Hwan

2010-11-26

Research highlights: {yields} Activation of Lymphocyte-specific protein tyrosine kinase (LCK) is involved in the fractionated radiation-induced expansion of glioma stem-like cells. {yields} Inhibition of LCK prevents acquisition of fractionated radiation-induced resistance to chemotherapeutic treatment. {yields} LCK activity is critical for the maintenance of self-renewal in glioma stem-like cells. -- Abstract: Brain cancers frequently recur or progress as focal masses after treatment with ionizing radiation. Radiation used to target gliomas may expand the cancer stem cell population and enhance the aggressiveness of tumors; however, the mechanisms underlying the expansion of cancer stem cell population after radiation have remained unclear. In thismore » study, we show that LCK (lymphocyte-specific protein tyrosine kinase) is involved in the fractionated radiation-induced expansion of the glioma-initiating cell population and acquisition of resistance to anticancer treatments. Fractionated radiation caused a selective increase in the activity of LCK, a Src family non-receptor tyrosine kinase. The activities of other Src family kinases Src, Fyn, and Lyn were not significantly increased. Moreover, knockdown of LCK expression with a specific small interfering RNA (siRNA) effectively blocked fractionated radiation-induced expansion of the CD133{sup +} cell population. siRNA targeting of LCK also suppressed fractionated radiation-induced expression of the glioma stem cell marker proteins CD133, Nestin, and Musashi. Expression of the known self-renewal-related proteins Notch2 and Sox2 in glioma cells treated with fractionated radiation was also downregulated by LCK inhibition. Moreover, siRNA-mediated knockdown of LCK effectively restored the sensitivity of glioma cells to cisplatin and etoposide. These results indicate that the non-receptor tyrosine kinase LCK is critically involved in fractionated radiation-induced expansion of the glioma-initiating cell population and decreased cellular sensitivity to anticancer treatments. These findings may provide pivotal insights in the context of fractionated radiation-based therapeutic interventions in brain cancer.« less

A Predictive Model for Readmissions Among Medicare Patients in a California Hospital.

PubMed

Duncan, Ian; Huynh, Nhan

2017-11-17

Predictive models for hospital readmission rates are in high demand because of the Centers for Medicare & Medicaid Services (CMS) Hospital Readmission Reduction Program (HRRP). The LACE index is one of the most popular predictive tools among hospitals in the United States. The LACE index is a simple tool with 4 parameters: Length of stay, Acuity of admission, Comorbidity, and Emergency visits in the previous 6 months. The authors applied logistic regression to develop a predictive model for a medium-sized not-for-profit community hospital in California using patient-level data with more specific patient information (including 13 explanatory variables). Specifically, the logistic regression is applied to 2 populations: a general population including all patients and the specific group of patients targeted by the CMS penalty (characterized as ages 65 or older with select conditions). The 2 resulting logistic regression models have a higher sensitivity rate compared to the sensitivity of the LACE index. The C statistic values of the model applied to both populations demonstrate moderate levels of predictive power. The authors also build an economic model to demonstrate the potential financial impact of the use of the model for targeting high-risk patients in a sample hospital and demonstrate that, on balance, whether the hospital gains or loses from reducing readmissions depends on its margin and the extent of its readmission penalties.

A Unique Opportunity to Test Whether Cell Fusion is a Mechanism of Breast Cancer Metastasis

DTIC Science & Technology

2013-07-01

populations. Last cycle we optimized electroporation conditions for T47D and human mesenchymal stem cell populations and this cycle we have improved our...specific receptor-ligand interactions necessary for cell fusion, to produce a target for drug therapy. Post-fusion events might also be investigated...new tools for the study of the complex processes of cell fusion. The inducible bipartite nature of these strategies assures the accurate

Identification and genetic analysis of cancer cells with PCR-activated cell sorting

PubMed Central

Eastburn, Dennis J.; Sciambi, Adam; Abate, Adam R.

2014-01-01

Cell sorting is a central tool in life science research for analyzing cellular heterogeneity or enriching rare cells out of large populations. Although methods like FACS and FISH-FC can characterize and isolate cells from heterogeneous populations, they are limited by their reliance on antibodies, or the requirement to chemically fix cells. We introduce a new cell sorting technology that robustly sorts based on sequence-specific analysis of cellular nucleic acids. Our approach, PCR-activated cell sorting (PACS), uses TaqMan PCR to detect nucleic acids within single cells and trigger their sorting. With this method, we identified and sorted prostate cancer cells from a heterogeneous population by performing >132 000 simultaneous single-cell TaqMan RT-PCR reactions targeting vimentin mRNA. Following vimentin-positive droplet sorting and downstream analysis of recovered nucleic acids, we found that cancer-specific genomes and transcripts were significantly enriched. Additionally, we demonstrate that PACS can be used to sort and enrich cells via TaqMan PCR reactions targeting single-copy genomic DNA. PACS provides a general new technical capability that expands the application space of cell sorting by enabling sorting based on cellular information not amenable to existing approaches. PMID:25030902

75 FR 28027 - Tobacco Products Scientific Advisory Committee; Notice of Meeting

Federal Register 2010, 2011, 2012, 2013, 2014

2010-05-19

.... Marketing strategies for various brands/subbrands of menthol cigarettes, including strategies targeted to particular demographic groups. 14. Marketing strategies for various brands/subbrands of menthol cigarettes... effects of menthol, biomarkers of disease risk, marketing data, and population effects. Specific areas of...

76 FR 35454 - Agency Information Collection Activities: Submission for OMB Review; Comment Request

Federal Register 2010, 2011, 2012, 2013, 2014

2011-06-17

..., selective and targeted prevention activities and services; and (4) to collect performance and outcome data... other Federal partners to use in working with States and Territories to improve their behavioral health... seventeen goals were population specific (pregnant [[Page 35456

Insertional Mutagenesis by CRISPR/Cas9 Ribonucleoprotein Gene Editing in Cells Targeted for Point Mutation Repair Directed by Short Single-Stranded DNA Oligonucleotides.

PubMed

Rivera-Torres, Natalia; Banas, Kelly; Bialk, Pawel; Bloh, Kevin M; Kmiec, Eric B

2017-01-01

CRISPR/Cas9 and single-stranded DNA oligonucleotides (ssODNs) have been used to direct the repair of a single base mutation in human genes. Here, we examine a method designed to increase the precision of RNA guided genome editing in human cells by utilizing a CRISPR/Cas9 ribonucleoprotein (RNP) complex to initiate DNA cleavage. The RNP is assembled in vitro and induces a double stranded break at a specific site surrounding the mutant base designated for correction by the ssODN. We use an integrated mutant eGFP gene, bearing a single base change rendering the expressed protein nonfunctional, as a single copy target in HCT 116 cells. We observe significant gene correction activity of the mutant base, promoted by the RNP and single-stranded DNA oligonucleotide with validation through genotypic and phenotypic readout. We demonstrate that all individual components must be present to obtain successful gene editing. Importantly, we examine the genotype of individually sorted corrected and uncorrected clonally expanded cell populations for the mutagenic footprint left by the action of these gene editing tools. While the DNA sequence of the corrected population is exact with no adjacent sequence modification, the uncorrected population exhibits heterogeneous mutagenicity with a wide variety of deletions and insertions surrounding the target site. We designate this type of DNA aberration as on-site mutagenicity. Analyses of two clonal populations bearing specific DNA insertions surrounding the target site, indicate that point mutation repair has occurred at the level of the gene. The phenotype, however, is not rescued because a section of the single-stranded oligonucleotide has been inserted altering the reading frame and generating truncated proteins. These data illustrate the importance of analysing mutagenicity in uncorrected cells. Our results also form the basis of a simple model for point mutation repair directed by a short single-stranded DNA oligonucleotides and CRISPR/Cas9 ribonucleoprotein complex.

Insertional Mutagenesis by CRISPR/Cas9 Ribonucleoprotein Gene Editing in Cells Targeted for Point Mutation Repair Directed by Short Single-Stranded DNA Oligonucleotides

PubMed Central

Rivera-Torres, Natalia; Bialk, Pawel; Bloh, Kevin M.; Kmiec, Eric B.

2017-01-01

CRISPR/Cas9 and single-stranded DNA oligonucleotides (ssODNs) have been used to direct the repair of a single base mutation in human genes. Here, we examine a method designed to increase the precision of RNA guided genome editing in human cells by utilizing a CRISPR/Cas9 ribonucleoprotein (RNP) complex to initiate DNA cleavage. The RNP is assembled in vitro and induces a double stranded break at a specific site surrounding the mutant base designated for correction by the ssODN. We use an integrated mutant eGFP gene, bearing a single base change rendering the expressed protein nonfunctional, as a single copy target in HCT 116 cells. We observe significant gene correction activity of the mutant base, promoted by the RNP and single-stranded DNA oligonucleotide with validation through genotypic and phenotypic readout. We demonstrate that all individual components must be present to obtain successful gene editing. Importantly, we examine the genotype of individually sorted corrected and uncorrected clonally expanded cell populations for the mutagenic footprint left by the action of these gene editing tools. While the DNA sequence of the corrected population is exact with no adjacent sequence modification, the uncorrected population exhibits heterogeneous mutagenicity with a wide variety of deletions and insertions surrounding the target site. We designate this type of DNA aberration as on-site mutagenicity. Analyses of two clonal populations bearing specific DNA insertions surrounding the target site, indicate that point mutation repair has occurred at the level of the gene. The phenotype, however, is not rescued because a section of the single-stranded oligonucleotide has been inserted altering the reading frame and generating truncated proteins. These data illustrate the importance of analysing mutagenicity in uncorrected cells. Our results also form the basis of a simple model for point mutation repair directed by a short single-stranded DNA oligonucleotides and CRISPR/Cas9 ribonucleoprotein complex. PMID:28052104

Retroviral integration: Site matters

PubMed Central

Demeulemeester, Jonas; De Rijck, Jan

2015-01-01

Here, we review genomic target site selection during retroviral integration as a multistep process in which specific biases are introduced at each level. The first asymmetries are introduced when the virus takes a specific route into the nucleus. Next, by co‐opting distinct host cofactors, the integration machinery is guided to particular chromatin contexts. As the viral integrase captures a local target nucleosome, specific contacts introduce fine‐grained biases in the integration site distribution. In vivo, the established population of proviruses is subject to both positive and negative selection, thereby continuously reshaping the integration site distribution. By affecting stochastic proviral expression as well as the mutagenic potential of the virus, integration site choice may be an inherent part of the evolutionary strategies used by different retroviruses to maximise reproductive success. PMID:26293289

Systemic approaches identify a garlic-derived chemical, Z-ajoene, as a glioblastoma multiforme cancer stem cell-specific targeting agent.

PubMed

Jung, Yuchae; Park, Heejoo; Zhao, Hui-Yuan; Jeon, Raok; Ryu, Jae-Ha; Kim, Woo-Young

2014-07-01

Glioblastoma multiforme (GBM) is one of the most common brain malignancies and has a very poor prognosis. Recent evidence suggests that the presence of cancer stem cells (CSC) in GBM and the rare CSC subpopulation that is resistant to chemotherapy may be responsible for the treatment failure and unfavorable prognosis of GBM. A garlic-derived compound, Z-ajoene, has shown a range of biological activities, including anti-proliferative effects on several cancers. Here, we demonstrated for the first time that Z-ajoene specifically inhibits the growth of the GBM CSC population. CSC sphere-forming inhibition was achieved at a concentration that did not exhibit a cytotoxic effect in regular cell culture conditions. The specificity of this inhibitory effect on the CSC population was confirmed by detecting CSC cell surface marker CD133 expression and biochemical marker ALDH activity. In addition, stem cell-related mRNA profiling and real-time PCR revealed the differential expression of CSC-specific genes, including Notch, Wnt, and Hedgehog, upon treatment with Z-ajoene. A proteomic approach, i.e., reverse-phase protein array (RPPA) and Western blot analysis, showed decreased SMAD4, p-AKT, 14.3.3 and FOXO3A expression. The protein interaction map (http://string-db.org/) of the identified molecules suggested that the AKT, ERK/p38 and TGFβ signaling pathways are key mediators of Z-ajoene's action, which affects the transcriptional network that includes FOXO3A. These biological and bioinformatic analyses collectively demonstrate that Z-ajoene is a potential candidate for the treatment of GBM by specifically targeting GBM CSCs. We also show how this systemic approach strengthens the identification of new therapeutic agents that target CSCs.

Evaluating Vaccination Strategies for Zika Virus in the Americas.

PubMed

Durham, David P; Fitzpatrick, Meagan C; Ndeffo-Mbah, Martial L; Parpia, Alyssa S; Michael, Nelson L; Galvani, Alison P

2018-05-01

Mosquito-borne and sexually transmitted Zika virus has become widespread across Central and South America and the Caribbean. Many Zika vaccine candidates are under active development. To quantify the effect of Zika vaccine prioritization of females aged 9 to 49 years, followed by males aged 9 to 49 years, on incidence of prenatal Zika infections. A compartmental model of Zika transmission between mosquitoes and humans was developed and calibrated to empirical estimates of country-specific mosquito density. Mosquitoes were stratified into susceptible, exposed, and infected groups; humans were stratified into susceptible, exposed, infected, recovered, and vaccinated groups. Age-specific fertility rates, Zika sexual transmission, and country-specific demographics were incorporated. 34 countries and territories in the Americas with documented Zika outbreaks. Males and females aged 9 to 49 years. Age- and sex-targeted immunization using a Zika vaccine with 75% efficacy. Annual prenatal Zika infections. For a base-case vaccine efficacy of 75% and vaccination coverage of 90%, immunizing females aged 9 to 49 years (the World Health Organization target population) would reduce the incidence of prenatal infections by at least 94%, depending on the country-specific Zika attack rate. In regions where an outbreak is not expected for at least 10 years, vaccination of women aged 15 to 29 years is more efficient than that of women aged 30 years or older. Population-level modeling may not capture all local and neighborhood-level heterogeneity in mosquito abundance or Zika incidence. A Zika vaccine of moderate to high efficacy may virtually eliminate prenatal infections through a combination of direct protection and transmission reduction. Efficiency of age-specific targeting of Zika vaccination depends on the timing of future outbreaks. National Institutes of Health.

Methylation-sensitive enrichment of minor DNA alleles using a double-strand DNA-specific nuclease.

PubMed

Liu, Yibin; Song, Chen; Ladas, Ioannis; Fitarelli-Kiehl, Mariana; Makrigiorgos, G Mike

2017-04-07

Aberrant methylation changes, often present in a minor allelic fraction in clinical samples such as plasma-circulating DNA (cfDNA), are potentially powerful prognostic and predictive biomarkers in human disease including cancer. We report on a novel, highly-multiplexed approach to facilitate analysis of clinically useful methylation changes in minor DNA populations. Methylation Specific Nuclease-assisted Minor-allele Enrichment (MS-NaME) employs a double-strand-specific DNA nuclease (DSN) to remove excess DNA with normal methylation patterns. The technique utilizes oligonucleotide-probes that direct DSN activity to multiple targets in bisulfite-treated DNA, simultaneously. Oligonucleotide probes targeting unmethylated sequences generate local double stranded regions resulting to digestion of unmethylated targets, and leaving methylated targets intact; and vice versa. Subsequent amplification of the targeted regions results in enrichment of the targeted methylated or unmethylated minority-epigenetic-alleles. We validate MS-NaME by demonstrating enrichment of RARb2, ATM, MGMT and GSTP1 promoters in multiplexed MS-NaME reactions (177-plex) using dilutions of methylated/unmethylated DNA and in DNA from clinical lung cancer samples and matched normal tissue. MS-NaME is a highly scalable single-step approach performed at the genomic DNA level in solution that combines with most downstream detection technologies including Sanger sequencing, methylation-sensitive-high-resolution melting (MS-HRM) and methylation-specific-Taqman-based-digital-PCR (digital Methylight) to boost detection of low-level aberrant methylation-changes. © The Author(s) 2016. Published by Oxford University Press on behalf of Nucleic Acids Research.

In vivo modulation of thymus-derived lymphocytes with monoclonal antibodies in mice. III. Spontaneous and natural cytotoxic effector cells.

PubMed Central

Herbert, A G; Le Gros, G S; Bidawid, S; Watson, J D

1984-01-01

Cytotoxic effector cell populations in murine spleen can be characterized by the phenotype of the cytotoxic cells or the nature of target cells. Lytic events can be antigen-specific, MHC-restricted and clonal, or target cell-specific but apparently non-MHC-restricted. Two cytotoxic effectors of this latter category are spontaneous and natural killers. Normal spleen cells from (BALB/c X DBA/2J)F1 mice (CDF1) cultured without added antigen develop a population of Thy-1+ spontaneous cytotoxic lymphocytes (SCTL) that lyse the DBA/2J mastocytoma P815, as well as the BALB/c-derived plasmacytomas MOPC-11 and SP2/0. Cold target competition experiments reveal the BALB/c-derived plasmacytomas MOPC-11, SP2/0, J558 and the A strain-derived T cell lymphoma YAC-1, but not normal lymphoblasts, block the lysis of P815 target cells. Thus, while these tumour cells appear to express common antigens which are recognized by SCTL cells, plasmacytomas such as J558 are not susceptible to lysis by SCTL. The relationship of SCTL to natural killer (NK) cells was examined. In-vivo treatment of mice with monoclonal anti-Thy-1 antibody leads to a rapid loss of SCTL and precursors from the spleen, but there is a concomitant increase in NK cell activity. PMID:6607213

Targeted delivery of anti-coxsackievirus siRNAs using ligand-conjugated packaging RNAs.

PubMed

Zhang, Huifang M; Su, Yue; Guo, Songchuan; Yuan, Ji; Lim, Travis; Liu, Jing; Guo, Peixuan; Yang, Decheng

2009-09-01

Coxsackievirus B3 (CVB3) is a common pathogen of myocarditis. We previously synthesized a siRNA targeting the CVB3 protease 2A (siRNA/2A) gene and achieved reduction of CVB3 replication by 92% in vitro. However, like other drugs under development, CVB3 siRNA faces a major challenge of targeted delivery. In this study, we investigated a novel approach to deliver CVB3 siRNAs to a specific cell population (e.g. HeLa cells containing folate receptor) using receptor ligand (folate)-linked packaging RNA (pRNA) from bacterial phage phi29. pRNA monomers can spontaneously form dimers and multimers under optimal conditions by base-pairing between their stem loops. By covalently linking a fluorescence-tag to folate, we delivered the conjugate specifically to HeLa cells without the need of transfection. We further demonstrated that pRNA covalently conjugated to siRNA/2A achieved an equivalent antiviral effect to that of the siRNA/2A alone. Finally, the drug targeted delivery was further evaluated by using pRNA monomers or dimers, which carried both the siRNA/2A and folate ligand and demonstrated that both of them strongly inhibited CVB3 replication. These data indicate that pRNA as a siRNA carrier can specifically deliver the drug to target cells via its ligand and specific receptor interaction and inhibit virus replication effectively.

IT-25DEVELOPMENTALLY REGULATED ANTIGENS FOR IMMUNOLOGIC TARGETING OF MEDULLOBLASTOMA SUBTYPES

PubMed Central

Pham, Christina; Flores, Catherine; Pei, Yanxin; Wechsler-Reya, Robert; Mitchell, Duane

2014-01-01

INTRODUCTION: Medulloblastoma (MB) remains incurable in one third of patients despite aggressive multi-modality standard therapies. Immunotherapy presents a promising alternative by specifically targeting cancer cells. To date, there have been no successful immunologic applications targeting MB. Emerging evidence from integrated genomic studies has suggested MB variants arise from deregulation of pathways affecting proliferation of progenitor cell populations within the developing cerebellum. Using total embryonic RNA as a source of tumor rejection antigens is attractive because it can be delivered as a single vaccine, target both known and unknown fetal proteins, and can be refined to preferentially treat distinct MB subtypes. METHODS: We have created two transplantable, syngeneic animal MB models recapitulating human SHH and Group 3 variants to investigate the immunologic targeting of different MB subtypes. We generated T cells specific to the developing mouse cerebellum (P5) and tested their reactivity to target cells pulsed with total RNA from two MB subtypes and the normal brain. Immune responses were evaluated by measuring cytokine secretion following re-stimulation of activated T cells with both normal and tumor cell targets. In vivo antitumor efficacy was also tested in survival studies of intracranial tumor-bearing animals. RESULTS: We generated T cells specific to the developing cerebellum in vitro, confirming the immunogenicity of developmentally regulated antigens. Additionally, we have shown that developmental antigen-specific T cells produce high levels of Th1-type cytokines in response to tumor cells of two immunologically distinct subtypes of MB. Interestingly, developmental antigen specific T cells do not show cross reactivity with the normal brain or subsequent stages of the developing brain after P5. Targeting developmental antigens also conferred a significant survival benefit in a treatment model of Group 3 tumor bearing animals. CONCLUSIONS: Developmental antigens can safely target multiple MB subtypes with equal effectiveness compared to previously established total tumor strategies.

Rapid transcriptional acclimation following transgenerational exposure of oysters to ocean acidification.

PubMed

Goncalves, Priscila; Anderson, Kelli; Thompson, Emma L; Melwani, Aroon; Parker, Laura M; Ross, Pauline M; Raftos, David A

2016-10-01

Marine organisms need to adapt in order to cope with the adverse effects of ocean acidification and warming. Transgenerational exposure to CO2 stress has been shown to enhance resilience to ocean acidification in offspring from a number of species. However, the molecular basis underlying such adaptive responses is currently unknown. Here, we compared the transcriptional profiles of two genetically distinct oyster breeding lines following transgenerational exposure to elevated CO2 in order to explore the molecular basis of acclimation or adaptation to ocean acidification in these organisms. The expression of key target genes associated with antioxidant defence, metabolism and the cytoskeleton was assessed in oysters exposed to elevated CO2 over three consecutive generations. This set of target genes was chosen specifically to test whether altered responsiveness of intracellular stress mechanisms contributes to the differential acclimation of oyster populations to climate stressors. Transgenerational exposure to elevated CO2 resulted in changes to both basal and inducible expression of those key target genes (e.g. ecSOD, catalase and peroxiredoxin 6), particularly in oysters derived from the disease-resistant, fast-growing B2 line. Exposure to CO2 stress over consecutive generations produced opposite and less evident effects on transcription in a second population that was derived from wild-type (nonselected) oysters. The analysis of key target genes revealed that the acute responses of oysters to CO2 stress appear to be affected by population-specific genetic and/or phenotypic traits and by the CO2 conditions to which their parents had been exposed. This supports the contention that the capacity for heritable change in response to ocean acidification varies between oyster breeding lines and is mediated by parental conditioning. © 2016 John Wiley & Sons Ltd.

An approximation of herd effect due to vaccinating children against seasonal influenza - a potential solution to the incorporation of indirect effects into static models.

PubMed

Van Vlaenderen, Ilse; Van Bellinghen, Laure-Anne; Meier, Genevieve; Nautrup, Barbara Poulsen

2013-01-22

Indirect herd effect from vaccination of children offers potential for improving the effectiveness of influenza prevention in the remaining unvaccinated population. Static models used in cost-effectiveness analyses cannot dynamically capture herd effects. The objective of this study was to develop a methodology to allow herd effect associated with vaccinating children against seasonal influenza to be incorporated into static models evaluating the cost-effectiveness of influenza vaccination. Two previously published linear equations for approximation of herd effects in general were compared with the results of a structured literature review undertaken using PubMed searches to identify data on herd effects specific to influenza vaccination. A linear function was fitted to point estimates from the literature using the sum of squared residuals. The literature review identified 21 publications on 20 studies for inclusion. Six studies provided data on a mathematical relationship between effective vaccine coverage in subgroups and reduction of influenza infection in a larger unvaccinated population. These supported a linear relationship when effective vaccine coverage in a subgroup population was between 20% and 80%. Three studies evaluating herd effect at a community level, specifically induced by vaccinating children, provided point estimates for fitting linear equations. The fitted linear equation for herd protection in the target population for vaccination (children) was slightly less conservative than a previously published equation for herd effects in general. The fitted linear equation for herd protection in the non-target population was considerably less conservative than the previously published equation. This method of approximating herd effect requires simple adjustments to the annual baseline risk of influenza in static models: (1) for the age group targeted by the childhood vaccination strategy (i.e. children); and (2) for other age groups not targeted (e.g. adults and/or elderly). Two approximations provide a linear relationship between effective coverage and reduction in the risk of infection. The first is a conservative approximation, recommended as a base-case for cost-effectiveness evaluations. The second, fitted to data extracted from a structured literature review, provides a less conservative estimate of herd effect, recommended for sensitivity analyses.

Surveillance and response for high-risk populations: what can malaria elimination programmes learn from the experience of HIV?

PubMed

Jacobson, Jerry O; Cueto, Carmen; Smith, Jennifer L; Hwang, Jimee; Gosling, Roly; Bennett, Adam

2017-01-18

To eliminate malaria, malaria programmes need to develop new strategies for surveillance and response appropriate for the changing epidemiology that accompanies transmission decline, in which transmission is increasingly driven by population subgroups whose behaviours place them at increased exposure. Conventional tools of malaria surveillance and response are likely not sufficient in many elimination settings for accessing high-risk population subgroups, such as mobile and migrant populations (MMPs), given their greater likelihood of asymptomatic infections, illegal risk behaviours, limited access to public health facilities, and high mobility including extended periods travelling away from home. More adaptive, targeted strategies are needed to monitor transmission and intervention coverage effectively in these groups. Much can be learned from HIV programmes' experience with "second generation surveillance", including how to rapidly adapt surveillance and response strategies to changing transmission patterns, biological and behavioural surveys that utilize targeted sampling methods for specific behavioural subgroups, and methods for population size estimation. This paper reviews the strategies employed effectively for HIV programmes and offers considerations and recommendations for adapting them to the malaria elimination context.

Computational identification of miRNAs, their targets and functions in three-spined stickleback (Gasterosteus aculeatus).

PubMed

Chaturvedi, Anurag; Raeymaekers, Joost A M; Volckaert, Filip A M

2014-07-01

An intriguing question in biology is how the evolution of gene regulation is shaped by natural selection in natural populations. Among the many known regulatory mechanisms, regulation of gene expression by microRNAs (miRNAs) is of critical importance. However, our understanding of their evolution in natural populations is limited. Studying the role of miRNAs in three-spined stickleback, an important natural model for speciation research, may provide new insights into adaptive polymorphisms. However, lack of annotation of miRNA genes in its genome is a bottleneck. To fill this research gap, we used the genome of three-spined stickleback to predict miRNAs and their targets. We predicted 1486 mature miRNAs using the homology-based miRNA prediction approach. We then performed functional annotation and enrichment analysis of these targets, which identified over-represented motifs. Further, a database resource (GAmiRdb) has been developed for dynamically searching miRNAs and their targets exclusively in three-spined stickleback. Finally, the database was used in two case studies focusing on freshwater adaptation in natural populations. In the first study, we found 44 genomic regions overlapping with predicted miRNA targets. In the second study, we identified two SNPs altering the MRE seed site of sperm-specific glyceraldehyde-3-phosphate gene. These findings highlight the importance of the GAmiRdb knowledge base in understanding adaptive evolution. © 2014 John Wiley & Sons Ltd.

Long-distance dispersal suppresses introgression of local alleles during range expansions

PubMed Central

Amorim, C E G; Hofer, T; Ray, N; Foll, M; Ruiz-Linares, A; Excoffier, L

2017-01-01

During range expansions, even low levels of interbreeding can lead to massive introgression of local alleles into an invader's genome. Nonetheless, this pattern is not always observed in human populations. For instance, European Americans in North America are barely introgressed by Amerindian genes in spite of known contact and admixture. With coalescent spatially explicit simulations, we examined the impact of long-distance dispersal (LDD) events on introgression of local alleles into the invading population using a set of different demographic scenarios applicable to a diverse range of natural populations and species. More specifically, we consider two distinct LDD models: one where LDD events originate in the range core and targets only the expansion front and a second one where LDD events can occur from any area to any other. We find that LDD generally prevents introgression, but that LDD events specifically targeting the expansion front are most efficient in suppressing introgression. This is likely due to the fact that LDD allows for the presence of a larger number of invader alleles at the wave front, where effective population size is thus increased and local introgressed alleles are rapidly outnumbered. We postulate that the documented settlement of pioneers directly on the wave front in North America has contributed to low levels of Amerindian admixture observed in European Americans and that this phenomenon may well explain the lack of introgression after a range expansion in natural populations without the need to evoke other mechanisms such as natural selection. PMID:27577693

Long-term evidence for the effect of pay-for-performance in primary care on mortality in the UK: a population study.

PubMed

Ryan, Andrew M; Krinsky, Sam; Kontopantelis, Evangelos; Doran, Tim

2016-07-16

Introduced in 2004, the UK's Quality and Outcomes Framework (QOF) is the world's largest primary care pay-for-performance programme. We tested whether the QOF was associated with reduced population mortality. We used population-level mortality statistics between 1994 and 2010 for the UK and other high-income countries that were not exposed to pay-for-performance. The primary outcome was age-adjusted and sex-adjusted mortality per 100,000 people for a composite outcome of chronic disorders that were targeted by the QOF. Secondary outcomes were age-adjusted and sex-adjusted mortality for ischaemic heart disease, cancer, and a composite of all non-targeted conditions. For each study outcome, we created a so-called synthetic UK as a weighted combination of comparison countries. We then estimated difference-in-differences models to test whether mortality fell more in the UK than in the synthetic UK after the QOF. Introduction of the QOF was not significantly associated with changes in population mortality for the composite outcome (-3.68 per 100,000 population [95% CI -8.16 to 0.80]; p=0.107), ischaemic heart disease (-2.21 per 100,000 [-6.86 to 2.44]; p=0.357), cancer (0.28 per 100,000 [-0.99 to 1.55]; p=0.679), or all non-targeted conditions (11.60 per 100,000 [-3.91 to 27.11]; p=0.143). Although we noted small mortality reductions for a composite outcome of targeted disorders, the QOF was not associated with significant changes in mortality. Our findings have implications for the probable effects of similar programmes on population health outcomes. The relation between incentives and mortality needs to be assessed in specific disease domains. None. Copyright © 2016 Elsevier Ltd. All rights reserved.

Genetic diversity of transmission-blocking vaccine candidate Pvs48/45 in Plasmodium vivax populations in China.

PubMed

Feng, Hui; Gupta, Bhavna; Wang, Meilian; Zheng, Wenqi; Zheng, Li; Zhu, Xiaotong; Yang, Yimei; Fang, Qiang; Luo, Enjie; Fan, Qi; Tsuboi, Takafumi; Cao, Yaming; Cui, Liwang

2015-12-01

The male gamete fertilization factor P48/45 in malaria parasites is a prime transmission-blocking vaccine (TBV) candidate. Efforts to develop antimalarial vaccines are often thwarted by genetic diversity of the target antigens. Here we evaluated the genetic diversity of Pvs48/45 gene in global Plasmodium vivax populations. We determined 200 Pvs48/45 sequences collected from temperate and subtropical parasite populations in China. Population genetic and evolutionary analyses were performed to determine the levels of genetic diversity, potential signature of selection, and population differentiation. Analysis of the Pvs48/45 sequences from 200 P. vivax parasites collected in a temperate and a tropical region revealed a low level of genetic diversity (π = 0.0012) with 14 single nucleotide polymorphisms, of which 11 were nonsynonymous. Analysis of 344 Pvs48/45 sequences from nine worldwide P. vivax populations detected a total of 38 haplotypes, of which 13 haplotypes were present only once. Multiple tests for selection confirmed a signature of positive selection on Pvs48/45 with selection skewed to the second cysteine domain. Haplotype network analysis and Wright's fixation index showed large geographical differentiation with the presence of continent-or region-specific mutations in this gene. Pvs48/45 displays low levels of genetic diversity with the presence of region-specific mutations. Some of the mutations may be potential epitope targets based on their positions in the predicted structure, highlighting the need for future evaluation of these mutations in designing Pvs48/45-based TBV.

Analysis of Individuals from a Dengue-Endemic Region Helps Define the Footprint and Repertoire of Antibodies Targeting Dengue Virus 3 Type-Specific Epitopes

PubMed Central

Andrade, Daniela V.; Katzelnick, Leah C.; Widman, Doug G.; Balmaseda, Angel; de Silva, Aravinda M.; Baric, Ralph S.

2017-01-01

ABSTRACT The four dengue virus serotypes (DENV1 to 4) cause dengue, a major public health problem worldwide. Individuals exposed to primary DENV infections develop serotype-specific neutralizing antibodies, including strongly neutralizing antibodies targeting quaternary epitopes. To date, no studies have measured the levels and kinetics of serum antibodies directed to such epitopes among populations in regions where dengue is endemic. Here, we use a recombinant DENV4 (rDENV4/3-M14) displaying a major DENV3 type-specific quaternary epitope recognized by human monoclonal antibody 5J7 to measure the proportion, magnitude, and kinetics of DENV3 type-specific neutralizing antibody responses targeting this epitope. Primary DENV3 sera from 30 individuals in a dengue hospital-based study in Nicaragua were studied 3, 6, 12, and 18 months post-infection, alongside samples collected annually 1 to 4 years post-primary DENV3 infection from 10 individuals in a cohort study in Nicaragua. We found substantial individual variation in the proportion of DENV3 type-specific neutralizing antibody titers attributed to the 5J7 epitope (range, 0 to 100%), with the mean significantly increasing from 22.6% to 41.4% from 3 to 18 months. We extended the transplanted DENV3 5J7 epitope on the virion (rDENV4/3-M16), resulting in increased recognition in several individuals, helping define the footprint of the epitope. However, 37% and 13% of the subjects still showed little to no recognition of the 5J7 epitope at 3 and 18 months, respectively, indicating that one or more additional DENV3 type-specific epitopes exist. Overall, this study demonstrates how DENV-immune plasma from populations from areas of endemicity, when coupled with structurally guided recombinant viruses, can help characterize the epitope-specific neutralizing antibody response in natural DENV infections, with direct implications for design and evaluation of dengue vaccines. PMID:28928210

Single-cell RNA-sequencing reveals a distinct population of proglucagon-expressing cells specific to the mouse upper small intestine.

PubMed

Glass, Leslie L; Calero-Nieto, Fernando J; Jawaid, Wajid; Larraufie, Pierre; Kay, Richard G; Göttgens, Berthold; Reimann, Frank; Gribble, Fiona M

2017-10-01

To identify sub-populations of intestinal preproglucagon-expressing (PPG) cells producing Glucagon-like Peptide-1, and their associated expression profiles of sensory receptors, thereby enabling the discovery of therapeutic strategies that target these cell populations for the treatment of diabetes and obesity. We performed single cell RNA sequencing of PPG-cells purified by flow cytometry from the upper small intestine of 3 GLU-Venus mice. Cells from 2 mice were sequenced at low depth, and from the third mouse at high depth. High quality sequencing data from 234 PPG-cells were used to identify clusters by tSNE analysis. qPCR was performed to compare the longitudinal and crypt/villus locations of cluster-specific genes. Immunofluorescence and mass spectrometry were used to confirm protein expression. PPG-cells formed 3 major clusters: a group with typical characteristics of classical L-cells, including high expression of Gcg and Pyy (comprising 51% of all PPG-cells); a cell type overlapping with Gip-expressing K-cells (14%); and a unique cluster expressing Tph1 and Pzp that was predominantly located in proximal small intestine villi and co-produced 5-HT (35%). Expression of G-protein coupled receptors differed between clusters, suggesting the cell types are differentially regulated and would be differentially targetable. Our findings support the emerging concept that many enteroendocrine cell populations are highly overlapping, with individual cells producing a range of peptides previously assigned to distinct cell types. Different receptor expression profiles across the clusters highlight potential drug targets to increase gut hormone secretion for the treatment of diabetes and obesity. Copyright © 2017 The Authors. Published by Elsevier GmbH.. All rights reserved.

Host specificity of microsporidia pathogenic to the gypsy moth, Lymantria dispar (L.): field studies in Slovakia.

PubMed

Solter, Leellen F; Pilarska, Daniela K; McManus, Michael L; Zúbrik, Milan; Patocka, Jan; Huang, Wei-Fone; Novotný, Julius

2010-09-01

Several species of microsporidia are important chronic pathogens of Lymantria dispar in Europe but have never been recovered from North American gypsy moth populations. The major issue for their introduction into North American L. dispar populations is concern about their safety to native non-target insects. In this study, we evaluated the susceptibility of sympatric non-target Lepidoptera to two species of microsporidia, Nosema lymantriae and Vairimorpha disparis, isolated from European populations of L. dispar and applied in field plots in Slovakia. Application of ultra low volume sprays of the microsporidia maximized coverage of infective spores in a complex natural environment and, thus, exposure of non-target species to the pathogens. Of 653 non-target larvae collected from plots treated with V. disparis in 2002, 18 individual larvae representing nine species in four families were infected. These plots were monitored for two subsequent seasons and V. disparis was not recovered from non-target species. Of 2571 non-target larvae collected in N. lymantriae-treated sites, one larva was found to be infected. Both species of microsporidia, particularly N. lymantriae, appear to have a very narrow host range in the field, even when an inundative technique is used for their introduction. V. disparis infections in L. dispar exceeded 40% of recovered larvae in the treated study sites; infection rates were lower in sites sprayed with N. lymantriae. Several naturally-occurring pathogens were recorded from the non-target species. The most common pathogen, isolated from 21 species in eight families, was a microsporidium in the genus Cystosporogenes. Copyright 2010 Elsevier Inc. All rights reserved.

Planning Developmental Interventions for Adult Students.

ERIC Educational Resources Information Center

Champagne, Delight E.

Student affairs professionals have come to realize that the student body on college campuses is changing. Adult students are filling the spaces left vacant by a diminishing traditional-aged student population. Interventions in student affairs, however, are often targeted for the specific developmental tasks of the traditional student. Student…

Optimisation modelling to assess cost of dietary improvement in remote Aboriginal Australia.

PubMed

Brimblecombe, Julie; Ferguson, Megan; Liberato, Selma C; O'Dea, Kerin; Riley, Malcolm

2013-01-01

The cost and dietary choices required to fulfil nutrient recommendations defined nationally, need investigation, particularly for disadvantaged populations. We used optimisation modelling to examine the dietary change required to achieve nutrient requirements at minimum cost for an Aboriginal population in remote Australia, using where possible minimally-processed whole foods. A twelve month cross-section of population-level purchased food, food price and nutrient content data was used as the baseline. Relative amounts from 34 food group categories were varied to achieve specific energy and nutrient density goals at minimum cost while meeting model constraints intended to minimise deviation from the purchased diet. Simultaneous achievement of all nutrient goals was not feasible. The two most successful models (A & B) met all nutrient targets except sodium (146.2% and 148.9% of the respective target) and saturated fat (12.0% and 11.7% of energy). Model A was achieved with 3.2% lower cost than the baseline diet (which cost approximately AUD$13.01/person/day) and Model B at 7.8% lower cost but with a reduction in energy of 4.4%. Both models required very large reductions in sugar sweetened beverages (-90%) and refined cereals (-90%) and an approximate four-fold increase in vegetables, fruit, dairy foods, eggs, fish and seafood, and wholegrain cereals. This modelling approach suggested population level dietary recommendations at minimal cost based on the baseline purchased diet. Large shifts in diet in remote Aboriginal Australian populations are needed to achieve national nutrient targets. The modeling approach used was not able to meet all nutrient targets at less than current food expenditure.

Emerging Vaccine Therapy Approaches for Prostate Cancer

PubMed Central

Sonpavde, Guru; Slawin, Kevin M; Spencer, David M; Levitt, Jonathan M

2010-01-01

Prostate cancer vaccines attempt to induce clinically relevant, cancer-specific systemic immune responses in patients with prostate cancer and represent a new class of targeted, nontoxic therapies. With a growing array of vaccine technologies in preclinical or clinical development, autologous antigen-presenting cell vaccines loaded with the antigen, prostate acid phosphatase, and poxvirus vaccines targeting prostate-specific antigen have recently demonstrated a significant survival benefit in randomized trials of patients with metastatic castration-resistant prostate cancer, whereas others have failed to demonstrate any benefit. The combination of vaccines with chemotherapy, radiotherapy, and other biologic agents is also being evaluated. Efforts to optimize vaccine approaches and select ideal patient populations need to continue to build on these early successes. PMID:20428291

Undoing an Epidemiological Paradox: The Tobacco Industry’s Targeting of US Immigrants

PubMed Central

Acevedo-Garcia, Dolores; Barbeau, Elizabeth; Bishop, Jennifer Anne; Pan, Jocelyn; Emmons, Karen M.

2004-01-01

Objectives. We sought to ascertain whether the tobacco industry has conceptualized the US immigrant population as a separate market. Methods. We conducted a content analysis of major tobacco industry documents. Results. The tobacco industry has engaged in 3 distinct marketing strategies aimed at US immigrants: geographically based marketing directed toward immigrant communities, segmentation based on immigrants’ assimilation status, and coordinated marketing focusing on US immigrant groups and their countries of origin. Conclusions. Public health researchers should investigate further the tobacco industry’s characterization of the assimilated and non-assimilated immigrant markets, and its specific strategies for targeting these groups, in order to develop informed national and international tobacco control countermarketing strategies designed to protect immigrant populations and their countries of origin. PMID:15569972

Retention of Ag-specific memory CD4+ T cells in the draining lymph node indicates lymphoid tissue resident memory populations.

PubMed

Marriott, Clare L; Dutton, Emma E; Tomura, Michio; Withers, David R

2017-05-01

Several different memory T-cell populations have now been described based upon surface receptor expression and migratory capabilities. Here we have assessed murine endogenous memory CD4 + T cells generated within a draining lymph node and their subsequent migration to other secondary lymphoid tissues. Having established a model response targeting a specific peripheral lymph node, we temporally labelled all the cells within draining lymph node using photoconversion. Tracking of photoconverted and non-photoconverted Ag-specific CD4 + T cells revealed the rapid establishment of a circulating memory population in all lymph nodes within days of immunisation. Strikingly, a resident memory CD4 + T cell population became established in the draining lymph node and persisted for several months in the absence of detectable migration to other lymphoid tissue. These cells most closely resembled effector memory T cells, usually associated with circulation through non-lymphoid tissue, but here, these cells were retained in the draining lymph node. These data indicate that lymphoid tissue resident memory CD4 + T-cell populations are generated in peripheral lymph nodes following immunisation. © 2017 The Authors. European Journal of Immunology published by WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Meta-analysis for deriving age- and gender-specific dose-response relationships between urinary cadmium concentration and {beta} {sub 2}-microglobulinuria under environmental exposure

DOE Office of Scientific and Technical Information (OSTI.GOV)

Gamo, Masashi; Ono, Kyoko; Nakanishi, Junko

2006-05-15

A meta-analysis was conducted to derive age- and gender-specific dose-response relationships between urinary cadmium (Cd) concentration and {beta} {sub 2}-microglobulinuria ({beta}2MG-uria) under environmental exposure. {beta}2MG-uria was defined by a cutoff point of 1000 {mu}g {beta} {sub 2}-microglobulin/g creatinine. We proposed a model for describing the relationships among the interindividual variabilities in urinary Cd concentration, the ratio of Cd concentrations in the target organ and in urine, and the threshold Cd concentration in the target organ. The parameters in the model were determined so that good agreement might be achieved between the prevalence rates of {beta}2MG-uria reported in the literature andmore » those estimated by the model. In this analysis, only the data from the literature on populations environmentally exposed to Cd were used. Using the model and estimated parameters, the prevalence rate of {beta}2MG-uria can be estimated for an age- and gender-specific subpopulation for which the distribution of urinary Cd concentrations is known. The maximum permissible level of urinary Cd concentration was defined as the maximum geometric mean of the urinary Cd concentration in an age- and gender-specific subpopulation that would not result in a statistically significant increase in the prevalence rate of {beta}2MG-uria. This was estimated to be approximately 3 {mu}g/g creatinine for a population in a small geographical area and approximately 2 {mu}g/g creatinine for a nationwide population.« less

Performance Assessment PCR-Based Assays Targeting Bacteroidales Genetic Markers of Bovine Fecal Pollution▿

PubMed Central

Shanks, Orin C.; White, Karen; Kelty, Catherine A.; Hayes, Sam; Sivaganesan, Mano; Jenkins, Michael; Varma, Manju; Haugland, Richard A.

2010-01-01

There are numerous PCR-based assays available to characterize bovine fecal pollution in ambient waters. The determination of which approaches are most suitable for field applications can be difficult because each assay targets a different gene, in many cases from different microorganisms, leading to variation in assay performance. We describe a performance evaluation of seven end-point PCR and real-time quantitative PCR (qPCR) assays reported to be associated with either ruminant or bovine feces. Each assay was tested against a reference collection of DNA extracts from 247 individual bovine fecal samples representing 11 different populations and 175 fecal DNA extracts from 24 different animal species. Bovine-associated genetic markers were broadly distributed among individual bovine samples ranging from 39 to 93%. Specificity levels of the assays spanned 47.4% to 100%. End-point PCR sensitivity also varied between assays and among different bovine populations. For qPCR assays, the abundance of each host-associated genetic marker was measured within each bovine population and compared to results of a qPCR assay targeting 16S rRNA gene sequences from Bacteroidales. Experiments indicate large discrepancies in the performance of bovine-associated assays across different bovine populations. Variability in assay performance between host populations suggests that the use of bovine microbial source-tracking applications will require a priori characterization at each watershed of interest. PMID:20061457

Exploring target-specific primer extension in combination with a bead-based suspension array for multiplexed detection and typing using Streptococcus suis as a model pathogen

PubMed Central

van der Wal, Fimme J.; Achterberg, René P.; van Solt-Smits, Conny; Bergervoet, Jan H. W.; de Weerdt, Marjanne; Wisselink, Henk J.

2017-01-01

We investigated the feasibility of an assay based on target-specific primer extension, combined with a suspension array, for the multiplexed detection and typing of a veterinary pathogen in animal samples, using Streptococcus suis as a model pathogen. A procedure was established for simultaneous detection of 6 S. suis targets in pig tonsil samples (i.e., 4 genes associated with serotype 1, 2, 7, or 9, the generic S. suis glutamate dehydrogenase gene [gdh], and the gene encoding the extracellular protein factor [epf]). The procedure was set up as a combination of protocols: DNA isolation from porcine tonsils, a multiplex PCR, a multiplex target-specific primer extension, and finally a suspension array as the readout. The resulting assay was compared with a panel of conventional PCR assays. The proposed multiplex assay can correctly identify the serotype of isolates and is capable of simultaneous detection of multiple targets in porcine tonsillar samples. The assay is not as sensitive as the current conventional PCR assays, but with the correct sampling strategy, the assay can be useful for screening pig herds to establish which S. suis serotypes are circulating in a pig population. PMID:28980519

Smoking Cessation Programs for Lesbian, Gay, Bisexual, Transgender, and Intersex People: A Content-Based Systematic Review.

PubMed

Berger, Israel; Mooney-Somers, Julie

2017-11-07

Tobacco use among lesbian, gay, bisexual, and transgender (LGBT) people is double the general population. Limited evidence suggests high smoking rates among intersex people. Lesbian, gay, bisexual, transgender, and intersex (LGBTI) people are a priority population in Australian health policy, particularly mental health and aging. Despite associations between smoking and noncommunicable diseases relevant to aging and mental health, LGBTI-targeted smoking cessation interventions in Australia have been limited to people living with HIV. Applying existing interventions to marginalized populations without modification and evaluation may fail and exacerbate inequities. To assess outcomes and characterize the populations served, cultural modifications, and behavior change techniques (BCTs) of interventions to reduce LGBTI smoking. We searched MEDLINE, six additional databases, and contacted authors to retrieve published and unpublished program evaluations. We retrieved 19 studies (3663 participants). None used control groups. Overall quit rate was 61.0% at the end of interventions and stabilized at 38.6% at 3-6 months. All studies included gay men, 13 included lesbians, 13 "LGBT," 12 bisexual people, five transgender people, and none included intersex people. Transgender people comprised 3% of participants. Of programs open to women, 27.8% of participants were women. Cultural modifications were used by 17 (89.5%) studies, commonly meeting in LGBT spaces, discussing social justice, and discussing LGBT-specific triggers. Common BCTs included providing normative information, boosting motivation/self-efficacy, relapse prevention, social support, action planning, and discussing consequences. Quit rates were high; using control groups would improve evaluation. Existing programs may fail to reach groups other than gay men. This review examines the evidence for LGBTI-targeted smoking cessation interventions. Populations within LGBTI are not proportionally represented in smoking cessation research, and no study addressed intersex smoking. Overall, LGBT-targeted interventions appear to be effective, and simply having an LGBT-specific group may be more effective than groups for the general population. More rigorous research is necessary to draw firm conclusions. Our study space analysis provides suggestions for areas of more targeted research on mechanisms underlying these complex interventions' success. © The Author 2016. Published by Oxford University Press on behalf of the Society for Research on Nicotine and Tobacco. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Target Abundance-Based Fitness Screening (TAFiS) Facilitates Rapid Identification of Target-Specific and Physiologically Active Chemical Probes

PubMed Central

Butts, Arielle; DeJarnette, Christian; Peters, Tracy L.; Parker, Josie E.; Kerns, Morgan E.; Eberle, Karen E.; Kelly, Steve L.

2017-01-01

ABSTRACT Traditional approaches to drug discovery are frustratingly inefficient and have several key limitations that severely constrain our capacity to rapidly identify and develop novel experimental therapeutics. To address this, we have devised a second-generation target-based whole-cell screening assay based on the principles of competitive fitness, which can rapidly identify target-specific and physiologically active compounds. Briefly, strains expressing high, intermediate, and low levels of a preselected target protein are constructed, tagged with spectrally distinct fluorescent proteins (FPs), and pooled. The pooled strains are then grown in the presence of various small molecules, and the relative growth of each strain within the mixed culture is compared by measuring the intensity of the corresponding FP tags. Chemical-induced population shifts indicate that the bioactivity of a small molecule is dependent upon the target protein’s abundance and thus establish a specific functional interaction. Here, we describe the molecular tools required to apply this technique in the prevalent human fungal pathogen Candida albicans and validate the approach using two well-characterized drug targets—lanosterol demethylase and dihydrofolate reductase. However, our approach, which we have termed target abundance-based fitness screening (TAFiS), should be applicable to a wide array of molecular targets and in essentially any genetically tractable microbe. IMPORTANCE Conventional drug screening typically employs either target-based or cell-based approaches. The first group relies on biochemical assays to detect modulators of a purified target. However, hits frequently lack drug-like characteristics such as membrane permeability and target specificity. Cell-based screens identify compounds that induce a desired phenotype, but the target is unknown, which severely restricts further development and optimization. To address these issues, we have developed a second-generation target-based whole-cell screening approach that incorporates the principles of both chemical genetics and competitive fitness, which enables the identification of target-specific and physiologically active compounds from a single screen. We have chosen to validate this approach using the important human fungal pathogen Candida albicans with the intention of pursuing novel antifungal targets. However, this approach is broadly applicable and is expected to dramatically reduce the time and resources required to progress from screening hit to lead compound. PMID:28989971

Spatial and Temporal Coordination of Bone Marrow-Derived Cell Activity During Arteriogenesis: Regulation of the Endogenous Response and Therapeutic Implications

PubMed Central

Meisner, Joshua K.; Price, Richard J.

2010-01-01

Arterial occlusive disease (AOD) is the leading cause of morbidity and mortality through the developed world, which creates a significant need for effective therapies to halt disease progression. Despite success of animal and small-scale human therapeutic arteriogenesis studies, this promising concept for treating AOD has yielded largely disappointing results in large-scale clinical trials. One reason for this lack of successful translation is that endogenous arteriogenesis is highly dependent on a poorly understood sequence of events and interactions between bone marrow derived cells (BMCs) and vascular cells, which makes designing effective therapies difficult. We contend that the process follows a complex, ordered sequence of events with multiple, specific BMC populations recruited at specific times and locations. Here we present the evidence suggesting roles for multiple BMC populations from neutrophils and mast cells to progenitor cells and propose how and where these cell populations fit within the sequence of events during arteriogenesis. Disruptions in these various BMC populations can impair the arteriogenesis process in patterns that characterize specific patient populations. We propose that an improved understanding of how arteriogenesis functions as a system can reveal individual BMC populations and functions that can be targeted for overcoming particular impairments in collateral vessel development. PMID:21044213

Suicide Prevention in a Diverse Campus Community

ERIC Educational Resources Information Center

Shadick, Richard; Akhter, Sarah

2013-01-01

As the college population in the United States rapidly diversifies, leaders of successful campus suicide prevention programs are recognizing the importance of targeting specific groups of students. Recent estimates from the National Center for Education Statistics indicated that in 2008 more than one-third (36.7 percent) of college students…

Population Ancestry and Genetic Risk for Diabetes and Kidney, Cardiovascular, and Bone Disease: Modifiable Environmental Factors May Produce the Cures

PubMed Central

Freedman, Barry I.; Divers, Jasmin; Palmer, Nicholette D.

2013-01-01

Variable rates of disease observed between members of different continental population groups may be mediated by inherited factors, environmental exposures, or their combination. This manuscript provides evidence in support of differential allele frequency distributions that underlie the higher rates of non-diabetic kidney disease in the focal segmental glomerulosclerosis spectrum of disease and lower rates of coronary artery calcified atherosclerotic plaque and osteoporosis in populations of African ancestry. With recognition that these and other common complex diseases are affected by biologic factors comes the realization that targeted manipulation of environmental exposures and pharmacologic treatments will have different effects based on genotype. The current era of precision medicine will couple one’s genetic make-up with specific therapies to reduce rates of disease based on presence of disease-specific alleles. PMID:23896482

Th1-like Plasmodium-Specific Memory CD4+ T Cells Support Humoral Immunity.

PubMed

Zander, Ryan A; Vijay, Rahul; Pack, Angela D; Guthmiller, Jenna J; Graham, Amy C; Lindner, Scott E; Vaughan, Ashley M; Kappe, Stefan H I; Butler, Noah S

2017-11-14

Effector T cells exhibiting features of either T helper 1 (Th1) or T follicular helper (Tfh) populations are essential to control experimental Plasmodium infection and are believed to be critical for resistance to clinical malaria. To determine whether Plasmodium-specific Th1- and Tfh-like effector cells generate memory populations that contribute to protection, we developed transgenic parasites that enable high-resolution study of anti-malarial memory CD4 T cells in experimental models. We found that populations of both Th1- and Tfh-like Plasmodium-specific memory CD4 T cells persist. Unexpectedly, Th1-like memory cells exhibit phenotypic and functional features of Tfh cells during recall and provide potent B cell help and protection following transfer, characteristics that are enhanced following ligation of the T cell co-stimulatory receptor OX40. Our findings delineate critical functional attributes of Plasmodium-specific memory CD4 T cells and identify a host-specific factor that can be targeted to improve resolution of acute malaria and provide durable, long-term protection against Plasmodium parasite re-exposure. Copyright © 2017 The Author(s). Published by Elsevier Inc. All rights reserved.

CRISPR Is an Optimal Target for the Design of Specific PCR Assays for Salmonella enterica Serotypes Typhi and Paratyphi A

PubMed Central

Fabre, Laetitia; Le Hello, Simon; Roux, Chrystelle; Issenhuth-Jeanjean, Sylvie; Weill, François-Xavier

2014-01-01

Background Serotype-specific PCR assays targeting Salmonella enterica serotypes Typhi and Paratyphi A, the causal agents of typhoid and paratyphoid fevers, are required to accelerate formal diagnosis and to overcome the lack of typing sera and, in some situations, the need for culture. However, the sensitivity and specificity of such assays must be demonstrated on large collections of strains representative of the targeted serotypes and all other bacterial populations producing similar clinical symptoms. Methodology Using a new family of repeated DNA sequences, CRISPR (clustered regularly interspaced short palindromic repeats), as a serotype-specific target, we developed a conventional multiplex PCR assay for the detection and differentiation of serotypes Typhi and Paratyphi A from cultured isolates. We also developed EvaGreen-based real-time singleplex PCR assays with the same two sets of primers. Principal findings We achieved 100% sensitivity and specificity for each protocol after validation of the assays on 188 serotype Typhi and 74 serotype Paratyphi A strains from diverse genetic groups, geographic origins and time periods and on 70 strains of bacteria frequently encountered in bloodstream infections, including 29 other Salmonella serotypes and 42 strains from 38 other bacterial species. Conclusions The performance and convenience of our serotype-specific PCR assays should facilitate the rapid and accurate identification of these two major serotypes in a large range of clinical and public health laboratories with access to PCR technology. These assays were developed for use with DNA from cultured isolates, but with modifications to the assay, the CRISPR targets could be used in the development of assays for use with clinical and other samples. PMID:24498453

In-depth resistome analysis by targeted metagenomics.

PubMed

Lanza, Val F; Baquero, Fernando; Martínez, José Luís; Ramos-Ruíz, Ricardo; González-Zorn, Bruno; Andremont, Antoine; Sánchez-Valenzuela, Antonio; Ehrlich, Stanislav Dusko; Kennedy, Sean; Ruppé, Etienne; van Schaik, Willem; Willems, Rob J; de la Cruz, Fernando; Coque, Teresa M

2018-01-15

Antimicrobial resistance is a major global health challenge. Metagenomics allows analyzing the presence and dynamics of "resistomes" (the ensemble of genes encoding antimicrobial resistance in a given microbiome) in disparate microbial ecosystems. However, the low sensitivity and specificity of available metagenomic methods preclude the detection of minority populations (often present below their detection threshold) and/or the identification of allelic variants that differ in the resulting phenotype. Here, we describe a novel strategy that combines targeted metagenomics using last generation in-solution capture platforms, with novel bioinformatics tools to establish a standardized framework that allows both quantitative and qualitative analyses of resistomes. We developed ResCap, a targeted sequence capture platform based on SeqCapEZ (NimbleGene) technology, which includes probes for 8667 canonical resistance genes (7963 antibiotic resistance genes and 704 genes conferring resistance to metals or biocides), and 2517 relaxase genes (plasmid markers) and 78,600 genes homologous to the previous identified targets (47,806 for antibiotics and 30,794 for biocides or metals). Its performance was compared with metagenomic shotgun sequencing (MSS) for 17 fecal samples (9 humans, 8 swine). ResCap significantly improves MSS to detect "gene abundance" (from 2.0 to 83.2%) and "gene diversity" (26 versus 14.9 genes unequivocally detected per sample per million of reads; the number of reads unequivocally mapped increasing up to 300-fold by using ResCap), which were calculated using novel bioinformatic tools. ResCap also facilitated the analysis of novel genes potentially involved in the resistance to antibiotics, metals, biocides, or any combination thereof. ResCap, the first targeted sequence capture, specifically developed to analyze resistomes, greatly enhances the sensitivity and specificity of available metagenomic methods and offers the possibility to analyze genes related to the selection and transfer of antimicrobial resistance (biocides, heavy metals, plasmids). The model opens the possibility to study other complex microbial systems in which minority populations play a relevant role.

Meeting the Housing and Care Needs of Older Homeless Adults: A Permanent Supportive Housing Program Targeting Homeless Elders.

PubMed

Brown, Rebecca T; Thomas, M Lori; Cutler, Deborah F; Hinderlie, Mark

2013-01-01

The homeless population is aging faster than the general population in the United States. As this vulnerable population continues to age, addressing complex care and housing needs will become increasingly important. This article reviews the often-overlooked issue of homelessness among older adults, including their poor health status and unique care needs, the factors that contribute to homelessness in this population, and the costs of homelessness to the U.S. health care system. Permanent supportive housing programs are presented as a potential solution to elder homelessness, and Hearth, an outreach and permanent supportive housing model in Boston, is described. Finally, specific policy changes are presented that could promote access to housing among the growing older homeless population.

Telecommunications technology and rural education in the United States

NASA Technical Reports Server (NTRS)

Perrine, J. R.

1975-01-01

The rural sector of the US is examined from the point of view of whether telecommunications technology can augment the development of rural education. Migratory farm workers and American Indians were the target groups which were examined as examples of groups with special needs in rural areas. The general rural population and the target groups were examined to identify problems and to ascertain specific educational needs. Educational projects utilizing telecommunications technology in target group settings were discussed. Large scale regional ATS-6 satellite-based experimental educational telecommunications projects were described. Costs and organizational factors were also examined for large scale rural telecommunications projects.

A model system for pathogen detection using a two-component bacteriophage/bioluminescent signal amplification assay

NASA Astrophysics Data System (ADS)

Bright, Nathan G.; Carroll, Richard J.; Applegate, Bruce M.

2004-03-01

Microbial contamination has become a mounting concern the last decade due to an increased emphasis of minimally processed food products specifically produce, and the recognition of foodborne pathogens such as Campylobacter jejuni, Escherichia coli O157:H7, and Listeria monocytogenes. This research investigates a detection approach utilizing bacteriophage pathogen specificity coupled with a bacterial bioluminescent bioreporter utilizing the quorum sensing molecule from Vibrio fischeri, N-(3-oxohexanoyl)-homoserine lactone (3-oxo-C6-HSL). The 3-oxo-C6-HSL molecules diffuse out of the target cell after infection and induce bioluminescence from a population of 3-oxo-C6-HSL bioreporters (ROLux). E. coli phage M13, a well-characterized bacteriophage, offers a model system testing the use of bacteriophage for pathogen detection through cell-to-cell communication via a LuxR/3-oxo-C6-HSL system. Simulated temperate phage assays tested functionality of the ROLux reporter and production of 3-oxo-C6-HSL by various test strains. These assays showed detection limits of 102cfu after 24 hours in a varietry of detection formats. Assays incorporating the bacteriophage M13-luxI with the ROLux reporter and a known population of target cells were subsequently developed and have shown consistent detection limits of 105cfu target organisms. Measurable light response from high concentrations of target cells was almost immediate, suggesting an enrichment step to further improve detection limits and reduce assay time.

Population Health Management for Older Adults

PubMed Central

Tkatch, Rifky; Musich, Shirley; MacLeod, Stephanie; Alsgaard, Kathleen; Hawkins, Kevin; Yeh, Charlotte S.

2016-01-01

Background: The older adult population is expanding, living longer, with multiple chronic conditions. Understanding and managing their needs over time is an integral part of defining successful aging. Population health is used to describe the measurement and health outcomes of a population. Objectives: To define population health as applied to older adults, summarize lessons learned from current research, and identify potential interventions designed to promote successful aging and improved health for this population. Method: Online search engines were utilized to identify research on population health and health interventions for older adults. Results: Population health management (PHM) is one strategy to promote the health and well-being of target populations. Interventions promoting health across a continuum tend to be disease, risk, or health behavior specific rather than encompassing a global concept of health. Conclusion: Many existing interventions for older adults are simply research based with limited generalizability; as such, further work in this area is warranted. PMID:28680938

Reinforcement Learning of Two-Joint Virtual Arm Reaching in a Computer Model of Sensorimotor Cortex

PubMed Central

Neymotin, Samuel A.; Chadderdon, George L.; Kerr, Cliff C.; Francis, Joseph T.; Lytton, William W.

2014-01-01

Neocortical mechanisms of learning sensorimotor control involve a complex series of interactions at multiple levels, from synaptic mechanisms to cellular dynamics to network connectomics. We developed a model of sensory and motor neocortex consisting of 704 spiking model neurons. Sensory and motor populations included excitatory cells and two types of interneurons. Neurons were interconnected with AMPA/NMDA and GABAA synapses. We trained our model using spike-timing-dependent reinforcement learning to control a two-joint virtual arm to reach to a fixed target. For each of 125 trained networks, we used 200 training sessions, each involving 15 s reaches to the target from 16 starting positions. Learning altered network dynamics, with enhancements to neuronal synchrony and behaviorally relevant information flow between neurons. After learning, networks demonstrated retention of behaviorally relevant memories by using proprioceptive information to perform reach-to-target from multiple starting positions. Networks dynamically controlled which joint rotations to use to reach a target, depending on current arm position. Learning-dependent network reorganization was evident in both sensory and motor populations: learned synaptic weights showed target-specific patterning optimized for particular reach movements. Our model embodies an integrative hypothesis of sensorimotor cortical learning that could be used to interpret future electrophysiological data recorded in vivo from sensorimotor learning experiments. We used our model to make the following predictions: learning enhances synchrony in neuronal populations and behaviorally relevant information flow across neuronal populations, enhanced sensory processing aids task-relevant motor performance and the relative ease of a particular movement in vivo depends on the amount of sensory information required to complete the movement. PMID:24047323

Demand for Colonoscopy in Colorectal Cancer Screening Using a Quantitative Fecal Immunochemical Test and Age/Sex-Specific Thresholds for Test Positivity.

PubMed

Chen, Sam Li-Sheng; Hsu, Chen-Yang; Yen, Amy Ming-Fang; Young, Graeme P; Chiu, Sherry Yueh-Hsia; Fann, Jean Ching-Yuan; Lee, Yi-Chia; Chiu, Han-Mo; Chiou, Shu-Ti; Chen, Hsiu-Hsi

2018-06-01

Background: Despite age and sex differences in fecal hemoglobin (f-Hb) concentrations, most fecal immunochemical test (FIT) screening programs use population-average cut-points for test positivity. The impact of age/sex-specific threshold on FIT accuracy and colonoscopy demand for colorectal cancer screening are unknown. Methods: Using data from 723,113 participants enrolled in a Taiwanese population-based colorectal cancer screening with single FIT between 2004 and 2009, sensitivity and specificity were estimated for various f-Hb thresholds for test positivity. This included estimates based on a "universal" threshold, receiver-operating-characteristic curve-derived threshold, targeted sensitivity, targeted false-positive rate, and a colonoscopy-capacity-adjusted method integrating colonoscopy workload with and without age/sex adjustments. Results: Optimal age/sex-specific thresholds were found to be equal to or lower than the universal 20 μg Hb/g threshold. For older males, a higher threshold (24 μg Hb/g) was identified using a 5% false-positive rate. Importantly, a nonlinear relationship was observed between sensitivity and colonoscopy workload with workload rising disproportionately to sensitivity at 16 μg Hb/g. At this "colonoscopy-capacity-adjusted" threshold, the test positivity (colonoscopy workload) was 4.67% and sensitivity was 79.5%, compared with a lower 4.0% workload and a lower 78.7% sensitivity using 20 μg Hb/g. When constrained on capacity, age/sex-adjusted estimates were generally lower. However, optimizing age/-sex-adjusted thresholds increased colonoscopy demand across models by 17% or greater compared with a universal threshold. Conclusions: Age/sex-specific thresholds improve FIT accuracy with modest increases in colonoscopy demand. Impact: Colonoscopy-capacity-adjusted and age/sex-specific f-Hb thresholds may be useful in optimizing individual screening programs based on detection accuracy, population characteristics, and clinical capacity. Cancer Epidemiol Biomarkers Prev; 27(6); 704-9. ©2018 AACR . ©2018 American Association for Cancer Research.

HLA Haplotype Frequency Estimation from Real-Life Data with the Hapl-o-Mat Software.

PubMed

Sauter, Jürgen; Schäfer, Christian; Schmidt, Alexander H

2018-01-01

HLA haplotype frequencies are of use in a variety of settings. Such data is typically derived either from family pedigree data by targeted typing or statistical analysis of large population-specific genotype samples. As established tools for the latter approach lacked ability to treat the amount, ambiguity, and inhomogeneity found in genotype data in hematopoietic stem cell donor registries, we developed Hapl-o-Mat to alleviate these specific shortcomings.

ExoData: A Python package to handle large exoplanet catalogue data

NASA Astrophysics Data System (ADS)

Varley, Ryan

2016-10-01

Exoplanet science often involves using the system parameters of real exoplanets for tasks such as simulations, fitting routines, and target selection for proposals. Several exoplanet catalogues are already well established but often lack a version history and code friendly interfaces. Software that bridges the barrier between the catalogues and code enables users to improve the specific repeatability of results by facilitating the retrieval of exact system parameters used in articles results along with unifying the equations and software used. As exoplanet science moves towards large data, gone are the days where researchers can recall the current population from memory. An interface able to query the population now becomes invaluable for target selection and population analysis. ExoData is a Python interface and exploratory analysis tool for the Open Exoplanet Catalogue. It allows the loading of exoplanet systems into Python as objects (Planet, Star, Binary, etc.) from which common orbital and system equations can be calculated and measured parameters retrieved. This allows researchers to use tested code of the common equations they require (with units) and provides a large science input catalogue of planets for easy plotting and use in research. Advanced querying of targets is possible using the database and Python programming language. ExoData is also able to parse spectral types and fill in missing parameters according to programmable specifications and equations. Examples of use cases are integration of equations into data reduction pipelines, selecting planets for observing proposals and as an input catalogue to large scale simulation and analysis of planets. ExoData is a Python package available freely on GitHub.

Organizational strategies for promoting patient and provider uptake of personal health records

PubMed Central

Wells, Susan; Rozenblum, Ronen; Park, Andrea; Dunn, Marie; Bates, David W

2015-01-01

Objective To investigate organizational strategies to promote personal health records (PHRs) adoption with a focus on patients with chronic disease. Methods Using semi-structured interviews and a web-based survey, we sampled US health delivery organizations which had implemented PHRs for at least 12 months, were recognized as PHR innovators, and had scored highly in national patient satisfaction surveys. Respondents had lead positions for clinical information systems or high-risk population management. Using grounded theory approach, thematic categories were derived from interviews and coupled with data from the survey. Results Interviews were conducted with 30 informants from 16 identified organizations. Organizational strategies were directed towards raising patient awareness via multimedia communications, and provider acceptance and uptake. Strategies for providers were grouped into six main themes: organizational vision, governance and policies, work process redesign, staff training, information technology (IT) support, and monitoring and incentives. Successful organizations actively communicated their vision, engaged leaders at all levels, had clear governance, planning, and protocols, set targets, and celebrated achievement. The most effective strategy for patient uptake was through health professional encouragement. No specific outreach efforts targeted patients with chronic disease. Registration and PHR activity was routinely measured but without reference to a denominator population or high risk subpopulations. Discussion and conclusion Successful PHR implementation represents a social change and operational project catalyzed by a technical solution. The key to clinician acceptance is making their work easier. However, organizations will likely not achieve the value they want from PHRs unless they target specific populations and monitor their uptake. PMID:25326601

Improving minority blood donation: anthropologic approach in a migrant community.

PubMed

Grassineau, Dominique; Papa, Kassim; Ducourneau, Axel; Duboz, Priscillia; Boëtsch, Gilles; Chiaroni, Jacques

2007-03-01

As a result of blood group polymorphism, distinctive blood types have evolved in populations around the world. In countries with large migrant populations, finding rare blood types for transfusion can be challenging. This is especially true for sub-Saharan African immigrants living in countries with predominantly European populations. This problem is further compounded by hereditary disorders such as sickle cell disease and by traditional cultural values that discourage routine donation. The purpose of this report is to describe the drive to recruit more safe rare blood type donors in a Comorian immigrant community living in Marseilles, France. With a culturally adapted message developed on an anthropologic approach and working in close collaboration with scientific and medical members of the Comorian community, it is proposed that this population be sensitized with the gift of blood. Targeted collection of specific sub-Saharan African blood types was achieved. Taking into account the high rate of infectious markers among products collected in this targeted collection, however, it was decided to promote blood donation in this minority by addressing people directly toward our principal blood center site. Since setup of this adapted communication, regular donors present themselves spontaneously without community pressure. Infectious markers rate is then equal to general blood donor population's rate. The results of this drive demonstrate the utility of an anthropologic approach and cultural mediation in identifying donors with specific blood types in migrant communities and recruiting second-generation donors. The techniques described in this study could also be applied to collection of other tissues including organs and peripheral blood progenitor cells in minorities.

Programmable removal of bacterial strains by use of genome-targeting CRISPR-Cas systems.

PubMed

Gomaa, Ahmed A; Klumpe, Heidi E; Luo, Michelle L; Selle, Kurt; Barrangou, Rodolphe; Beisel, Chase L

2014-01-28

CRISPR (clustered regularly interspaced short palindromic repeats)-Cas (CRISPR-associated) systems in bacteria and archaea employ CRISPR RNAs to specifically recognize the complementary DNA of foreign invaders, leading to sequence-specific cleavage or degradation of the target DNA. Recent work has shown that the accidental or intentional targeting of the bacterial genome is cytotoxic and can lead to cell death. Here, we have demonstrated that genome targeting with CRISPR-Cas systems can be employed for the sequence-specific and titratable removal of individual bacterial strains and species. Using the type I-E CRISPR-Cas system in Escherichia coli as a model, we found that this effect could be elicited using native or imported systems and was similarly potent regardless of the genomic location, strand, or transcriptional activity of the target sequence. Furthermore, the specificity of targeting with CRISPR RNAs could readily distinguish between even highly similar strains in pure or mixed cultures. Finally, varying the collection of delivered CRISPR RNAs could quantitatively control the relative number of individual strains within a mixed culture. Critically, the observed selectivity and programmability of bacterial removal would be virtually impossible with traditional antibiotics, bacteriophages, selectable markers, or tailored growth conditions. Once delivery challenges are addressed, we envision that this approach could offer a novel means to quantitatively control the composition of environmental and industrial microbial consortia and may open new avenues for the development of "smart" antibiotics that circumvent multidrug resistance and differentiate between pathogenic and beneficial microorganisms. Controlling the composition of microbial populations is a critical aspect in medicine, biotechnology, and environmental cycles. While different antimicrobial strategies, such as antibiotics, antimicrobial peptides, and lytic bacteriophages, offer partial solutions, what remains elusive is a generalized and programmable strategy that can distinguish between even closely related microorganisms and that allows for fine control over the composition of a microbial population. This study demonstrates that RNA-directed immune systems in bacteria and archaea called CRISPR-Cas systems can provide such a strategy. These systems can be employed to selectively and quantitatively remove individual bacterial strains based purely on sequence information, creating opportunities in the treatment of multidrug-resistant infections, the control of industrial fermentations, and the study of microbial consortia.

Strategic planning to reduce the burden of stroke among veterans: using simulation modeling to inform decision making.

PubMed

Lich, Kristen Hassmiller; Tian, Yuan; Beadles, Christopher A; Williams, Linda S; Bravata, Dawn M; Cheng, Eric M; Bosworth, Hayden B; Homer, Jack B; Matchar, David B

2014-07-01

Reducing the burden of stroke is a priority for the Veterans Affairs Health System, reflected by the creation of the Veterans Affairs Stroke Quality Enhancement Research Initiative. To inform the initiative's strategic planning, we estimated the relative population-level impact and efficiency of distinct approaches to improving stroke care in the US Veteran population to inform policy and practice. A System Dynamics stroke model of the Veteran population was constructed to evaluate the relative impact of 15 intervention scenarios including both broad and targeted primary and secondary prevention and acute care/rehabilitation on cumulative (20 years) outcomes including quality-adjusted life years (QALYs) gained, strokes prevented, stroke fatalities prevented, and the number-needed-to-treat per QALY gained. At the population level, a broad hypertension control effort yielded the largest increase in QALYs (35,517), followed by targeted prevention addressing hypertension and anticoagulation among Veterans with prior cardiovascular disease (27,856) and hypertension control among diabetics (23,100). Adjusting QALYs gained by the number of Veterans needed to treat, thrombolytic therapy with tissue-type plasminogen activator was most efficient, needing 3.1 Veterans to be treated per QALY gained. This was followed by rehabilitation (3.9) and targeted prevention addressing hypertension and anticoagulation among those with prior cardiovascular disease (5.1). Probabilistic sensitivity analysis showed that the ranking of interventions was robust to uncertainty in input parameter values. Prevention strategies tend to have larger population impacts, though interventions targeting specific high-risk groups tend to be more efficient in terms of number-needed-to-treat per QALY gained. © 2014 American Heart Association, Inc.

Optimisation Modelling to Assess Cost of Dietary Improvement in Remote Aboriginal Australia

PubMed Central

Brimblecombe, Julie; Ferguson, Megan; Liberato, Selma C.; O'Dea, Kerin; Riley, Malcolm

2013-01-01

Background The cost and dietary choices required to fulfil nutrient recommendations defined nationally, need investigation, particularly for disadvantaged populations. Objective We used optimisation modelling to examine the dietary change required to achieve nutrient requirements at minimum cost for an Aboriginal population in remote Australia, using where possible minimally-processed whole foods. Design A twelve month cross-section of population-level purchased food, food price and nutrient content data was used as the baseline. Relative amounts from 34 food group categories were varied to achieve specific energy and nutrient density goals at minimum cost while meeting model constraints intended to minimise deviation from the purchased diet. Results Simultaneous achievement of all nutrient goals was not feasible. The two most successful models (A & B) met all nutrient targets except sodium (146.2% and 148.9% of the respective target) and saturated fat (12.0% and 11.7% of energy). Model A was achieved with 3.2% lower cost than the baseline diet (which cost approximately AUD$13.01/person/day) and Model B at 7.8% lower cost but with a reduction in energy of 4.4%. Both models required very large reductions in sugar sweetened beverages (−90%) and refined cereals (−90%) and an approximate four-fold increase in vegetables, fruit, dairy foods, eggs, fish and seafood, and wholegrain cereals. Conclusion This modelling approach suggested population level dietary recommendations at minimal cost based on the baseline purchased diet. Large shifts in diet in remote Aboriginal Australian populations are needed to achieve national nutrient targets. The modeling approach used was not able to meet all nutrient targets at less than current food expenditure. PMID:24391790

Strategic Planning to Reduce the Burden of Stroke among Veterans: Using Simulation Modeling to Inform Decision Making

PubMed Central

Lich, Kristen Hassmiller; Tian, Yuan; Beadles, Christopher A.; Williams, Linda S.; Bravata, Dawn M.; Cheng, Eric M.; Bosworth, Hayden B.; Homer, Jack B.; Matchar, David B.

2014-01-01

Background and Purpose Reducing the burden of stroke is a priority for the Veterans Affairs (VA) Health System, reflected by the creation of the VA Stroke Quality Enhancement Research Initiative (QUERI). To inform the initiative's strategic planning, we estimated the relative population-level impact and efficiency of distinct approaches to improving stroke care in the United States Veteran population to inform policy and practice. Methods A System Dynamics stroke model of the Veteran population was constructed to evaluate the relative impact of 15 intervention scenarios including both broad and targeted primary and secondary prevention and acute care/rehabilitation on cumulative (20-year) outcomes including quality-adjusted life years (QALYs) gained, strokes prevented, stroke fatalities prevented and the number-needed-to-treat (NNT) per QALY gained. Results At the population level, a broad hypertension control effort yielded the largest increase in QALYs (35,517), followed by targeted prevention addressing hypertension and anticoagulation among Veterans with prior cardiovascular disease (27,856) and hypertension control among diabetics (23,100). Adjusting QALYs gained by the number of Veterans needed to treat, thrombolytic therapy with tissue plasminogen activator was most efficient, needing 3.1 Veterans to be treated per QALY gained. This was followed by rehabilitation (3.9) and targeted prevention addressing hypertension and anticoagulation among those with prior cardiovascular disease (5.1). Probabilistic sensitivity analysis showed that the ranking of interventions was robust to uncertainty in input parameter values. Conclusions Prevention strategies tend to have larger population impacts, though interventions targeting specific high-risk groups tend to be more efficient in terms of NNT per QALY gained. PMID:24923722

Kennedy Space Center Coronary Heart Disease Risk Screening Program

NASA Technical Reports Server (NTRS)

Tipton, David A.; Scarpa, Philip J.

1999-01-01

The number one cause of death in the U.S. is coronary heart disease (CHD). It is probably a major cause of death and disability in the lives of employees at Kennedy Space Center (KSC) as well. The KSC Biomedical Office used a multifactorial mathematical formula from the Framingham Heart Study to calculate CHD risk probabilities for individuals in a segment of the KSC population that required medical evaluation for job certification. Those assessed to be high-risk probabilities will be targeted for intervention. Every year, several thousand KSC employees require medical evaluations for job related certifications. Most medical information for these evaluations is gathered on-site at one of the KSC or Cape Canaveral Air Station (CCAS) medical clinics. The formula used in the Framingham Heart Study allows calculation of a person's probability of acquiring CHD within 10 years. The formula contains the following variables: Age, Diabetes, Smoking, Left Ventricular Hypertrophy, Blood Pressure (Systolic or Diastolic), Cholesterol, and HDL cholesterol. The formula is also gender specific. It was used to calculate the 10-year probabilities of CHD in KSC employees who required medical evaluations for job certifications during a one-year time frame. This KSC population was profiled and CHD risk reduction interventions could be targeted to those at high risk. Population risk could also be periodically reevaluated to determine the effectiveness of intervention. A 10-year CHD risk probability can be calculated for an individual quite easily while gathering routine medical information. An employee population's CHD risk probability can be profiled graphically revealing high risk segments of the population which can be targeted for risk reduction intervention. The small audience of NASA/contractor physicians, nurses and exercise/fitness professionals at the breakout session received the lecture very well. Approximately one third indicated by a show of hands that they would be interested in implementing a similar program at their NASA Center. Questions were asked pertaining to standardization for age, the validity of using the idealized male values also for the female population, and indications of the screening test's sensitivity and specificity.

Development of a human-specific B. thetaiotaomicron IMS ...

EPA Pesticide Factsheets

Immunomagnetic separation/adenosine triphosphate (IMS/ATP) assays utilize paramagnetic beads and target-specific antibodies to isolate target organisms. Following isolation, adenosine tri-phosphate (ATP) is extracted from the target population and quantified. An inversely-coupled (Inv-IMS/ATP)assay for detection of Bacteroides thetaiotaomicron was developed and applied for rapid detection of human-associated fecal contamination in surface waters in Baja California. Specificity of the assay was tested against challenge solutions of varying concentrations of dog, gull, horse and chicken feces, and a field validation survey of coastal and WWTP effluent water quality in Rosarito and Enseneda, Baja California was conducted. Inv IMS/ATP measurements made shown to be specific and sensitive to human fecal contamination. At test concentrations of less than 1000 MPN ENT/100 mL, sensitivity and specificity of the assay both exceeded 80%. Moreover, the Inv-IMS/ATP assay yielded measurements of viable B. thetaiotaomicron that were comparable to the HF183 human marker in complex surface waters impacted with both wastewater and runoff, and the Inv-IMS/ATP assay was able to effectively differentiate between surface waters impacted with adequately and inadequately treated wastewater. The Inv-IMS/ATP assays shows promise for rapid evaluation of recreational water quality in areas where access to more expensive methods is limited and in areas where water quality in unpredicta

Targeted delivery of CRISPR/Cas9 to prostate cancer by modified gRNA using a flexible aptamer-cationic liposome.

PubMed

Zhen, Shuai; Takahashi, Yoichiro; Narita, Shunichi; Yang, Yi-Chen; Li, Xu

2017-02-07

The potent ability of CRISPR/Cas9 system to inhibit the expression of targeted gene is being exploited as a new class of therapeutics for a variety of diseases. However, the efficient and safe delivery of CRISPR/Cas9 into specific cell populations is still the principal challenge in the clinical development of CRISPR/Cas9 therapeutics. In this study, a flexible aptamer-liposome-CRISPR/Cas9 chimera was designed to combine efficient delivery and increased flexibility. Our chimera incorporated an RNA aptamer that specifically binds prostate cancer cells expressing the prostate-specific membrane antigen as a ligand. Cationic liposomes were linked to aptamers by the post-insertion method and were used to deliver therapeutic CRISPR/Cas9 that target the survival gene, polo-like kinase 1, in tumor cells. We demonstrate that the aptamer-liposome-CRISPR/Cas9 chimeras had a significant cell-type binding specificity and a remarkable gene silencing effect in vitro. Furthermore, silencing promoted a conspicuous regression of prostate cancer in vivo. Importantly, the approach described here provides a universal means of cell type-specific CRISPR/Cas9 delivery, which is a critical goal for the widespread therapeutic applicability of CRISPR/Cas9 or other nucleic acid drugs.

Targeted delivery of CRISPR/Cas9 to prostate cancer by modified gRNA using a flexible aptamer-cationic liposome

PubMed Central

Zhen, Shuai; Takahashi, Yoichiro; Narita, Shunichi; Yang, Yi-Chen; Li, Xu

2017-01-01

The potent ability of CRISPR/Cas9 system to inhibit the expression of targeted gene is being exploited as a new class of therapeutics for a variety of diseases. However, the efficient and safe delivery of CRISPR/Cas9 into specific cell populations is still the principal challenge in the clinical development of CRISPR/Cas9 therapeutics. In this study, a flexible aptamer-liposome-CRISPR/Cas9 chimera was designed to combine efficient delivery and increased flexibility. Our chimera incorporated an RNA aptamer that specifically binds prostate cancer cells expressing the prostate-specific membrane antigen as a ligand. Cationic liposomes were linked to aptamers by the post-insertion method and were used to deliver therapeutic CRISPR/Cas9 that target the survival gene, polo-like kinase 1, in tumor cells. We demonstrate that the aptamer-liposome-CRISPR/Cas9 chimeras had a significant cell-type binding specificity and a remarkable gene silencing effect in vitro. Furthermore, silencing promoted a conspicuous regression of prostate cancer in vivo. Importantly, the approach described here provides a universal means of cell type–specific CRISPR/Cas9 delivery, which is a critical goal for the widespread therapeutic applicability of CRISPR/Cas9 or other nucleic acid drugs. PMID:28030843

The Behavioral Assessment of Social Interactions in Young Children: An Examination of Convergent and Incremental Validity

ERIC Educational Resources Information Center

Callahan, Emily H.; Gillis, Jennifer M.; Romanczyk, Raymond G.; Mattson, Richard E.

2011-01-01

Many treatment programs for individuals with an autism spectrum disorder (ASD) target social skills, and there is growing attention directed toward the development of specific interventions to improve social skills and social interactions in this population (Hestenes & Carroll, 2000; Strain & Hoyson, 2000). However, there are limited tools…

Needs Assessment of Parents of Typical Children Ages 4 to 5 Years Old

ERIC Educational Resources Information Center

Brady, Deon LaMount

2010-01-01

Parent education programs have been very successful in meeting the pre-established goals and expectations of their program without the input of parent participants prior to program implementation. Although programs continue to improve, it is important that programs begin to consider the specific needs of their target population. One parent…

Pre-release biological control agent recommendations for swallow-wort (Vincetoxicum spp.) informed by demographic matrix models

USDA-ARS?s Scientific Manuscript database

Weed biological control workers have advocated for the advance assessment of agent efficacy in order to minimize the release of host-specific but ineffective agents. One method involves demographic matrix modeling of target weed populations in order to identify plant life stage transitions that cont...

34 CFR 491.21 - What selection criteria does the Secretary use?

Code of Federal Regulations, 2012 CFR

2012-07-01

.... Support services must be designed to bring members of the target group to a state of readiness for... application to determine the extent to which— (1) The program design is tailored to the literacy and basic skills needs of the specific homeless population being served (for example, designs to address the...

Building Air Quality: A Guide for Building Owners and Facility Managers.

ERIC Educational Resources Information Center

Agle, Elizabeth; Galbraith, Susan

The past two decades have witnessed increased concerns over the health and comfort of indoor air quality (IAQ), but little indoor air-related information has been targeted at building owners and facility managers of public and commercial buildings. This manual, specifically created for such a population, provides guidance on preventing,…

Recommendations for the Recruitment and Retention of Transfer Students

ERIC Educational Resources Information Center

Kippenhan, Heidi

2004-01-01

The purpose of this article is to gain practical knowledge about a population of students that is vital and necessary to any university community. The history of transfer students lends itself to the assumption that there is no targeted marketing, specific recruitment materials, equity in events or outreach activities, or equal data gathered in…

Biological control agents elevate hantavirus by subsidizing deer mouse populations

Treesearch

Dean E. Pearson; Ragan M. Callaway

2006-01-01

Biological control of exotic invasive plants using exotic insects is practiced under the assumption that biological control agents are safe if they do not directly attack non-target species. We tested this assumption by evaluating the potential for two host-specific biological control agents (Urophora spp.), widely established in North America for spotted...

Literacy and Education for Sustainable Development and Women's Empowerment

ERIC Educational Resources Information Center

Robinson-Pant, Anna

2014-01-01

The fact that women constitute two-thirds of the world's non-literate population has been a cause for concern for several decades. Despite a number of high-profile literacy interventions specifically targeting women--including UNESCO's LIFE initiative--the disparity between male and female literacy rates persists in many countries of the world…

Neptune: a bioinformatics tool for rapid discovery of genomic variation in bacterial populations

PubMed Central

Marinier, Eric; Zaheer, Rahat; Berry, Chrystal; Weedmark, Kelly A.; Domaratzki, Michael; Mabon, Philip; Knox, Natalie C.; Reimer, Aleisha R.; Graham, Morag R.; Chui, Linda; Patterson-Fortin, Laura; Zhang, Jian; Pagotto, Franco; Farber, Jeff; Mahony, Jim; Seyer, Karine; Bekal, Sadjia; Tremblay, Cécile; Isaac-Renton, Judy; Prystajecky, Natalie; Chen, Jessica; Slade, Peter

2017-01-01

Abstract The ready availability of vast amounts of genomic sequence data has created the need to rethink comparative genomics algorithms using ‘big data’ approaches. Neptune is an efficient system for rapidly locating differentially abundant genomic content in bacterial populations using an exact k-mer matching strategy, while accommodating k-mer mismatches. Neptune’s loci discovery process identifies sequences that are sufficiently common to a group of target sequences and sufficiently absent from non-targets using probabilistic models. Neptune uses parallel computing to efficiently identify and extract these loci from draft genome assemblies without requiring multiple sequence alignments or other computationally expensive comparative sequence analyses. Tests on simulated and real datasets showed that Neptune rapidly identifies regions that are both sensitive and specific. We demonstrate that this system can identify trait-specific loci from different bacterial lineages. Neptune is broadly applicable for comparative bacterial analyses, yet will particularly benefit pathogenomic applications, owing to efficient and sensitive discovery of differentially abundant genomic loci. The software is available for download at: http://github.com/phac-nml/neptune. PMID:29048594

Improving the quality of communication in organised cervical cancer screening programmes.

PubMed

Giordano, Livia; Webster, Premila; Anthony, Charles; Szarewski, Anne; Davies, Philip; Arbyn, Marc; Segnan, Nereo; Austoker, Joan

2008-07-01

To provide health professionals involved in cervical cancer screening with an insight into the complex issues relating to communication about screening and to provide a framework for a more effective communication strategy. This paper has been compiled by a multidisciplinary pan-European group of health professionals and cancer advocates from several European screening programmes. European surveys on screening communication, literature reviews and group discussion were used for this purpose. Information on cervical screening must be accessible, relevant, comprehensible, comprehensive, client-centred, phase-specific and multilevel. An effective communication strategy should consider health professionals' screening knowledge and their communication skills, consumers' health literacy skills and the communication needs of specific sub-groups in the target population. Co-operation between screening professionals, advocacy groups and journalists should be promoted. To communicate effectively and appropriately is a complex task which can be influenced by a number of factors. Screening workers need better information themselves and must take into account the needs and characteristics of the target population. This document should provide a useful tool to help screening professionals in designing and developing good quality and effective communication strategies.

Use of a Hierarchical Oligonucleotide Primer Extension Approach for Multiplexed Relative Abundance Analysis of Methanogens in Anaerobic Digestion Systems

PubMed Central

Chuang, Hui-Ping; Hsu, Mao-Hsuan; Chen, Wei-Yu

2013-01-01

In this study, we established a rapid multiplex method to detect the relative abundances of amplified 16S rRNA genes from known cultivatable methanogens at hierarchical specificities in anaerobic digestion systems treating industrial wastewater and sewage sludge. The method was based on the hierarchical oligonucleotide primer extension (HOPE) technique and combined with a set of 27 primers designed to target the total archaeal populations and methanogens from 22 genera within 4 taxonomic orders. After optimization for their specificities and detection sensitivity under the conditions of multiple single-nucleotide primer extension reactions, the HOPE approach was applied to analyze the methanogens in 19 consortium samples from 7 anaerobic treatment systems (i.e., 513 reactions). Among the samples, the methanogen populations detected with order-level primers accounted for >77.2% of the PCR-amplified 16S rRNA genes detected using an Archaea-specific primer. The archaeal communities typically consisted of 2 to 7 known methanogen genera within the Methanobacteriales, Methanomicrobiales, and Methanosarcinales and displayed population dynamic and spatial distributions in anaerobic reactor operations. Principal component analysis of the HOPE data further showed that the methanogen communities could be clustered into 3 distinctive groups, in accordance with the distribution of the Methanosaeta, Methanolinea, and Methanomethylovorans, respectively. This finding suggested that in addition to acetotrophic and hydrogenotrophic methanogens, the methylotrophic methanogens might play a key role in the anaerobic treatment of industrial wastewater. Overall, the results demonstrated that the HOPE approach is a specific, rapid, and multiplexing platform to determine the relative abundances of targeted methanogens in PCR-amplified 16S rRNA gene products. PMID:24077716

Initial Design of Culturally Informed Behavioral Intervention Technologies: Developing an mHealth Intervention for Young Sexual Minority Men With Generalized Anxiety Disorder and Major Depression

PubMed Central

Montague, Enid; Mohr, David C

2013-01-01

Background To our knowledge, there is no well-articulated process for the design of culturally informed behavioral intervention technologies. Objective This paper describes the early stages of such a process, illustrated by the methodology for the ongoing development of a behavioral intervention technology targeting generalized anxiety disorder and major depression among young sexual minority men. Methods We integrated instructional design for Internet behavioral intervention technologies with greater detail on information sources that can identify user needs in understudied populations, as well as advances in the understanding of technology-specific behavioral intervention technology dimensions that may need to be culturally tailored. Results General psychological theory describing how to effect change in the clinical target is first integrated with theory describing potentially malleable factors that help explain the clinical problem within the population. Additional information sources are then used to (1) evaluate the theory, (2) identify population-specific factors that may affect users’ ability to relate to and benefit from the behavioral intervention technology, and (3) establish specific skills, attitudes, knowledge, etc, required to change malleable factors posited in the theory. User needs result from synthesis of this information. Product requirements are then generated through application of the user needs to specific behavioral intervention technology dimensions (eg, technology platform). We provide examples of considerations relevant to each stage of this process and how they were applied. Conclusions This process can guide the initial design of other culturally informed behavioral intervention technologies. This first attempt to create a systematic design process can spur development of guidelines for design of behavioral intervention technologies aimed to reduce health disparities. PMID:24311444

International variation in the prevalence of preclinical colorectal cancer: Implications for predictive values of noninvasive screening tests and potential target populations for screening

PubMed Central

Stock, Christian; Brenner, Hermann

2017-01-01

Screening for colorectal cancer (CRC) is implemented in an increasing number of countries. We aimed to assess international variation in the prevalence of preclinical CRC and the resulting variation in positive and negative predictive values (PPVs, NPVs) of existing and potential CRC screening tests in various countries. Using age‐ and sex‐specific CRC incidence data and transition rates from preclinical to clinical CRC we estimated overall and age‐ and sex‐specific prevalence of preclinical CRC in the target population aged 50–74 years in different parts of the world. These prevalence estimates were used to derive PPVs and NPVs for existing and potential noninvasive screening tests with varying levels of sensitivity and specificity. Within all regions and countries, prevalence strongly increases with age and is higher in men than in women. In addition, major variation was seen between regions and countries, with overall prevalence varying between 1 and 0.1%. As a result, PPVs are expected to strongly vary between ∼10% for men in high incidence countries, such as Australia and Germany, and 1% for women in low incidence countries, whereas NPVs are expected to be consistently well above 99%. Variation in CRC prevalence profoundly affects expected PPVs of screening tests, and PPVs should be carefully considered when decisions on screening tests and strategies are made for specific populations and health care systems. Here, we provide estimates of preclinical CRC and expected PPVs and NPVs of noninvasive screening tests, which may enhance the empirical basis for planning of population‐based CRC screening strategies. PMID:28670788

Four-Dimensional Dose Reconstruction for Scanned Proton Therapy Using Liver 4DCT-MRI

DOE Office of Scientific and Technical Information (OSTI.GOV)

Bernatowicz, Kinga, E-mail: kinga.bernatowicz@psi.ch; Proton Therapy Center, Paul Scherrer Institute, PSI Villigen; Peroni, Marta

Purpose: Four-dimensional computed tomography-magnetic resonance imaging (4DCT-MRI) is an image-processing technique for simulating many 4DCT data sets from a static reference CT and motions extracted from 4DMRI studies performed using either volunteers or patients. In this work, different motion extraction approaches were tested using 6 liver cases, and a detailed comparison between 4DCT-MRI and 4DCT was performed. Methods and Materials: 4DCT-MRI has been generated using 2 approaches. The first approach used motion extracted from 4DMRI as being “most similar” to that of 4DCT from the same patient (subject-specific), and the second approach used the most similar motion obtained from amore » motion library derived from 4DMRI liver studies of 13 healthy volunteers (population-based). The resulting 4DCT-MRI and 4DCTs were compared using scanned proton 4D dose calculations (4DDC). Results: Dosimetric analysis showed that 93% ± 8% of points inside the clinical target volume (CTV) agreed between 4DCT and subject-specific 4DCT-MRI (gamma analysis: 3%/3 mm). The population-based approach however showed lower dosimetric agreement with only 79% ± 14% points in the CTV reaching the 3%/3 mm criteria. Conclusions: 4D CT-MRI extends the capabilities of motion modeling for dose calculations by accounting for realistic and variable motion patterns, which can be directly employed in clinical research studies. We have found that the subject-specific liver modeling appears more accurate than the population-based approach. The former is particularly interesting for clinical applications, such as improved target delineation and 4D dose reconstruction for patient-specific QA to allow for inter- and/or intra-fractional plan corrections.« less

Targeted suppression of autoreactive CD8+ T-cell activation using blocking anti-CD8 antibodies.

PubMed

Clement, Mathew; Pearson, James A; Gras, Stephanie; van den Berg, Hugo A; Lissina, Anya; Llewellyn-Lacey, Sian; Willis, Mark D; Dockree, Tamsin; McLaren, James E; Ekeruche-Makinde, Julia; Gostick, Emma; Robertson, Neil P; Rossjohn, Jamie; Burrows, Scott R; Price, David A; Wong, F Susan; Peakman, Mark; Skowera, Ania; Wooldridge, Linda

2016-10-17

CD8 + T-cells play a role in the pathogenesis of autoimmune diseases such as multiple sclerosis and type 1 diabetes. However, drugs that target the entire CD8 + T-cell population are not desirable because the associated lack of specificity can lead to unwanted consequences, most notably an enhanced susceptibility to infection. Here, we show that autoreactive CD8 + T-cells are highly dependent on CD8 for ligand-induced activation via the T-cell receptor (TCR). In contrast, pathogen-specific CD8 + T-cells are relatively CD8-independent. These generic differences relate to an intrinsic dichotomy that segregates self-derived and exogenous antigen-specific TCRs according to the monomeric interaction affinity with cognate peptide-major histocompatibility complex class I (pMHCI). As a consequence, "blocking" anti-CD8 antibodies can suppress autoreactive CD8 + T-cell activation in a relatively selective manner. These findings provide a rational basis for the development and in vivo assessment of novel therapeutic strategies that preferentially target disease-relevant autoimmune responses within the CD8 + T-cell compartment.

In situ identification of nocardioform actinomycetes in activated sludge using fluorescent rRNA-targeted oligonucleotide probes.

PubMed

Schuppler, M; Wagner, M; Schön, G; Göbel, U B

1998-01-01

Hitherto, few environmental samples have been investigated by a 'full cycle rRNA analysis'. Here the results of in situ hybridization experiments with specific rRNA-targeted oligonucleotide probes developed on the basis of new sequences derived from a previously described comparative 16S rRNA analysis of nocardioform actinomycetes in activated sludge are reported. Application of the specific probes enabled identification and discrimination of the distinct populations of nocardioform actinomycetes in activated sludge. One of the specific probes (DLP) detected rod-shaped bacteria which were found in 13 of the 16 investigated sludge samples from various wastewater treatment plants, suggesting their importance in the wastewater treatment process. Another probe (GLP2) hybridized with typically branched filaments of nocardioforms mainly found in samples from enhanced biological phosphorus removal plants, suggesting that these bacteria are involved in sludge foaming. The combination of in situ hybridization with fluorescently labelled rRNA-targeted oligonucleotide probes and confocal laser scanning microscopy improved the detection of nocardioform actinomycetes, which often showed only weak signals inside the activated-sludge flocs.

Reweighting anthropometric data using a nearest neighbour approach.

PubMed

Kumar, Kannan Anil; Parkinson, Matthew B

2018-07-01

When designing products and environments, detailed data on body size and shape are seldom available for the specific user population. One way to mitigate this issue is to reweight available data such that they provide an accurate estimate of the target population of interest. This is done by assigning a statistical weight to each individual in the reference data, increasing or decreasing their influence on statistical models of the whole. This paper presents a new approach to reweighting these data. Instead of stratified sampling, the proposed method uses a clustering algorithm to identify relationships between the detailed and reference populations using their height, mass, and body mass index (BMI). The newly weighted data are shown to provide more accurate estimates than traditional approaches. The improved accuracy that accompanies this method provides designers with an alternative to data synthesis techniques as they seek appropriate data to guide their design practice.Practitioner Summary: Design practice is best guided by data on body size and shape that accurately represents the target user population. This research presents an alternative to data synthesis (e.g. regression or proportionality constants) for adapting data from one population for use in modelling another.

Setting an Agenda to Address Intimate Partner Violence Among Young Men Who Have Sex With Men: A Conceptual Model and Review.

PubMed

Kubicek, Katrina

2016-10-18

Research investigating intimate partner violence (IPV) among sexual minorities is limited. The research that does exist has found that rates of IPV are similar to or higher than the rates found for heterosexual women, the most commonly studied population in this area. This limited research has resulted in a dearth of prevention/intervention programs targeted for these populations. While some may argue that existing IPV programs can be used for these populations, this review presents an argument for more targeted work with sexual minority populations, using young men who have sex with men (YMSM) as an example. Drawing on the framework of intersectionality, this article argues that the intersectionality of age, sexual identity, and gender combines to create a spectrum of unique factors that require specific attention. This framework allows for the identification of known correlates for IPV as well as factors that may be unique to YMSM or other sexual minority populations. The article presents a conceptual model that suggests new areas of research as well as a foundation for the topics and issues that should be addressed in an intervention. © The Author(s) 2016.

Interventions promoting healthy eating as a tool for reducing social inequalities in diet in low- and middle-income countries: a systematic review.

PubMed

Mayén, Ana-Lucia; de Mestral, Carlos; Zamora, Gerardo; Paccaud, Fred; Marques-Vidal, Pedro; Bovet, Pascal; Stringhini, Silvia

2016-12-22

Diet is a major risk factor for non-communicable diseases (NCDs) and is also strongly patterned by socioeconomic factors. Whether interventions promoting healthy eating reduce social inequalities in diet in low- and middle-income countries (LMICs) remains uncertain. This paper aims to summarize current evidence on interventions promoting healthy eating in LMICs, and to establish whether they reduce social inequalities in diet. Systematic review of cross-sectional or quasi-experimental studies (pre- and post-assessment of interventions) in Pubmed, Scielo and Google Scholar databases, including adults in LMICs, assessing at least one outcome of healthy eating and showing results stratified by socioeconomic status. Seven intervention studies including healthy eating promotion, conducted in seven LMICs (Brazil, Chile, Colombia, Iran, Panama, Trinidad and Tobago, and Tunisia), met our inclusion criteria. To promote healthy eating, all interventions used nutrition education and three of them combined nutrition education with improved acces to foods or social support. Interventions targeted mostly women and varied widely regarding communication tools and duration of the nutrition education sessions. Most interventions used printed material, media use or face-to-face training and lasted from 6 weeks to 5 years. Four interventions targeted disadvantaged populations, and three targeted the entire population. In three out of four interventions targeting disadvantaged populations, healthy eating outcomes were improved suggesting they were likely to reduce social inequalities in diet. All interventions directed to the entire population showed improved healthy eating outcomes in all social strata, and were considered as having no impact on social inequalities in diet. In LMICs, agentic interventions promoting healthy eating reduced social inequalities in diet when specifically targeting disadvantaged populations. Further research should assess the impact on social inequalities in diet of a combination of agentic and structural approaches in interventions promoting healthy eating.

Optical Measurements of Tumbling Rocket Bodies

NASA Technical Reports Server (NTRS)

Read, J.; Cowardin, H.; Liou, J.-C.

2012-01-01

A component of interest in the active debris removal (ADR) effort in low Earth orbit is spent rocket upper stages. Proximity operations for such missions require an understanding of the tumbling characteristics of these targets. This research was conducted to assist in laying the ground work for realistic ADR mission planning. To better understand the tumbling characteristics of these spent upper stages, the NASA Orbital Debris Program Office has acquired over 400 recorded lightcurves using telescopes located in Colorado and New Mexico. This effort focuses on a population of over 250 Russian SL-8 and SL-16 spent upper stages. The oldest of these have been in orbit for 45 years, and some have exhibited unplanned orbit changes up to 22 years after launch. This paper describes the techniques of how this optical data was acquired and summarizes the optical signatures for this population of targets, including categorization, tumbling period, and investigations into specific targets in which the optical signature changed dramatically over different time periods. Results from period analysis performed on these lightcurves are summarized.

Vancomycin Dosing in Obese Patients: Special Considerations and Novel Dosing Strategies.

PubMed

Durand, Cheryl; Bylo, Mary; Howard, Brian; Belliveau, Paul

2018-06-01

To review the literature regarding vancomycin pharmacokinetics in obese patients and strategies used to improve dosing in this population. PubMed, EMBASE (1974 to November 2017), and Google Scholar searches were conducted using the search terms vancomycin, obese, obesity, pharmacokinetics, strategy, and dosing. Additional articles were selected from reference lists of selected studies. Included articles were those published in English with a primary focus on vancomycin pharmacokinetic parameters in obese patients and practical vancomycin dosing strategies, clinical experiences, or challenges of dosing vancomycin in this population. Volume of distribution and clearance are the pharmacokinetic parameters that most often affect vancomycin dosing in obese patients; both are increased in this population. Challenges with dosing in obese patients include inconsistent and inadequate dosing, observations that the obese population may not be homogeneous, and reports of an increased likelihood of supratherapeutic trough concentrations. Investigators have revised and developed dosing and monitoring protocols to address these challenges. These approaches improved target trough attainment to varying degrees. Some of the vancomycin dosing approaches provided promising results in obese patients, but there were notable differences in methods used to develop these approaches, and sample sizes were small. Although some approaches can be considered for validation in individual institutions, further research is warranted. This may include validating approaches in larger populations with narrower obesity severity ranges, investigating target attainment in indication-specific target ranges, and evaluating the impact of different dosing weights and methods of creatinine clearance calculation.

Pooled Resequencing of 122 Ulcerative Colitis Genes in a Large Dutch Cohort Suggests Population-Specific Associations of Rare Variants in MUC2.

PubMed

Visschedijk, Marijn C; Alberts, Rudi; Mucha, Soren; Deelen, Patrick; de Jong, Dirk J; Pierik, Marieke; Spekhorst, Lieke M; Imhann, Floris; van der Meulen-de Jong, Andrea E; van der Woude, C Janneke; van Bodegraven, Adriaan A; Oldenburg, Bas; Löwenberg, Mark; Dijkstra, Gerard; Ellinghaus, David; Schreiber, Stefan; Wijmenga, Cisca; Rivas, Manuel A; Franke, Andre; van Diemen, Cleo C; Weersma, Rinse K

2016-01-01

Genome-wide association studies have revealed several common genetic risk variants for ulcerative colitis (UC). However, little is known about the contribution of rare, large effect genetic variants to UC susceptibility. In this study, we performed a deep targeted re-sequencing of 122 genes in Dutch UC patients in order to investigate the contribution of rare variants to the genetic susceptibility to UC. The selection of genes consists of 111 established human UC susceptibility genes and 11 genes that lead to spontaneous colitis when knocked-out in mice. In addition, we sequenced the promoter regions of 45 genes where known variants exert cis-eQTL-effects. Targeted pooled re-sequencing was performed on DNA of 790 Dutch UC cases. The Genome of the Netherlands project provided sequence data of 500 healthy controls. After quality control and prioritization based on allele frequency and pathogenicity probability, follow-up genotyping of 171 rare variants was performed on 1021 Dutch UC cases and 1166 Dutch controls. Single-variant association and gene-based analyses identified an association of rare variants in the MUC2 gene with UC. The associated variants in the Dutch population could not be replicated in a German replication cohort (1026 UC cases, 3532 controls). In conclusion, this study has identified a putative role for MUC2 on UC susceptibility in the Dutch population and suggests a population-specific contribution of rare variants to UC.

Designing Peptide-Based HIV Vaccine for Chinese

PubMed Central

Fan, Xiaojuan

2014-01-01

CD4+ T cells are central to the induction and maintenance of CD8+ T cell and antibody-producing B cell responses, and the latter are essential for the protection against disease in subjects with HIV infection. How to elicit HIV-specific CD4+ T cell responses in a given population using vaccines is one of the major areas of current HIV vaccine research. To design vaccine that targets specifically Chinese, we assembled a database that is comprised of sequences from 821 Chinese HIV isolates and 46 human leukocyte antigen (HLA) DR alleles identified in Chinese population. We then predicted 20 potential HIV epitopes using bioinformatics approaches. The combination of these 20 epitopes has a theoretical coverage of 98.1% of the population for both the prevalent HIV genotypes and also Chinese HLA-DR types. We suggest that testing this vaccine experimentally will facilitate the development of a CD4+ T cell vaccine especially catered for Chinese. PMID:25136573

Designing peptide-based HIV vaccine for Chinese.

PubMed

Shu, Jiayi; Fan, Xiaojuan; Ping, Jie; Jin, Xia; Hao, Pei

2014-01-01

CD4+ T cells are central to the induction and maintenance of CD8+ T cell and antibody-producing B cell responses, and the latter are essential for the protection against disease in subjects with HIV infection. How to elicit HIV-specific CD4+ T cell responses in a given population using vaccines is one of the major areas of current HIV vaccine research. To design vaccine that targets specifically Chinese, we assembled a database that is comprised of sequences from 821 Chinese HIV isolates and 46 human leukocyte antigen (HLA) DR alleles identified in Chinese population. We then predicted 20 potential HIV epitopes using bioinformatics approaches. The combination of these 20 epitopes has a theoretical coverage of 98.1% of the population for both the prevalent HIV genotypes and also Chinese HLA-DR types. We suggest that testing this vaccine experimentally will facilitate the development of a CD4+ T cell vaccine especially catered for Chinese.

Food and Drug Administration Perspective on Negative Symptoms in Schizophrenia as a Target for a Drug Treatment Claim

PubMed Central

Laughren, Thomas; Levin, Robert

2006-01-01

Negative symptoms of schizophrenia are not adequately addressed by available treatments for schizophrenia. Thus, it is reasonable to consider them as a target for a drug claim. This article describes the thought process that the Food and Drug Administration (FDA) will undertake in considering negative symptoms of schizophrenia as a novel and distinct drug target. Beyond this basic question, this article identifies a number of design issues that the FDA needs to consider regarding how best to conduct studies to support claims for this target. These design issues include (1) what population to study, (2) what phase of illness to target, (3) whether to focus on the negative symptom domain overall or on some specific aspect of negative symptoms, (4) the role of functional measures in negative symptom trials, and (5) optimal designs for targeting drugs for add-on therapy or broad-spectrum agents. PMID:16079389

Mutational spectrum in a worldwide study of 29,700 families with BRCA1 or BRCA2 mutations.

PubMed

Rebbeck, Timothy R; Friebel, Tara M; Friedman, Eitan; Hamann, Ute; Huo, Dezheng; Kwong, Ava; Olah, Edith; Olopade, Olufunmilayo I; Solano, Angela R; Teo, Soo-Hwang; Thomassen, Mads; Weitzel, Jeffrey N; Chan, T L; Couch, Fergus J; Goldgar, David E; Kruse, Torben A; Palmero, Edenir Inêz; Park, Sue Kyung; Torres, Diana; van Rensburg, Elizabeth J; McGuffog, Lesley; Parsons, Michael T; Leslie, Goska; Aalfs, Cora M; Abugattas, Julio; Adlard, Julian; Agata, Simona; Aittomäki, Kristiina; Andrews, Lesley; Andrulis, Irene L; Arason, Adalgeir; Arnold, Norbert; Arun, Banu K; Asseryanis, Ella; Auerbach, Leo; Azzollini, Jacopo; Balmaña, Judith; Barile, Monica; Barkardottir, Rosa B; Barrowdale, Daniel; Benitez, Javier; Berger, Andreas; Berger, Raanan; Blanco, Amie M; Blazer, Kathleen R; Blok, Marinus J; Bonadona, Valérie; Bonanni, Bernardo; Bradbury, Angela R; Brewer, Carole; Buecher, Bruno; Buys, Saundra S; Caldes, Trinidad; Caliebe, Almuth; Caligo, Maria A; Campbell, Ian; Caputo, Sandrine M; Chiquette, Jocelyne; Chung, Wendy K; Claes, Kathleen B M; Collée, J Margriet; Cook, Jackie; Davidson, Rosemarie; de la Hoya, Miguel; De Leeneer, Kim; de Pauw, Antoine; Delnatte, Capucine; Diez, Orland; Ding, Yuan Chun; Ditsch, Nina; Domchek, Susan M; Dorfling, Cecilia M; Velazquez, Carolina; Dworniczak, Bernd; Eason, Jacqueline; Easton, Douglas F; Eeles, Ros; Ehrencrona, Hans; Ejlertsen, Bent; Engel, Christoph; Engert, Stefanie; Evans, D Gareth; Faivre, Laurence; Feliubadaló, Lidia; Ferrer, Sandra Fert; Foretova, Lenka; Fowler, Jeffrey; Frost, Debra; Galvão, Henrique C R; Ganz, Patricia A; Garber, Judy; Gauthier-Villars, Marion; Gehrig, Andrea; Gerdes, Anne-Marie; Gesta, Paul; Giannini, Giuseppe; Giraud, Sophie; Glendon, Gord; Godwin, Andrew K; Greene, Mark H; Gronwald, Jacek; Gutierrez-Barrera, Angelica; Hahnen, Eric; Hauke, Jan; Henderson, Alex; Hentschel, Julia; Hogervorst, Frans B L; Honisch, Ellen; Imyanitov, Evgeny N; Isaacs, Claudine; Izatt, Louise; Izquierdo, Angel; Jakubowska, Anna; James, Paul; Janavicius, Ramunas; Jensen, Uffe Birk; John, Esther M; Vijai, Joseph; Kaczmarek, Katarzyna; Karlan, Beth Y; Kast, Karin; Investigators, KConFab; Kim, Sung-Won; Konstantopoulou, Irene; Korach, Jacob; Laitman, Yael; Lasa, Adriana; Lasset, Christine; Lázaro, Conxi; Lee, Annette; Lee, Min Hyuk; Lester, Jenny; Lesueur, Fabienne; Liljegren, Annelie; Lindor, Noralane M; Longy, Michel; Loud, Jennifer T; Lu, Karen H; Lubinski, Jan; Machackova, Eva; Manoukian, Siranoush; Mari, Véronique; Martínez-Bouzas, Cristina; Matrai, Zoltan; Mebirouk, Noura; Meijers-Heijboer, Hanne E J; Meindl, Alfons; Mensenkamp, Arjen R; Mickys, Ugnius; Miller, Austin; Montagna, Marco; Moysich, Kirsten B; Mulligan, Anna Marie; Musinsky, Jacob; Neuhausen, Susan L; Nevanlinna, Heli; Ngeow, Joanne; Nguyen, Huu Phuc; Niederacher, Dieter; Nielsen, Henriette Roed; Nielsen, Finn Cilius; Nussbaum, Robert L; Offit, Kenneth; Öfverholm, Anna; Ong, Kai-Ren; Osorio, Ana; Papi, Laura; Papp, Janos; Pasini, Barbara; Pedersen, Inge Sokilde; Peixoto, Ana; Peruga, Nina; Peterlongo, Paolo; Pohl, Esther; Pradhan, Nisha; Prajzendanc, Karolina; Prieur, Fabienne; Pujol, Pascal; Radice, Paolo; Ramus, Susan J; Rantala, Johanna; Rashid, Muhammad Usman; Rhiem, Kerstin; Robson, Mark; Rodriguez, Gustavo C; Rogers, Mark T; Rudaitis, Vilius; Schmidt, Ane Y; Schmutzler, Rita Katharina; Senter, Leigha; Shah, Payal D; Sharma, Priyanka; Side, Lucy E; Simard, Jacques; Singer, Christian F; Skytte, Anne-Bine; Slavin, Thomas P; Snape, Katie; Sobol, Hagay; Southey, Melissa; Steele, Linda; Steinemann, Doris; Sukiennicki, Grzegorz; Sutter, Christian; Szabo, Csilla I; Tan, Yen Y; Teixeira, Manuel R; Terry, Mary Beth; Teulé, Alex; Thomas, Abigail; Thull, Darcy L; Tischkowitz, Marc; Tognazzo, Silvia; Toland, Amanda Ewart; Topka, Sabine; Trainer, Alison H; Tung, Nadine; van Asperen, Christi J; van der Hout, Annemieke H; van der Kolk, Lizet E; van der Luijt, Rob B; Van Heetvelde, Mattias; Varesco, Liliana; Varon-Mateeva, Raymonda; Vega, Ana; Villarreal-Garza, Cynthia; von Wachenfeldt, Anna; Walker, Lisa; Wang-Gohrke, Shan; Wappenschmidt, Barbara; Weber, Bernhard H F; Yannoukakos, Drakoulis; Yoon, Sook-Yee; Zanzottera, Cristina; Zidan, Jamal; Zorn, Kristin K; Hutten Selkirk, Christina G; Hulick, Peter J; Chenevix-Trench, Georgia; Spurdle, Amanda B; Antoniou, Antonis C; Nathanson, Katherine L

2018-05-01

The prevalence and spectrum of germline mutations in BRCA1 and BRCA2 have been reported in single populations, with the majority of reports focused on White in Europe and North America. The Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA) has assembled data on 18,435 families with BRCA1 mutations and 11,351 families with BRCA2 mutations ascertained from 69 centers in 49 countries on six continents. This study comprehensively describes the characteristics of the 1,650 unique BRCA1 and 1,731 unique BRCA2 deleterious (disease-associated) mutations identified in the CIMBA database. We observed substantial variation in mutation type and frequency by geographical region and race/ethnicity. In addition to known founder mutations, mutations of relatively high frequency were identified in specific racial/ethnic or geographic groups that may reflect founder mutations and which could be used in targeted (panel) first pass genotyping for specific populations. Knowledge of the population-specific mutational spectrum in BRCA1 and BRCA2 could inform efficient strategies for genetic testing and may justify a more broad-based oncogenetic testing in some populations. © 2018 Wiley Periodicals, Inc.

Treatment Considerations of Clinical Physician on Hypertension Management in Asia.

PubMed

Hoshide, Satoshi; Wang, Ji-Guang; Park, Sungha; Chen, Chen-Huan; Cheng, Hao-Min; Huang, Qi-Fang; Park, Chang-Gyu; Kario, Kazuomi

2016-01-01

There are important differences in the lifestyle and cardiovascular disease risks between Asian and Western populations. The objective of this survey was to investigate the awareness of these factors in the practice of hypertension management among Asian physicians. General practitioners and specialists in Asia were surveyed by questionnaire with regard to their management of hypertension. Physicians attending international conferences or meetings on hypertension between March and May 2014 were asked to participate. In their treatment of hypertensive patients, 87% of the 133 respondents said they considered the Asian lifestyle and region-specific characteristics of hypertension in their treatment decisions, while just less than 11% did not. Almost all physicians (92%) recognized the necessity for an Asian-specific guideline for the management of hypertension. For patients with diabetes, 37% and 59% of the respondents used target systolic blood pressure (SBP) levels of 140 mmHg and 130 mmHg, respectively; for elderly patients, 37% and 53% of respondents used target SBP levels of 140 and l50 mmHg, respectively. Forty-eight percent of Asian physicians used calcium channel blockers as the first-line choice of antihypertensive drug while 34% selected angiotensin II receptor blockers, 14% angiotensin converting enzyme inhibitors and 3% diuretics. Asian physicians consider that an Asian-specific guideline is needed for hypertension management in the Asian population.

Developing a framework of gastronomic systems research to unravel drivers of food choice.

PubMed

Cuevas, Rosa Paula; de Guia, Annalyn; Demont, Matty

2017-10-01

Nutritional and dietary interventions and the introduction of novel food products and ingredients require a thorough understanding of the drivers of food choice, which are embedded in local context and culture. We developed a framework of "gastronomic systems research" (GSR) to understand culture-specific consumer food choice, and contextualise it to a target population of urban, middle- to high-income Filipino consumers to assess the domestic niche market potential of traditional rice varieties in the Philippines. The GSR framework was contextualised through expert elicitation involving chefs and nutritionists, and validated through a consumer survey conducted during a food exposition. Using the GSR framework, we determined indicative rice consumption patterns of the target population and the specific rice quality attributes they require for specific rice-based dishes and rice consumption occasions. The GSR framework also reveals possible entry points for nutritional and dietary interventions and the introduction of novel food products and ingredients. The GSR framework, therefore, has the potential to aid policymakers and food value chain stakeholders in designing culture-sensitive and context-appropriate interventions not only to help consumers improve their diets, but also to help farmers access niche markets for novel food products and ingredients and thereby improve their livelihoods and preserve cultural heritage.

Managing American Oystercatcher (Haematopus palliatus) population qrowth by targeting nesting season vital rates

USGS Publications Warehouse

Felton, Shilo K.; Hostetter, Nathan J.; Pollock, Kenneth H.; Simons, Theodore R.

2017-01-01

In populations of long-lived species, adult survival typically has a relatively high influence on population growth. From a management perspective, however, adult survival can be difficult to increase in some instances, so other component rates must be considered to reverse population declines. In North Carolina, USA, management to conserve the American Oystercatcher (Haematopus palliatus) targets component vital rates related to fecundity, specifically nest and chick survival. The effectiveness of such a management approach in North Carolina was assessed by creating a three-stage female-based deterministic matrix model. Isoclines were produced from the matrix model to evaluate minimum nest and chick survival rates necessary to reverse population decline, assuming all other vital rates remained stable at mean values. Assuming accurate vital rates, breeding populations within North Carolina appear to be declining. To reverse this decline, combined nest and chick survival would need to increase from 0.14 to ≤ 0.27, a rate that appears to be attainable based on historical estimates. Results are heavily dependent on assumptions of other vital rates, most notably adult survival, revealing the need for accurate estimates of all vital rates to inform management actions. This approach provides valuable insights for evaluating conservation goals for species of concern.

How health systems could avert 'triple fail' events that are harmful, are costly, and result in poor patient satisfaction.

PubMed

Lewis, Geraint; Kirkham, Heather; Duncan, Ian; Vaithianathan, Rhema

2013-04-01

Health care systems in many countries are using the "Triple Aim"--to improve patients' experience of care, to advance population health, and to lower per capita costs--as a focus for improving quality. Population strategies for addressing the Triple Aim are becoming increasingly prevalent in developed countries, but ultimately success will also require targeting specific subgroups and individuals. Certain events, which we call "Triple Fail" events, constitute a simultaneous failure to meet all three Triple Aim goals. The risk of experiencing different Triple Fail events varies widely across people. We argue that by stratifying populations according to each person's risk and anticipated response to an intervention, health systems could more effectively target different preventive interventions at particular risk strata. In this article we describe how such an approach could be planned and operationalized. Policy makers should consider using this stratified approach to reduce the incidence of Triple Fail events, thereby improving outcomes, enhancing patient experience, and lowering costs.

Best Fitting Prediction Equations for Basal Metabolic Rate: Informing Obesity Interventions in Diverse Populations

PubMed Central

Sabounchi, Nasim S.; Rahmandad, Hazhir; Ammerman, Alice

2014-01-01

Basal Metabolic Rate (BMR) represents the largest component of total energy expenditure and is a major contributor to energy balance. Therefore, accurately estimating BMR is critical for developing rigorous obesity prevention and control strategies. Over the past several decades, numerous BMR formulas have been developed targeted to different population groups. A comprehensive literature search revealed 248 BMR estimation equations developed using diverse ranges of age, gender, race, fat free mass, fat mass, height, waist-to-hip ratio, body mass index, and weight. A subset of 47 studies included enough detail to allow for development of meta-regression equations. Utilizing these studies, meta-equations were developed targeted to twenty specific population groups. This review provides a comprehensive summary of available BMR equations and an estimate of their accuracy. An accompanying online BMR prediction tool (available at http://www.sdl.ise.vt.edu/tutorials.html) was developed to automatically estimate BMR based on the most appropriate equation after user-entry of individual age, race, gender, and weight. PMID:23318720

Winnowing DNA for rare sequences: highly specific sequence and methylation based enrichment.

PubMed

Thompson, Jason D; Shibahara, Gosuke; Rajan, Sweta; Pel, Joel; Marziali, Andre

2012-01-01

Rare mutations in cell populations are known to be hallmarks of many diseases and cancers. Similarly, differential DNA methylation patterns arise in rare cell populations with diagnostic potential such as fetal cells circulating in maternal blood. Unfortunately, the frequency of alleles with diagnostic potential, relative to wild-type background sequence, is often well below the frequency of errors in currently available methods for sequence analysis, including very high throughput DNA sequencing. We demonstrate a DNA preparation and purification method that through non-linear electrophoretic separation in media containing oligonucleotide probes, achieves 10,000 fold enrichment of target DNA with single nucleotide specificity, and 100 fold enrichment of unmodified methylated DNA differing from the background by the methylation of a single cytosine residue.

Dynamic conservation of forest genetic resources in 33 European countries.

PubMed

Lefèvre, François; Koskela, Jarkko; Hubert, Jason; Kraigher, Hojka; Longauer, Roman; Olrik, Ditte C; Schüler, Silvio; Bozzano, Michele; Alizoti, Paraskevi; Bakys, Remigijus; Baldwin, Cathleen; Ballian, Dalibor; Black-Samuelsson, Sanna; Bednarova, Dagmar; Bordács, Sándor; Collin, Eric; de Cuyper, Bart; de Vries, Sven M G; Eysteinsson, Thröstur; Frýdl, Josef; Haverkamp, Michaela; Ivankovic, Mladen; Konrad, Heino; Koziol, Czesław; Maaten, Tiit; Notivol Paino, Eduardo; Oztürk, Hikmet; Pandeva, Ivanova Denitsa; Parnuta, Gheorghe; Pilipovič, Andrej; Postolache, Dragos; Ryan, Cathal; Steffenrem, Arne; Varela, Maria Carolina; Vessella, Federico; Volosyanchuk, Roman T; Westergren, Marjana; Wolter, Frank; Yrjänä, Leena; Zariŋa, Inga

2013-04-01

Dynamic conservation of forest genetic resources (FGR) means maintaining the genetic diversity of trees within an evolutionary process and allowing generation turnover in the forest. We assessed the network of forests areas managed for the dynamic conservation of FGR (conservation units) across Europe (33 countries). On the basis of information available in the European Information System on FGR (EUFGIS Portal), species distribution maps, and environmental stratification of the continent, we developed ecogeographic indicators, a marginality index, and demographic indicators to assess and monitor forest conservation efforts. The pan-European network has 1967 conservation units, 2737 populations of target trees, and 86 species of target trees. We detected a poor coincidence between FGR conservation and other biodiversity conservation objectives within this network. We identified 2 complementary strategies: a species-oriented strategy in which national conservation networks are specifically designed for key target species and a site-oriented strategy in which multiple-target units include so-called secondary species conserved within a few sites. The network is highly unbalanced in terms of species representation, and 7 key target species are conserved in 60% of the conservation units. We performed specific gap analyses for 11 tree species, including assessment of ecogeographic, demographic, and genetic criteria. For each species, we identified gaps, particularly in the marginal parts of their distribution range, and found multiple redundant conservation units in other areas. The Mediterranean forests and to a lesser extent the boreal forests are underrepresented. Monitoring the conservation efficiency of each unit remains challenging; however, <2% of the conserved populations seem to be at risk of extinction. On the basis of our results, we recommend combining species-oriented and site-oriented strategies. © 2012 Society for Conservation Biology.

An approximation of herd effect due to vaccinating children against seasonal influenza – a potential solution to the incorporation of indirect effects into static models

PubMed Central

2013-01-01

Background Indirect herd effect from vaccination of children offers potential for improving the effectiveness of influenza prevention in the remaining unvaccinated population. Static models used in cost-effectiveness analyses cannot dynamically capture herd effects. The objective of this study was to develop a methodology to allow herd effect associated with vaccinating children against seasonal influenza to be incorporated into static models evaluating the cost-effectiveness of influenza vaccination. Methods Two previously published linear equations for approximation of herd effects in general were compared with the results of a structured literature review undertaken using PubMed searches to identify data on herd effects specific to influenza vaccination. A linear function was fitted to point estimates from the literature using the sum of squared residuals. Results The literature review identified 21 publications on 20 studies for inclusion. Six studies provided data on a mathematical relationship between effective vaccine coverage in subgroups and reduction of influenza infection in a larger unvaccinated population. These supported a linear relationship when effective vaccine coverage in a subgroup population was between 20% and 80%. Three studies evaluating herd effect at a community level, specifically induced by vaccinating children, provided point estimates for fitting linear equations. The fitted linear equation for herd protection in the target population for vaccination (children) was slightly less conservative than a previously published equation for herd effects in general. The fitted linear equation for herd protection in the non-target population was considerably less conservative than the previously published equation. Conclusions This method of approximating herd effect requires simple adjustments to the annual baseline risk of influenza in static models: (1) for the age group targeted by the childhood vaccination strategy (i.e. children); and (2) for other age groups not targeted (e.g. adults and/or elderly). Two approximations provide a linear relationship between effective coverage and reduction in the risk of infection. The first is a conservative approximation, recommended as a base-case for cost-effectiveness evaluations. The second, fitted to data extracted from a structured literature review, provides a less conservative estimate of herd effect, recommended for sensitivity analyses. PMID:23339290

Global Analysis of Small RNA Dynamics during Seed Development of Picea glauca and Arabidopsis thaliana Populations Reveals Insights on their Evolutionary Trajectories

PubMed Central

Liu, Yang; El-Kassaby, Yousry A.

2017-01-01

While DNA methylation carries genetic signals and is instrumental in the evolution of organismal complexity, small RNAs (sRNAs), ~18–24 ribonucleotide (nt) sequences, are crucial mediators of methylation as well as gene silencing. However, scant study deals with sRNA evolution via featuring their expression dynamics coupled with species of different evolutionary time. Here we report an atlas of sRNAs and microRNAs (miRNAs, single-stranded sRNAs) produced over time at seed-set of two major spermatophytes represented by populations of Picea glauca and Arabidopsis thaliana with different seed-set duration. We applied diverse profiling methods to examine sRNA and miRNA features, including size distribution, sequence conservation and reproduction-specific regulation, as well as to predict their putative targets. The top 27 most abundant miRNAs were highly overlapped between the two species (e.g., miR166,−319 and−396), but in P. glauca, they were less abundant and significantly less correlated with seed-set phases. The most abundant sRNAs in libraries were deeply conserved miRNAs in the plant kingdom for Arabidopsis but long sRNAs (24-nt) for P. glauca. We also found significant difference in normalized expression between populations for population-specific sRNAs but not for lineage-specific ones. Moreover, lineage-specific sRNAs were enriched in the 21-nt size class. This pattern is consistent in both species and alludes to a specific type of sRNAs (e.g., miRNA, tasiRNA) being selected for. In addition, we deemed 24 and 9 sRNAs in P. glauca and Arabidopsis, respectively, as sRNA candidates targeting known adaptive genes. Temperature had significant influence on selected gene and miRNA expression at seed development in both species. This study increases our integrated understanding of sRNA evolution and its potential link to genomic architecture (e.g., sRNA derivation from genome and sRNA-mediated genomic events) and organismal complexity (e.g., association between different sRNA expression and their functionality). PMID:29046688

Incidence of listeriosis and related mortality among groups at risk of acquiring listeriosis.

PubMed

Goulet, Véronique; Hebert, Marjolaine; Hedberg, Craig; Laurent, Edith; Vaillant, Véronique; De Valk, Henriette; Desenclos, Jean-Claude

2012-03-01

Listeriosis is a foodborne disease of significant public health concern that primarily affects persons with recognized underlying conditions or diseases that impair cell-mediated immunity. The degree of risk posed by the different underlying conditions is crucial to prioritize prevention programs that target the highest risk populations. We reviewed cases of listeriosis reported in France from 2001 to 2008. Numbers of cases and deaths were tabulated by age and underlying condition. Measures of the impact of specific underlying conditions on the occurrence of listeriosis were calculated. For estimating the total number of persons living with specific diseases, we applied prevalence estimates of these diseases to the French population. Underlying conditions were ranked by the degree to which they increased the risk of listeriosis. From 2001 to 2008, 1959 cases of listeriosis were reported in France (mean annual incidence 0.39 per 100,000 residents). Compared with persons <65 years with no underlying conditions, those with chronic lymphocytic leukemia had a >1000-fold increased risk of acquiring listeriosis, and those with liver cancer; myeoloproliferative disorder; multiple myeloma; acute leukemia; giant cell arteritis; dialysis; esophageal, stomach, pancreas, lung, and brain cancer; cirrhosis; organ transplantation; and pregnancy had a 100-1000-fold increased risk of listeriosis. To be effective and acceptable to physicians and patients, listeriosis prevention strategies should be targeted based on evidence of increased risk. Stringent dietary guidance, to avoid specific foods with a high risk for Listeria contamination, should be targeted to pregnant women and to others at highest risk of listeriosis.

Human immune cell targeting of protein nanoparticles - caveospheres

NASA Astrophysics Data System (ADS)

Glass, Joshua J.; Yuen, Daniel; Rae, James; Johnston, Angus P. R.; Parton, Robert G.; Kent, Stephen J.; de Rose, Robert

2016-04-01

Nanotechnology has the power to transform vaccine and drug delivery through protection of payloads from both metabolism and off-target effects, while facilitating specific delivery of cargo to immune cells. However, evaluation of immune cell nanoparticle targeting is conventionally restricted to monocultured cell line models. We generated human caveolin-1 nanoparticles, termed caveospheres, which were efficiently functionalized with monoclonal antibodies. Using this platform, we investigated CD4+ T cell and CD20+ B cell targeting within physiological mixtures of primary human blood immune cells using flow cytometry, imaging flow cytometry and confocal microscopy. Antibody-functionalization enhanced caveosphere binding to targeted immune cells (6.6 to 43.9-fold) within mixed populations and in the presence of protein-containing fluids. Moreover, targeting caveospheres to CCR5 enabled caveosphere internalization by non-phagocytic CD4+ T cells--an important therapeutic target for HIV treatment. This efficient and flexible system of immune cell-targeted caveosphere nanoparticles holds promise for the development of advanced immunotherapeutics and vaccines.

Meeting the Housing and Care Needs of Older Homeless Adults: A Permanent Supportive Housing Program Targeting Homeless Elders

PubMed Central

Brown, Rebecca T.; Thomas, M. Lori; Cutler, Deborah F.; Hinderlie, Mark

2014-01-01

The homeless population is aging faster than the general population in the United States. As this vulnerable population continues to age, addressing complex care and housing needs will become increasingly important. This article reviews the often-overlooked issue of homelessness among older adults, including their poor health status and unique care needs, the factors that contribute to homelessness in this population, and the costs of homelessness to the U.S. health care system. Permanent supportive housing programs are presented as a potential solution to elder homelessness, and Hearth, an outreach and permanent supportive housing model in Boston, is described. Finally, specific policy changes are presented that could promote access to housing among the growing older homeless population. PMID:24729832

Bacillus thuringiensis Is an Environmental Pathogen and Host-Specificity Has Developed as an Adaptation to Human-Generated Ecological Niches

PubMed Central

Argôlo-Filho, Ronaldo Costa; Loguercio, Leandro Lopes

2013-01-01

Bacillus thuringiensis (Bt) has been used successfully as a biopesticide for more than 60 years. More recently, genes encoding their toxins have been used to transform plants and other organisms. Despite the large amount of research on this bacterium, its true ecology is still a matter of debate, with two major viewpoints dominating: while some understand Bt as an insect pathogen, others see it as a saprophytic bacteria from soil. In this context, Bt’s pathogenicity to other taxa and the possibility that insects may not be the primary targets of Bt are also ideas that further complicate this scenario. The existence of conflicting research results, the difficulty in developing broader ecological and genetics studies, and the great genetic plasticity of this species has cluttered a definitive concept. In this review, we gathered information on the aspects of Bt ecology that are often ignored, in the attempt to clarify the lifestyle, mechanisms of transmission and target host range of this bacterial species. As a result, we propose an integrated view to account for Bt ecology. Although Bt is indeed a pathogenic bacterium that possesses a broad arsenal for virulence and defense mechanisms, as well as a wide range of target hosts, this seems to be an adaptation to specific ecological changes acting on a versatile and cosmopolitan environmental bacterium. Bt pathogenicity and host-specificity was favored evolutionarily by increased populations of certain insect species (or other host animals), whose availability for colonization were mostly caused by anthropogenic activities. These have generated the conditions for ecological imbalances that favored dominance of specific populations of insects, arachnids, nematodes, etc., in certain areas, with narrower genetic backgrounds. These conditions provided the selective pressure for development of new hosts for pathogenic interactions, and so, host specificity of certain strains. PMID:26462580

Modelling the Transport of Nanoparticles under Blood Flow using an Agent-based Approach.

PubMed

Fullstone, Gavin; Wood, Jonathan; Holcombe, Mike; Battaglia, Giuseppe

2015-06-10

Blood-mediated nanoparticle delivery is a new and growing field in the development of therapeutics and diagnostics. Nanoparticle properties such as size, shape and surface chemistry can be controlled to improve their performance in biological systems. This enables modulation of immune system interactions, blood clearance profile and interaction with target cells, thereby aiding effective delivery of cargo within cells or tissues. Their ability to target and enter tissues from the blood is highly dependent on their behaviour under blood flow. Here we have produced an agent-based model of nanoparticle behaviour under blood flow in capillaries. We demonstrate that red blood cells are highly important for effective nanoparticle distribution within capillaries. Furthermore, we use this model to demonstrate how nanoparticle size can selectively target tumour tissue over normal tissue. We demonstrate that the polydispersity of nanoparticle populations is an important consideration in achieving optimal specificity and to avoid off-target effects. In future this model could be used for informing new nanoparticle design and to predict general and specific uptake properties under blood flow.

A multicolor panel of TALE-KRAB based transcriptional repressor vectors enabling knockdown of multiple gene targets

PubMed Central

Zhang, Zhonghui; Wu, Elise; Qian, Zhijian; Wu, Wen-Shu

2014-01-01

Stable and efficient knockdown of multiple gene targets is highly desirable for dissection of molecular pathways. Because it allows sequence-specific DNA binding, transcription activator-like effector (TALE) offers a new genetic perturbation technique that allows for gene-specific repression. Here, we constructed a multicolor lentiviral TALE-Kruppel-associated box (KRAB) expression vector platform that enables knockdown of multiple gene targets. This platform is fully compatible with the Golden Gate TALEN and TAL Effector Kit 2.0, a widely used and efficient method for TALE assembly. We showed that this multicolor TALE-KRAB vector system when combined together with bone marrow transplantation could quickly knock down c-kit and PU.1 genes in hematopoietic stem and progenitor cells of recipient mice. Furthermore, our data demonstrated that this platform simultaneously knocked down both c-Kit and PU.1 genes in the same primary cell populations. Together, our results suggest that this multicolor TALE-KRAB vector platform is a promising and versatile tool for knockdown of multiple gene targets and could greatly facilitate dissection of molecular pathways. PMID:25475013

A multicolor panel of TALE-KRAB based transcriptional repressor vectors enabling knockdown of multiple gene targets.

PubMed

Zhang, Zhonghui; Wu, Elise; Qian, Zhijian; Wu, Wen-Shu

2014-12-05

Stable and efficient knockdown of multiple gene targets is highly desirable for dissection of molecular pathways. Because it allows sequence-specific DNA binding, transcription activator-like effector (TALE) offers a new genetic perturbation technique that allows for gene-specific repression. Here, we constructed a multicolor lentiviral TALE-Kruppel-associated box (KRAB) expression vector platform that enables knockdown of multiple gene targets. This platform is fully compatible with the Golden Gate TALEN and TAL Effector Kit 2.0, a widely used and efficient method for TALE assembly. We showed that this multicolor TALE-KRAB vector system when combined together with bone marrow transplantation could quickly knock down c-kit and PU.1 genes in hematopoietic stem and progenitor cells of recipient mice. Furthermore, our data demonstrated that this platform simultaneously knocked down both c-Kit and PU.1 genes in the same primary cell populations. Together, our results suggest that this multicolor TALE-KRAB vector platform is a promising and versatile tool for knockdown of multiple gene targets and could greatly facilitate dissection of molecular pathways.

Demographic history and rare allele sharing among human populations.

PubMed

Gravel, Simon; Henn, Brenna M; Gutenkunst, Ryan N; Indap, Amit R; Marth, Gabor T; Clark, Andrew G; Yu, Fuli; Gibbs, Richard A; Bustamante, Carlos D

2011-07-19

High-throughput sequencing technology enables population-level surveys of human genomic variation. Here, we examine the joint allele frequency distributions across continental human populations and present an approach for combining complementary aspects of whole-genome, low-coverage data and targeted high-coverage data. We apply this approach to data generated by the pilot phase of the Thousand Genomes Project, including whole-genome 2-4× coverage data for 179 samples from HapMap European, Asian, and African panels as well as high-coverage target sequencing of the exons of 800 genes from 697 individuals in seven populations. We use the site frequency spectra obtained from these data to infer demographic parameters for an Out-of-Africa model for populations of African, European, and Asian descent and to predict, by a jackknife-based approach, the amount of genetic diversity that will be discovered as sample sizes are increased. We predict that the number of discovered nonsynonymous coding variants will reach 100,000 in each population after ∼1,000 sequenced chromosomes per population, whereas ∼2,500 chromosomes will be needed for the same number of synonymous variants. Beyond this point, the number of segregating sites in the European and Asian panel populations is expected to overcome that of the African panel because of faster recent population growth. Overall, we find that the majority of human genomic variable sites are rare and exhibit little sharing among diverged populations. Our results emphasize that replication of disease association for specific rare genetic variants across diverged populations must overcome both reduced statistical power because of rarity and higher population divergence.

Demographic history and rare allele sharing among human populations

PubMed Central

Gravel, Simon; Henn, Brenna M.; Gutenkunst, Ryan N.; Indap, Amit R.; Marth, Gabor T.; Clark, Andrew G.; Yu, Fuli; Gibbs, Richard A.; Bustamante, Carlos D.; Altshuler, David L.; Durbin, Richard M.; Abecasis, Gonçalo R.; Bentley, David R.; Chakravarti, Aravinda; Clark, Andrew G.; Collins, Francis S.; De La Vega, Francisco M.; Donnelly, Peter; Egholm, Michael; Flicek, Paul; Gabriel, Stacey B.; Gibbs, Richard A.; Knoppers, Bartha M.; Lander, Eric S.; Lehrach, Hans; Mardis, Elaine R.; McVean, Gil A.; Nickerson, Debbie A.; Peltonen, Leena; Schafer, Alan J.; Sherry, Stephen T.; Wang, Jun; Wilson, Richard K.; Gibbs, Richard A.; Deiros, David; Metzker, Mike; Muzny, Donna; Reid, Jeff; Wheeler, David; Wang, Jun; Li, Jingxiang; Jian, Min; Li, Guoqing; Li, Ruiqiang; Liang, Huiqing; Tian, Geng; Wang, Bo; Wang, Jian; Wang, Wei; Yang, Huanming; Zhang, Xiuqing; Zheng, Huisong; Lander, Eric S.; Altshuler, David L.; Ambrogio, Lauren; Bloom, Toby; Cibulskis, Kristian; Fennell, Tim J.; Gabriel, Stacey B.; Jaffe, David B.; Shefler, Erica; Sougnez, Carrie L.; Bentley, David R.; Gormley, Niall; Humphray, Sean; Kingsbury, Zoya; Koko-Gonzales, Paula; Stone, Jennifer; McKernan, Kevin J.; Costa, Gina L.; Ichikawa, Jeffry K.; Lee, Clarence C.; Sudbrak, Ralf; Lehrach, Hans; Borodina, Tatiana A.; Dahl, Andreas; Davydov, Alexey N.; Marquardt, Peter; Mertes, Florian; Nietfeld, Wilfiried; Rosenstiel, Philip; Schreiber, Stefan; Soldatov, Aleksey V.; Timmermann, Bernd; Tolzmann, Marius; Egholm, Michael; Affourtit, Jason; Ashworth, Dana; Attiya, Said; Bachorski, Melissa; Buglione, Eli; Burke, Adam; Caprio, Amanda; Celone, Christopher; Clark, Shauna; Conners, David; Desany, Brian; Gu, Lisa; Guccione, Lorri; Kao, Kalvin; Kebbel, Andrew; Knowlton, Jennifer; Labrecque, Matthew; McDade, Louise; Mealmaker, Craig; Minderman, Melissa; Nawrocki, Anne; Niazi, Faheem; Pareja, Kristen; Ramenani, Ravi; Riches, David; Song, Wanmin; Turcotte, Cynthia; Wang, Shally; Mardis, Elaine R.; Wilson, Richard K.; Dooling, David; Fulton, Lucinda; Fulton, Robert; Weinstock, George; Durbin, Richard M.; Burton, John; Carter, David M.; Churcher, Carol; Coffey, Alison; Cox, Anthony; Palotie, Aarno; Quail, Michael; Skelly, Tom; Stalker, James; Swerdlow, Harold P.; Turner, Daniel; De Witte, Anniek; Giles, Shane; Gibbs, Richard A.; Wheeler, David; Bainbridge, Matthew; Challis, Danny; Sabo, Aniko; Yu, Fuli; Yu, Jin; Wang, Jun; Fang, Xiaodong; Guo, Xiaosen; Li, Ruiqiang; Li, Yingrui; Luo, Ruibang; Tai, Shuaishuai; Wu, Honglong; Zheng, Hancheng; Zheng, Xiaole; Zhou, Yan; Li, Guoqing; Wang, Jian; Yang, Huanming; Marth, Gabor T.; Garrison, Erik P.; Huang, Weichun; Indap, Amit; Kural, Deniz; Lee, Wan-Ping; Leong, Wen Fung; Quinlan, Aaron R.; Stewart, Chip; Stromberg, Michael P.; Ward, Alistair N.; Wu, Jiantao; Lee, Charles; Mills, Ryan E.; Shi, Xinghua; Daly, Mark J.; DePristo, Mark A.; Altshuler, David L.; Ball, Aaron D.; Banks, Eric; Bloom, Toby; Browning, Brian L.; Cibulskis, Kristian; Fennell, Tim J.; Garimella, Kiran V.; Grossman, Sharon R.; Handsaker, Robert E.; Hanna, Matt; Hartl, Chris; Jaffe, David B.; Kernytsky, Andrew M.; Korn, Joshua M.; Li, Heng; Maguire, Jared R.; McCarroll, Steven A.; McKenna, Aaron; Nemesh, James C.; Philippakis, Anthony A.; Poplin, Ryan E.; Price, Alkes; Rivas, Manuel A.; Sabeti, Pardis C.; Schaffner, Stephen F.; Shefler, Erica; Shlyakhter, Ilya A.; Cooper, David N.; Ball, Edward V.; Mort, Matthew; Phillips, Andrew D.; Stenson, Peter D.; Sebat, Jonathan; Makarov, Vladimir; Ye, Kenny; Yoon, Seungtai C.; Bustamante, Carlos D.; Clark, Andrew G.; Boyko, Adam; Degenhardt, Jeremiah; Gravel, Simon; Gutenkunst, Ryan N.; Kaganovich, Mark; Keinan, Alon; Lacroute, Phil; Ma, Xin; Reynolds, Andy; Clarke, Laura; Flicek, Paul; Cunningham, Fiona; Herrero, Javier; Keenen, Stephen; Kulesha, Eugene; Leinonen, Rasko; McLaren, William M.; Radhakrishnan, Rajesh; Smith, Richard E.; Zalunin, Vadim; Zheng-Bradley, Xiangqun; Korbel, Jan O.; Stütz, Adrian M.; Humphray, Sean; Bauer, Markus; Cheetham, R. Keira; Cox, Tony; Eberle, Michael; James, Terena; Kahn, Scott; Murray, Lisa; Chakravarti, Aravinda; Ye, Kai; De La Vega, Francisco M.; Fu, Yutao; Hyland, Fiona C. L.; Manning, Jonathan M.; McLaughlin, Stephen F.; Peckham, Heather E.; Sakarya, Onur; Sun, Yongming A.; Tsung, Eric F.; Batzer, Mark A.; Konkel, Miriam K.; Walker, Jerilyn A.; Sudbrak, Ralf; Albrecht, Marcus W.; Amstislavskiy, Vyacheslav S.; Herwig, Ralf; Parkhomchuk, Dimitri V.; Sherry, Stephen T.; Agarwala, Richa; Khouri, Hoda M.; Morgulis, Aleksandr O.; Paschall, Justin E.; Phan, Lon D.; Rotmistrovsky, Kirill E.; Sanders, Robert D.; Shumway, Martin F.; Xiao, Chunlin; McVean, Gil A.; Auton, Adam; Iqbal, Zamin; Lunter, Gerton; Marchini, Jonathan L.; Moutsianas, Loukas; Myers, Simon; Tumian, Afidalina; Desany, Brian; Knight, James; Winer, Roger; Craig, David W.; Beckstrom-Sternberg, Steve M.; Christoforides, Alexis; Kurdoglu, Ahmet A.; Pearson, John V.; Sinari, Shripad A.; Tembe, Waibhav D.; Haussler, David; Hinrichs, Angie S.; Katzman, Sol J.; Kern, Andrew; Kuhn, Robert M.; Przeworski, Molly; Hernandez, Ryan D.; Howie, Bryan; Kelley, Joanna L.; Melton, S. Cord; Abecasis, Gonçalo R.; Li, Yun; Anderson, Paul; Blackwell, Tom; Chen, Wei; Cookson, William O.; Ding, Jun; Kang, Hyun Min; Lathrop, Mark; Liang, Liming; Moffatt, Miriam F.; Scheet, Paul; Sidore, Carlo; Snyder, Matthew; Zhan, Xiaowei; Zöllner, Sebastian; Awadalla, Philip; Casals, Ferran; Idaghdour, Youssef; Keebler, John; Stone, Eric A.; Zilversmit, Martine; Jorde, Lynn; Xing, Jinchuan; Eichler, Evan E.; Aksay, Gozde; Alkan, Can; Hajirasouliha, Iman; Hormozdiari, Fereydoun; Kidd, Jeffrey M.; Sahinalp, S. Cenk; Sudmant, Peter H.; Mardis, Elaine R.; Chen, Ken; Chinwalla, Asif; Ding, Li; Koboldt, Daniel C.; McLellan, Mike D.; Dooling, David; Weinstock, George; Wallis, John W.; Wendl, Michael C.; Zhang, Qunyuan; Durbin, Richard M.; Albers, Cornelis A.; Ayub, Qasim; Balasubramaniam, Senduran; Barrett, Jeffrey C.; Carter, David M.; Chen, Yuan; Conrad, Donald F.; Danecek, Petr; Dermitzakis, Emmanouil T.; Hu, Min; Huang, Ni; Hurles, Matt E.; Jin, Hanjun; Jostins, Luke; Keane, Thomas M.; Le, Si Quang; Lindsay, Sarah; Long, Quan; MacArthur, Daniel G.; Montgomery, Stephen B.; Parts, Leopold; Stalker, James; Tyler-Smith, Chris; Walter, Klaudia; Zhang, Yujun; Gerstein, Mark B.; Snyder, Michael; Abyzov, Alexej; Balasubramanian, Suganthi; Bjornson, Robert; Du, Jiang; Grubert, Fabian; Habegger, Lukas; Haraksingh, Rajini; Jee, Justin; Khurana, Ekta; Lam, Hugo Y. K.; Leng, Jing; Mu, Xinmeng Jasmine; Urban, Alexander E.; Zhang, Zhengdong; Li, Yingrui; Luo, Ruibang; Marth, Gabor T.; Garrison, Erik P.; Kural, Deniz; Quinlan, Aaron R.; Stewart, Chip; Stromberg, Michael P.; Ward, Alistair N.; Wu, Jiantao; Lee, Charles; Mills, Ryan E.; Shi, Xinghua; McCarroll, Steven A.; Banks, Eric; DePristo, Mark A.; Handsaker, Robert E.; Hartl, Chris; Korn, Joshua M.; Li, Heng; Nemesh, James C.; Sebat, Jonathan; Makarov, Vladimir; Ye, Kenny; Yoon, Seungtai C.; Degenhardt, Jeremiah; Kaganovich, Mark; Clarke, Laura; Smith, Richard E.; Zheng-Bradley, Xiangqun; Korbel, Jan O.; Humphray, Sean; Cheetham, R. Keira; Eberle, Michael; Kahn, Scott; Murray, Lisa; Ye, Kai; De La Vega, Francisco M.; Fu, Yutao; Peckham, Heather E.; Sun, Yongming A.; Batzer, Mark A.; Konkel, Miriam K.; Walker, Jerilyn A.; Xiao, Chunlin; Iqbal, Zamin; Desany, Brian; Blackwell, Tom; Snyder, Matthew; Xing, Jinchuan; Eichler, Evan E.; Aksay, Gozde; Alkan, Can; Hajirasouliha, Iman; Hormozdiari, Fereydoun; Kidd, Jeffrey M.; Chen, Ken; Chinwalla, Asif; Ding, Li; McLellan, Mike D.; Wallis, John W.; Hurles, Matt E.; Conrad, Donald F.; Walter, Klaudia; Zhang, Yujun; Gerstein, Mark B.; Snyder, Michael; Abyzov, Alexej; Du, Jiang; Grubert, Fabian; Haraksingh, Rajini; Jee, Justin; Khurana, Ekta; Lam, Hugo Y. K.; Leng, Jing; Mu, Xinmeng Jasmine; Urban, Alexander E.; Zhang, Zhengdong; Gibbs, Richard A.; Bainbridge, Matthew; Challis, Danny; Coafra, Cristian; Dinh, Huyen; Kovar, Christie; Lee, Sandy; Muzny, Donna; Nazareth, Lynne; Reid, Jeff; Sabo, Aniko; Yu, Fuli; Yu, Jin; Marth, Gabor T.; Garrison, Erik P.; Indap, Amit; Leong, Wen Fung; Quinlan, Aaron R.; Stewart, Chip; Ward, Alistair N.; Wu, Jiantao; Cibulskis, Kristian; Fennell, Tim J.; Gabriel, Stacey B.; Garimella, Kiran V.; Hartl, Chris; Shefler, Erica; Sougnez, Carrie L.; Wilkinson, Jane; Clark, Andrew G.; Gravel, Simon; Grubert, Fabian; Clarke, Laura; Flicek, Paul; Smith, Richard E.; Zheng-Bradley, Xiangqun; Sherry, Stephen T.; Khouri, Hoda M.; Paschall, Justin E.; Shumway, Martin F.; Xiao, Chunlin; McVean, Gil A.; Katzman, Sol J.; Abecasis, Gonçalo R.; Blackwell, Tom; Mardis, Elaine R.; Dooling, David; Fulton, Lucinda; Fulton, Robert; Koboldt, Daniel C.; Durbin, Richard M.; Balasubramaniam, Senduran; Coffey, Allison; Keane, Thomas M.; MacArthur, Daniel G.; Palotie, Aarno; Scott, Carol; Stalker, James; Tyler-Smith, Chris; Gerstein, Mark B.; Balasubramanian, Suganthi; Chakravarti, Aravinda; Knoppers, Bartha M.; Abecasis, Gonçalo R.; Bustamante, Carlos D.; Gharani, Neda; Gibbs, Richard A.; Jorde, Lynn; Kaye, Jane S.; Kent, Alastair; Li, Taosha; McGuire, Amy L.; McVean, Gil A.; Ossorio, Pilar N.; Rotimi, Charles N.; Su, Yeyang; Toji, Lorraine H.; TylerSmith, Chris; Brooks, Lisa D.; Felsenfeld, Adam L.; McEwen, Jean E.; Abdallah, Assya; Juenger, Christopher R.; Clemm, Nicholas C.; Collins, Francis S.; Duncanson, Audrey; Green, Eric D.; Guyer, Mark S.; Peterson, Jane L.; Schafer, Alan J.; Abecasis, Gonçalo R.; Altshuler, David L.; Auton, Adam; Brooks, Lisa D.; Durbin, Richard M.; Gibbs, Richard A.; Hurles, Matt E.; McVean, Gil A.

2011-01-01

High-throughput sequencing technology enables population-level surveys of human genomic variation. Here, we examine the joint allele frequency distributions across continental human populations and present an approach for combining complementary aspects of whole-genome, low-coverage data and targeted high-coverage data. We apply this approach to data generated by the pilot phase of the Thousand Genomes Project, including whole-genome 2–4× coverage data for 179 samples from HapMap European, Asian, and African panels as well as high-coverage target sequencing of the exons of 800 genes from 697 individuals in seven populations. We use the site frequency spectra obtained from these data to infer demographic parameters for an Out-of-Africa model for populations of African, European, and Asian descent and to predict, by a jackknife-based approach, the amount of genetic diversity that will be discovered as sample sizes are increased. We predict that the number of discovered nonsynonymous coding variants will reach 100,000 in each population after ∼1,000 sequenced chromosomes per population, whereas ∼2,500 chromosomes will be needed for the same number of synonymous variants. Beyond this point, the number of segregating sites in the European and Asian panel populations is expected to overcome that of the African panel because of faster recent population growth. Overall, we find that the majority of human genomic variable sites are rare and exhibit little sharing among diverged populations. Our results emphasize that replication of disease association for specific rare genetic variants across diverged populations must overcome both reduced statistical power because of rarity and higher population divergence. PMID:21730125

Measles outbreak response decision-making under uncertainty: a retrospective analysis.

PubMed

Fonnesbeck, Christopher J; Shea, Katriona; Carran, Spencer; Cassio de Moraes, Jose; Gregory, Christopher; Goodson, James L; Ferrari, Matthew J

2018-03-01

Resurgent outbreaks of vaccine-preventable diseases that have previously been controlled or eliminated have been observed in many settings. Reactive vaccination campaigns may successfully control outbreaks but must necessarily be implemented in the face of considerable uncertainty. Real-time surveillance may provide critical information about at-risk population and optimal vaccination targets, but may itself be limited by the specificity of disease confirmation. We propose an integrated modelling approach that synthesizes historical demographic and vaccination data with real-time outbreak surveillance via a dynamic transmission model and an age-specific disease confirmation model. We apply this framework to data from the 1996-1997 measles outbreak in São Paulo, Brazil. To simulate the information available to decision-makers, we truncated the surveillance data to what would have been available at 1 or 2 months prior to the realized interventions. We use the model, fitted to real-time observations, to evaluate the likelihood that candidate age-targeted interventions could control the outbreak. Using only data available prior to the interventions, we estimate that a significant excess of susceptible adults would prevent child-targeted campaigns from controlling the outbreak and that failing to account for age-specific confirmation rates would underestimate the importance of adult-targeted vaccination. © 2018 The Author(s).

Using a Marginal Structural Model to Design a Theory-Based Mass Media Campaign.

PubMed

Nishiuchi, Hiromu; Taguri, Masataka; Ishikawa, Yoshiki

2016-01-01

The essential first step in the development of mass media health campaigns is to identify specific beliefs of the target audience. The challenge is to prioritize suitable beliefs derived from behavioral theory. The purpose of this study was to identify suitable beliefs to target in a mass media campaign to change behavior using a new method to estimate the possible effect size of a small set of beliefs. Data were drawn from the 2010 Japanese Young Female Smoker Survey (n = 500), conducted by the Japanese Ministry of Health, Labor and Welfare. Survey measures included intention to quit smoking, psychological beliefs (attitude, norms, and perceived control) based on the theory of planned behavior and socioeconomic status (age, education, household income, and marital status). To identify suitable candidate beliefs for a mass media health campaign, we estimated the possible effect size required to change the intention to quit smoking among the population of young Japanese women using the population attributable fraction from a marginal structural model. Thirteen percent of study participants intended to quit smoking. The marginal structural model estimated a population attributable fraction of 47 psychological beliefs (21 attitudes, 6 norms, and 19 perceived controls) after controlling for socioeconomic status. The belief, "I could quit smoking if my husband or significant other recommended it" suggested a promising target for a mass media campaign (population attributable fraction = 0.12, 95% CI = 0.02-0.23). Messages targeting this belief could possibly improve intention rates by up to 12% among this population. The analysis also suggested the potential for regulatory action. This study proposed a method by which campaign planners can develop theory-based mass communication strategies to change health behaviors at the population level. This method might contribute to improving the quality of future mass health communication strategies and further research is needed.

Using a Marginal Structural Model to Design a Theory-Based Mass Media Campaign

PubMed Central

Taguri, Masataka; Ishikawa, Yoshiki

2016-01-01

Background The essential first step in the development of mass media health campaigns is to identify specific beliefs of the target audience. The challenge is to prioritize suitable beliefs derived from behavioral theory. The purpose of this study was to identify suitable beliefs to target in a mass media campaign to change behavior using a new method to estimate the possible effect size of a small set of beliefs. Methods Data were drawn from the 2010 Japanese Young Female Smoker Survey (n = 500), conducted by the Japanese Ministry of Health, Labor and Welfare. Survey measures included intention to quit smoking, psychological beliefs (attitude, norms, and perceived control) based on the theory of planned behavior and socioeconomic status (age, education, household income, and marital status). To identify suitable candidate beliefs for a mass media health campaign, we estimated the possible effect size required to change the intention to quit smoking among the population of young Japanese women using the population attributable fraction from a marginal structural model. Results Thirteen percent of study participants intended to quit smoking. The marginal structural model estimated a population attributable fraction of 47 psychological beliefs (21 attitudes, 6 norms, and 19 perceived controls) after controlling for socioeconomic status. The belief, “I could quit smoking if my husband or significant other recommended it” suggested a promising target for a mass media campaign (population attributable fraction = 0.12, 95% CI = 0.02–0.23). Messages targeting this belief could possibly improve intention rates by up to 12% among this population. The analysis also suggested the potential for regulatory action. Conclusions This study proposed a method by which campaign planners can develop theory-based mass communication strategies to change health behaviors at the population level. This method might contribute to improving the quality of future mass health communication strategies and further research is needed. PMID:27441626

Targeted Mentoring: Evaluation of a Program

PubMed Central

McAllister, Carolyn A.; Harold, Rena D.; Ahmedani, Brian K.; Cramer, Elizabeth P.

2009-01-01

Targeted mentoring refers to mentoring aimed at a particular population. This article presents the evaluation of a mentoring program for lesbian, gay, bisexual, and transgender (LGBT) persons in social work education. Forty-three mentors and protégés responded to a survey regarding their program experiences. The results highlight the need for targeted mentoring, although some disparities of experience for mentors and protégés in this program are apparent. In general, mentors felt positive about participating, giving back to the LGBT community, and were more satisfied with their experiences than were the protégés, who were looking for more specific types of instrumental and psychosocial support. PMID:20046917

The precision problem in conservation and restoration

USGS Publications Warehouse

Hiers, J. Kevin; Jackson, Stephen T.; Hobbs, Richard J.; Bernhardt, Emily S.; Valentine, Leonie E.

2016-01-01

Within the varied contexts of environmental policy, conservation of imperilled species populations, and restoration of damaged habitats, an emphasis on idealized optimal conditions has led to increasingly specific targets for management. Overly-precise conservation targets can reduce habitat variability at multiple scales, with unintended consequences for future ecological resilience. We describe this dilemma in the context of endangered species management, stream restoration, and climate-change adaptation. Inappropriate application of conservation targets can be expensive, with marginal conservation benefit. Reduced habitat variability can limit options for managers trying to balance competing objectives with limited resources. Conservation policies should embrace habitat variability, expand decision-space appropriately, and support adaptation to local circumstances to increase ecological resilience in a rapidly changing world.

Huntington disease in the South African population occurs on diverse and ethnically distinct genetic haplotypes

PubMed Central

Baine, Fiona K; Kay, Chris; Ketelaar, Maria E; Collins, Jennifer A; Semaka, Alicia; Doty, Crystal N; Krause, Amanda; Jacquie Greenberg, L; Hayden, Michael R

2013-01-01

Huntington disease (HD) is a neurodegenerative disorder resulting from the expansion of a CAG trinucleotide repeat in the huntingtin (HTT) gene. Worldwide prevalence varies geographically with the highest figures reported in populations of European ancestry. HD in South Africa has been reported in Caucasian, black and mixed subpopulations, with similar estimated prevalence in the Caucasian and mixed groups and a lower estimate in the black subpopulation. Recent studies have associated specific HTT haplotypes with HD in distinct populations. Expanded HD alleles in Europe occur predominantly on haplogroup A (specifically high-risk variants A1/A2), whereas in East Asian populations, HD alleles are associated with haplogroup C. Whether specific HTT haplotypes associate with HD in black Africans and how these compare with haplotypes found in European and East Asian populations remains unknown. The current study genotyped the HTT region in unaffected individuals and HD patients from each of the South African subpopulations, and haplotypes were constructed. CAG repeat sizes were determined and phased to haplotype. Results indicate that HD alleles from Caucasian and mixed patients are predominantly associated with haplogroup A, signifying a similar European origin for HD. However, in black patients, HD occurs predominantly on haplogroup B, suggesting several distinct origins of the mutation in South Africa. The absence of high-risk variants (A1/A2) in the black subpopulation may also explain the reported low prevalence of HD. Identification of haplotypes associated with HD-expanded alleles is particularly relevant to the development of population-specific therapeutic targets for selective suppression of the expanded HTT transcript. PMID:23463025

Prioritizing vulnerable children: why should we address inequity?

PubMed

Joshua, P; Zwi, K; Moran, P; White, L

2015-11-01

Children and young people from vulnerable population groups, including Indigenous Australians, those in out of home care, those with disabilities and those from refugee families, have difficulties in accessing health services and are at high risk of adverse outcomes, driving population health inequity. Although heterogeneous, these groups face common disadvantage and shared challenges in health service utilization. This study aims to analyse the demographics of vulnerable child populations in NSW, the rationale for focussing on their health needs and strategies for addressing population health inequity. A literature review was undertaken on vulnerable child populations and successful strategies for improving their health outcomes. NSW data on vulnerable children were collated. Vulnerable children in NSW are estimated to comprise 10-20% of the childhood population. Efforts to improve their health and well-being can be justified based on child rights, a focus on equity and effectiveness of care, public opinion and the evidence base supporting such interventions. Targeted (subpopulation specific) interventions and delivery of universally applied (population wide) strategies that disproportionately benefit vulnerable populations have been shown to be effective in reducing healthcare disparities. Most available information relates to specific vulnerable population groups. However, some effective strategies and key principles are broadly applicable to the vulnerable child population as a whole. Vulnerable children should be a key focus of healthcare interventions if inequities are to be addressed. © 2015 John Wiley & Sons Ltd.

Targeted cardiopulmonary resuscitation training focused on the family members of high-risk patients at a regional medical center: A comparison between family members of high-risk and no-risk patients.

PubMed

Han, Kap Su; Lee, Ji Sung; Kim, Su Jin; Lee, Sung Woo

2018-05-01

We developed a hospital-based cardiopulmonary resuscitation (CPR) training model focused on the target population (family members of patients with potential risks for cardiac arrest) and compared the outcome of CPR training between target and non-target populations for validity. Family members of patients in training were divided into three groups on the basis of patients' diseases, as follows: 1) the cardio-specific (CS) risk group, including family members of patients with cardiac disease at risk of cardiac arrest; 2) the cardiovascular (CV) risk group, including family members of patients with risk factors for cardiovascular disease; and 3) the no-risk group. Pre- and posttraining surveys and skill tests as well as a post-training 3-month telephone survey were conducted. Educational outcomes were analyzed. A total of 203 family members were enrolled into 21 CPR training classes. The CS group (n=88) included elderly persons and housewives with a lower level of education compared with the CV (n=79) and no-risk groups (n=36). The CS group was motivated by healthcare professionals and participated in the training course. The CS, CV, and no-risk groups showed improvements in knowledge, willingness to perform CPR, and skills. Despite the older age and lower level of education in the CS group, the effects of education were similar to those in the other groups. A high rate of response and secondary propagation of CPR training were observed in the CS group. Family members of patients with heart disease could be an appropriate target population for CPR training, particularly in terms of recruitment and secondary propagation. Targeted intervention may be an effective training strategy to improve bystander CPR rates.

Color-Blindness Study: Color Discrimination on the TICCIT System.

ERIC Educational Resources Information Center

Asay, Calvin S.; Schneider, Edward W.

The question studied whether the specific seven TICCIT system colors used within color coding schemes can be a source of confusion, or not seen at all, by the color-blind segment of target populations. Subjects were 11 color-blind and three normally sighted students at Brigham Young University. After a preliminary training exercise to acquaint the…

Group Training in Interpersonal Problem-Solving Skills for Workplace Adaptation of Adolescents and Adults with Asperger Syndrome: A Preliminary Study

ERIC Educational Resources Information Center

Bonete, Saray; Calero, María Dolores; Fernández-Parra, Antonio

2015-01-01

Adults with Asperger syndrome show persistent difficulties in social situations which psychosocial treatments may address. Despite the multiple studies focusing on social skills interventions, only some have focused specifically on problem-solving skills and have not targeted workplace adaptation training in the adult population. This study…

The Sports Guide: NHLBI Planning Guide for Cardiovascular Risk Reduction Projects at Sporting Events.

ERIC Educational Resources Information Center

National Heart, Lung, and Blood Inst. (DHHS/NIH), Bethesda, MD.

The most recent national surveys of public awareness and knowledge of treatment and control of cardiovascular disease (CVD) show that health initiatives targeting specific populations are effective ways to support health promotion and disease prevention. Projects and activities outlined in this guide are directed to spectators at sporting events,…

Case Study of Chinese Exclusion Act Enforcement

ERIC Educational Resources Information Center

Dufour, Joanne, Comp.

2012-01-01

While nearly 85 percent of the U.S. population is currently made up of immigrants and their descendants, some groups were specifically targeted for exclusion and deliberately expelled. The Chinese were the first to experience this. In the 1850s, many Chinese who came to this land to search for gold or to help build the transcontinental railroad,…

Statewide Needs Assessment: Target Populations--Displaced Homemakers, Single Heads of Households, and Other Special Groups.

ERIC Educational Resources Information Center

Bromley, Ann

A statewide needs assessment in vocational education focused on the needs of displaced homemakers and other special groups in Florida. Specifically, the survey provided (1) a demographic profile of adults in Florida, particularly those described as displaced homemakers, single heads of households, part-time workers, and people desiring work in…

Pride on the Other Side: The Emergence of LGBT Web Sites for Prospective Students

ERIC Educational Resources Information Center

Mathis, Daniel; Tremblay, Christopher

2010-01-01

For several decades, colleges have maintained an LGBT Web presence for currently enrolled students. These Web sites inform students about resources, services, events, and staff . They serve as a way to communicate a school's inclusivity and commitment to the LGBT population. Only recently have Web sites specifically targeted for the prospective…

Developing a Multiple Caregiver Group for Caregivers of Adolescents With Disruptive Behaviors.

PubMed

Oruche, Ukamaka M; Robb, Sheri L; Aalsma, Matt; Pescosolido, Bernice; Brown-Podgorski, Brittany; Draucker, Claire Burke

2017-12-01

This article describes the development of a 6-week multiple caregiver group intervention for primary caregivers of adolescents diagnosed with Oppositional Defiant Disorder or Conduct Disorder in low-income African American families. The intervention is aimed at increasing the primary caregivers' self-efficacy in managing interactions within the family and especially with child serving educational, mental health, juvenile justice, and child welfare systems. Development of the intervention involved seven iterative activities performed in a collaborative effort between an interdisciplinary academic team, community engagement specialists, members of the targeted population, and clinical partners from a large public mental health system. The intervention development process described in this article can provide guidance for teams that aim to develop new mental health interventions that target specific outcomes in populations with unique needs. Copyright © 2017 Elsevier Inc. All rights reserved.

Use of thermodynamic coupling between antibody-antigen binding and phospholipid acyl chain phase transition energetics to predict immunoliposome targeting affinity.

PubMed

Klegerman, Melvin E; Zou, Yuejiao; Golunski, Eva; Peng, Tao; Huang, Shao-Ling; McPherson, David D

2014-09-01

Thermodynamic analysis of ligand-target binding has been a useful tool for dissecting the nature of the binding mechanism and, therefore, potentially can provide valuable information regarding the utility of targeted formulations. Based on a consistent coupling of antibody-antigen binding and gel-liquid crystal transition energetics observed for antibody-phosphatidylethanolamine (Ab-PE) conjugates, we hypothesized that the thermodynamic parameters and the affinity for antigen of the Ab-PE conjugates could be effectively predicted once the corresponding information for the unconjugated antibody is determined. This hypothesis has now been tested in nine different antibody-targeted echogenic liposome (ELIP) preparations, where antibody is conjugated to dipalmitoylphosphatidylethanolamine (DPPE) head groups through a thioether linkage. Predictions were satisfactory (affinity not significantly different from the population of values found) in five cases (55.6%), but the affinity of the unconjugated antibody was not significantly different from the population of values found in six cases (66.7%), indicating that the affinities of the conjugated antibody tended not to deviate appreciably from those of the free antibody. While knowledge of the affinities of free antibodies may be sufficient to judge their suitability as targeting agents, thermodynamic analysis may still provide valuable information regarding their usefulness for specific applications.

Characterization of Gag and Nef-specific ELISpot-based CTL responses in HIV-1 infected Indian individuals.

PubMed

Mendiratta, Sanjay; Vajpayee, Madhu; Malhotra, Uma; Kaushik, Shweta; Dar, Lalit; Mojumdar, Kamalika; Chauhan, Neeraj Kumar; Sreenivas, Vishnubhatla

2009-02-01

Cytotoxic T lymphocyte (CTL) responses to Gag have been most frequently linked to control of viremia whereas CTL responses to Nef have direct relationship with viral load. IFN-gamma ELISpot assay was used to screen CTL responses at single peptide level directed at HIV-1 subtype C Gag and Nef proteins in 30 antiretroviral therapy naive HIV-1 infected Indian individuals. PBMCs from 73.3% and 90% of the study population showed response to Gag and Nef antigens, respectively. The magnitude of Gag-specific CTL responses was inversely correlated with plasma viral load (r = -0.45, P = 0.001), whereas magnitude of Nef-specific responses was directly correlated (r = 0.115). Thirteen immunodominant regions (6 in Gag, 7 in Nef) were identified in the current study. The identification of Gag and Nef-specific responses across HIV-1 infected Indian population and targeting epitopes from multiple immunodominant regions may provide useful insight into the designing of new immunotherapy and vaccines.

Targeted mass media interventions promoting healthy behaviours to reduce risk of non-communicable diseases in adult, ethnic minorities.

PubMed

Mosdøl, Annhild; Lidal, Ingeborg B; Straumann, Gyri H; Vist, Gunn E

2017-02-17

Physical activity, a balanced diet, avoidance of tobacco exposure, and limited alcohol consumption may reduce morbidity and mortality from non-communicable diseases (NCDs). Mass media interventions are commonly used to encourage healthier behaviours in population groups. It is unclear whether targeted mass media interventions for ethnic minority groups are more or less effective in changing behaviours than those developed for the general population. To determine the effects of mass media interventions targeting adult ethnic minorities with messages about physical activity, dietary patterns, tobacco use or alcohol consumption to reduce the risk of NCDs. We searched CENTRAL, MEDLINE, Embase, PsycINFO, CINAHL, ERIC, SweMed+, and ISI Web of Science until August 2016. We also searched for grey literature in OpenGrey, Grey Literature Report, Eldis, and two relevant websites until October 2016. The searches were not restricted by language. We searched for individual and cluster-randomised controlled trials, controlled before-and-after studies (CBA) and interrupted time series studies (ITS). Relevant interventions promoted healthier behaviours related to physical activity, dietary patterns, tobacco use or alcohol consumption; were disseminated via mass media channels; and targeted ethnic minority groups. The population of interest comprised adults (≥ 18 years) from ethnic minority groups in the focal countries. Primary outcomes included indicators of behavioural change, self-reported behavioural change and knowledge and attitudes towards change. Secondary outcomes were the use of health promotion services and costs related to the project. Two authors independently reviewed the references to identify studies for inclusion. We extracted data and assessed the risk of bias in all included studies. We did not pool the results due to heterogeneity in comparisons made, outcomes, and study designs. We describe the results narratively and present them in 'Summary of findings' tables. We judged the quality of the evidence using the GRADE (Grading of Recommendations Assessment, Development, and Evaluation) methodology. Six studies met the inclusion criteria, including three RCTs, two cluster-RCTs and one ITS. All were conducted in the USA and comprised targeted mass media interventions for people of African descent (four studies), Spanish-language dominant Latino immigrants (one study), and Chinese immigrants (one study). The two latter studies offered the intervention in the participants' first language (Spanish, Cantonese, or Mandarin). Three interventions targeted towards women only, one pregnant women specifically. We judged all studies as being at unclear risk of bias in at least one domain and three studies as being at high risk of bias in at least one domain.We categorised the findings into three comparisons. The first comparison examined mass media interventions targeted at ethnic minorities versus an equivalent mass media intervention intended for the general population. The one study in this category (255 participants of African decent) found little or no difference in effect on self-reported behavioural change for smoking and only small differences in attitudes to change between participants who were given a culturally specific smoking cessation booklet versus a booklet intended for the general population. We are uncertain about the effect estimates, as assessed by the GRADE methodology (very low quality evidence of effect). No study provided data for indicators of behavioural change or adverse effects.The second comparison assessed targeted mass media interventions versus no intervention. One study (154 participants of African decent) reported effects for our primary outcomes. Participants in the intervention group had access to 12 one-hour live programmes on cable TV and received print material over three months regarding nutrition and physical activity to improve health and weight control. Change in body mass index (BMI) was comparable between groups 12 months after the baseline (low quality evidence). Scores on a food habits (fat behaviours) and total leisure activity scores changed favourably for the intervention group (very low quality evidence). Two other studies exposed entire populations in geographical areas to radio advertisements targeted towards African American communities. Authors presented effects on two of our secondary outcomes, use of health promotion services and project costs. The campaign message was to call smoking quit lines. The outcome was the number of calls received. After one year, one study reported 18 calls per estimated 10,000 targeted smokers from the intervention communities (estimated target population 310,500 persons), compared to 0.2 calls per estimated 10,000 targeted smokers from the control communities (estimated target population 331,400 persons) (moderate quality evidence). The ITS study also reported an increase in the number of calls from the target population during campaigns (low quality evidence). The proportion of African American callers increased in both studies (low to very low quality evidence). No study provided data on knowledge and attitudes for change and adverse effects. Information on costs were sparse.The third comparison assessed targeted mass media interventions versus a mass media intervention plus personalised content. Findings are based on three studies (1361 participants). Participants in these comparison groups received personal feedback. Two of the studies recorded weight changes over time. Neither found significant differences between the groups (low quality evidence). Evidence on behavioural changes, and knowledge and attitudes typically found some effects in favour of receiving personalised content or no significant differences between groups (very low quality evidence). No study provided data on adverse effects. Information on costs were sparse. The available evidence is inadequate for understanding whether mass media interventions targeted toward ethnic minority populations are more effective in changing health behaviours than mass media interventions intended for the population at large. When compared to no intervention, a targeted mass media intervention may increase the number of calls to smoking quit line, but the effect on health behaviours is unclear. These studies could not distinguish the impact of different components, for instance the effect of hearing a message regarding behavioural change, the cultural adaptation to the ethnic minority group, or increase reach to the target group through more appropriate mass media channels. New studies should explore targeted interventions for ethnic minorities with a first language other than the dominant language in their resident country, as well as directly compare targeted versus general population mass media interventions.

Conceptual framework and rationale

PubMed Central

Robinson, Alan S; Knols, Bart GJ; Voigt, Gabriella; Hendrichs, Jorge

2009-01-01

The sterile insect technique (SIT) has been shown to be an effective and sustainable genetic approach to control populations of selected major pest insects, when part of area-wide integrated pest management (AW-IPM) programmes. The technique introduces genetic sterility in females of the target population in the field following their mating with released sterile males. This process results in population reduction or elimination via embryo lethality caused by dominant lethal mutations induced in sperm of the released males. In the past, several field trials have been carried out for mosquitoes with varying degrees of success. New technology and experience gained with other species of insect pests has encouraged a reassessment of the use of the sterility principle as part of integrated control of malaria vectors. Significant technical and logistic hurdles will need to be overcome to develop the technology and make it effective to suppress selected vector populations, and its application will probably be limited to specific ecological situations. Using sterile males to control mosquito vector populations can only be effective as part of an AW-IPM programme. The area-wide concept entails the targeting of the total mosquito population within a defined area. It requires, therefore, a thorough understanding of the target pest population biology especially as regards mating behaviour, population dynamics, dispersal and level of reproductive isolation. The key challenges for success are: 1) devising methods to monitor vector populations and measuring competitiveness of sterile males in the field, 2) designing mass rearing, sterilization and release strategies that maintain competitiveness of the sterile male mosquitoes, 3) developing methods to separate sexes in order to release only male mosquitoes and 4) adapting suppression measures and release rates to take into account the high reproductive rate of mosquitoes. Finally, success in area-wide implementation in the field can only be achieved if close attention is paid to political, socio-economic and environmental sensitivities and an efficient management organization is established taking into account the interests of all potential stakeholders of an AW-IPM programme. PMID:19917070

Cost effectiveness of a government supported policy strategy to decrease sodium intake: global analysis across 183 nations

PubMed Central

Webb, Michael; Fahimi, Saman; Singh, Gitanjali M; Khatibzadeh, Shahab; Micha, Renata; Powles, John

2017-01-01

Objective To quantify the cost effectiveness of a government policy combining targeted industry agreements and public education to reduce sodium intake in 183 countries worldwide. Design Global modeling study. Setting 183 countries. Population Full adult population in each country. Intervention A “soft regulation” national policy that combines targeted industry agreements, government monitoring, and public education to reduce population sodium intake, modeled on the recent successful UK program. To account for heterogeneity in efficacy across countries, a range of scenarios were evaluated, including 10%, 30%, 0.5 g/day, and 1.5 g/day sodium reductions achieved over 10 years. We characterized global sodium intakes, blood pressure levels, effects of sodium on blood pressure and of blood pressure on cardiovascular disease, and cardiovascular disease rates in 2010, each by age and sex, in 183 countries. Country specific costs of a sodium reduction policy were estimated using the World Health Organization Noncommunicable Disease Costing Tool. Country specific impacts on mortality and disability adjusted life years (DALYs) were modeled using comparative risk assessment. We only evaluated program costs, without incorporating potential healthcare savings from prevented events, to provide conservative estimates of cost effectiveness Main outcome measure Cost effectiveness ratio, evaluated as purchasing power parity adjusted international dollars (equivalent to the country specific purchasing power of US$) per DALY saved over 10 years. Results Worldwide, a 10% reduction in sodium consumption over 10 years within each country was projected to avert approximately 5.8 million DALYs/year related to cardiovascular diseases, at a population weighted mean cost of I$1.13 per capita over the 10 year intervention. The population weighted mean cost effectiveness ratio was approximately I$204/DALY. Across nine world regions, estimated cost effectiveness of sodium reduction was best in South Asia (I$116/DALY); across the world’s 30 most populous countries, best in Uzbekistan (I$26.08/DALY) and Myanmar (I$33.30/DALY). Cost effectiveness was lowest in Australia/New Zealand (I$880/DALY, or 0.02×gross domestic product (GDP) per capita), although still substantially better than standard thresholds for cost effective (<3.0×GDP per capita) or highly cost effective (<1.0×GDP per capita) interventions. Most (96.0%) of the world’s adult population lived in countries in which this intervention had a cost effectiveness ratio <0.1×GDP per capita, and 99.6% in countries with a cost effectiveness ratio <1.0×GDP per capita. Conclusion A government “soft regulation” strategy combining targeted industry agreements and public education to reduce dietary sodium is projected to be highly cost effective worldwide, even without accounting for potential healthcare savings. PMID:28073749

Electrochemical Branched-DNA Assay for Polymerase Chain Reaction-Free Detection and Quantification of Oncogenes in Messenger RNA

DOE Office of Scientific and Technical Information (OSTI.GOV)

Lee, Ai Cheng; Dai, Ziyu; Chen, Baowei

2008-12-01

We describe a novel electrochemical branched-DNA (bDNA) assay for polymerase chain reaction (PCR)-free detection and quantification of p185 BCR-ABL leukemia fusion transcript in the population of messenger RNA (mRNA) extracted from cell lines. The bDNA amplifier carrying high loading of alkaline phosphatase (ALP) tracers was used to amplify targets signal. The targets were captured on microplate well surfaces through cooperative sandwich hybridization prior to the labeling of bDNA. The activity of captured ALP was monitored by square-wave voltammetric (SWV) analysis of the electroactive enzymatic product in the presence of 1-napthyl-phosphate. The specificity and sensitivity of assay enabled direct detection ofmore » target transcript in as little as 4.6 ng mRNA without PCR amplification. In combination with the use of a well-quantified standard, the electrochemical bDNA assay was capable of direct use for a PCR-free quantitative analysis of target transcript in total mRNA population. The approach thus provides a simple, sensitive, accurate and quantitative tool alternate to the RQ-PCR for early disease diagnosis.« less

Cultural sensitivity in public health: defined and demystified.

PubMed

Resnicow, K; Baranowski, T; Ahluwalia, J S; Braithwaite, R L

1999-01-01

There is consensus that health promotion programs should be culturally sensitive (CS). Yet, despite the ubiquitous nature of CS within public health research and practice, there has been surprisingly little attention given to defining CS or delineating a framework for developing culturally sensitive programs and practitioners. This paper describes a model for understanding CS from a public health perspective; describes a process for applying this model in the development of health promotion and disease prevention interventions; and highlights research priorities. Cultural sensitivity is defined by two dimensions: surface and deep structures. Surface structure involves matching intervention materials and messages to observable, "superficial" characteristics of a target population. This may involve using people, places, language, music, food, locations, and clothing familiar to, and preferred by, the target audience. Surface structure refers to how well interventions fit within a specific culture. Deep structure involves incorporating the cultural, social, historical, environmental and psychological forces that influence the target health behavior in the proposed target population. Whereas surface structure generally increases the "receptivity" or "acceptance" of messages, deep structure conveys salience. Techniques, borrowed from social marketing and health communication theory, for developing culturally sensitive interventions are described. Research is needed to determine the effectiveness of culturally sensitive programs.

Stroke prevalence among the Spanish elderly: an analysis based on screening surveys

PubMed Central

Boix, Raquel; del Barrio, José Luis; Saz, Pedro; Reñé, Ramón; Manubens, José María; Lobo, Antonio; Gascón, Jordi; de Arce, Ana; Díaz-Guzmán, Jaime; Bergareche, Alberto; Bermejo-Pareja, Félix; de Pedro-Cuesta, Jesús

2006-01-01

Background This study sought to describe stroke prevalence in Spanish elderly populations and compare it against that of other European countries. Methods We identified screening surveys -both published and unpublished- in Spanish populations, which fulfilled specific quality requirements and targeted prevalence of stroke in populations aged 70 years and over. Surveys covering seven geographically different populations with prevalence years in the period 1991–2002 were selected, and the respective authors were then asked to provide descriptions of the methodology and raw age-specific data by completing a questionnaire. In addition, five reported screening surveys in European populations furnished useful data for comparison purposes. Prevalence data were combined, using direct adjustment and logistic regression. Results The overall study population, resident in central and north-eastern Spain, totalled 10,647 persons and yielded 715 cases. Age-adjusted prevalences, using the European standard population, were 7.3% for men, 5.6% for women, and 6.4% for both sexes. Prevalence was significantly lower in women, OR 0.79 95% CI 0.68–0.93, increased with age, particularly among women, and displayed a threefold spatial variation with statistically significant differences. Prevalences were highest, 8.7%, in suburban, and lowest, 3.8%, in rural populations. Compared to pooled Spanish populations, statistically significant differences were seen in eight Italian populations, OR 1.39 95%CI (1.18–1.64), and in Kungsholmen, Sweden, OR 0.40 95%CI (0.27–0.58). Conclusion Prevalence in central and north-eastern Spain is higher in males and in suburban areas, and displays a threefold geographic variation, with women constituting the majority of elderly stroke sufferers. Compared to reported European data, stroke prevalence in Spain can be said to be medium and presents similar age- and sex-specific traits. PMID:17042941

Strategies and Tools for Public Health Workforce Training Needs Assessments in Diverse and Changing Population Health Contexts.

PubMed

Aidala, Angela A; Cavaliere, Brittney; Cinnick, Samantha

2018-06-07

A key component of the improvement of public health infrastructure in the United States revolves around public health workforce development and training. Workforce challenges faced by the public health system have long been recognized, but there are additional challenges facing any region-wide or cross-jurisdictional effort to accurately assess priority workforce training needs and develop training resources to address those needs. These challenges include structural variability of public health organizations; diverse population health contexts; capturing both topic-specific skill sets and foundational competencies among public health workers; and reaching/representing the target population despite suspicion, disinterest, and/or assessment "fatigue" among employees asked to participate in workforce development surveys. The purpose of this article is to describe the challenges, strategies to meet those challenges, and lessons learned conducting public health workforce training needs assessments by academic and practice partners of the Region 2 Public Health Training Center (R2/PHTC). The R2/PHTC is hosted by the Mailman School of Public Health at Columbia University and serves New York, New Jersey, Puerto Rico, and the US Virgin Islands within its jurisdiction. Strategies for responding to diverse organizational structures and population health contexts across the region; defining training priorities that address both foundational competencies for public health professionals and content-specific training to address local public health needs; reaching/representing target populations of public health workers; and analysis and report writing to encourage rapid response to identified needs and comprehensive workforce development planning are discussed. Lessons learned are likely instructive to other workforce training needs assessments in complex and ever-changing public health environments.

Prevalence of dementia and major dementia subtypes in Spanish populations: A reanalysis of dementia prevalence surveys, 1990-2008

PubMed Central

de Pedro-Cuesta, Jesús; Virués-Ortega, Javier; Vega, Saturio; Seijo-Martínez, Manuel; Saz, Pedro; Rodríguez, Fernanda; Rodríguez-Laso, Angel; Reñé, Ramón; de las Heras, Susana Pérez; Mateos, Raimundo; Martínez-Martín, Pablo; Manubens, José María; Mahillo-Fernandez, Ignacio; López-Pousa, Secundino; Lobo, Antonio; Reglà, Jordi Llinàs; Gascón, Jordi; García, Francisco José; Fernández-Martínez, Manuel; Boix, Raquel; Bermejo-Pareja, Félix; Bergareche, Alberto; Benito-León, Julián; de Arce, Ana; del Barrio, José Luis

2009-01-01

Background This study describes the prevalence of dementia and major dementia subtypes in Spanish elderly. Methods We identified screening surveys, both published and unpublished, in Spanish populations, which fulfilled specific quality criteria and targeted prevalence of dementia in populations aged 70 years and above. Surveys covering 13 geographically different populations were selected (prevalence period: 1990-2008). Authors of original surveys provided methodological details of their studies through a systematic questionnaire and also raw age-specific data. Prevalence data were compared using direct adjustment and logistic regression. Results The reanalyzed study population (aged 70 year and above) was composed of Central and North-Eastern Spanish sub-populations obtained from 9 surveys and totaled 12,232 persons and 1,194 cases of dementia (707 of Alzheimer's disease, 238 of vascular dementia). Results showed high variation in age- and sex-specific prevalence across studies. The reanalyzed prevalence of dementia was significantly higher in women; increased with age, particularly for Alzheimer's disease; and displayed a significant geographical variation among men. Prevalence was lowest in surveys reporting participation below 85%, studies referred to urban-mixed populations and populations diagnosed by psychiatrists. Conclusion Prevalence of dementia and Alzheimer's disease in Central and North-Eastern Spain is higher in females, increases with age, and displays considerable geographic variation that may be method-related. People suffering from dementia and Alzheimer's disease in Spain may approach 600,000 and 400,000 respectively. However, existing studies may not be completely appropriate to infer prevalence of dementia and its subtypes in Spain until surveys in Southern Spain are conducted. PMID:19840375

Organizational strategies for promoting patient and provider uptake of personal health records.

PubMed

Wells, Susan; Rozenblum, Ronen; Park, Andrea; Dunn, Marie; Bates, David W

2015-01-01

To investigate organizational strategies to promote personal health records (PHRs) adoption with a focus on patients with chronic disease. Using semi-structured interviews and a web-based survey, we sampled US health delivery organizations which had implemented PHRs for at least 12 months, were recognized as PHR innovators, and had scored highly in national patient satisfaction surveys. Respondents had lead positions for clinical information systems or high-risk population management. Using grounded theory approach, thematic categories were derived from interviews and coupled with data from the survey. Interviews were conducted with 30 informants from 16 identified organizations. Organizational strategies were directed towards raising patient awareness via multimedia communications, and provider acceptance and uptake. Strategies for providers were grouped into six main themes: organizational vision, governance and policies, work process redesign, staff training, information technology (IT) support, and monitoring and incentives. Successful organizations actively communicated their vision, engaged leaders at all levels, had clear governance, planning, and protocols, set targets, and celebrated achievement. The most effective strategy for patient uptake was through health professional encouragement. No specific outreach efforts targeted patients with chronic disease. Registration and PHR activity was routinely measured but without reference to a denominator population or high risk subpopulations. Successful PHR implementation represents a social change and operational project catalyzed by a technical solution. The key to clinician acceptance is making their work easier. However, organizations will likely not achieve the value they want from PHRs unless they target specific populations and monitor their uptake. © The Author 2014. Published by Oxford University Press on behalf of the American Medical Informatics Association. All rights reserved. For Permissions, please email: journals.permissions@oup.comFor numbered affiliations see end of article.

EGFR, HER2 and VEGF pathways: validated targets for cancer treatment.

PubMed

Press, Michael F; Lenz, Heinz-Josef

2007-01-01

Targeted therapies are rationally designed to interfere with specific molecular events that are important in tumour growth, progression or survival. Several targeted therapies with anti-tumour activity in human cancer cell lines and xenograft models have now been shown to produce objective responses, delay disease progression and, in some cases, improve survival of patients with advanced malignancies. These targeted therapies include cetuximab, an anti-epidermal growth factor receptor (EGFR) monoclonal antibody; gefitinib and erlotinib, EGFR-specific tyrosine kinase inhibitors; trastuzumab, an anti-human EGFR type 2 (HER2)-related monoclonal antibody; lapatinib, a dual inhibitor of both EGFR- and HER2-associated tyrosine kinases; and bevacizumab, an anti-vascular endothelial growth factor (VEGF) monoclonal antibody. On the basis of preclinical and clinical evidence, EGFR, HER2 and VEGF represent validated targets for cancer therapy and remain the subject of intensive investigation. Both EGFR and HER2 are targets found on cancer cells, whereas VEGF is a target that acts in the tumour microenvironment. Clinical studies are focusing on how to best incorporate targeted therapy into current treatment regimens and other studies are exploring whether different strategies for inhibiting these targets will offer greater benefit. It is clear that optimal use of targeted therapy will depend on understanding how these drugs work mechanistically, and recognising that their activities may differ across patient populations, tumour types and disease stages, as well as when and how they are used in cancer treatment. The results achieved with targeted therapies to date are promising, although they illustrate the need for additional preclinical and clinical study.

Transferring and generalizing deep-learning-based neural encoding models across subjects.

PubMed

Wen, Haiguang; Shi, Junxing; Chen, Wei; Liu, Zhongming

2018-08-01

Recent studies have shown the value of using deep learning models for mapping and characterizing how the brain represents and organizes information for natural vision. However, modeling the relationship between deep learning models and the brain (or encoding models), requires measuring cortical responses to large and diverse sets of natural visual stimuli from single subjects. This requirement limits prior studies to few subjects, making it difficult to generalize findings across subjects or for a population. In this study, we developed new methods to transfer and generalize encoding models across subjects. To train encoding models specific to a target subject, the models trained for other subjects were used as the prior models and were refined efficiently using Bayesian inference with a limited amount of data from the target subject. To train encoding models for a population, the models were progressively trained and updated with incremental data from different subjects. For the proof of principle, we applied these methods to functional magnetic resonance imaging (fMRI) data from three subjects watching tens of hours of naturalistic videos, while a deep residual neural network driven by image recognition was used to model visual cortical processing. Results demonstrate that the methods developed herein provide an efficient and effective strategy to establish both subject-specific and population-wide predictive models of cortical representations of high-dimensional and hierarchical visual features. Copyright © 2018 Elsevier Inc. All rights reserved.

Why Targeted Therapies are Necessary for Systemic Lupus Erythematosus

PubMed Central

Durcan, Laura; Petri, Michelle

2016-01-01

Systemic lupus erythematosus (SLE) continues to have important morbidity and accelerated mortality despite therapeutic advances. Targeted therapies offer the possibility of improved efficacy with fewer side-effects. Current management strategies rely heavily on non-specific immunosuppressive agents. Prednisone, in particular, is responsible for a considerable burden of later organ damage. There are a multitude of diverse mechanisms of disease activity, immunogenic abnormalities and clinical manifestations to take into consideration in SLE. Many targeted agents with robust mechanistic pre-clinical data and promising early phase studies have ultimately been disappointing in phase III randomized controlled studies. Recent efforts have focused on B cell therapies, in particular given the success of belimumab in clinical trials, with limited success. We remain optimistic regarding other specific therapies being evaluated including interferon alpha blockade. It is likely that in SLE, given the heterogeneity of the population involved, precision medicine is needed, rather than expecting that any single biologic will be universally effective. PMID:27497251

Global Cerebral Ischemia: Synaptic and Cognitive Dysfunction

PubMed Central

Neumann, Jake T.; Cohan, Charles H.; Dave, Kunjan R.; Wright, Clinton B.; Perez-Pinzon, Miguel A.

2018-01-01

Cardiopulmonary arrest is one of the leading causes of death and disability, primarily occurring in the aged population. Numerous global cerebral ischemia animal models induce neuronal damage similar to cardiac arrest. These global cerebral ischemia models range from vessel occlusion to total cessation of cardiac function, both of which have allowed for the investigation of this multifaceted disease and detection of numerous agents that are neuroprotective. Synapses endure a variety of alterations after global cerebral ischemia from the resulting excitotoxicity and have been a major target for neuroprotection; however, neuroprotective agents have proven unsuccessful in clinical trials, as neurological outcomes have not displayed significant improvements in patients. A majority of these neuroprotective agents have specific neuronal targets, where the success of future neuroprotective agents may depend on non-specific targets and numerous cognitive improvements. This review focuses on the different models of global cerebral ischemia, neuronal synaptic alterations, synaptic neuroprotection and behavioral tests that can be used to determine deficits in cognitive function after global cerebral ischemia. PMID:23170794

Smooth Muscle Cell Genome Browser: Enabling the Identification of Novel Serum Response Factor Target Genes

PubMed Central

Lee, Moon Young; Park, Chanjae; Berent, Robyn M.; Park, Paul J.; Fuchs, Robert; Syn, Hannah; Chin, Albert; Townsend, Jared; Benson, Craig C.; Redelman, Doug; Shen, Tsai-wei; Park, Jong Kun; Miano, Joseph M.; Sanders, Kenton M.; Ro, Seungil

2015-01-01

Genome-scale expression data on the absolute numbers of gene isoforms offers essential clues in cellular functions and biological processes. Smooth muscle cells (SMCs) perform a unique contractile function through expression of specific genes controlled by serum response factor (SRF), a transcription factor that binds to DNA sites known as the CArG boxes. To identify SRF-regulated genes specifically expressed in SMCs, we isolated SMC populations from mouse small intestine and colon, obtained their transcriptomes, and constructed an interactive SMC genome and CArGome browser. To our knowledge, this is the first online resource that provides a comprehensive library of all genetic transcripts expressed in primary SMCs. The browser also serves as the first genome-wide map of SRF binding sites. The browser analysis revealed novel SMC-specific transcriptional variants and SRF target genes, which provided new and unique insights into the cellular and biological functions of the cells in gastrointestinal (GI) physiology. The SRF target genes in SMCs, which were discovered in silico, were confirmed by proteomic analysis of SMC-specific Srf knockout mice. Our genome browser offers a new perspective into the alternative expression of genes in the context of SRF binding sites in SMCs and provides a valuable reference for future functional studies. PMID:26241044

Genome-wide patterns of genetic distances reveal candidate Loci contributing to human population-specific traits.

PubMed

de Magalhães, João Pedro; Matsuda, Alex

2012-03-01

Modern humans originated in Africa before migrating across the world with founder effects and adaptations to new environments contributing to their present phenotypic diversity. Determining the genetic basis of differences between populations may provide clues about our evolutionary history and may have clinical implications. Herein, we develop a method to detect genes and biological processes in which populations most differ by calculating the genetic distance between modern populations and a hypothetical ancestral population. We apply our method to large-scale single nucleotide polymorphism (SNP) data from human populations of African, European and Asian origin. As expected, ancestral alleles were more conserved in the African populations and we found evidence of high divergence in genes previously suggested as targets of selection related to skin pigmentation, immune response, senses and dietary adaptations. Our genome-wide scan also reveals novel candidates for contributing to population-specific traits. These include genes related to neuronal development and behavior that may have been influenced by cultural processes. Moreover, in the African populations, we found a high divergence in genes related to UV protection and to the male reproductive system. Taken together, these results confirm and expand previous findings, providing new clues about the evolution and genetics of human phenotypic diversity. © 2011 The Authors Annals of Human Genetics © 2011 Blackwell Publishing Ltd/University College London.

Target prioritization and strategy selection for active case-finding of pulmonary tuberculosis: a tool to support country-level project planning.

PubMed

Nishikiori, Nobuyuki; Van Weezenbeek, Catharina

2013-02-02

Despite the progress made in the past decade, tuberculosis (TB) control still faces significant challenges. In many countries with declining TB incidence, the disease tends to concentrate in vulnerable populations that often have limited access to health care. In light of the limitations of the current case-finding approach and the global urgency to improve case detection, active case-finding (ACF) has been suggested as an important complementary strategy to accelerate tuberculosis control especially among high-risk populations. The present exercise aims to develop a model that can be used for county-level project planning. A simple deterministic model was developed to calculate the number of estimated TB cases diagnosed and the associated costs of diagnosis. The model was designed to compare cost-effectiveness parameters, such as the cost per case detected, for different diagnostic algorithms when they are applied to different risk populations. The model was transformed into a web-based tool that can support national TB programmes and civil society partners in designing ACF activities. According to the model output, tuberculosis active case-finding can be a costly endeavor, depending on the target population and the diagnostic strategy. The analysis suggests the following: (1) Active case-finding activities are cost-effective only if the tuberculosis prevalence among the target population is high. (2) Extensive diagnostic methods (e.g. X-ray screening for the entire group, use of sputum culture or molecular diagnostics) can be applied only to very high-risk groups such as TB contacts, prisoners or people living with human immunodeficiency virus (HIV) infection. (3) Basic diagnostic approaches such as TB symptom screening are always applicable although the diagnostic yield is very limited. The cost-effectiveness parameter was sensitive to local diagnostic costs and the tuberculosis prevalence of target populations. The prioritization of appropriate target populations and careful selection of cost-effective diagnostic strategies are critical prerequisites for rational active case-finding activities. A decision to conduct such activities should be based on the setting-specific cost-effectiveness analysis and programmatic assessment. A web-based tool was developed and is available to support national tuberculosis programmes and partners in the formulation of cost-effective active case-finding activities at the national and subnational levels.

SOX2 regulates common and specific stem cell features in the CNS and endoderm derived organs.

PubMed

Hagey, Daniel W; Klum, Susanne; Kurtsdotter, Idha; Zaouter, Cecile; Topcic, Danijal; Andersson, Olov; Bergsland, Maria; Muhr, Jonas

2018-02-01

Stem cells are defined by their capacities to self-renew and generate progeny of multiple lineages. The transcription factor SOX2 has key roles in the regulation of stem cell characteristics, but whether SOX2 achieves these functions through similar mechanisms in distinct stem cell populations is not known. To address this question, we performed RNA-seq and SOX2 ChIP-seq on embryonic mouse cortex, spinal cord, stomach and lung/esophagus. We demonstrate that, although SOX2 binds a similar motif in the different cell types, its target regions are primarily cell-type-specific and enriched for the distinct binding motifs of appropriately expressed interacting co-factors. Furthermore, cell-type-specific SOX2 binding in endodermal and neural cells is most often found around genes specifically expressed in the corresponding tissue. Consistent with this, we demonstrate that SOX2 target regions can act as cis-regulatory modules capable of directing reporter expression to appropriate tissues in a zebrafish reporter assay. In contrast, SOX2 binding sites found in both endodermal and neural tissues are associated with genes regulating general stem cell features, such as proliferation. Notably, we provide evidence that SOX2 regulates proliferation through conserved mechanisms and target genes in both germ layers examined. Together, these findings demonstrate how SOX2 simultaneously regulates cell-type-specific, as well as core transcriptional programs in neural and endodermal stem cells.

Patient centric drug product design in modern drug delivery as an opportunity to increase safety and effectiveness.

PubMed

Stegemann, Sven

2018-06-01

The advances in drug delivery technologies have enabled pharmaceutical scientists to deliver a drug through various administration routes and optimize the drug release and absorption. The wide range of drug delivery systems and dosage forms represent a toolbox of technology for the development of pharmaceutical drug products but might also be a source of medication errors and nonadherence. Patient centric drug product development is being suggested as an important factor to increase therapeutic outcomes. Areas covered: Patients have impaired health and potentially disabilities and they are not medical or pharmaceutical experts but are requested to manage complex therapeutic regimens. As such the application of technology should also serve to reduce complexity, build on patients' intuition and ease of use. Patients form distinct populations based on the targeted disease, disease cluster or age group with specific characteristics or therapeutic contexts. Expert opinion: Establishing a target product and patient profile is essential to guide drug product design development. Including the targeted patient populations in the process is a prerequisite to achieve patient-centric pharmaceutical drug product design. Addressing the needs early on in the product design process, will create more universal design, avoiding the necessity for multiple product presentations to cover the different patient populations.

MaCH-Admix: Genotype Imputation for Admixed Populations

PubMed Central

Liu, Eric Yi; Li, Mingyao; Wang, Wei; Li, Yun

2012-01-01

Imputation in admixed populations is an important problem but challenging due to the complex linkage disequilibrium (LD) pattern. The emergence of large reference panels such as that from the 1,000 Genomes Project enables more accurate imputation in general, and in particular for admixed populations and for uncommon variants. To efficiently benefit from these large reference panels, one key issue to consider in modern genotype imputation framework is the selection of effective reference panels. In this work, we consider a number of methods for effective reference panel construction inside a hidden Markov model and specific to each target individual. These methods fall into two categories: identity-by-state (IBS) based and ancestry-weighted approach. We evaluated the performance on individuals from recently admixed populations. Our target samples include 8,421 African Americans and 3,587 Hispanic Americans from the Women’s Health Initiative, which allow assessment of imputation quality for uncommon variants. Our experiments include both large and small reference panels; large, medium, and small target samples; and in genome regions of varying levels of LD. We also include BEAGLE and IMPUTE2 for comparison. Experiment results with large reference panel suggest that our novel piecewise IBS method yields consistently higher imputation quality than other methods/software. The advantage is particularly noteworthy among uncommon variants where we observe up to 5.1% information gain with the difference being highly significant (Wilcoxon signed rank test P-value < 0.0001). Our work is the first that considers various sensible approaches for imputation in admixed populations and presents a comprehensive comparison. PMID:23074066

Effectiveness of Cultural Adaptations of Interventions Aimed at Smoking Cessation, Diet, and/or Physical Activity in Ethnic Minorities. A Systematic Review

PubMed Central

Nierkens, Vera; Hartman, Marieke A.; Nicolaou, Mary; Vissenberg, Charlotte; Beune, Erik J. A. J.; Hosper, Karen; van Valkengoed, Irene G.; Stronks, Karien

2013-01-01

Background The importance of cultural adaptations in behavioral interventions targeting ethnic minorities in high-income societies is widely recognized. Little is known, however, about the effectiveness of specific cultural adaptations in such interventions. Aim To systematically review the effectiveness of specific cultural adaptations in interventions that target smoking cessation, diet, and/or physical activity and to explore features of such adaptations that may account for their effectiveness. Methods Systematic review using MEDLINE, PsycINFO, Embase, and the Cochrane Central Register of Controlled Trials registers (1997–2009). Inclusion criteria: a) effectiveness study of a lifestyle intervention targeted to ethnic minority populations living in a high income society; b) interventions included cultural adaptations and a control group that was exposed to the intervention without the cultural adaptation under study; c) primary outcome measures included smoking cessation, diet, or physical activity. Results Out of 44904 hits, we identified 17 studies, all conducted in the United States. In five studies, specific cultural adaptations had a statistically significant effect on primary outcomes. The remaining studies showed no significant effects on primary outcomes, but some presented trends favorable for cultural adaptations. We observed that interventions incorporating a package of cultural adaptations, cultural adaptations that implied higher intensity and those incorporating family values were more likely to report statistically significant effects. Adaptations in smoking cessation interventions seem to be more effective than adaptations in interventions aimed at diet and physical activity. Conclusion This review indicates that culturally targeted behavioral interventions may be more effective if cultural adaptations are implemented as a package of adaptations, the adaptation includes family level, and where the adaptation results in a higher intensity of the intervention. More systematic experiments are needed in which the aim is to gain insight in the best mix of cultural adaptations among diverse populations in various settings, particularly outside the US. PMID:24116000

Effectiveness of cultural adaptations of interventions aimed at smoking cessation, diet, and/or physical activity in ethnic minorities. a systematic review.

PubMed

Nierkens, Vera; Hartman, Marieke A; Nicolaou, Mary; Vissenberg, Charlotte; Beune, Erik J A J; Hosper, Karen; van Valkengoed, Irene G; Stronks, Karien

2013-01-01

The importance of cultural adaptations in behavioral interventions targeting ethnic minorities in high-income societies is widely recognized. Little is known, however, about the effectiveness of specific cultural adaptations in such interventions. To systematically review the effectiveness of specific cultural adaptations in interventions that target smoking cessation, diet, and/or physical activity and to explore features of such adaptations that may account for their effectiveness. Systematic review using MEDLINE, PsycINFO, Embase, and the Cochrane Central Register of Controlled Trials registers (1997-2009). a) effectiveness study of a lifestyle intervention targeted to ethnic minority populations living in a high income society; b) interventions included cultural adaptations and a control group that was exposed to the intervention without the cultural adaptation under study; c) primary outcome measures included smoking cessation, diet, or physical activity. Out of 44904 hits, we identified 17 studies, all conducted in the United States. In five studies, specific cultural adaptations had a statistically significant effect on primary outcomes. The remaining studies showed no significant effects on primary outcomes, but some presented trends favorable for cultural adaptations. We observed that interventions incorporating a package of cultural adaptations, cultural adaptations that implied higher intensity and those incorporating family values were more likely to report statistically significant effects. Adaptations in smoking cessation interventions seem to be more effective than adaptations in interventions aimed at diet and physical activity. This review indicates that culturally targeted behavioral interventions may be more effective if cultural adaptations are implemented as a package of adaptations, the adaptation includes family level, and where the adaptation results in a higher intensity of the intervention. More systematic experiments are needed in which the aim is to gain insight in the best mix of cultural adaptations among diverse populations in various settings, particularly outside the US.

Advances in antivirals for non-influenza respiratory virus infections.

PubMed

Hayden, Frederick G

2013-11-01

Progress in the development of antivirals for non-influenza respiratory viruses has been slow with the result that many unmet medical needs and few approved agents currently exist. This commentary selectively reviews examples of where specific agents have provided promising clinical benefits in selected target populations and also considers potential therapeutics for emerging threats like the SARS and Middle East respiratory syndrome coronaviruses. Recent studies have provided encouraging results in treating respiratory syncytial virus infections in lung transplant recipients, serious parainfluenza virus and adenovirus infections in immunocompromised hosts, and rhinovirus colds in outpatient asthmatics. While additional studies are needed to confirm the efficacy and safety of the specific agents tested, these observations offer the opportunity to expand therapeutic studies to other patient populations. © 2013 Blackwell Publishing Ltd.

Winnowing DNA for Rare Sequences: Highly Specific Sequence and Methylation Based Enrichment

PubMed Central

Thompson, Jason D.; Shibahara, Gosuke; Rajan, Sweta; Pel, Joel; Marziali, Andre

2012-01-01

Rare mutations in cell populations are known to be hallmarks of many diseases and cancers. Similarly, differential DNA methylation patterns arise in rare cell populations with diagnostic potential such as fetal cells circulating in maternal blood. Unfortunately, the frequency of alleles with diagnostic potential, relative to wild-type background sequence, is often well below the frequency of errors in currently available methods for sequence analysis, including very high throughput DNA sequencing. We demonstrate a DNA preparation and purification method that through non-linear electrophoretic separation in media containing oligonucleotide probes, achieves 10,000 fold enrichment of target DNA with single nucleotide specificity, and 100 fold enrichment of unmodified methylated DNA differing from the background by the methylation of a single cytosine residue. PMID:22355378

Fillers in the skin of color population.

PubMed

Heath, Candrice R; Taylor, Susan C

2011-05-01

The skin of color population in the United States is rapidly growing and the cosmetic industry is responding to the demand for skin of color targeted treatments. The aging face in skin of color patients has a unique pattern that can be successfully augmented by dermal fillers. Though many subjects with skin of color were not included in the pre-market dermal filler clinical trials, some post-market studies have examined the safety and risks of adverse events in this population. The safety data from a selection of these studies was examined. Though pigmentary changes occurred, there have been no reports of keloid development. Developing a patient-specific care plan and instituting close follow up is emphasized.

Correlates of Leisure Time Physical Inactivity in a Scandinavian Population: A Basis for Interventions.

PubMed

Bonn, Stephanie E; Alfredsson, Lars; Saevarsdottir, Saedis; Schelin, Maria E C

2016-11-01

Effective interventions are needed to increase physical activity in the general population. To target interventions, we need knowledge of insufficiently active groups in society. This study aims to identify demographic and health-related correlates of leisure-time physical inactivity in a general Scandinavian population. Study participants comprised 5734 control subjects, age 18 to 70 years, from 2 ongoing Swedish case-control studies. Participants self-reported their leisure-time physical activity level. The odds of being physically inactive were calculated using logistic regression. A total of 42% of participants were classified as physically inactive during leisure time. A lower prevalence of inactivity was associated with middle age, higher education, having previous experience of sports participation, following a low glycemic index/Mediterranean diet and having a light physical workload. A high prevalence of inactivity was associated with greater age, high body mass index, smoking, never drinking alcohol, having children, having a weak social network or lower levels of emotional support, and a low vegetable intake. Several factors were associated with leisure-time physical inactivity. Directing interventions to target groups defined by specific factors associated with physical inactivity could be an efficient way to increase activity and improve health in the general population.

Population-level interventions to reduce alcohol-related harm: an overview of systematic reviews.

PubMed

Martineau, Fred; Tyner, Elizabeth; Lorenc, Theo; Petticrew, Mark; Lock, Karen

2013-10-01

To analyse available review-level evidence on the effectiveness of population-level interventions in non-clinical settings to reduce alcohol consumption or related health or social harm. Health, social policy and specialist review databases between 2002 and 2012 were searched for systematic reviews of the effectiveness of population-level alcohol interventions on consumption or alcohol-related health or social outcomes. Data were extracted on review research aim, inclusion criteria, outcome indicators, results, conclusions and limitations. Reviews were quality-assessed using AMSTAR criteria. A narrative synthesis was conducted overall and by policy area. Fifty-two reviews were included from ten policy areas. There is good evidence for policies and interventions to limit alcohol sale availability, to reduce drink-driving, to increase alcohol price or taxation. There is mixed evidence for family- and community-level interventions, school-based interventions, and interventions in the alcohol server setting and the mass media. There is weak evidence for workplace interventions and for interventions targeting illicit alcohol sales. There is evidence of the ineffectiveness of interventions in higher education settings. There is a pattern of support from the evidence base for regulatory or statutory enforcement interventions over local non-regulatory approaches targeting specific population groups. © 2013.

Targeting populations at higher risk for malaria: a survey of national malaria elimination programmes in the Asia Pacific.

PubMed

Wen, Shawn; Harvard, Kelly E; Gueye, Cara Smith; Canavati, Sara E; Chancellor, Arna; Ahmed, Be-Nazir; Leaburi, John; Lek, Dysoley; Namgay, Rinzin; Surya, Asik; Thakur, Garib D; Whittaker, Maxine Anne; Gosling, Roly D

2016-05-10

Significant progress has been made in reducing the malaria burden in the Asia Pacific region, which is aggressively pursuing a 2030 regional elimination goal. Moving from malaria control to elimination requires National Malaria Control Programmes (NMCPs) to target interventions at populations at higher risk, who are often not reached by health services, highly mobile and difficult to test, treat, and track with routine measures, and if undiagnosed, can maintain parasite reservoirs and contribute to ongoing transmission. A qualitative, free-text questionnaire was developed and disseminated among 17 of the 18 partner countries of the Asia Pacific Malaria Elimination Network (APMEN). All 14 countries that responded to the survey identified key populations at higher risk of malaria in their respective countries. Thirteen countries engage in the dissemination of malaria-related Information, Education, and Communication (IEC) materials. Eight countries engage in diagnostic screening, including of mobile and migrant workers, military staff, and/or overseas workers. Ten countries reported distributing or recommending the use of long-lasting insecticide-treated nets (LLINs) among populations at higher risk with fewer countries engaging in other prevention measures such as indoor residual spraying (IRS) (two countries), spatial repellents (four countries), chemoprophylaxis (five countries), and mass drug administration (MDA) (three countries). Though not specifically tailored to populations at higher risk, 11 countries reported using mass blood surveys as a surveillance tool and ten countries map case data. Most NMCPs lack a monitoring and evaluation structure. Countries in the Asia Pacific have identified populations at higher risk and targeted interventions to these groups but there is limited information on the effectiveness of these interventions. Platforms like APMEN offer the opportunity for the sharing of protocols and lessons learned related to finding, targeting and successfully clearing malaria from populations at higher risk. The sharing of programme data across borders may further strengthen national and regional efforts to eliminate malaria. This exchange of real-life experience is invaluable to NMCPs when scarce scientific evidence on the topic exists to aid decision-making and can further support NMCPs to develop strategies that will deliver a malaria-free Asia Pacific by 2030.

Recommendations for the use of Serious Games in people with Alzheimer's Disease, related disorders and frailty.

PubMed

Robert, Philippe H; König, Alexandra; Amieva, Hélene; Andrieu, Sandrine; Bremond, François; Bullock, Roger; Ceccaldi, Mathieu; Dubois, Bruno; Gauthier, Serge; Kenigsberg, Paul-Ariel; Nave, Stéphane; Orgogozo, Jean M; Piano, Julie; Benoit, Michel; Touchon, Jacques; Vellas, Bruno; Yesavage, Jerome; Manera, Valeria

2014-01-01

Alzheimer's disease and other related disorders (ADRD) represent a major challenge for health care systems within the aging population. It is therefore important to develop better instruments to assess the disease severity and progression, as well as to improve its treatment, stimulation, and rehabilitation. This is the underlying idea for the development of Serious Games (SG). These are digital applications specially adapted for purposes other than entertaining; such as rehabilitation, training and education. Recently, there has been an increase of interest in the use of SG targeting patients with ADRD. However, this field is completely uncharted, and the clinical, ethical, economic and research impact of the employment of SG in these target populations has never been systematically addressed. The aim of this paper is to systematically analyze the Strengths, Weaknesses, Opportunities, and Threats (SWOT) of employing SG with patients with ADRD in order to provide practical recommendations for the development and use of SG in these populations. These analyses and recommendations were gathered, commented on and validated during a 2-round workshop in the context of the 2013 Clinical Trial of Alzheimer's Disease (CTAD) conference, and endorsed by stakeholders in the field. The results revealed that SG may offer very useful tools for professionals involved in the care of patients suffering from ADRD. However, more interdisciplinary work should be done in order to create SG specifically targeting these populations. Furthermore, in order to acquire more academic and professional credibility and acceptance, it will be necessary to invest more in research targeting efficacy and feasibility. Finally, the emerging ethical challenges should be considered a priority.

Recommendations for the use of Serious Games in people with Alzheimer's Disease, related disorders and frailty

PubMed Central

Robert, Philippe H.; König, Alexandra; Amieva, Hélene; Andrieu, Sandrine; Bremond, François; Bullock, Roger; Ceccaldi, Mathieu; Dubois, Bruno; Gauthier, Serge; Kenigsberg, Paul-Ariel; Nave, Stéphane; Orgogozo, Jean M.; Piano, Julie; Benoit, Michel; Touchon, Jacques; Vellas, Bruno; Yesavage, Jerome; Manera, Valeria

2014-01-01

Alzheimer's disease and other related disorders (ADRD) represent a major challenge for health care systems within the aging population. It is therefore important to develop better instruments to assess the disease severity and progression, as well as to improve its treatment, stimulation, and rehabilitation. This is the underlying idea for the development of Serious Games (SG). These are digital applications specially adapted for purposes other than entertaining; such as rehabilitation, training and education. Recently, there has been an increase of interest in the use of SG targeting patients with ADRD. However, this field is completely uncharted, and the clinical, ethical, economic and research impact of the employment of SG in these target populations has never been systematically addressed. The aim of this paper is to systematically analyze the Strengths, Weaknesses, Opportunities, and Threats (SWOT) of employing SG with patients with ADRD in order to provide practical recommendations for the development and use of SG in these populations. These analyses and recommendations were gathered, commented on and validated during a 2-round workshop in the context of the 2013 Clinical Trial of Alzheimer's Disease (CTAD) conference, and endorsed by stakeholders in the field. The results revealed that SG may offer very useful tools for professionals involved in the care of patients suffering from ADRD. However, more interdisciplinary work should be done in order to create SG specifically targeting these populations. Furthermore, in order to acquire more academic and professional credibility and acceptance, it will be necessary to invest more in research targeting efficacy and feasibility. Finally, the emerging ethical challenges should be considered a priority. PMID:24715864

T LYMPHOCYTES TARGETING NATIVE RECEPTORS

PubMed Central

Rooney, Cliona M; Leen, Ann M; Vera, Juan F; Heslop, Helen E

2013-01-01

Summary The adoptive transfer of T cells specific for native tumor antigens (TAs) is an increasingly popular cancer treatment option because of the ability of these cells to discriminate between normal and tumor tissues and corresponding lack of short or long-term toxicities. Infusions of antigen-specific CD4+ and CD8+ T cells targeting viral antigens derived from Epstein Barr virus (EBV) induce sustained complete tumor remissions in patients with highly immunogenic tumor’s such as post-transplant lymphoproliferative disease, although resistance occurred when the infused T-cell population had restricted antigen specificity. T cells specific for EBV antigens have also produced complete remissions of EBV-positive nasopharyngeal carcinomas and lymphomas developing in immunocompetent individuals, even though in these patients tumor survival is dependent on their ability to evade T-cell immunity. Adapting this strategy to non-viral tumors is more challenging, as the target antigens expressed are less immunogenic and the tumors lack the potent danger signals that are characteristic of viruses. The goals of current studies are to define conditions that promote expansion of antigen-specific T cells ex vivo and to ensure their in vivo persistence and survival by combining with maneuvers such as lymphodepletion, checkpoint inhibition, cytokine infusions, or genetic manipulations. More pragmatic goals are to streamline manufacturing to facilitate the transition of these therapies to late phase trials and to evaluate closely histocompatibility antigen (HLA)-matched banked antigen-specific T-cells so that T-cell therapies can be made more broadly available. PMID:24329788

Neuronal Surface Autoantibodies in Neuropsychiatric Disorders: Are There Implications for Depression?

PubMed Central

Zong, Shenghua; Hoffmann, Carolin; Mané-Damas, Marina; Molenaar, Peter; Losen, Mario; Martinez-Martinez, Pilar

2017-01-01

Autoimmune diseases are affecting around 7.6–9.4% of the general population. A number of central nervous system disorders, including encephalitis and severe psychiatric disorders, have been demonstrated to associate with specific neuronal surface autoantibodies (NSAbs). It has become clear that specific autoantibodies targeting neuronal surface antigens and ion channels could cause severe mental disturbances. A number of studies have focused or are currently investigating the presence of autoantibodies in specific mental conditions such as schizophrenia and bipolar disorders. However, less is known about other conditions such as depression. Depression is a psychiatric disorder with complex etiology and pathogenesis. The diagnosis criteria of depression are largely based on symptoms but not on the origin of the disease. The question which arises is whether in a subgroup of patients with depression, the symptoms might be caused by autoantibodies targeting membrane-associated antigens. Here, we describe how autoantibodies targeting membrane proteins and ion channels cause pathological effects. We discuss the physiology of these antigens and their role in relation to depression. Finally, we summarize a number of studies detecting NSAbs with a special focus on cohorts that include depression diagnosis and/or show depressive symptoms. PMID:28725222

Isolation of hair follicle bulge stem cells from YFP-expressing reporter mice.

PubMed

Nakrieko, Kerry-Ann; Irvine, Timothy S; Dagnino, Lina

2013-01-01

In this article we provide a method to isolate hair follicle stem cells that have undergone targeted gene inactivation. The mice from which these cells are isolated are bred into a Rosa26-yellow fluorescent protein (YFP) reporter background, which results in YFP expression in the targeted stem cell population. These cells are isolated and purified by fluorescence-activated cell sorting, using epidermal stem cell-specific markers in conjunction with YFP fluorescence. The purified cells can be used for gene expression studies, clonogenic experiments, and biological assays, such as viability and capacity for directional migration.

'Known unknowns - examining the burden of neurocognitive impairment in the end-stage renal failure population'.

PubMed

Wilson, Scott; Dhar, Arup; Tregaskis, Peter; Lambert, Gavin; Barton, David; Walker, Rowan

2018-01-18

The burden of neurocognitive impairment (NCI) in patients receiving maintenance dialysis represents a spectrum of deficits across multiple cognitive domains which are associated with hospitalisation, reduced quality-of-life, mortality and forced decision-making around dialysis withdrawal. Point prevalence data suggests that dialysis patients manifest NCI at rates 3-5 fold higher than the general population with executive function the most commonly affected cognitive domain. The unique physiology of the renal failure state and maintenance dialysis appears to drive an excess of vascular dementia subtype compared to the general population where classical Alzheimer's disease predominates. Despite the absence of evidence based cost-effective therapies for NCI, detecting it in this population creates opportunity to proactively personalise care through education, supported decision making and targeted communication strategies to cover specific areas of deficit and help define goals of care. This review discusses NCI in the dialysis setting, including developments in the definition of neurocognitive impairment, dialysis-specific epidemiology across modalities, screening strategies and opportunities for dialysis providers in this space. This article is protected by copyright. All rights reserved.

Heart failure in patients with kidney disease.

PubMed

Tuegel, Courtney; Bansal, Nisha

2017-12-01

Heart failure (HF) is a leading cause of morbidity and mortality in patients with chronic kidney disease (CKD), and the population of CKD patients with concurrent HF continues to grow. The accurate diagnosis of HF is challenging in patients with CKD in part due to a lack of validated imaging and biomarkers specifically in this population. The pathophysiology between the heart and the kidneys is complex and bidirectional. Patients with CKD have greater prevalence of traditional HF risk factors as well as unique kidney-specific risk factors including malnutrition, acid-base alterations, uraemic toxins, bone mineral changes, anemia and myocardial stunning. These risk factors also contribute to the decline of kidney function seen in patients with subclinical and clinical HF. More targeted HF therapies may improve outcomes in patients with kidney disease as current HF therapies are underutilised in this population. Further work is also needed to develop novel HF therapies for the CKD population. © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

Demographic Profile and Needs Assessment of Single Parents and Homemakers in New Jersey Vocational Education Programs 1990-1991.

ERIC Educational Resources Information Center

Montclair State Coll., Upper Montclair, NJ. Life Skills Center.

A 5-year (1986-91) follow-up needs assessment was conducted to evaluate current single parent and displaced homemaker programs in New Jersey. Suggestions were offered to help them continue effectively helping the changing target population attain long-term economic self-sufficiency. Recommendations made in response to specific findings included…

Factor Analysis of a Modified Version of the California Brief Multicultural Competence Scale with Minority Pharmacy Students

ERIC Educational Resources Information Center

Echeverri, Margarita; Brookover, Cecile; Kennedy, Kathleen

2011-01-01

While most of the more frequently used self-report measures of cultural competence in health professionals are targeted to practicing physicians and mental health providers from the majority-white population, no measures have been specifically developed for minority pharmacy students. With the objective to find a suitable tool to be used for…

Comparative genetic responses to climate in the varieties of Pinus ponderosa and Pseudotsuga menziesii: reforestation

Treesearch

Gerald E. Rehfeldt; Barry C. Jaquish; Cuauhtemoc Saenz-Romero; Dennis G. Joyce; Laura P. Leites; J. Bradley St Clair; Javier Lopez-Upton

2014-01-01

Impacts of climate change on the climatic niche of the sub-specific varieties of Pinus ponderosa and Pseudotsuga menziesii and on the adaptedness of their populations are considered from the viewpoint of reforestation. In using climate projections from an ensemble of 17 general circulation models targeting the decade surrounding 2060, our analyses suggest that a...

Optical Neural Interfaces

PubMed Central

Warden, Melissa R.; Cardin, Jessica A.; Deisseroth, Karl

2014-01-01

Genetically encoded optical actuators and indicators have changed the landscape of neuroscience, enabling targetable control and readout of specific components of intact neural circuits in behaving animals. Here, we review the development of optical neural interfaces, focusing on hardware designed for optical control of neural activity, integrated optical control and electrical readout, and optical readout of population and single-cell neural activity in freely moving mammals. PMID:25014785

Improving Memory and Cognition in Individuals with Down Syndrome.

PubMed

Rafii, Michael S

2016-07-01

Down syndrome (DS), often due to trisomy 21, is the most common genetic cause of intellectual disability (ID). In addition, virtually all individuals with DS develop the neuropathology of Alzheimer's disease (AD) by the age of 40 years and almost 60 % will manifest symptoms of AD dementia by the age of 65 years. Currently, there are no pharmacological treatments available for ID in individuals with DS and only limited symptomatic treatments for AD dementia. Advances in our understanding in both the molecular basis of ID and the pathogenesis of AD have created opportunities to study potential therapeutic targets. Recent studies in animal models of DS continue to provide a rational basis for translating specific compounds into human clinical trials. However, target and compound selection are only initial steps in the drug development pathway. Other necessary considerations include appropriate study designs to assess efficacy in the DS population, as well as operational aspects specifically tailored to assess cognition in this population. We discuss recent progress in the development of compounds for both ID and AD in individuals with DS, as well as concepts for the design and conduct of clinical trials with such compounds.

Optimization of the transductional efficiency of lentiviral vectors: effect of sera and polycations

PubMed Central

Denning, Warren; Das, Suvendu; Guo, Siqi; Xu, Jun; Kappes, John C.; Hel, Zdenek

2012-01-01

Lentiviral vectors are widely used as effective gene-delivery vehicles. Optimization of the conditions for efficient lentiviral transduction is of a high importance for a variety of research applications. Presence of positively-charged polycations reduces the electrostatic repulsion forces between a negatively-charged cell and an approaching enveloped lentiviral particle resulting in an increase in the transduction efficiency. Although a variety of polycations are commonly used to enhance the transduction with retroviruses, the relative effect of various types of polycations on the efficiency of transduction and on the potential bias in the determination of titer of lentiviral vectors is not fully understood. Here we present data suggesting that DEAE-dextran provides superior results in enhancing lentiviral transduction of most tested cell lines and primary cell cultures. Specific type and source of serum affects the efficiency of transduction of target cell populations. Non-specific binding of enhanced green fluorescent protein (EGFP)-containing membrane aggregates in the presence of DEAE-dextran does not significantly affect the determination of the titer of EGFP-expressing lentiviral vectors. In conclusion, various polycations and types of sera should be tested when optimizing lentiviral transduction of target cell populations. PMID:22407723

Optimization of the transductional efficiency of lentiviral vectors: effect of sera and polycations.

PubMed

Denning, Warren; Das, Suvendu; Guo, Siqi; Xu, Jun; Kappes, John C; Hel, Zdenek

2013-03-01

Lentiviral vectors are widely used as effective gene-delivery vehicles. Optimization of the conditions for efficient lentiviral transduction is of a high importance for a variety of research applications. Presence of positively charged polycations reduces the electrostatic repulsion forces between a negatively charged cell and an approaching enveloped lentiviral particle resulting in an increase in the transduction efficiency. Although a variety of polycations are commonly used to enhance the transduction with retroviruses, the relative effect of various types of polycations on the efficiency of transduction and on the potential bias in the determination of titer of lentiviral vectors is not fully understood. Here, we present data suggesting that DEAE-dextran provides superior results in enhancing lentiviral transduction of most tested cell lines and primary cell cultures. Specific type and source of serum affects the efficiency of transduction of target cell populations. Non-specific binding of enhanced green fluorescent protein (EGFP)-containing membrane aggregates in the presence of DEAE-dextran does not significantly affect the determination of the titer of EGFP-expressing lentiviral vectors. In conclusion, various polycations and types of sera should be tested when optimizing lentiviral transduction of target cell populations.

Paid advertising for AIDS prevention--would the ends justify the means?

PubMed Central

Donovan, R J; Jason, J; Gibbs, D A; Kroger, F

1991-01-01

An examination by the Centers for Disease Control and the Research Triangle Institute concluded that "hard-to-reach" populations could be reached with AIDS prevention messages through the broadcast and print media and that a study should be undertaken to assess whether paid placement of these messages could have an effect on HIV-related behaviors. The recommended target population for a study of paid advertising would be sexually active 18-24-year-old black urban dwellers. Its behavioral objectives would include abstinence and safer sex practices. For any evaluation of a paid advertising campaign to be valid, there would have to be extensive audience profiling, research into the development of the message, pretesting of the message, and involvement of the community. The proposed study would include measurement of various "dosage" levels of paid advertising, use of a no-intervention comparison group, and a novel data collection technique. Although a specific target group and specific messages would be involved, the evaluation would make a substantial contribution to resolving the broader issue of whether and how mass media should be used directly or indirectly to change or reinforce health-related behaviors. PMID:1659711

Fine-mapping of lipid regions in global populations discovers ethnic-specific signals and refines previously identified lipid loci

PubMed Central

Zubair, Niha; Luis Ambite, Jose; Bush, William S.; Kichaev, Gleb; Lu, Yingchang; Manichaikul, Ani; Sheu, Wayne H-H.; Absher, Devin; Assimes, Themistocles L.; Bielinski, Suzette J.; Bottinger, Erwin P.; Buzkova, Petra; Chuang, Lee-Ming; Chung, Ren-Hua; Cochran, Barbara; Dumitrescu, Logan; Gottesman, Omri; Haessler, Jeffrey W.; Haiman, Christopher; Heiss, Gerardo; Hsiung, Chao A.; Hung, Yi-Jen; Hwu, Chii-Min; Juang, Jyh-Ming J.; Le Marchand, Loic; Lee, I-Te; Lee, Wen-Jane; Lin, Li-An; Lin, Danyu; Lin, Shih-Yi; Mackey, Rachel H.; Martin, Lisa W.; Pasaniuc, Bogdan; Peters, Ulrike; Predazzi, Irene; Quertermous, Thomas; Reiner, Alex P.; Robinson, Jennifer; Rotter, Jerome I.; Ryckman, Kelli K.; Schreiner, Pamela J.; Stahl, Eli; Tao, Ran; Tsai, Michael Y.; Waite, Lindsay L.; Wang, Tzung-Dau; Buyske, Steven; Ida Chen, Yii-Der; Cheng, Iona; Crawford, Dana C.; Loos, Ruth J.F.; Rich, Stephen S.; Fornage, Myriam; North, Kari E.; Kooperberg, Charles; Carty, Cara L.

2016-01-01

Abstract Genome-wide association studies have identified over 150 loci associated with lipid traits, however, no large-scale studies exist for Hispanics and other minority populations. Additionally, the genetic architecture of lipid-influencing loci remains largely unknown. We performed one of the most racially/ethnically diverse fine-mapping genetic studies of HDL-C, LDL-C, and triglycerides to-date using SNPs on the MetaboChip array on 54,119 individuals: 21,304 African Americans, 19,829 Hispanic Americans, 12,456 Asians, and 530 American Indians. The majority of signals found in these groups generalize to European Americans. While we uncovered signals unique to racial/ethnic populations, we also observed systematically consistent lipid associations across these groups. In African Americans, we identified three novel signals associated with HDL-C (LPL, APOA5, LCAT) and two associated with LDL-C (ABCG8, DHODH). In addition, using this population, we refined the location for 16 out of the 58 known MetaboChip lipid loci. These results can guide tailored screening efforts, reveal population-specific responses to lipid-lowering medications, and aid in the development of new targeted drug therapies. PMID:28426890

Identification and characterization of microRNAs in Phaseolus vulgaris by high-throughput sequencing

PubMed Central

2012-01-01

Background MicroRNAs (miRNAs) are endogenously encoded small RNAs that post-transcriptionally regulate gene expression. MiRNAs play essential roles in almost all plant biological processes. Currently, few miRNAs have been identified in the model food legume Phaseolus vulgaris (common bean). Recent advances in next generation sequencing technologies have allowed the identification of conserved and novel miRNAs in many plant species. Here, we used Illumina's sequencing by synthesis (SBS) technology to identify and characterize the miRNA population of Phaseolus vulgaris. Results Small RNA libraries were generated from roots, flowers, leaves, and seedlings of P. vulgaris. Based on similarity to previously reported plant miRNAs,114 miRNAs belonging to 33 conserved miRNA families were identified. Stem-loop precursors and target gene sequences for several conserved common bean miRNAs were determined from publicly available databases. Less conserved miRNA families and species-specific common bean miRNA isoforms were also characterized. Moreover, novel miRNAs based on the small RNAs were found and their potential precursors were predicted. In addition, new target candidates for novel and conserved miRNAs were proposed. Finally, we studied organ-specific miRNA family expression levels through miRNA read frequencies. Conclusions This work represents the first massive-scale RNA sequencing study performed in Phaseolus vulgaris to identify and characterize its miRNA population. It significantly increases the number of miRNAs, precursors, and targets identified in this agronomically important species. The miRNA expression analysis provides a foundation for understanding common bean miRNA organ-specific expression patterns. The present study offers an expanded picture of P. vulgaris miRNAs in relation to those of other legumes. PMID:22394504

Estimating age-specific reproductive numbers-A comparison of methods.

PubMed

Moser, Carlee B; White, Laura F

2016-01-01

Large outbreaks, such as those caused by influenza, put a strain on resources necessary for their control. In particular, children have been shown to play a key role in influenza transmission during recent outbreaks, and targeted interventions, such as school closures, could positively impact the course of emerging epidemics. As an outbreak is unfolding, it is important to be able to estimate reproductive numbers that incorporate this heterogeneity and to use surveillance data that is routinely collected to more effectively target interventions and obtain an accurate understanding of transmission dynamics. There are a growing number of methods that estimate age-group specific reproductive numbers with limited data that build on methods assuming a homogenously mixing population. In this article, we introduce a new approach that is flexible and improves on many aspects of existing methods. We apply this method to influenza data from two outbreaks, the 2009 H1N1 outbreaks in South Africa and Japan, to estimate age-group specific reproductive numbers and compare it to three other methods that also use existing data from social mixing surveys to quantify contact rates among different age groups. In this exercise, all estimates of the reproductive numbers for children exceeded the critical threshold of one and in most cases exceeded those of adults. We introduce a flexible new method to estimate reproductive numbers that describe heterogeneity in the population.

Promising personalized therapeutic options for diffuse large B-cell Lymphoma Subtypes with oncogene addictions.

PubMed

Steinhardt, James J; Gartenhaus, Ronald B

2012-09-01

Currently, two major classification systems segregate diffuse large B-cell lymphoma (DLBCL) into subtypes based on gene expression profiles and provide great insights about the oncogenic mechanisms that may be crucial for lymphomagenesis as well as prognostic information regarding response to current therapies. However, these current classification systems primarily look at expression and not dependency and are thus limited to inductive or probabilistic reasoning when evaluating alternative therapeutic options. The development of a deductive classification system that identifies subtypes in which all patients with a given phenotype require the same oncogenic drivers, and would therefore have a similar response to a rational therapy targeting the essential drivers, would significantly advance the treatment of DLBCL. This review highlights the putative drivers identified as well as the work done to identify potentially dependent populations. These studies integrated genomic analysis and functional screens to provide a rationale for targeted therapies within defined populations. Personalizing treatments by identifying patients with oncogenic dependencies via genotyping and specifically targeting the responsible drivers may constitute a novel approach for the treatment of DLBCL. ©2012 AACR.

Culture-Independent Identification of Periodontitis-Associated Porphyromonas and Tannerella Populations by Targeted Molecular Analysis

PubMed Central

de Lillo, A.; Booth, V.; Kyriacou, L.; Weightman, A. J.; Wade, W. G.

2004-01-01

Periodontitis is the commonest bacterial disease of humans and is the major cause of adult tooth loss. About half of the oral microflora is unculturable; and 16S rRNA PCR, cloning, and sequencing techniques have demonstrated the high level of species richness of the oral microflora. In the present study, a PCR primer set specific for the genera Porphyromonas and Tannerella was designed and used to analyze the bacterial populations in subgingival plaque samples from inflamed shallow and deep sites in subjects with periodontitis and shallow sites in age- and sex-matched controls. A total of 308 clones were sequenced and found to belong to one of six Porphyromonas or Tannerella species or phylotypes, one of which, Porphyromonas P3, was novel. Tannerella forsythensis was found in significantly higher proportions in patients than in controls. Porphyromonas catoniae and Tannerella phylotype BU063 appeared to be associated with shallow sites. Targeted culture-independent molecular ecology studies have a valuable role to play in the identification of bacterial targets for further investigations of the pathogenesis of bacterial infections. PMID:15583276

Strategies to target non-T-cell HIV reservoirs.

PubMed

Sacha, Jonah B; Ndhlovu, Lishomwa C

2016-07-01

A central question for the HIV cure field is to determine new ways to target clinically relevant, latently and actively replicating HIV-infected cells beyond resting memory CD4 T cells, particularly in anatomical areas of low drug penetrability. HIV eradication strategies being positioned for targeting HIV for extinction in the CD4 T-cell compartment may also show promise in non-CD4 T-cells reservoirs. Furthermore, several exciting novel therapeutic approaches specifically focused on HIV clearance from non-CD4 T-cell populations are being developed. Although reservoir validity in these non-CD4 T cells continues to remain debated, this review will highlight recent advances and make an argument as to their clinical relevancy as we progress towards an HIV cure.

Tumor Vessel Development and Expansion in Ewing's Sarcoma: A Review of the Vasculogenesis Process and Clinical Trials with Vascular-Targeting Agents

PubMed Central

Stewart, Keri S.; Kleinerman, Eugenie S.

2011-01-01

Ewing's sarcoma accounts for a disproportionately high portion of the overall pediatric mortality rate compared to its rare incidence in the pediatric population. Little progress has been made since the introduction of traditional chemotherapies, and understanding the biology of the tumor is critical for developing new therapies. Ewing's sarcomas rely on a functional vascular supply, which is formed by a combination of angiogenesis and vasculogenesis. Recent insights into the molecular regulation of bone marrow (BM) cell participation in vascular development have identified VEGF, SDF-1α, and DLL4 as critical players in the vasculogenesis process. Clinical trials using vascular targeting agents, specifically targeting VEGF or DLL4, are underway. PMID:21785569

Joint Stability in Total Knee Arthroplasty: What Is the Target for a Stable Knee?

PubMed

Wright, Timothy M

2017-02-01

Instability remains a common cause of failure in total knee arthroplasty. Although approaches for surgical treatment of instability exist, the target for initial stability remains elusive, increasing the likelihood that failures will persist because adequate stability is not restored when performing the primary arthroplasty. Although the mechanisms that stabilize the knee joint-contact between the articular surfaces, ligamentous constraints, and muscle forces-are well-defined, their relative importance and the interplay among them throughout functions of daily living are poorly understood. The problem is exacerbated by the complex multiplanar motions that occur across the joint and the large variations in these motions across the population, suggesting that stability targets may need to be patient-specific.

The Precision Problem in Conservation and Restoration.

PubMed

Hiers, J Kevin; Jackson, Stephen T; Hobbs, Richard J; Bernhardt, Emily S; Valentine, Leonie E

2016-11-01

Within the varied contexts of environmental policy, conservation of imperilled species populations, and restoration of damaged habitats, an emphasis on idealized optimal conditions has led to increasingly specific targets for management. Overly-precise conservation targets can reduce habitat variability at multiple scales, with unintended consequences for future ecological resilience. We describe this dilemma in the context of endangered species management, stream restoration, and climate-change adaptation. Inappropriate application of conservation targets can be expensive, with marginal conservation benefit. Reduced habitat variability can limit options for managers trying to balance competing objectives with limited resources. Conservation policies should embrace habitat variability, expand decision-space appropriately, and support adaptation to local circumstances to increase ecological resilience in a rapidly changing world. Copyright © 2016 Elsevier Ltd. All rights reserved.

Construction of population-specific Indian MRI brain template: Morphometric comparison with Chinese and Caucasian templates.

PubMed

Bhalerao, Gaurav Vivek; Parlikar, Rujuta; Agrawal, Rimjhim; Shivakumar, Venkataram; Kalmady, Sunil V; Rao, Naren P; Agarwal, Sri Mahavir; Narayanaswamy, Janardhanan C; Reddy, Y C Janardhan; Venkatasubramanian, Ganesan

2018-06-01

Spatial normalization of brain MR images is highly dependent on the choice of target brain template. Morphological differences caused by factors like genetic and environmental exposures, generates a necessity to construct population specific brain templates. Brain image analysis performed using brain templates from Caucasian population may not be appropriate for non-Caucasian population. In this study, our objective was to construct an Indian brain template from a large population (N = 157 subjects) and compare the morphometric parameters of this template with that of Chinese-56 and MNI-152 templates. In addition, using an independent MRI data of 15 Indian subjects, we also evaluated the potential registration accuracy differences using these three templates. Indian brain template was constructed using iterative routines as per established procedures. We compared our Indian template with standard MNI-152 template and Chinese template by measuring global brain features. We also examined accuracy of registration by aligning 15 new Indian brains to Indian, Chinese and MNI templates. Furthermore, we supported our measurement protocol with inter-rater and intra-rater reliability analysis. Our results showed that there were significant differences in global brain features of Indian template in comparison with Chinese and MNI brain templates. The results of registration accuracy analysis revealed that fewer deformations are required when Indian brains are registered to Indian template as compared to Chinese and MNI templates. This study concludes that population specific Indian template is likely to be more appropriate for structural and functional image analysis of Indian population. Copyright © 2018 Elsevier B.V. All rights reserved.

Long-term benefits of full-day kindergarten: a longitudinal population-based study

PubMed Central

Brownell, M.D.; Nickel, N.C.; Chateau, D.; Martens, P.J.; Taylor, C.; Crockett, L.; Katz, A.; Sarkar, J.; Burland, E.; Goh, C.Y.

2015-01-01

In the first longitudinal, population-based study of full-day kindergarten (FDK) outcomes beyond primary school in Canada, we used linked administrative data to follow 15 kindergarten cohorts (n ranging from 112 to 736) up to grade 9. Provincial assessments conducted in grades 3, 7, and 8 and course marks and credits earned in grade 9 were compared between FDK and half-day kindergarten (HDK) students in both targeted and universal FDK programmes. Propensity score matched cohort and stepped-wedge designs allowed for stronger causal inferences than previous research on FDK. We found limited long-term benefits of FDK, specific to the type of programme, outcomes examined, and subpopulations. FDK programmes targeted at low-income areas showed long-term improvements in numeracy for lower income girls. Our results suggest that expectations for wide-ranging long-term academic benefits of FDK are unwarranted. PMID:25632172

Using qualitative and quantitative formative research to develop tailored nutrition intervention materials for a diverse low-income audience.

PubMed

Strolla, Leslie O; Gans, Kim M; Risica, Patricia M

2006-08-01

More effective nutrition education to reach low-income and ethnic minority populations is needed. As part of a project to develop a tailored nutrition education intervention to meet the needs of low-income Hispanics and non-Hispanics, complementary, mixed methods of formative research were used to determine specific characteristics of the target population. The aim was to ensure that the full array of nutrition messages would be comprehensive enough to effectively tailor to the level of the individual. Barriers to healthy eating were delineated for three main dietary behaviors (number of items delineated in parentheses): lowering fat (11), increasing fruit (8) and increasing vegetables (6). Information was also collected regarding motivators for healthy eating (5), situational barriers to making healthy choices (4), other nutrition-related interests (8) and typical eating habits and food-related choices of the target audience.

Asthma in pregnancy: management strategies.

PubMed

McCallister, Jennifer W

2013-01-01

Asthma is one of the most prevalent chronic medical conditions to complicate pregnancy. With approximately one-third of women experiencing a worsening of control during the course of their pregnancy, identifying those at greatest risk has the potential to improve maternal and fetal outcomes for a large number of pregnancies. Similarly, active management strategies that prioritize asthma control in this vulnerable population can have a far-reaching impact. Demographic characteristics and patient noncompliance place certain populations of pregnant women at increased risk of poor asthma control during pregnancy. In addition, undertreatment and disparities in care of acute exacerbations during pregnancy likely contribute. Targeted educational interventions and treatment algorithms using objective markers of disease activity have shown improved outcomes in asthma control. Active management strategies which focus on identifying patient-specific risk factors, patient and provider education, and targeted treatment interventions can improve asthma care for women during pregnancy.

Expression microdissection adapted to commercial laser dissection instruments

PubMed Central

Hanson, Jeffrey C; Tangrea, Michael A; Kim, Skye; Armani, Michael D; Pohida, Thomas J; Bonner, Robert F; Rodriguez-Canales, Jaime; Emmert-Buck, Michael R

2016-01-01

Laser-based microdissection facilitates the isolation of specific cell populations from clinical or animal model tissue specimens for molecular analysis. Expression microdissection (xMD) is a second-generation technology that offers considerable advantages in dissection capabilities; however, until recently the method has not been accessible to investigators. This protocol describes the adaptation of xMD to commonly used laser microdissection instruments and to a commercially available handheld laser device in order to make the technique widely available to the biomedical research community. The method improves dissection speed for many applications by using a targeting probe for cell procurement in place of an operator-based, cell-by-cell selection process. Moreover, xMD can provide improved dissection precision because of the unique characteristics of film activation. The time to complete the protocol is highly dependent on the target cell population and the number of cells needed for subsequent molecular analysis. PMID:21412274

[Poverty profile regarding households participating in a food assistance program].

PubMed

Álvarez-Uribe, Martha C; Aguirre-Acevedo, Daniel C

2012-06-01

This study was aimed at establishing subgroups having specific socioeconomic characteristics by using latent class analysis as a method for segmenting target population members of the MANA-ICBF supplementary food program in the Antioquia department of Colombia and determine their differences regarding poverty and health conditions in efficiently addressing pertinent resources, programs and policies. The target population consisted of 200,000 children and their households involved in the MANA food assistance program; a representative sample by region was used. Latent class analysis was used, as were the expectation-maximization and Newton Raphson algorithms for identifying the appropriate number of classes. The final model classified the households into four clusters or classes, differing according to well-defined socio-demographic conditions affecting children's health. Some homes had a greater depth of poverty, therefore lowering the families' quality of life and affecting the health of the children in this age group.

Neuro-immune interactions at barrier surfaces

PubMed Central

Veiga-Fernandes, Henrique; Mucida, Daniel

2016-01-01

Multidirectional interactions between the nervous and immune systems have been documented in homeostasis and pathologies ranging from multiple sclerosis to autism, and from leukemia to acute and chronic inflammation. Recent studies have addressed this crosstalk using cell-specific targeting, novel sequencing, imaging and analytical tools, shedding light on unappreciated mechanisms of neuro-immune regulation. This review focuses on neuro-immune interactions at barrier surfaces, mostly the gut, but also including the skin and the airways, areas densely populated by neurons and immune cells that constantly sense and adapt to tissue-specific environmental challenges. PMID:27153494

Isolation and Phenotyping of Intestinal Macrophages.

PubMed

Petit, Vanessa

2018-01-01

Macrophages are one of the most abundant leucocytes in the intestinal mucosa where they are essential for maintaining homeostasis. However they are also implicated in the pathogenesis of disorders such as inflammatory bowel disease (IBD), offering potential targets for novel therapies.Tissue macrophages are a heterogeneous population of immune cells that fulfill tissue-specific and niche-specific functions. These unique phenotypes likely reflect the heterogeneity of tissue macrophage origins and influence the tissue environment in which they reside. Here we describe how we can characterize and isolate the colonic macrophages.

Population-Level Persistence of Immunity 2 Years After the PsA-TT Mass-Vaccination Campaign in Mali.

PubMed

Basta, Nicole E; Borrow, Ray; Berthe, Abdoulaye; Dembélé, Awa Traoré Eps; Onwuchekwa, Uma; Townsend, Kelly; Boukary, Rahamatou M; Mabey, Lesley; Findlow, Helen; Bai, Xilian; Sow, Samba O

2015-11-15

In 2010, Africa's first preventive meningococcal mass vaccination campaign was launched using a newly developed Neisseria meningitidis group A (NmA) polysaccharide-tetanus toxoid conjugate vaccine, PsA-TT (MenAfriVac), designed specifically for the meningitis belt. Given PsA-TT's recent introduction, the duration of protection against meningococcal group A is unknown. We conducted a household-based, age-stratified seroprevalence survey in Bamako, Mali, in 2012, 2 years after the vaccination campaign targeted all 1- to 29-year-olds. Randomly selected participants who had been eligible for PsA-TT provided a blood sample and responded to a questionnaire. Sera were analyzed to assess NmA-specific serum bactericidal antibody titers using rabbit complement (rSBA) and NmA-specific immunoglobulin G (IgG) by enzyme-linked immunosorbent assay. The proportion of participants putatively protected and the age group- and sex-specific rSBA geometric mean titers (GMTs) and IgG geometric mean concentrations (GMCs) were determined. Two years postvaccination, nearly all of the 800 participants (99.0%; 95% confidence interval [CI], 98.3%-99.7%) maintained NmA-specific rSBA titers ≥8, the accepted threshold for protection; 98.6% (95% CI, 97.8%-99.4%) had titers ≥128, and 89.5% (95% CI, 87.4%-91.6%) had titers ≥1024. The rSBA GMTs were significantly higher in females than in males aged <18 years at vaccination (P < .0001). NmA-specific IgG levels ≥2 µg/mL were found in 88.5% (95% CI, 86.3%-90.7%) of participants. Two years after PsA-TT introduction, a very high proportion of the population targeted for vaccination maintains high antibody titers against NmA. Assessing the duration of protection provided by PsA-TT is a priority for implementing evidence-based vaccination strategies. Representative, population-based seroprevalence studies complement clinical trials and provide this key evidence. © The Author 2015. Published by Oxford University Press on behalf of the Infectious Diseases Society of America.

Reaching Hard-to-Reach Individuals: Nonselective Versus Targeted Outbreak Response Vaccination for Measles

PubMed Central

Minetti, Andrea; Hurtado, Northan; Grais, Rebecca F.; Ferrari, Matthew

2014-01-01

Current mass vaccination campaigns in measles outbreak response are nonselective with respect to the immune status of individuals. However, the heterogeneity in immunity, due to previous vaccination coverage or infection, may lead to potential bias of such campaigns toward those with previous high access to vaccination and may result in a lower-than-expected effective impact. During the 2010 measles outbreak in Malawi, only 3 of the 8 districts where vaccination occurred achieved a measureable effective campaign impact (i.e., a reduction in measles cases in the targeted age groups greater than that observed in nonvaccinated districts). Simulation models suggest that selective campaigns targeting hard-to-reach individuals are of greater benefit, particularly in highly vaccinated populations, even for low target coverage and with late implementation. However, the choice between targeted and nonselective campaigns should be context specific, achieving a reasonable balance of feasibility, cost, and expected impact. In addition, it is critical to develop operational strategies to identify and target hard-to-reach individuals. PMID:24131555

Target specific delivery of anticancer drug in silk fibroin based 3D distribution model of bone-breast cancer cells.

PubMed

Subia, Bano; Dey, Tuli; Sharma, Shaily; Kundu, Subhas C

2015-02-04

To avoid the indiscriminating action of anticancer drugs, the cancer cell specific targeting of drug molecule becomes a preferred choice for the treatment. The successful screening of the drug molecules in 2D culture system requires further validation. The failure of target specific drug in animal model raises the issue of creating a platform in between the in vitro (2D) and in vivo animal testing. The metastatic breast cancer cells migrate and settle at different sites such as bone tissue. This work evaluates the in vitro 3D model of the breast cancer and bone cells to understand the cellular interactions in the presence of a targeted anticancer drug delivery system. The silk fibroin based cytocompatible 3D scaffold is used as in vitro 3D distribution model. Human breast adenocarcinoma and osteoblast like cells are cocultured to evaluate the efficiency of doxorubicin loaded folic acid conjugated silk fibroin nanoparticle as drug delivery system. Decreasing population of the cancer cells, which lower the levels of vascular endothelial growth factors, glucose consumption, and lactate production are observed in the drug treated coculture constructs. The drug treated constructs do not show any major impact on bone mineralization. The diminished expression of osteogenic markers such as osteocalcein and alkaline phosphatase are recorded. The result indicates that this type of silk based 3D in vitro coculture model may be utilized as a bridge between the traditional 2D and animal model system to evaluate the new drug molecule (s) or to reassay the known drug molecules or to develop target specific drug in cancer research.

Diversity of killer cell immunoglobulin-like receptor genes in Indonesian populations of Java, Kalimantan, Timor and Irian Jaya.

PubMed

Velickovic, M; Velickovic, Z; Panigoro, R; Dunckley, H

2009-01-01

Killer cell immunoglobulin-like receptors (KIRs) regulate the activity of natural killer and T cells through interactions with specific human leucocyte antigen class I molecules on target cells. Population studies performed over the last several years have established that KIR gene frequencies (GFs) and genotype content vary considerably among different ethnic groups, indicating the extent of KIR diversity, some of which have also shown the effect of the presence or absence of specific KIR genes in human disease. We have determined the frequencies of 16 KIR genes and pseudogenes and genotypes in 193 Indonesian individuals from Java, East Timor, Irian Jaya (western half of the island of New Guinea) and Kalimantan provinces of Indonesian Borneo. All 16 KIR genes were observed in all four populations. Variation in GFs between populations was observed, except for KIR2DL4, KIR3DL2, KIR3DL3, KIR2DP1 and KIR3DP1 genes, which were present in every individual tested. When comparing KIR GFs between populations, both principal component analysis and a phylogenetic tree showed close clustering of the Kalimantan and Javanese populations, while Irianese populations were clearly separated from the other three populations. Our results indicate a high level of KIR polymorphism in Indonesian populations that probably reflects the large geographical spread of the Indonesian archipelago and the complex evolutionary history and population migration in this region.

Nontarget herbivory by a weed biocontrol insect is limited to spillover, reducing the chance of population-level impacts.

PubMed

Catton, Haley A; Lalonde, Robert G; De Clerck-Floate, Rosemarie A

2015-03-01

Insects approved for classical biocontrol of weeds are often capable of using close relatives of their target weed for feeding, oviposition, or larval development, with reduced preference and performance. When nontarget herbivory occurs and is suspected to reduce survival, growth, or fecundity of individual plants, and insects are capable of reproducing on their nontarget host, characterization of spatial and temporal patterns of the occurrence and intensity of herbivory is valuable for predicting potential population-level effects. Here, we perform a novel post-release manipulative field experiment with a root-feeding biocontrol weevil, Mogulones crucifer, released in Canada to control the rangeland weed Cynoglossum officinale, to test for its ability to establish on the nontarget plant Hackelia micrantha. After Cynoglossum, M. crucifer exhibits its highest preference for and performance on Hackelia spp. We released M. crucifer on Canadian rangeland sites with naturally occurring populations of H. micrantha growing interspersed with the target weed or in the near absence of the target weed. Adult weevil feeding on surrounding plants was monitored for three summers after release (years 0, 1, and 2), and, subsequently, subsets of plants were destructively sampled to determine M. crucifer oviposition levels. Additional oviposition and larval development data were obtained from seven non-experimental sites where weevils were released zero, three, or four years earlier. M. crucifer was not detected on experimental sites without C. officinale after two years, and nontarget herbivory was restricted to rare, low-level spillover. Visible evidence of adult herbivory (i.e., scars on shoots) was associated with oviposition in 90% of targets but only 30% of nontarget plants. We infer, through ecological refuge theory, that nontarget population-level impacts from M. crucifer spillover are unlikely because of temporal, spatial, and probabilistic refuges from herbivory, and make recommendations for monitoring and management of biocontrol systems with similar attributes, such as removing target plants around nontarget populations of interest. Because M. crucifer is among the least host-specific of the modern weed biocontrol agents, and H. micrantha is likely one of its most highly preferred nontargets, these conclusions are, arguably, generally applicable to other nontarget plants and biocontrol systems.

Childhood cancer survivorship research in minority populations: A position paper from the Childhood Cancer Survivor Study.

PubMed

Bhatia, Smita; Gibson, Todd M; Ness, Kirsten K; Liu, Qi; Oeffinger, Kevin C; Krull, Kevin R; Nathan, Paul C; Neglia, Joseph P; Leisenring, Wendy; Yasui, Yutaka; Robison, Leslie L; Armstrong, Gregory T

2016-08-01

By the middle of this century, racial/ethnic minority populations will collectively constitute 50% of the US population. This temporal shift in the racial/ethnic composition of the US population demands a close look at the race/ethnicity-specific burden of morbidity and premature mortality among survivors of childhood cancer. To optimize targeted long-term follow-up care, it is essential to understand whether the burden of morbidity borne by survivors of childhood cancer differs by race/ethnicity. This is challenging because the number of minority participants is often limited in current childhood cancer survivorship research, resulting in a paucity of race/ethnicity-specific recommendations and/or interventions. Although the overall childhood cancer incidence increased between 1973 and 2003, the mortality rate declined; however, these changes did not differ appreciably by race/ethnicity. The authors speculated that any racial/ethnic differences in outcome are likely to be multifactorial, and drew on data from the Childhood Cancer Survivor Study to illustrate the various contributors (socioeconomic characteristics, health behaviors, and comorbidities) that could explain any observed differences in key treatment-related complications. Finally, the authors outlined challenges in conducting race/ethnicity-specific childhood cancer survivorship research, demonstrating that there are limited absolute numbers of children who are diagnosed and survive cancer in any one racial/ethnic minority population, thereby precluding a rigorous evaluation of adverse events among specific primary cancer diagnoses and treatment exposure groups. Cancer 2016;122:2426-2439. © 2016 American Cancer Society. © 2016 American Cancer Society.

United States Department of Agriculture-Agricultural Research Service research on biological control of arthropods.

PubMed

Hopper, Keith R

2003-01-01

During 1999-2001, ARS scientists published over 100 papers on more than 30 species of insect pest and 60 species of predator and parasitoid. These papers address issues crucial to the three strategies of biological control: conservation, augmentation and introduction. Conservation biological control includes both conserving extant populations of natural enemies by using relatively non-toxic pesticides and increasing the abundance of natural enemies in crops by providing or improving refuges for population growth and dispersal into crops. ARS scientists have been very active in determining the effects of pesticides on beneficial arthropods and in studying movement of natural enemies from refuges into crops. Augmentation involves repeated releases of natural enemies in the field, which can be inoculative or inundative. Inoculative releases are used to initiate self-propagating populations at times or in places where they would be slow to colonize. ARS scientists have studied augmentative biological control of a variety of pest insects. The targets are mostly pests in annual crops or other ephemeral habitats, where self-reproducing populations of natural enemies are not sufficiently abundant early enough to keep pest populations in check. ARS research in augmentative biological control centers on methods for rearing large numbers of healthy, effective natural enemies and for releasing them where and when they are needed at a cost less than the value of the reduction in damage to the crop. ARS scientists have researched various aspects of introductions of exotic biological control agents against a diversity of pest insects. The major issues in biological control introductions are accurate identification and adequate systematics of both natural enemies and target pests, exploration for natural enemies, predicting the success of candidates for introduction and the likelihood of non-target impacts, quarantine and rearing methods, and post-introduction evaluation of establishment, control and non-target impacts. ARS scientists have published research on several general issues in biological control. Among the most important are the mechanisms affecting mate- and host-finding and host specificity.

Training and transfer effects of N-back training for brain-injured and healthy subjects.

PubMed

Lindeløv, Jonas Kristoffer; Dall, Jonas Olsen; Kristensen, Casper Daniel; Aagesen, Marie Holt; Olsen, Stine Almgren; Snuggerud, Therese Ruud; Sikorska, Anna

2016-10-01

Working memory impairments are prevalent among patients with acquired brain injury (ABI). Computerised training targeting working memory has been researched extensively using samples from healthy populations but this field remains isolated from similar research in ABI patients. We report the results of an actively controlled randomised controlled trial in which 17 patients and 18 healthy subjects completed training on an N-back task. The healthy group had superior improvements on both training tasks (SMD = 6.1 and 3.3) whereas the ABI group improved much less (SMD = 0.5 and 1.1). Neither group demonstrated transfer to untrained tasks. We conclude that computerised training facilitates improvement of specific skills rather than high-level cognition in healthy and ABI subjects alike. The acquisition of these specific skills seems to be impaired by brain injury. The most effective use of computer-based cognitive training may be to make the task resemble the targeted behaviour(s) closely in order to exploit the stimulus-specificity of learning.

Near-Infrared 1064 nm Laser Modulates Migratory Dendritic Cells To Augment the Immune Response to Intradermal Influenza Vaccine.

PubMed

Morse, Kaitlyn; Kimizuka, Yoshifumi; Chan, Megan P K; Shibata, Mai; Shimaoka, Yusuke; Takeuchi, Shu; Forbes, Benjamin; Nirschl, Christopher; Li, Binghao; Zeng, Yang; Bronson, Roderick T; Katagiri, Wataru; Shigeta, Ayako; Sîrbulescu, Ruxandra F; Chen, Huabiao; Tan, Rhea Y Y; Tsukada, Kosuke; Brauns, Timothy; Gelfand, Jeffrey; Sluder, Ann; Locascio, Joseph J; Poznansky, Mark C; Anandasabapathy, Niroshana; Kashiwagi, Satoshi

2017-08-15

Brief exposure of skin to near-infrared (NIR) laser light has been shown to augment the immune response to intradermal vaccination and thus act as an immunologic adjuvant. Although evidence indicates that the NIR laser adjuvant has the capacity to activate innate subsets including dendritic cells (DCs) in skin as conventional adjuvants do, the precise immunological mechanism by which the NIR laser adjuvant acts is largely unknown. In this study we sought to identify the cellular target of the NIR laser adjuvant by using an established mouse model of intradermal influenza vaccination and examining the alteration of responses resulting from genetic ablation of specific DC populations. We found that a continuous wave (CW) NIR laser adjuvant broadly modulates migratory DC (migDC) populations, specifically increasing and activating the Lang + and CD11b - Lang - subsets in skin, and that the Ab responses augmented by the CW NIR laser are dependent on DC subsets expressing CCR2 and Langerin. In comparison, a pulsed wave NIR laser adjuvant showed limited effects on the migDC subsets. Our vaccination study demonstrated that the efficacy of the CW NIR laser is significantly better than that of the pulsed wave laser, indicating that the CW NIR laser offers a desirable immunostimulatory microenvironment for migDCs. These results demonstrate the unique ability of the NIR laser adjuvant to selectively target specific migDC populations in skin depending on its parameters, and highlight the importance of optimization of laser parameters for desirable immune protection induced by an NIR laser-adjuvanted vaccine. Copyright © 2017 by The American Association of Immunologists, Inc.

Worldwide genetic variability of the Duffy binding protein: insights into Plasmodium vivax vaccine development.

PubMed

Nóbrega de Sousa, Taís; Carvalho, Luzia Helena; Alves de Brito, Cristiana Ferreira

2011-01-01

The dependence of Plasmodium vivax on invasion mediated by Duffy binding protein (DBP) makes this protein a prime candidate for development of a vaccine. However, the development of a DBP-based vaccine might be hampered by the high variability of the protein ligand (DBP(II)), known to bias the immune response toward a specific DBP variant. Here, the hypothesis being investigated is that the analysis of the worldwide DBP(II) sequences will allow us to determine the minimum number of haplotypes (MNH) to be included in a DBP-based vaccine of broad coverage. For that, all DBP(II) sequences available were compiled and MNH was based on the most frequent nonsynonymous single nucleotide polymorphisms, the majority mapped on B and T cell epitopes. A preliminary analysis of DBP(II) genetic diversity from eight malaria-endemic countries estimated that a number between two to six DBP haplotypes (17 in total) would target at least 50% of parasite population circulating in each endemic region. Aiming to avoid region-specific haplotypes, we next analyzed the MNH that broadly cover worldwide parasite population. The results demonstrated that seven haplotypes would be required to cover around 60% of DBP(II) sequences available. Trying to validate these selected haplotypes per country, we found that five out of the eight countries will be covered by the MNH (67% of parasite populations, range 48-84%). In addition, to identify related subgroups of DBP(II) sequences we used a Bayesian clustering algorithm. The algorithm grouped all DBP(II) sequences in six populations that were independent of geographic origin, with ancestral populations present in different proportions in each country. In conclusion, in this first attempt to undertake a global analysis about DBP(II) variability, the results suggest that the development of DBP-based vaccine should consider multi-haplotype strategies; otherwise a putative P. vivax vaccine may not target some parasite populations.

G5G2.5 core-shell tecto-dendrimer specifically targets reactive glia in brain ischemia.

PubMed

Murta, Veronica; Schilrreff, Priscila; Rosciszewski, Gerardo; Morilla, Maria Jose; Ramos, Alberto Javier

2018-03-01

Secondary neuronal death is a serious stroke complication. This process is facilitated by the conversion of glial cells to the reactive pro-inflammatory phenotype that induces neurodegeneration. Therefore, regulation of glial activation is a compelling strategy to reduce brain damage after stroke. However, drugs have difficulties to access the CNS, and to specifically target glial cells. In the present work, we explored the use core-shell polyamidoamine tecto-dendrimer (G5G2.5 PAMAM) and studied its ability to target distinct populations of stroke-activated glial cells. We found that G5G2.5 tecto-dendrimer is actively engulfed by primary glial cells in a time- and dose-dependent manner showing high cellular selectivity and lysosomal localization. In addition, oxygen-glucose deprivation or lipopolysaccharides exposure in vitro and brain ischemia in vivo increase glial G5G2.5 uptake; not being incorporated by neurons or other cell types. We conclude that G5G2.5 tecto-dendrimer is a highly suitable carrier for targeted drug delivery to reactive glial cells in vitro and in vivo after brain ischemia. © 2017 International Society for Neurochemistry.

Diagnostic performance of power doppler and ultrasound contrast agents in early imaging-based diagnosis of organ-confined prostate cancer: Is it possible to spare cores with contrast-guided biopsy?

PubMed

Delgado Oliva, F; Arlandis Guzman, S; Bonillo García, M; Broseta Rico, E; Boronat Tormo, F

2016-10-01

To evaluate the diagnostic performance of gray scale transrectal ultrasound-B-mode US (BMUS), power Doppler (PDUS), and sonographic contrast (CEUS) in early imaging-based diagnosis of localized prostate cancer (PCa) and to compare the diagnostic profitability of randomized biopsy (RB), US-targeted prostate biopsy by means of PDUS and CEUS. A single-center, prospective, transversal, epidemiological study was conducted from January 2010 to January 2014. We consecutively included patients who an imaging study of the prostate with BMUS, PDUS, and CEUS was performed, followed by prostate biopsy due to clinical suspicion of prostate cancer (PSA 4-20ng/mL and/or rectal exam suggestive of malignancy). The diagnostic performance of BMUS, PDUS, and CEUS was determined by calculating the Sensitivity (S), Specificity (Sp), Predictive values (PV), and diagnostic odds ratio (OR) of the diagnosis tests and, for these variables, in the population general and based on their clinical stage according to rectal exam (cT1 and cT2). PCa detection rates determined by means of a randomized 10-core biopsy scheme were compared with detection rates of CEUS-targeted (SonoVue) 2-core biopsies. Of the initial 984 patients, US contrast SonoVue was administered to 179 (18.2%). The PCa detection rate by organ of BMUS/PDUS in the global population was 38% versus 43% in the subpopulation with CEUS. The mean age of the patients was 64.3±7.01years (95% CI, 63.75-64.70); mean total PSA was 8.9±3.61ng/mL (95% CI, 8.67-9.13) and the mean prostate volume was 56.2±29cc (95% CI, 54.2-58.1). The detection rate by organ of targeted biopsy with BMUS, PDUS, and CEUS were as follows: Global population (10.6, 8.2, 24.5%), stage cT1 (5.6, 4.2, 16.4%), and stage cT2 (32.4, 22.3, 43.5%). Comparing the detection rates of the CEUS-targeted biopsy and randomized biopsy, the following results were obtained: Global population (24.5% vs. 41.8%), stage cT1 (16% vs. 35%), and stage cT2 (43.5% vs. 66.6%), with a p value<0.05. Following the "core-by-core" analysis, the detection rates by core of CEUS-targeted biopsy versus randomized biopsy were: Global population (16% vs. 13%), stage cT1 (30.3% vs. 28%), and stage cT2 (48% vs. 37%), with a p value>0.05. The NNT for CEUS-targeted biopsy was 83.3. The low sensitivity, specificity, positive predictive and negative predictive values of gray scale-B-mode, PDUS and CEUS represent scant diagnostic performance of these variables in prostate cancer detection. Prostate cancer detection rates yielded by randomized biopsy were superior than the detection rate of targeted biopsy using B-mode, PDUS and CEUS; as a result, randomized biopsy versus CEUS-targeted biopsies cannot be excluded from biopsy strategy plans for the diagnosis of prostate cancer. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Dissecting local circuits in vivo: integrated optogenetic and electrophysiology approaches for exploring inhibitory regulation of cortical activity.

PubMed

Cardin, Jessica A

2012-01-01

Local cortical circuit activity in vivo comprises a complex and flexible series of interactions between excitatory and inhibitory neurons. Our understanding of the functional interactions between these different neural populations has been limited by the difficulty of identifying and selectively manipulating the diverse and sparsely represented inhibitory interneuron classes in the intact brain. The integration of recently developed optical tools with traditional electrophysiological techniques provides a powerful window into the role of inhibition in regulating the activity of excitatory neurons. In particular, optogenetic targeting of specific cell classes reveals the distinct impacts of local inhibitory populations on other neurons in the surrounding local network. In addition to providing the ability to activate or suppress spiking in target cells, optogenetic activation identifies extracellularly recorded neurons by class, even when naturally occurring spike rates are extremely low. However, there are several important limitations on the use of these tools and the interpretation of resulting data. The purpose of this article is to outline the uses and limitations of optogenetic tools, along with current methods for achieving cell type-specific expression, and to highlight the advantages of an experimental approach combining optogenetics and electrophysiology to explore the role of inhibition in active networks. To illustrate the efficacy of these combined approaches, I present data comparing targeted manipulations of cortical fast-spiking, parvalbumin-expressing and low threshold-spiking, somatostatin-expressing interneurons in vivo. Copyright © 2011 Elsevier Ltd. All rights reserved.

TTK/hMPS1 Is an Attractive Therapeutic Target for Triple-Negative Breast Cancer

PubMed Central

Maire, Virginie; Baldeyron, Céline; Richardson, Marion; Tesson, Bruno; Vincent-Salomon, Anne; Gravier, Eléonore; Marty-Prouvost, Bérengère; De Koning, Leanne; Rigaill, Guillem; Dumont, Aurélie; Gentien, David; Barillot, Emmanuel; Roman-Roman, Sergio; Depil, Stéphane; Cruzalegui, Francisco; Pierré, Alain; Tucker, Gordon C.; Dubois, Thierry

2013-01-01

Triple-negative breast cancer (TNBC) represents a subgroup of breast cancers (BC) associated with the most aggressive clinical behavior. No targeted therapy is currently available for the treatment of patients with TNBC. In order to discover potential therapeutic targets, we searched for protein kinases that are overexpressed in human TNBC biopsies and whose silencing in TNBC cell lines causes cell death. A cohort including human BC biopsies obtained at Institut Curie as well as normal tissues has been analyzed at a gene-expression level. The data revealed that the human protein kinase monopolar spindle 1 (hMPS1), also known as TTK and involved in mitotic checkpoint, is specifically overexpressed in TNBC, compared to the other BC subgroups and healthy tissues. We confirmed by immunohistochemistry and reverse phase protein array that TNBC expressed higher levels of TTK protein compared to the other BC subgroups. We then determined the biological effects of TTK depletion by RNA interference, through analyses of tumorigenic capacity and cell viability in different human TNBC cell lines. We found that RNAi-mediated depletion of TTK in various TNBC cell lines severely compromised their viability and their ability to form colonies in an anchorage-independent manner. Moreover, we observed that TTK silencing led to an increase in H2AX phosphorylation, activation of caspases 3/7, sub-G1 cell population accumulation and high annexin V staining, as well as to a decrease in G1 phase cell population and an increased aneuploidy. Altogether, these data indicate that TTK depletion in TNBC cells induces apoptosis. These results point out TTK as a protein kinase overexpressed in TNBC that may represent an attractive therapeutic target specifically for this poor prognosis associated subgroup of breast cancer. PMID:23700430

Neurochemical differences between target-specific populations of rat dorsal raphe projection neurons.

PubMed

Prouty, Eric W; Chandler, Daniel J; Waterhouse, Barry D

2017-11-15

Serotonin (5-HT)-containing neurons in the dorsal raphe (DR) nucleus project throughout the forebrain and are implicated in many physiological processes and neuropsychiatric disorders. Diversity among these neurons has been characterized in terms of their neurochemistry and anatomical organization, but a clear sense of whether these attributes align with specific brain functions or terminal fields is lacking. DR 5-HT neurons can co-express additional neuroactive substances, increasing the potential for individualized regulation of target circuits. The goal of this study was to link DR neurons to a specific functional role by characterizing cells according to both their neurotransmitter expression and efferent connectivity; specifically, cells projecting to the medial prefrontal cortex (mPFC), a region implicated in cognition, emotion, and responses to stress. Following retrograde tracer injection, brainstem sections from Sprague-Dawley rats were immunohistochemically stained for markers of serotonin, glutamate, GABA, and nitric oxide (NO). 98% of the mPFC-projecting serotonergic neurons co-expressed the marker for glutamate, while the markers for NO and GABA were observed in 60% and less than 1% of those neurons, respectively. To identify potential target-specific differences in co-transmitter expression, we also characterized DR neurons projecting to a visual sensory structure, the lateral geniculate nucleus (LGN). The proportion of serotonergic neurons co-expressing NO was greater amongst cells targeting the mPFC vs LGN (60% vs 22%). The established role of 5-HT in affective disorders and the emerging role of NO in stress signaling suggest that the impact of 5-HT/NO co-localization in DR neurons that regulate mPFC circuit function may be clinically relevant. Copyright © 2017 Elsevier B.V. All rights reserved.

Laser pulses for coherent xuv Raman excitation

NASA Astrophysics Data System (ADS)

Greenman, Loren; Koch, Christiane P.; Whaley, K. Birgitta

2015-07-01

We combine multichannel electronic structure theory with quantum optimal control to derive femtosecond-time-scale Raman pulse sequences that coherently populate a valence excited state. For a neon atom, Raman target populations of up to 13% are obtained. Superpositions of the ground and valence Raman states with a controllable relative phase are found to be reachable with up to 4.5% population and arbitrary phase control facilitated by the pump pulse carrier-envelope phase. Analysis of the optimized pulse structure reveals a sequential mechanism in which the valence excitation is reached via a fast (femtosecond) population transfer through an intermediate resonance state in the continuum rather than avoiding intermediate-state population with simultaneous or counterintuitive (stimulated Raman adiabatic passage) pulse sequences. Our results open a route to coupling valence excitations and core-hole excitations in molecules and aggregates that locally address specific atoms and represent an initial step towards realization of multidimensional spectroscopy in the xuv and x-ray regimes.

Targeting Hispanic populations: future research and prevention strategies.

PubMed Central

Ramirez, A G; McAlister, A; Gallion, K J; Villarreal, R

1995-01-01

Minority populations face a wide variety of economic, institutional, and cultural barriers to health care. These barriers and low levels of education and income pose significant challenges for health professionals in developing cancer research and prevention-control strategies. It is suggested that specific segments of Hispanic populations fit the model of an underdeveloped country in the intermediate stage of epidemiological transition. Since noncommunicable diseases have not yet fully emerged in some of these Hispanic population segments, the opportunity exists to apply primordial prevention strategies. Such campaigns would focus on dissuading members of these populations from adopting negative health behaviors while promoting positive lifestyle choices. Optimal programs would increase cancer screening participation and discourage risk behaviors through community-oriented, population-based interventions. Future directions in prevention and control efforts for minority populations should include expanded health insurance coverage, improved access to health care, greater emphasis on minority recruitment in health care fields, focused epidemiologic and clinical research, and identification and replication of effective components within existing prevention-control programs. PMID:8741800

Wetland Suitability and Connectivity for Trans-Saharan Migratory Waterbirds

PubMed Central

Teunen, Joachim; Saura, Santiago; Koedam, Nico

2015-01-01

To complete their life cycle waterbirds rely on patchily distributed and often ephemeral wetlands along their migration route in a vast unsuitable matrix. However, further loss and degradation of remaining wetland habitats might lead to a configuration and size of stopovers that is no longer sufficient to ensure long-term survival of waterbird populations. By identifying optimal conservation targets to maintain overall habitat availability en route, we can accommodate an as yet absent functional connectivity component in larger management frameworks for migratory waterbirds, such as the Ramsar Convention and the EU Natura 2000 Network. Using a graph-based habitat availability metric (Equivalent Connected Area) we determine the functional connectivity of wetland networks for seven migratory waterbirds with divergent habitat requirements. Analyses are performed at two spatial extents both spanning the Mediterranean Sea and centered around Greece (Balkan-Cyrenaica and Greece-Cyrenaica). We create species-specific suitable habitat maps and account for human disturbance by species-specific disturbance buffers, based on expert estimates of Flight Initiation Distances. At both spatial extents we quantitatively determine the habitat networks’ overall functional connectivity and identify wetland sites that are crucial for maintaining a well-connected network. We show that the wetland networks for both spatial extents are relatively well connected and identify several wetland sites in Greece and Libya as important for maintaining connectivity. The application of disturbance buffers results in wetland site-specific reduction of suitable habitat area (0.90–7.36%) and an overall decrease of the network’s connectivity (0.65–6.82%). In addition, we show that the habitat networks of a limited set of species can be combined into a single network which accounts for their autoecological requirements. We conclude that targeted management in few but specific wetland complexes could benefit migratory waterbird populations. Deterioration of these vital wetland sites in Greece and Libya will have disproportionate consequences to the waterbird populations they support. PMID:26258590

PD-1 identifies the patient-specific CD8+ tumor-reactive repertoire infiltrating human tumors

PubMed Central

Gros, Alena; Robbins, Paul F.; Yao, Xin; Li, Yong F.; Turcotte, Simon; Tran, Eric; Wunderlich, John R.; Mixon, Arnold; Farid, Shawn; Dudley, Mark E.; Hanada, Ken-ichi; Almeida, Jorge R.; Darko, Sam; Douek, Daniel C.; Yang, James C.; Rosenberg, Steven A.

2014-01-01

Adoptive transfer of tumor-infiltrating lymphocytes (TILs) can mediate regression of metastatic melanoma; however, TILs are a heterogeneous population, and there are no effective markers to specifically identify and select the repertoire of tumor-reactive and mutation-specific CD8+ lymphocytes. The lack of biomarkers limits the ability to study these cells and develop strategies to enhance clinical efficacy and extend this therapy to other malignancies. Here, we evaluated unique phenotypic traits of CD8+ TILs and TCR β chain (TCRβ) clonotypic frequency in melanoma tumors to identify patient-specific repertoires of tumor-reactive CD8+ lymphocytes. In all 6 tumors studied, expression of the inhibitory receptors programmed cell death 1 (PD-1; also known as CD279), lymphocyte-activation gene 3 (LAG-3; also known as CD223), and T cell immunoglobulin and mucin domain 3 (TIM-3) on CD8+ TILs identified the autologous tumor-reactive repertoire, including mutated neoantigen-specific CD8+ lymphocytes, whereas only a fraction of the tumor-reactive population expressed the costimulatory receptor 4-1BB (also known as CD137). TCRβ deep sequencing revealed oligoclonal expansion of specific TCRβ clonotypes in CD8+PD-1+ compared with CD8+PD-1– TIL populations. Furthermore, the most highly expanded TCRβ clonotypes in the CD8+ and the CD8+PD-1+ populations recognized the autologous tumor and included clonotypes targeting mutated antigens. Thus, in addition to the well-documented negative regulatory role of PD-1 in T cells, our findings demonstrate that PD-1 expression on CD8+ TILs also accurately identifies the repertoire of clonally expanded tumor-reactive cells and reveal a dual importance of PD-1 expression in the tumor microenvironment. PMID:24667641

Registry-based analysis of participator representativeness: a source of concern for sickness absence research?

PubMed

Knapstad, Marit; Löve, Jesper; Holmgren, Kristina; Hensing, Gunnel; Øverland, Simon

2016-10-21

Selective participation can bias results in epidemiological surveys. The importance of health status is often suggested as a possible explanation for non-participation but few empirical studies exist. In a population-based study, explicitly focused on sickness absence, health and work, we examined whether a history of high levels of sickness absence was associated with non-participation. The study is based on data from official sickness absence registers from participants, non-participants and the total target population of the baseline survey of the Health Assets Project (HAP). HAP is a population-based cohort study in the Västra Götaland region in South Western Sweden. HAP included a random population cohort (n=7984) and 2 cohorts with recent sickness absence (employees (n=6140) and non-employees (n=990)), extracted from the same overall general working-age population. We examined differences in participation rates between cohorts (2008), and differences in previous sickness absence (2001-2008) between participants (individual-level data) and non-participants or the target population (group-level data) within cohorts. Participants had statistically significant less registered sickness absence in the past than non-participants and the target population for some, but not all, of the years analysed. Yet these differences were not of substantial size. Other factors than sickness absence were more important in explaining differences in participation, whereby participants were more likely to be women, older, born in Nordic countries, married and have higher incomes than non-participants. Although specifically addressing sickness absence, having such experience did not add any substantial layer to selective participation in the present survey. Detailed measures are needed to gain a better understanding for health selection in health-related surveys such as those addressing sickness absence, for instance in order to discriminate between selection due to ability or motivation for participation. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.

Mutation-profile-based methods for understanding selection forces in cancer somatic mutations: a comparative analysis.

PubMed

Zhou, Zhan; Zou, Yangyun; Liu, Gangbiao; Zhou, Jingqi; Wu, Jingcheng; Zhao, Shimin; Su, Zhixi; Gu, Xun

2017-08-29

Human genes exhibit different effects on fitness in cancer and normal cells. Here, we present an evolutionary approach to measure the selection pressure on human genes, using the well-known ratio of the nonsynonymous to synonymous substitution rate in both cancer genomes ( C N / C S ) and normal populations ( p N / p S ). A new mutation-profile-based method that adopts sample-specific mutation rate profiles instead of conventional substitution models was developed. We found that cancer-specific selection pressure is quite different from the selection pressure at the species and population levels. Both the relaxation of purifying selection on passenger mutations and the positive selection of driver mutations may contribute to the increased C N / C S values of human genes in cancer genomes compared with the p N / p S values in human populations. The C N / C S values also contribute to the improved classification of cancer genes and a better understanding of the onco-functionalization of cancer genes during oncogenesis. The use of our computational pipeline to identify cancer-specific positively and negatively selected genes may provide useful information for understanding the evolution of cancers and identifying possible targets for therapeutic intervention.

Selection enhanced estimates of µ-calpain, calpastatin, and dacylglycerol O-acyltransferase 1 genetic effects on pre-weaning performance, carcass quality traits, and residual variance of tenderness in composite ... cattle

USDA-ARS?s Scientific Manuscript database

Selection of the composite MARC III population for markers allowed better estimates of effects and inheritance of markers for targeted carcass quality traits (n=254) and nontargeted traits and an evaluation of SNP specific residual variance models for tenderness. Genotypic effects of CAPN1 haplotyp...

Field cage studies and progressive evaluation of genetically-engineered mosquitoes.

PubMed

Facchinelli, Luca; Valerio, Laura; Ramsey, Janine M; Gould, Fred; Walsh, Rachael K; Bond, Guillermo; Robert, Michael A; Lloyd, Alun L; James, Anthony A; Alphey, Luke; Scott, Thomas W

2013-01-01

A genetically-engineered strain of the dengue mosquito vector Aedes aegypti, designated OX3604C, was evaluated in large outdoor cage trials for its potential to improve dengue prevention efforts by inducing population suppression. OX3604C is engineered with a repressible genetic construct that causes a female-specific flightless phenotype. Wild-type females that mate with homozygous OX3604C males will not produce reproductive female offspring. Weekly introductions of OX3604C males eliminated all three targeted Ae. aegypti populations after 10-20 weeks in a previous laboratory cage experiment. As part of the phased, progressive evaluation of this technology, we carried out an assessment in large outdoor field enclosures in dengue endemic southern Mexico. OX3604C males were introduced weekly into field cages containing stable target populations, initially at 10:1 ratios. Statistically significant target population decreases were detected in 4 of 5 treatment cages after 17 weeks, but none of the treatment populations were eliminated. Mating competitiveness experiments, carried out to explore the discrepancy between lab and field cage results revealed a maximum mating disadvantage of up 59.1% for OX3604C males, which accounted for a significant part of the 97% fitness cost predicted by a mathematical model to be necessary to produce the field cage results. Our results indicate that OX3604C may not be effective in large-scale releases. A strain with the same transgene that is not encumbered by a large mating disadvantage, however, could have improved prospects for dengue prevention. Insights from large outdoor cage experiments may provide an important part of the progressive, stepwise evaluation of genetically-engineered mosquitoes.

Population and habitat viability assessments for Golden-cheeked Warblers and Black-capped Vireos: Usefulness to Partners in Flight Conservation Planning

USGS Publications Warehouse

Beardmore, C.J.; Hatfield, J.S.; Bonney, Rick; Pashley, David N.; Cooper, Robert; Niles, Larry

2000-01-01

Golden-cheeked Warblers and Black-capped Vireos are Neotropical migratory birds that are federally listed as endangered. Recovery plans for both species advise the use of viability modeling as a tool for setting specific recovery and management targets. Population and Habitat Viability Assessment workshops were conducted to develop population targets and conservation recommendations for these species. Results of the workshops were based on modeling demographic and environmental factors, as well as discussions of management issues, management options, and public outreach strategies. The approach is intended to be iterative, and to be tracked by research and monitoring efforts. This paper discusses the consensus-building workshop process and how the approach could be useful to Partners in Flight. Population and Habitat Viability Assessments (PHVA) were used to develop population targets and conservation recommendations for Golden-cheeked Warblers (Dendroica chrysoparia) and Black-capped Vireos (Vireo atricapillus). This paper explains what PHVAs are, discusses how they are conducted, describes the general results that are produced, and suggests how Partners in Flight (PIF) might use a similar process for bird conservation planning. Detailed results of the assessments are not discussed here; however they can be found elsewhere (U. S. Fish and Wildlife Service 1996a, U. S. Fish and Wildlife Service 1996b). PHVAs were considered for Golden-cheeked Warblers and Black-capped Vireos because they are controversial, endangered species, and the species? recovery plans list PHVAs as tools to develop recovery recommendations. The U. S. Fish and Wildlife Service (USFWS) realized that the data needed to perform PHVAs for these species is limited, but that various conservation efforts, such as the Balcones Canyonlands Conservation Plan and other endeavors, were proceeding without benefit of the biological summarization and guidance that a PHVA could provide.

Field Cage Studies and Progressive Evaluation of Genetically-Engineered Mosquitoes

PubMed Central

Facchinelli, Luca; Valerio, Laura; Ramsey, Janine M.; Gould, Fred; Walsh, Rachael K.; Bond, Guillermo; Robert, Michael A.; Lloyd, Alun L.; James, Anthony A.; Alphey, Luke; Scott, Thomas W.

2013-01-01

Background A genetically-engineered strain of the dengue mosquito vector Aedes aegypti, designated OX3604C, was evaluated in large outdoor cage trials for its potential to improve dengue prevention efforts by inducing population suppression. OX3604C is engineered with a repressible genetic construct that causes a female-specific flightless phenotype. Wild-type females that mate with homozygous OX3604C males will not produce reproductive female offspring. Weekly introductions of OX3604C males eliminated all three targeted Ae. aegypti populations after 10–20 weeks in a previous laboratory cage experiment. As part of the phased, progressive evaluation of this technology, we carried out an assessment in large outdoor field enclosures in dengue endemic southern Mexico. Methodology/Principal Findings OX3604C males were introduced weekly into field cages containing stable target populations, initially at 10∶1 ratios. Statistically significant target population decreases were detected in 4 of 5 treatment cages after 17 weeks, but none of the treatment populations were eliminated. Mating competitiveness experiments, carried out to explore the discrepancy between lab and field cage results revealed a maximum mating disadvantage of up 59.1% for OX3604C males, which accounted for a significant part of the 97% fitness cost predicted by a mathematical model to be necessary to produce the field cage results. Conclusions/Significance Our results indicate that OX3604C may not be effective in large-scale releases. A strain with the same transgene that is not encumbered by a large mating disadvantage, however, could have improved prospects for dengue prevention. Insights from large outdoor cage experiments may provide an important part of the progressive, stepwise evaluation of genetically-engineered mosquitoes. PMID:23350003

Comparing the Information and Support Needs of Different Population Groups in Preparation for 2015 Government Approval for HIV Self-testing in France

PubMed Central

Greacen, Tim; Kersaudy-Rahib, Delphine; Le Gall, Jean-Marie; Lydié, Nathalie; Ghosn, Jade; Champenois, Karen

2016-01-01

Context HIV self-tests are currently being introduced in France with the aim of promoting screening both for the general population and for high-risk populations. Objective The current study aimed to identify and compare the information and support needs of the different target population groups. Methods The Delphi process was used to synthesize expert opinions for each population group. Experts were chosen for their experience and expertise in the area of HIV and HIV screening for each population. Each group developed recommendations for a specific population: six high HIV prevalence populations (men who have sex with men; transgender people; substance users; migrants from sub-Saharan Africa; French West Indies; French Guiana) and two low prevalence populations (the general population; people under 25). Each group included expertise from four areas: research, screening and care, policy-making, and community groups. Results A final total of 263 recommendations were grouped into eight main themes: Communicating at both national and community levels about self-test arrival (24% of all recommendations); Providing information adapted to the different community groups’ needs (23%); Providing counselling on self-test use and access to care (15%); Making self-tests available to all in terms of accessibility and cost (13%); Preparing community healthcare and screening systems for the arrival of the self-test (11%); Approving only high quality self-tests (6%); Defending self-test users’ legal rights (5%); Evaluating self-test use (3%). Although a large number of recommendations were common to several groups of experts, the study highlighted a certain number of recommendations specific to each different population group, particularly with regard to information content and access both to information and to the self-tests themselves. Conclusion Results from the current study should make a significant contribution to policy decisions concerning catering for the specific access, information and support needs of different potential HIV self-test user groups in France. PMID:27031234

Comparing the Information and Support Needs of Different Population Groups in Preparation for 2015 Government Approval for HIV Self-testing in France.

PubMed

Greacen, Tim; Kersaudy-Rahib, Delphine; Le Gall, Jean-Marie; Lydié, Nathalie; Ghosn, Jade; Champenois, Karen

2016-01-01

HIV self-tests are currently being introduced in France with the aim of promoting screening both for the general population and for high-risk populations. The current study aimed to identify and compare the information and support needs of the different target population groups. The Delphi process was used to synthesize expert opinions for each population group. Experts were chosen for their experience and expertise in the area of HIV and HIV screening for each population. Each group developed recommendations for a specific population: six high HIV prevalence populations (men who have sex with men; transgender people; substance users; migrants from sub-Saharan Africa; French West Indies; French Guiana) and two low prevalence populations (the general population; people under 25). Each group included expertise from four areas: research, screening and care, policy-making, and community groups. A final total of 263 recommendations were grouped into eight main themes: Communicating at both national and community levels about self-test arrival (24% of all recommendations); Providing information adapted to the different community groups' needs (23%); Providing counselling on self-test use and access to care (15%); Making self-tests available to all in terms of accessibility and cost (13%); Preparing community healthcare and screening systems for the arrival of the self-test (11%); Approving only high quality self-tests (6%); Defending self-test users' legal rights (5%); Evaluating self-test use (3%). Although a large number of recommendations were common to several groups of experts, the study highlighted a certain number of recommendations specific to each different population group, particularly with regard to information content and access both to information and to the self-tests themselves. Results from the current study should make a significant contribution to policy decisions concerning catering for the specific access, information and support needs of different potential HIV self-test user groups in France.

Lytic bacteriophages

PubMed Central

Sharma, Manan

2013-01-01

Foodborne illnesses resulting from the consumption of produce commodities contaminated with enteric pathogens continue to be a significant public health issue. Lytic bacteriophages may provide an effective and natural intervention to reduce bacterial pathogens on fresh and fresh-cut produce commodities. The use of multi-phage cocktails specific for a single pathogen has been most frequently assessed on produce commodities to minimize the development of bacteriophage insensitive mutants (BIM) in target pathogen populations. Regulatory approval for the use of several lytic phage products specific for bacterial pathogens such as Escherichia coli O157:H7, Salmonella spp. and Listeria monocytogenes in foods and on food processing surfaces has been granted by various agencies in the US and other countries, possibly allowing for the more widespread use of bacteriophages in the decontamination of fresh and minimally processed produce. Research studies have shown lytic bacteriophages specific for E. coli O157:H7, Salmonella spp. and Listeria monocytogenes have been effective in reducing pathogen populations on leafy greens, sprouts and tomatoes. PMID:24228223

Behavioral and Social Correlates of Methamphetamine Use in a Population-based Sample of Early and Later Adolescents

PubMed Central

Embry, Dennis; Hankins, Martin; Biglan, Anthony; Boles, Shawn

2009-01-01

This paper reports relationships between methamphetamine use and behaviors and social influences using data from a population-based survey of 8th- and 11th-grade students in Oregon for the 2001–2003 school years. We analyze methamphetamine use within a general problem behavior framework to identify malleable correlates of behavior for future prevention interventions. We specifically test two models of methamphetamine use employing logistic regression analysis: one comprised of behaviors and traits of the individual students and another focusing on peer and parental influences. This study finds adolescent methamphetamine use related to several problem behaviors. However, the specific problems vary by grade and are moderated by gender. Findings indicate the need for tailored interventions targeting gender/grade-specific behaviors or problems such as antisocial activities, risky sex, and depression, as well as social influences such as peers engaging in antisocial behaviors or using drugs and parents favoring drug use or poorly monitoring or setting limits for their children. PMID:19138821

The Epstein-Barr virus lytic protein BZLF1 as a candidate target antigen for vaccine development1

PubMed Central

Hartlage, Alex S.; Liu, Tom; Patton, John T.; Garman, Sabrina L.; Zhang, Xiaoli; Kurt, Habibe; Lozanski, Gerard; Lustberg, Mark E.; Caligiuri, Michael A.; Baiocchi, Robert A.

2015-01-01

The Epstein-Barr virus (EBV) is an oncogenic, γ-herpesvirus associated with a broad spectrum of disease. While most immune-competent individuals can effectivley develop efficient adaptive immune responses to EBV, immunocompromised individuals are at serious risk for developing life threatening diseases such as Hodgkin’s lymphoma and post-transplant lymphoproliferative disorder (PTLD). Given the significant morbidity associated with EBV infection in high-risk populations, there is a need to develop vaccine strategies that restore or enhance EBV-specific immune responses. Here, we identify the EBV immediate-early protein BZLF1 as a potential target antigen for vaccine development. Primary tumors from patients with PTLD and a chimeric human-murine model of EBV-driven lymphoproliferative disorder (EBV-LPD) express BZLF1 protein. Pulsing human dendritic cells (DC) with recombinant BZLF1 followed by incubation with autologous mononuclear cells led to expansion of BZLF1-specific CD8(+) T cells in vitro and primed BZLF1-specific T-cell responses in vivo. In addition, vaccination of hu-PBL-SCID mice with BZLF1-transduced DCs induced specific cellular immunity and significantly prolonged survival from fatal EBV-LPD. These findings identify BZLF1 as a candidate target protein in the immunosurveillance of EBV and provide rationale for considering BZLF1 in vaccine strategies to enhance primary and recall immune responses and potentially prevent EBV-associated diseases. PMID:25735952

Gold-manganese nanoparticles for targeted diagnostic and imaging

DOE Office of Scientific and Technical Information (OSTI.GOV)

Murph, Simona Hunyadi

Imagine the possibility of non-invasive, non-radiation based Magnetic resonance imaging (MRI) in combating cardiac disease. Researchers at the Savannah River National Laboratory (SRNL) are developing a process that would use nanotechnology in a novel, targeted approach that would allow MRIs to be more descriptive and brighter, and to target specific organs. Researchers at SRNL have discovered a way to use multifunctional metallic gold-manganese nanoparticles to create a unique, targeted positive contrast agent. SRNL Senior Scientist Dr. Simona Hunyadi Murph says she first thought of using the nanoparticles for cardiac disease applications after learning that people who survive an infarct exhibitmore » up to 15 times higher rate of developing chronic heart failure, arrhythmias and/or sudden death compared to the general population. Without question, nanotechnology will revolutionize the future of technology. The development of functional nanomaterials with multi-detection modalities opens up new avenues for creating multi-purpose technologies for biomedical applications.« less

Target biomarker profile for the clinical management of paracetamol overdose

PubMed Central

Vliegenthart, A D Bastiaan; Antoine, Daniel J; Dear, James W

2015-01-01

Paracetamol (acetaminophen) overdose is one of the most common causes of acute liver injury in the Western world. To improve patient care and reduce pressure on already stretched health care providers new biomarkers are needed that identify or exclude liver injury soon after an overdose of paracetamol is ingested. This review highlights the current state of paracetamol poisoning management and how novel biomarkers could improve patient care and save healthcare providers money. Based on the widely used concept of defining a target product profile, a target biomarker profile is proposed that identifies desirable and acceptable key properties for a biomarker in development to enable the improved treatment of this patient population. The current biomarker candidates, with improved hepatic specificity and based on the fundamental mechanistic basis of paracetamol-induced liver injury, are reviewed and their performance compared with our target profile. PMID:26076366

The surprising costs of silence: Asymmetric preferences for prosocial lies of commission and omission.

PubMed

Levine, Emma; Hart, Joanna; Moore, Kendra; Rubin, Emily; Yadav, Kuldeep; Halpern, Scott

2018-01-01

Across 7 experiments (N = 3883), we demonstrate that communicators and targets make egocentric moral judgments of deception. Specifically, communicators focus more on the costs of deception to them-for example, the guilt they feel when they break a moral rule-whereas targets focus more on whether deception helps or harms them. As a result, communicators and targets make asymmetric judgments of prosocial lies of commission and omission: Communicators often believe that omitting information is more ethical than telling a prosocial lie, whereas targets often believe the opposite. We document these effects within the context of health care discussions, employee layoffs, and economic games, among both clinical populations (i.e., oncologists and cancer patients) and lay people. We identify moderators and downstream consequences of this asymmetry. We conclude by discussing psychological and practical implications for medicine, management, behavioral ethics, and human communication. (PsycINFO Database Record (c) 2018 APA, all rights reserved).

Targeted drug delivery using genetically engineered diatom biosilica.

PubMed

Delalat, Bahman; Sheppard, Vonda C; Rasi Ghaemi, Soraya; Rao, Shasha; Prestidge, Clive A; McPhee, Gordon; Rogers, Mary-Louise; Donoghue, Jacqueline F; Pillay, Vinochani; Johns, Terrance G; Kröger, Nils; Voelcker, Nicolas H

2015-11-10

The ability to selectively kill cancerous cell populations while leaving healthy cells unaffected is a key goal in anticancer therapeutics. The use of nanoporous silica-based materials as drug-delivery vehicles has recently proven successful, yet production of these materials requires costly and toxic chemicals. Here we use diatom microalgae-derived nanoporous biosilica to deliver chemotherapeutic drugs to cancer cells. The diatom Thalassiosira pseudonana is genetically engineered to display an IgG-binding domain of protein G on the biosilica surface, enabling attachment of cell-targeting antibodies. Neuroblastoma and B-lymphoma cells are selectively targeted and killed by biosilica displaying specific antibodies sorbed with drug-loaded nanoparticles. Treatment with the same biosilica leads to tumour growth regression in a subcutaneous mouse xenograft model of neuroblastoma. These data indicate that genetically engineered biosilica frustules may be used as versatile 'backpacks' for the targeted delivery of poorly water-soluble anticancer drugs to tumour sites.

Prostate-Specific Antigen (PSA)–Based Population Screening for Prostate Cancer: An Economic Analysis

PubMed Central

Tawfik, A

2015-01-01

Background The prostate-specific antigen (PSA) blood test has become widely used in Canada to test for prostate cancer (PC), the most common cancer among Canadian men. Data suggest that population-based PSA screening may not improve overall survival. Objectives This analysis aimed to review existing economic evaluations of population-based PSA screening, determine current spending on opportunistic PSA screening in Ontario, and estimate the cost of introducing a population-based PSA screening program in the province. Methods A systematic literature search was performed to identify economic evaluations of population-based PSA screening strategies published from 1998 to 2013. Studies were assessed for their methodological quality and applicability to the Ontario setting. An original cost analysis was also performed, using data from Ontario administrative sources and from the published literature. One-year costs were estimated for 4 strategies: no screening, current (opportunistic) screening of men aged 40 years and older, current (opportunistic) screening of men aged 50 to 74 years, and population-based screening of men aged 50 to 74 years. The analysis was conducted from the payer perspective. Results The literature review demonstrated that, overall, population-based PSA screening is costly and cost-ineffective but may be cost-effective in specific populations. Only 1 Canadian study, published 15 years ago, was identified. Approximately $119.2 million is being spent annually on PSA screening of men aged 40 years and older in Ontario, including close to $22 million to screen men younger than 50 and older than 74 years of age (i.e., outside the target age range for a population-based program). A population-based screening program in Ontario would cost approximately $149.4 million in the first year. Limitations Estimates were based on the synthesis of data from a variety of sources, requiring several assumptions and causing uncertainty in the results. For example, where Ontario-specific data were unavailable, data from the United States were used. Conclusions PSA screening is associated with significant costs to the health care system when the cost of the PSA test itself is considered in addition to the costs of diagnosis, staging, and treatment of screen-detected PCs. PMID:26366237

Future shifts in African air quality and the resulting impacts on human health and climate: Design of efficient mitigation strategies.

NASA Astrophysics Data System (ADS)

Lacey, F.; Marais, E. A.; Wiedinmyer, C.; Coffey, E.; Pfotenhauer, D.; Henze, D. K.; Evans, M. J.; Hannigan, M.; Morris, E.; Davila, Y.; Mesenbring, E. C.

2017-12-01

Population in Africa is currently projected to double by 2050, which will have significant impacts on anthropogenic emissions and in turn the ambient air quality, especially near population centers. Recent research has also shown that the emissions factors used for global inventories are misrepresented when compared to field measurements in Africa, which leads to inaccuracies in the magnitude and spatial distribution of emissions throughout the continent. As the population in Africa increases, the combination of anthropogenic and biogenic emissions in many regions will lead to changes in atmospheric pollutant concentrations, including particulate matter (PM2.5) and ozone. Combining updated emissions estimates created using measured emissions factors reported from field studies in Africa with the Community Earth System Model (CESM2) improves predictions of the present day ambient air quality; validated based on available observations from field measurements and satellite data. We use these tools to quantify the impacts of anthropogenic emissions on both climate and human health, shown here as estimated premature deaths from chronic exposure to pollutants. Sensitivities derived from model source attribution calculations using the GEOS-Chem adjoint model are then used to examine the impacts of changes in population distribution and shifts in technology moving to the mid-21st century. With these results, we are able to identify efficient mitigation pathways that target specific regions and anthropogenic activities. These targeted control measures include shifts from traditional to modern cooking technologies, as well as other sector-specific interventions that represent feasible adoptions in Africa over the next several decades. This work provides a potential roadmap towards improved air quality to both government and non-governmental organizations as Africa transitions through this period of rapid growth.

WE-AB-209-08: Novel Beam-Specific Adaptive Margins for Reducing Organ-At-Risk Doses

DOE Office of Scientific and Technical Information (OSTI.GOV)

Tsang, H; Kamerling, CP; Ziegenhein, P

2016-06-15

Purpose: Current practice of using 3D margins in radiotherapy with high-energy photon beams provides larger-than-required target coverage. According to the photon depth-dose curve, target displacements in beam direction result in minute changes in dose delivered. We exploit this behavior by generating margins on a per-beam basis which simultaneously account for the relative distance of the target and adjacent organs-at-risk (OARs). Methods: For each beam, we consider only geometrical uncertainties of the target location perpendicular to beam direction. By weighting voxels based on its proximity to an OAR, we generate adaptive margins that yield similar overall target coverage probability and reducedmore » OAR dose-burden, at the expense of increased target volume. Three IMRT plans, using 3D margins and 2D per-beam margins with and without adaptation, were generated for five prostate patients with a prescription dose Dpres of 78Gy in 2Gy fractions using identical optimisation constraints. Systematic uncertainties of 1.1, 1.1, 1.5mm in the LR, SI, and AP directions, respectively, and 0.9, 1.1, 1.0mm for the random uncertainties, were assumed. A verification tool was employed to simulate the effects of systematic and random errors using a population size of 50,000. The fraction of the population that satisfies or violates a given DVH constraint was used for comparison. Results: We observe similar target coverage across all plans, with at least 97.5% of the population meeting the D98%>95%Dpres constraint. When looking at the probability of the population receiving D5<70Gy for the rectum, we observed median absolute increases of 23.61% (range, 2.15%–27.85%) and 6.97% (range, 0.65%–17.76%) using per-beam margins with and without adaptation, respectively, relative to using 3D margins. Conclusion: We observed sufficient and similar target coverage using per-beam margins. By adapting each per-beam margin away from an OAR, we can further reduce OAR dose without significantly lowering target coverage probability by irradiating more less-important tissues. This work is supported by Cancer Research UK under Programme C33589/A19908. Research at ICR is also supported by Cancer Research UK under Programme C33589/A19727 and NHS funding to the NIHR Biomedical Research Centre at RMH and ICR.« less

Measurement of sedentary behaviour in population health surveys: a review and recommendations

PubMed Central

LeBlanc, Allana G.; Colley, Rachel C.; Saunders, Travis J.

2017-01-01

Background The purpose of this review was to determine the most valid and reliable questions for targeting key modes of sedentary behaviour (SB) in a broad range of national and international health surveillance surveys. This was done by reviewing the SB modules currently used in population health surveys, as well as examining SB questionnaires that have performed well in psychometric testing. Methods Health surveillance surveys were identified via scoping review and contact with experts in the field. Previous systematic reviews provided psychometric information on pediatric questionnaires. A comprehensive search of four bibliographic databases was used to identify studies reporting psychometric information for adult questionnaires. Only surveys/studies published/used in English or French were included. Results The review identified a total of 16 pediatric and 18 adult national/international surveys assessing SB, few of which have undergone psychometric testing. Fourteen pediatric and 35 adult questionnaires with psychometric information were included. While reliability was generally good to excellent for questions targeting key modes of SB, validity was poor to moderate, and reported much less frequently. The most valid and reliable questions targeting specific modes of SB were combined to create a single questionnaire targeting key modes of SB. Discussion Our results highlight the importance of including SB questions in survey modules that are adaptable, able to assess various modes of SB, and that exhibit adequate reliability and validity. Future research could investigate the psychometric properties of the module we have proposed in this paper, as well as other questionnaires currently used in national and international population health surveys. PMID:29250468

Measurement of sedentary behaviour in population health surveys: a review and recommendations.

PubMed

Prince, Stephanie A; LeBlanc, Allana G; Colley, Rachel C; Saunders, Travis J

2017-01-01

The purpose of this review was to determine the most valid and reliable questions for targeting key modes of sedentary behaviour (SB) in a broad range of national and international health surveillance surveys. This was done by reviewing the SB modules currently used in population health surveys, as well as examining SB questionnaires that have performed well in psychometric testing. Health surveillance surveys were identified via scoping review and contact with experts in the field. Previous systematic reviews provided psychometric information on pediatric questionnaires. A comprehensive search of four bibliographic databases was used to identify studies reporting psychometric information for adult questionnaires. Only surveys/studies published/used in English or French were included. The review identified a total of 16 pediatric and 18 adult national/international surveys assessing SB, few of which have undergone psychometric testing. Fourteen pediatric and 35 adult questionnaires with psychometric information were included. While reliability was generally good to excellent for questions targeting key modes of SB, validity was poor to moderate, and reported much less frequently. The most valid and reliable questions targeting specific modes of SB were combined to create a single questionnaire targeting key modes of SB. Our results highlight the importance of including SB questions in survey modules that are adaptable, able to assess various modes of SB, and that exhibit adequate reliability and validity. Future research could investigate the psychometric properties of the module we have proposed in this paper, as well as other questionnaires currently used in national and international population health surveys.

Stem-like tumor-initiating cells isolated from IL13Rα2 expressing gliomas are targeted and killed by IL13-zetakine-redirected T Cells.

PubMed

Brown, Christine E; Starr, Renate; Aguilar, Brenda; Shami, Andrew F; Martinez, Catalina; D'Apuzzo, Massimo; Barish, Michael E; Forman, Stephen J; Jensen, Michael C

2012-04-15

To evaluate IL13Rα2 as an immunotherapeutic target for eliminating glioma stem-like cancer initiating cells (GSC) of high-grade gliomas, with particular focus on the potential of genetically engineered IL13Rα2-specific primary human CD8(+) CTLs (IL13-zetakine(+) CTL) to target this therapeutically resistant glioma subpopulation. A panel of low-passage GSC tumor sphere (TS) and serum-differentiated glioma lines were expanded from patient glioblastoma specimens. These glioblastoma lines were evaluated for expression of IL13Rα2 and for susceptibility to IL13-zetakine(+) CTL-mediated killing in vitro and in vivo. We observed that although glioma IL13Rα2 expression varies between patients, for IL13Rα2(pos) cases this antigen was detected on both GSCs and more differentiated tumor cell populations. IL13-zetakine(+) CTL were capable of efficient recognition and killing of both IL13Rα2(pos) GSCs and IL13Rα2(pos) differentiated cells in vitro, as well as eliminating glioma-initiating activity in an orthotopic mouse tumor model. Furthermore, intracranial administration of IL13-zetakine(+) CTL displayed robust antitumor activity against established IL13Rα2(pos) GSC TS-initiated orthotopic tumors in mice. Within IL13Rα2 expressing high-grade gliomas, this receptor is expressed by GSCs and differentiated tumor populations, rendering both targetable by IL13-zetakine(+) CTLs. Thus, our results support the potential usefullness of IL13Rα2-directed immunotherapeutic approaches for eradicating therapeutically resistant GSC populations. ©2012 AACR.

Delivery of therapeutics using nanocarriers for targeting cancer cells and cancer stem cells.

PubMed

Krishnamurthy, Sangeetha; Ke, Xiyu; Yang, Yi Yan

2015-01-01

Development of cancer resistance, cancer relapse and metastasis are attributed to the presence of cancer stem cells (CSCs). Eradication of this subpopulation has been shown to increase life expectancy of patients. Since the discovery of CSCs a decade ago, several strategies have been devised to specifically target them but with limited success. Nanocarriers have recently been employed to deliver anti-CSC therapeutics for reducing the population of CSCs at the tumor site with great success. This review discusses the different therapeutic strategies that have been employed using nanocarriers, their advantages, success in targeting CSCs and the challenges that are to be overcome. Exploiting this new modality of cancer treatment in the coming decade may improve outcomes profoundly with promise of effective treatment response and reducing relapse and metastasis.

The therapeutic potential of Na+ and Ca2+ channel blockers in pain management.

PubMed

Sabido-David, Cibele; Faravelli, Laura; Salvati, Patricia

2004-10-01

Chronic pain affects a large percentage of the population, representing a socio-economic burden. Current treatments are characterised by suboptimal efficacy and/or side effects that limit their use. Among several approaches to treating chronic pain, voltage-sensitive Ca(2+) and Na(+) channels are promising targets. This review evaluates the preclinical evidence that supports the involvement of these targets, with specific attention to those subtypes that appear more strictly correlated with pain generation and sustainment, as well as those compounds that modulate the activity of Ca(2+) and/or Na(+) channels that are currently in clinical development for chronic pain conditions.

Behavioural surveillance: the value of national coordination

PubMed Central

McGarrigle, C; Fenton, K; Gill, O; Hughes, G; Morgan, D; Evans, B

2002-01-01

Behavioural surveillance programmes have enabled the description of population patterns of risk behaviours for STI and HIV transmission and aid in the understanding of how epidemics of STI are generated. They have been instrumental in helping to refine public health interventions and inform the targeting of sexual health promotion and disease control strategies. The formalisation and coordination of behavioural surveillance in England and Wales could optimise our ability to measure the impact of interventions and health promotion strategies on behaviour. This will be particularly useful for monitoring the progress towards specific disease control targets set in the Department of Health's new Sexual Health and HIV Strategy. PMID:12473798

Harnessing the apoptotic programs in cancer stem-like cells

PubMed Central

Wang, Ying-Hua; Scadden, David T

2015-01-01

Elimination of malignant cells is an unmet challenge for most human cancer types even with therapies targeting specific driver mutations. Therefore, a multi-pronged strategy to alter cancer cell biology on multiple levels is increasingly recognized as essential for cancer cure. One such aspect of cancer cell biology is the relative apoptosis resistance of tumor-initiating cells. Here, we provide an overview of the mechanisms affecting the apoptotic process in tumor cells emphasizing the differences in the tumor-initiating or stem-like cells of cancer. Further, we summarize efforts to exploit these differences to design therapies targeting that important cancer cell population. PMID:26253117

Plant extracts as potential mosquito larvicides

PubMed Central

Ghosh, Anupam; Chowdhury, Nandita; Chandra, Goutam

2012-01-01

Mosquitoes act as a vector for most of the life threatening diseases like malaria, yellow fever, dengue fever, chikungunya ferver, filariasis, encephalitis, West Nile Virus infection, etc. Under the Integrated Mosquito Management (IMM), emphasis was given on the application of alternative strategies in mosquito control. The continuous application of synthetic insecticides causes development of resistance in vector species, biological magnification of toxic substances through the food chain and adverse effects on environmental quality and non target organisms including human health. Application of active toxic agents from plant extracts as an alternative mosquito control strategy was available from ancient times. These are non-toxic, easily available at affordable prices, biodegradable and show broad-spectrum target-specific activities against different species of vector mosquitoes. In this article, the current state of knowledge on phytochemical sources and mosquitocidal activity, their mechanism of action on target population, variation of their larvicidal activity according to mosquito species, instar specificity, polarity of solvents used during extraction, nature of active ingredient and promising advances made in biological control of mosquitoes by plant derived secondary metabolites have been reviewed. PMID:22771587

Plant extracts as potential mosquito larvicides.

PubMed

Ghosh, Anupam; Chowdhury, Nandita; Chandra, Goutam

2012-05-01

Mosquitoes act as a vector for most of the life threatening diseases like malaria, yellow fever, dengue fever, chikungunya ferver, filariasis, encephalitis, West Nile Virus infection, etc. Under the Integrated Mosquito Management (IMM), emphasis was given on the application of alternative strategies in mosquito control. The continuous application of synthetic insecticides causes development of resistance in vector species, biological magnification of toxic substances through the food chain and adverse effects on environmental quality and non target organisms including human health. Application of active toxic agents from plant extracts as an alternative mosquito control strategy was available from ancient times. These are non-toxic, easily available at affordable prices, biodegradable and show broad-spectrum target-specific activities against different species of vector mosquitoes. In this article, the current state of knowledge on phytochemical sources and mosquitocidal activity, their mechanism of action on target population, variation of their larvicidal activity according to mosquito species, instar specificity, polarity of solvents used during extraction, nature of active ingredient and promising advances made in biological control of mosquitoes by plant derived secondary metabolites have been reviewed.

Characterization and in vitro properties of potentially probiotic Bifidobacterium strains isolated from breast-milk.

PubMed

Arboleya, Silvia; Ruas-Madiedo, Patricia; Margolles, Abelardo; Solís, Gonzalo; Salminen, Seppo; de Los Reyes-Gavilán, Clara G; Gueimonde, Miguel

2011-09-01

Most of the current commercial probiotic strains have not been selected for specific applications, but rather on the basis of their technological potential for use in diverse applications. Therefore, by selecting them from appropriate sources, depending on the target population, it is likely that better performing strains may be identified. Few strains have been specifically selected for human neonates, where the applications of probiotics may have a great positive impact. Breast-milk constitutes an interesting source of potentially probiotic bifidobacteria for inclusion in infant formulas and foods targeted to both pre-term and full-term infants. In this study six Bifidobacterium strains isolated from breast-milk were phenotypically and genotypically characterised according to international guidelines for probiotics. In addition, different in vitro tests were used to assess the safety and probiotic potential of the strains. Although clinical data would be needed before drawing any conclusion on the probiotic properties of the strains, our results indicate that some of them may have probiotic potential for their inclusion in products targeting infants. Copyright © 2010 Elsevier B.V. All rights reserved.

Disruption of de Novo Adenosine Triphosphate (ATP) Biosynthesis Abolishes Virulence in Cryptococcus neoformans.

PubMed

Blundell, Ross D; Williams, Simon J; Arras, Samantha D M; Chitty, Jessica L; Blake, Kirsten L; Ericsson, Daniel J; Tibrewal, Nidhi; Rohr, Jurgen; Koh, Y Q Andre E; Kappler, Ulrike; Robertson, Avril A B; Butler, Mark S; Cooper, Matthew A; Kobe, Bostjan; Fraser, James A

2016-09-09

Opportunistic fungal pathogens such as Cryptococcus neoformans are a growing cause of morbidity and mortality among immunocompromised populations worldwide. To address the current paucity of antifungal therapeutic agents, further research into fungal-specific drug targets is required. Adenylosuccinate synthetase (AdSS) is a crucial enzyme in the adeosine triphosphate (ATP) biosynthetic pathway, catalyzing the formation of adenylosuccinate from inosine monophosphate and aspartate. We have investigated the potential of this enzyme as an antifungal drug target, finding that loss of function results in adenine auxotrophy in C. neoformans, as well as complete loss of virulence in a murine model. Cryptococcal AdSS was expressed and purified in Escherichia coli and the enzyme's crystal structure determined, the first example of a structure of this enzyme from fungi. Together with enzyme kinetic studies, this structural information enabled comparison of the fungal enzyme with the human orthologue and revealed species-specific differences potentially exploitable via rational drug design. These results validate AdSS as a promising antifungal drug target and lay a foundation for future in silico and in vitro screens for novel antifungal compounds.

A systematic review of suicide prevention interventions targeting indigenous peoples in Australia, United States, Canada and New Zealand

PubMed Central

2013-01-01

Background Indigenous peoples of Australia, Canada, United States and New Zealand experience disproportionately high rates of suicide. As such, the methodological quality of evaluations of suicide prevention interventions targeting these Indigenous populations should be rigorously examined, in order to determine the extent to which they are effective for reducing rates of Indigenous suicide and suicidal behaviours. This systematic review aims to: 1) identify published evaluations of suicide prevention interventions targeting Indigenous peoples in Australia, Canada, United States and New Zealand; 2) critique their methodological quality; and 3) describe their main characteristics. Methods A systematic search of 17 electronic databases and 13 websites for the period 1981–2012 (inclusive) was undertaken. The reference lists of reviews of suicide prevention interventions were hand-searched for additional relevant studies not identified by the electronic and web search. The methodological quality of evaluations of suicide prevention interventions was assessed using a standardised assessment tool. Results Nine evaluations of suicide prevention interventions were identified: five targeting Native Americans; three targeting Aboriginal Australians; and one First Nation Canadians. The main intervention strategies employed included: Community Prevention, Gatekeeper Training, and Education. Only three of the nine evaluations measured changes in rates of suicide or suicidal behaviour, all of which reported significant improvements. The methodological quality of evaluations was variable. Particular problems included weak study designs, reliance on self-report measures, highly variable consent and follow-up rates, and the absence of economic or cost analyses. Conclusions There is an urgent need for an increase in the number of evaluations of preventive interventions targeting reductions in Indigenous suicide using methodologically rigorous study designs across geographically and culturally diverse Indigenous populations. Combining and tailoring best evidence and culturally-specific individual strategies into one coherent suicide prevention program for delivery to whole Indigenous communities and/or population groups at high risk of suicide offers considerable promise. PMID:23663493

A systematic review of suicide prevention interventions targeting indigenous peoples in Australia, United States, Canada and New Zealand.

PubMed

Clifford, Anton C; Doran, Christopher M; Tsey, Komla

2013-05-13

Indigenous peoples of Australia, Canada, United States and New Zealand experience disproportionately high rates of suicide. As such, the methodological quality of evaluations of suicide prevention interventions targeting these Indigenous populations should be rigorously examined, in order to determine the extent to which they are effective for reducing rates of Indigenous suicide and suicidal behaviours. This systematic review aims to: 1) identify published evaluations of suicide prevention interventions targeting Indigenous peoples in Australia, Canada, United States and New Zealand; 2) critique their methodological quality; and 3) describe their main characteristics. A systematic search of 17 electronic databases and 13 websites for the period 1981-2012 (inclusive) was undertaken. The reference lists of reviews of suicide prevention interventions were hand-searched for additional relevant studies not identified by the electronic and web search. The methodological quality of evaluations of suicide prevention interventions was assessed using a standardised assessment tool. Nine evaluations of suicide prevention interventions were identified: five targeting Native Americans; three targeting Aboriginal Australians; and one First Nation Canadians. The main intervention strategies employed included: Community Prevention, Gatekeeper Training, and Education. Only three of the nine evaluations measured changes in rates of suicide or suicidal behaviour, all of which reported significant improvements. The methodological quality of evaluations was variable. Particular problems included weak study designs, reliance on self-report measures, highly variable consent and follow-up rates, and the absence of economic or cost analyses. There is an urgent need for an increase in the number of evaluations of preventive interventions targeting reductions in Indigenous suicide using methodologically rigorous study designs across geographically and culturally diverse Indigenous populations. Combining and tailoring best evidence and culturally-specific individual strategies into one coherent suicide prevention program for delivery to whole Indigenous communities and/or population groups at high risk of suicide offers considerable promise.

Use of Technology for HIV Prevention Among Adolescent and Adult Women in the United States.

PubMed

Blackstock, Oni J; Patel, Viraj V; Cunningham, Chinazo O

2015-12-01

Although the proportion of new HIV infections in the USA among women has decreased over the last few years, still, approximately 20 % of new infections occur annually among adolescent and adult women. The development of effective evidence-based prevention interventions remains an important approach to further decreasing these numbers. Technology-delivered prevention interventions hold tremendous potential due, in part, to their ability to reach beyond the walls of brick-and-mortar intervention sites to engage individuals where they are. While most technology-delivered interventions have focused on adolescents and men who have sex with men, much fewer have specifically targeted adolescent or adult women despite evidence showing that interventions tailored to specific target populations are most effective. We summarize the recently published literature on technology-delivered HIV prevention interventions for US adolescent and adult women and provide suggestions for next steps in this nascent but emergent area of prevention research.

PCR-activated cell sorting as a general, cultivation-free method for high-throughput identification and enrichment of virus hosts

PubMed Central

Lim, Shaun W.; Lance, Shea T.; Stedman, Kenneth M.; Abate, Adam R.

2017-01-01

Characterizing virus-host relationships is critical for understanding the impact of a virus on an ecosystem, but is challenging with existing techniques, particularly for uncultivable species. We present a general, cultivation-free approach for identifying phage-associated bacterial cells. Using PCR-activated cell sorting, we interrogate millions of individual bacteria for the presence of specific phage nucleic acids. If the nucleic acids are present, the bacteria are recovered via sorting and their genomes analyzed. This allows targeted recovery of all possible host species in a diverse population associated with a specific phage, and can be easily targeted to identify the hosts of different phages by modifying the PCR primers used for detection. Moreover, this technique allows quantification of free phage particles, as benchmarked against the “gold standard” of virus enumeration, the plaque assay. PMID:28042018

PCR-activated cell sorting as a general, cultivation-free method for high-throughput identification and enrichment of virus hosts.

PubMed

Lim, Shaun W; Lance, Shea T; Stedman, Kenneth M; Abate, Adam R

2017-04-01

Characterizing virus-host relationships is critical for understanding the impact of a virus on an ecosystem, but is challenging with existing techniques, particularly for uncultivable species. We present a general, cultivation-free approach for identifying phage-associated bacterial cells. Using PCR-activated cell sorting, we interrogate millions of individual bacteria for the presence of specific phage nucleic acids. If the nucleic acids are present, the bacteria are recovered via sorting and their genomes analyzed. This allows targeted recovery of all possible host species in a diverse population associated with a specific phage, and can be easily targeted to identify the hosts of different phages by modifying the PCR primers used for detection. Moreover, this technique allows quantification of free phage particles, as benchmarked against the "gold standard" of virus enumeration, the plaque assay. Copyright © 2017 Elsevier B.V. All rights reserved.

A pretargeted nanoparticle system for tumor cell labeling

PubMed Central

Gunn, Jonathan; Park, Steven I.; Veiseh, Omid; Press, Oliver W.; Zhang, Miqin

2011-01-01

Nanoparticle-based cancer diagnostics and therapeutics can be significantly enhanced by selective tissue localization, but the strategy can be complicated by the requirement of a targeting ligand conjugated on nanoparticles, that is specific to only one or a limited few types of neoplastic cells, necessitating the development of multiple nanoparticle systems for different diseases. Here, we present a new nanoparticle system that capitalizes on a targeting pretreatment strategy, where a circulating fusion protein (FP) selectively prelabels the targeted cellular epitope, and a biotinylated iron oxide nanoparticle serves as a secondary label that binds to the FP on the target cell. This approach enables a single nanoparticle formulation to be used with any one of existing fusion proteins to bind a variety of target cells. We demonstrated this approach with two fusion proteins against two model cancer cell lines: lymphoma (Ramos) and leukemia (Jurkat), which showed 72.2% and 91.1% positive labeling, respectively. Notably, TEM analysis showed that a large nanoparticle population was endocytosed via attachment to the non-internalizing CD20 epitope. PMID:21107453

A pretargeted nanoparticle system for tumor cell labeling.

PubMed

Gunn, Jonathan; Park, Steven I; Veiseh, Omid; Press, Oliver W; Zhang, Miqin

2011-03-01

Nanoparticle-based cancer diagnostics and therapeutics can be significantly enhanced by selective tissue localization, but the strategy can be complicated by the requirement of a targeting ligand conjugated on nanoparticles, that is specific to only one or a limited few types of neoplastic cells, necessitating the development of multiple nanoparticle systems for different diseases. Here, we present a new nanoparticle system that capitalizes on a targeting pretreatment strategy, where a circulating fusion protein (FP) selectively prelabels the targeted cellular epitope, and a biotinylated iron oxide nanoparticle serves as a secondary label that binds to the FP on the target cell. This approach enables a single nanoparticle formulation to be used with any one of existing fusion proteins to bind a variety of target cells. We demonstrated this approach with two fusion proteins against two model cancer cell lines: lymphoma (Ramos) and leukemia (Jurkat), which showed 72.2% and 91.1% positive labeling, respectively. Notably, TEM analysis showed that a large nanoparticle population was endocytosed via attachment to the non-internalizing CD20 epitope.

Systematic Identification of Molecular Subtype-Selective Vulnerabilities in Non Small Cell Lung Cancer

PubMed Central

Kim, Hyun Seok; Mendiratta, Saurabh; Kim, Jiyeon; Pecot, Chad Victor; Larsen, Jill E.; Zubovych, Iryna; Seo, Bo Yeun; Kim, Jimi; Eskiocak, Banu; Chung, Hannah; McMillan, Elizabeth; Wu, Sherry; De Brabander, Jef; Komurov, Kakajan; Toombs, Jason E.; Wei, Shuguang; Peyton, Michael; Williams, Noelle; Gazdar, Adi F.; Posner, Bruce A.; Brekken, Rolf; Sood, Anil K.; Deberardinis, Ralph J.; Roth, Michael G.; Minna, John D.; White, Michael A.

2013-01-01

SUMMARY Context-specific molecular vulnerabilities that arise during tumor evolution represent an attractive intervention target class. However, the frequency and diversity of somatic lesions detected among lung tumors can confound efforts to identify these targets. To confront this challenge, we have applied parallel screening of chemical and genetic perturbations within a panel of molecularly annotated NSCLC lines to identify intervention opportunities tightly linked to molecular response indicators predictive of target sensitivity. Anchoring this analysis on a matched tumor/normal cell model from a lung adenocarcinoma patient identified three distinct target/response-indicator pairings that are represented with significant frequencies (6–16%) in the patient population. These include NLRP3 mutation/inflammasome activation-dependent FLIP addiction, co-occuring KRAS and LKB1 mutation-driven COPI addiction, and selective sensitivity to a synthetic indolotriazine that is specified by a 7-gene expression signature. Target efficacies were validated in vivo, and mechanism of action studies uncovered new cancer cell biology. PMID:24243015

Systematic identification of molecular subtype-selective vulnerabilities in non-small-cell lung cancer.

PubMed

Kim, Hyun Seok; Mendiratta, Saurabh; Kim, Jiyeon; Pecot, Chad Victor; Larsen, Jill E; Zubovych, Iryna; Seo, Bo Yeun; Kim, Jimi; Eskiocak, Banu; Chung, Hannah; McMillan, Elizabeth; Wu, Sherry; De Brabander, Jef; Komurov, Kakajan; Toombs, Jason E; Wei, Shuguang; Peyton, Michael; Williams, Noelle; Gazdar, Adi F; Posner, Bruce A; Brekken, Rolf A; Sood, Anil K; Deberardinis, Ralph J; Roth, Michael G; Minna, John D; White, Michael A

2013-10-24

Context-specific molecular vulnerabilities that arise during tumor evolution represent an attractive intervention target class. However, the frequency and diversity of somatic lesions detected among lung tumors can confound efforts to identify these targets. To confront this challenge, we have applied parallel screening of chemical and genetic perturbations within a panel of molecularly annotated NSCLC lines to identify intervention opportunities tightly linked to molecular response indicators predictive of target sensitivity. Anchoring this analysis on a matched tumor/normal cell model from a lung adenocarcinoma patient identified three distinct target/response-indicator pairings that are represented with significant frequencies (6%-16%) in the patient population. These include NLRP3 mutation/inflammasome activation-dependent FLIP addiction, co-occurring KRAS and LKB1 mutation-driven COPI addiction, and selective sensitivity to a synthetic indolotriazine that is specified by a seven-gene expression signature. Target efficacies were validated in vivo, and mechanism-of-action studies informed generalizable principles underpinning cancer cell biology. Copyright © 2013 Elsevier Inc. All rights reserved.

MUC4 stabilizes HER2 expression and maintains the cancer stem cell population in ovarian cancer cells.

PubMed

Ponnusamy, Moorthy P; Seshacharyulu, Parthasarathy; Vaz, Arokiapriyanka; Dey, Parama; Batra, Surinder K

2011-04-26

Recent evidence has suggested that the capability of cancer to grow, propagate and relapse after therapy is dependent on a small subset of the cell population within the tumor, called cancer stem cells. Therefore, this subpopulation of cells needs to be targeted with different approaches by identification of unique stem-cell specific target antigens. One of the well known tumor antigens is the epithelial cell mucin MUC4, which is aberrantly expressed in ovarian cancer as compared to the normal ovary and plays a pivotal role in the aggressiveness and metastasis of ovarian cancer cells. In the present study, we aimed to analyze the cancer stem cell population in MUC4 overexpressed ovarian cancer cells. MUC4 was ectopically overexpressed in SKOV3 ovarian cancer cells. Western blot analysis was performed for MUC4, HER2, CD133, ALDH1 and Shh expression in MUC4 overexpressed cells. Confocal analysis of MUC4, HER2 and CD133 was also done in the MUC4 overexpressed cells. CD133 and Hoechst33342 dye staining was used to analyze the cancer stem cell population via FACS method in SKOV3-MUC4 cells. MUC4 overexpressed SKOV3 cells showed an increased expression of HER2 compared to control cells. MUC4 overexpression leads to increased (0.1%) side population (SP) and CD133-positive cancer stem cells compared to the control cells. Interestingly, the tumor sphere type circular colony formation was observed only in the MUC4 overexpressed ovarian cancer cells. Furthermore, the cancer stem cell marker CD133 was expressed along with MUC4 in the isolated circular colonies as analyzed by both confocal and western blot analysis. HER2 and cancer stem cell specific marker ALDH1 along with Shh, a self-renewal marker, showed increased expression in the isolated circular colonies compared to MUC4-transfected cells. These studies demonstrate that MUC4 overexpression leads to an enriched ovarian cancer stem cell population either directly or indirectly through HER2. In future, this study would be helpful for MUC4-directed therapy for the ovarian cancer stem cell population.

MUC4 stabilizes HER2 expression and maintains the cancer stem cell population in ovarian cancer cells

PubMed Central

2011-01-01

Background Recent evidence has suggested that the capability of cancer to grow, propagate and relapse after therapy is dependent on a small subset of the cell population within the tumor, called cancer stem cells. Therefore, this subpopulation of cells needs to be targeted with different approaches by identification of unique stem-cell specific target antigens. One of the well known tumor antigens is the epithelial cell mucin MUC4, which is aberrantly expressed in ovarian cancer as compared to the normal ovary and plays a pivotal role in the aggressiveness and metastasis of ovarian cancer cells. In the present study, we aimed to analyze the cancer stem cell population in MUC4 overexpressed ovarian cancer cells. Methods MUC4 was ectopically overexpressed in SKOV3 ovarian cancer cells. Western blot analysis was performed for MUC4, HER2, CD133, ALDH1 and Shh expression in MUC4 overexpressed cells. Confocal analysis of MUC4, HER2 and CD133 was also done in the MUC4 overexpressed cells. CD133 and Hoechst33342 dye staining was used to analyze the cancer stem cell population via FACS method in SKOV3-MUC4 cells. Results MUC4 overexpressed SKOV3 cells showed an increased expression of HER2 compared to control cells. MUC4 overexpression leads to increased (0.1%) side population (SP) and CD133-positive cancer stem cells compared to the control cells. Interestingly, the tumor sphere type circular colony formation was observed only in the MUC4 overexpressed ovarian cancer cells. Furthermore, the cancer stem cell marker CD133 was expressed along with MUC4 in the isolated circular colonies as analyzed by both confocal and western blot analysis. HER2 and cancer stem cell specific marker ALDH1 along with Shh, a self-renewal marker, showed increased expression in the isolated circular colonies compared to MUC4-transfected cells. Conclusion These studies demonstrate that MUC4 overexpression leads to an enriched ovarian cancer stem cell population either directly or indirectly through HER2. In future, this study would be helpful for MUC4-directed therapy for the ovarian cancer stem cell population. PMID:21521521

Dynamics of adaptive immunity against phage in bacterial populations

NASA Astrophysics Data System (ADS)

Bradde, Serena; Vucelja, Marija; Tesileanu, Tiberiu; Balasubramanian, Vijay

The CRISPR (clustered regularly interspaced short palindromic repeats) mechanism allows bacteria to adaptively defend against phages by acquiring short genomic sequences (spacers) that target specific sequences in the viral genome. We propose a population dynamical model where immunity can be both acquired and lost. The model predicts regimes where bacterial and phage populations can co-exist, others where the populations oscillate, and still others where one population is driven to extinction. Our model considers two key parameters: (1) ease of acquisition and (2) spacer effectiveness in conferring immunity. Analytical calculations and numerical simulations show that if spacers differ mainly in ease of acquisition, or if the probability of acquiring them is sufficiently high, bacteria develop a diverse population of spacers. On the other hand, if spacers differ mainly in their effectiveness, their final distribution will be highly peaked, akin to a ``winner-take-all'' scenario, leading to a specialized spacer distribution. Bacteria can interpolate between these limiting behaviors by actively tuning their overall acquisition rate.

Are HIV and reproductive health services adapted to the needs of female sex workers? Results of a policy and situational analysis in Tete, Mozambique.

PubMed

Lafort, Yves; Jocitala, Osvaldo; Candrinho, Balthazar; Greener, Letitia; Beksinska, Mags; Smit, Jenni A; Chersich, Matthew; Delva, Wim

2016-07-26

In the context of an implementation research project aiming at improving use of HIV and sexual and reproductive health (SRH) services for female sex workers (FSWs), a broad situational analysis was conducted in Tete, Mozambique, assessing if services are adapted to the needs of FSWs. Methods comprised (1) a policy analysis including a review of national guidelines and interviews with policy makers, and (2) health facility assessments at 6 public and 1 private health facilities, and 1 clinic specifically targeting FSWs, consisting of an audit checklist, interviews with 18 HIV/SRH care providers and interviews of 99 HIV/SRH care users. There exist national guidelines for most HIV/SRH care services, but none provides guidance for care adapted to the needs of high-risk women such as FSWs. The Ministry of Health recently initiated the process of establishing guidelines for attendance of key populations, including FSWs, at public health facilities. Policy makers have different views on the best approach for providing services to FSWs-integrated in the general health services or through parallel services for key populations-and there exists no national strategy. The most important provider of HIV/SRH services in the study area is the government. Most basic services are widely available, with the exception of certain family planning methods, cervical cancer screening, services for victims of sexual and gender-based violence, and termination of pregnancy (TOP). The public facilities face serious limitations in term of space, staff, equipment, regular supplies and adequate provider practices. A stand-alone clinic targeting key populations offers a limited range of services to the FSW population in part of the area. Private clinics offer only a few services, at commercial prices. There is a need to improve the availability of quality HIV/SRH services in general and to FSWs specifically, and to develop guidelines for care adapted to the needs of FSWs. Access for FSWs can be improved by either expanding the range of services and the coverage of the targeted clinic and/or by improving access to adapted care at the public health services and ensure a minimum standard of quality.

Fine-mapping of lipid regions in global populations discovers ethnic-specific signals and refines previously identified lipid loci.

PubMed

Zubair, Niha; Graff, Mariaelisa; Luis Ambite, Jose; Bush, William S; Kichaev, Gleb; Lu, Yingchang; Manichaikul, Ani; Sheu, Wayne H-H; Absher, Devin; Assimes, Themistocles L; Bielinski, Suzette J; Bottinger, Erwin P; Buzkova, Petra; Chuang, Lee-Ming; Chung, Ren-Hua; Cochran, Barbara; Dumitrescu, Logan; Gottesman, Omri; Haessler, Jeffrey W; Haiman, Christopher; Heiss, Gerardo; Hsiung, Chao A; Hung, Yi-Jen; Hwu, Chii-Min; Juang, Jyh-Ming J; Le Marchand, Loic; Lee, I-Te; Lee, Wen-Jane; Lin, Li-An; Lin, Danyu; Lin, Shih-Yi; Mackey, Rachel H; Martin, Lisa W; Pasaniuc, Bogdan; Peters, Ulrike; Predazzi, Irene; Quertermous, Thomas; Reiner, Alex P; Robinson, Jennifer; Rotter, Jerome I; Ryckman, Kelli K; Schreiner, Pamela J; Stahl, Eli; Tao, Ran; Tsai, Michael Y; Waite, Lindsay L; Wang, Tzung-Dau; Buyske, Steven; Ida Chen, Yii-Der; Cheng, Iona; Crawford, Dana C; Loos, Ruth J F; Rich, Stephen S; Fornage, Myriam; North, Kari E; Kooperberg, Charles; Carty, Cara L

2016-12-15

Genome-wide association studies have identified over 150 loci associated with lipid traits, however, no large-scale studies exist for Hispanics and other minority populations. Additionally, the genetic architecture of lipid-influencing loci remains largely unknown. We performed one of the most racially/ethnically diverse fine-mapping genetic studies of HDL-C, LDL-C, and triglycerides to-date using SNPs on the MetaboChip array on 54,119 individuals: 21,304 African Americans, 19,829 Hispanic Americans, 12,456 Asians, and 530 American Indians. The majority of signals found in these groups generalize to European Americans. While we uncovered signals unique to racial/ethnic populations, we also observed systematically consistent lipid associations across these groups. In African Americans, we identified three novel signals associated with HDL-C (LPL, APOA5, LCAT) and two associated with LDL-C (ABCG8, DHODH). In addition, using this population, we refined the location for 16 out of the 58 known MetaboChip lipid loci. These results can guide tailored screening efforts, reveal population-specific responses to lipid-lowering medications, and aid in the development of new targeted drug therapies. © The Author 2016. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Identifying EGFR-Expressed Cells and Detecting EGFR Multi-Mutations at Single-Cell Level by Microfluidic Chip

NASA Astrophysics Data System (ADS)

Li, Ren; Zhou, Mingxing; Li, Jine; Wang, Zihua; Zhang, Weikai; Yue, Chunyan; Ma, Yan; Peng, Hailin; Wei, Zewen; Hu, Zhiyuan

2018-03-01

EGFR mutations companion diagnostics have been proved to be crucial for the efficacy of tyrosine kinase inhibitor targeted cancer therapies. To uncover multiple mutations occurred in minority of EGFR-mutated cells, which may be covered by the noises from majority of un-mutated cells, is currently becoming an urgent clinical requirement. Here we present the validation of a microfluidic-chip-based method for detecting EGFR multi-mutations at single-cell level. By trapping and immunofluorescently imaging single cells in specifically designed silicon microwells, the EGFR-expressed cells were easily identified. By in situ lysing single cells, the cell lysates of EGFR-expressed cells were retrieved without cross-contamination. Benefited from excluding the noise from cells without EGFR expression, the simple and cost-effective Sanger's sequencing, but not the expensive deep sequencing of the whole cell population, was used to discover multi-mutations. We verified the new method with precisely discovering three most important EGFR drug-related mutations from a sample in which EGFR-mutated cells only account for a small percentage of whole cell population. The microfluidic chip is capable of discovering not only the existence of specific EGFR multi-mutations, but also other valuable single-cell-level information: on which specific cells the mutations occurred, or whether different mutations coexist on the same cells. This microfluidic chip constitutes a promising method to promote simple and cost-effective Sanger's sequencing to be a routine test before performing targeted cancer therapy.[Figure not available: see fulltext.

Diversity in case management modalities: the Summit model.

PubMed

Peterson, G A; Drone, I D; Munetz, M R

1997-06-01

Though ubiquitous in community mental health agencies, case management suffers from a lack of consensus regarding its definition, essential components, and appropriate application. Meaningful comparisons of various case management models await such a consensus. Global assessments of case management must be replaced by empirical studies of specific interventions with respect to the needs of specific populations. The authors describe a highly differentiated and prescriptive system of case management involving the application of more than one model of service delivery. Such a diversified and targeted system offers an opportunity to study the technology of case management in a more meaningful manner.

Development of the Juvenile Justice Anger Management Treatment for Girls

PubMed Central

Goldstein, Naomi E. S.; Serico, Jennifer M.; Riggs Romaine, Christina L.; Zelechoski, Amanda D.; Kalbeitzer, Rachel; Kemp, Kathleen; Lane, Christy

2016-01-01

Female juvenile offenders exhibit high levels of anger, relational aggression, and physical aggression, but the population has long been ignored in research and practice. No anger management treatments have been developed specifically for this population, and no established anger management treatments are empirically supported for use with delinquent girls. Thus, to alleviate anger and reduce the frequency and severity of aggressive behaviors in this underserved population, we developed the gender-specific, Juvenile Justice Anger Management (JJAM) Treatment for Girls. This cognitive-behavioral intervention was adapted from the Coping Power Program (Lochman & Wells, 2002), a school-based anger management treatment for younger children that has established efficacy and effectiveness findings with its target populations. This paper describes how the content of JJAM was developed to meet the unique needs of adolescent girls in residential juvenile justice placements. It also traces the process of developing a manualized treatment and the steps taken to enhance efficacy and clinical utility. An overview of the treatment, a session-by-session outline, an example session activity, and an example homework assignment are provided. A randomized controlled trial is currently being conducted to evaluate the efficacy of the JJAM Treatment for Girls. PMID:27642247

Experiments Toward the Application of Multi-Robot Systems to Disaster-Relief Scenarios

DTIC Science & Technology

2015-09-01

responsibility is assessment, such as dislocated populations, degree of property damage, and remaining communications infrastructure . These are all...specific problems: evaluating of damage to infrastructure in the environment, e.g., traversability of roads; and localizing particular targets of interest...regarding hardware and software infrastructure are driven by the need for these systems to “survive the field” and allow for reliable evaluation of autonomy

Animal and Rabies Control in Joint Operations Areas (Working Paper)

DTIC Science & Technology

2012-08-13

vaccination program (Meslin 2007). Mixed populations of free-ranging dogs, cats, foxes, jackals , or other wildlife species makes U.S. FOBs in JOAs a...prime venue for oral rabies vaccination. Species that are difficult to trap, such as jackals , can be specifically targeted for oral rabies...vaccination. Anecdotal reports from various vector control and preventive medicine groups in Iraq indicate that packs of jackals exist in particular

Preventing delirium in dementia: Managing risk factors.

PubMed

Ford, Andrew H

2016-10-01

Delirium is a common, disabling medical condition that is associated with numerous adverse outcomes. A number of inter-related factors, including pre-existing cognitive impairment, usually contribute to the development of delirium in a particular susceptible individual. Non-pharmacological approaches to prevention typically target multiple risk factors in a systematic manner (multicomponent interventions). There is generally good evidence that multicomponent interventions reduce the incidence of delirium in hospital populations but there are limited data in people with dementia and those living in the community. It is likely that there is a differential effect of specific interventions in those with cognitive impairment (e.g. people with dementia may respond better to simpler, more pragmatic interventions rather than complex procedures) but this cannot be determined from the existing data. Targeted interventions focussed on hydration, medication rationalization and sleep promotion may also be effective in reducing the incidence of delirium, as well as the active involvement of family members in the care of the elderly hospitalized patient. Hospitalization itself is a potential risk factor for delirium and promising data are emerging of the benefits of home-based care as an alternative to hospitalization but this is restricted to specific sub-populations of patients and is reliant on these services being available. Crown Copyright © 2016. Published by Elsevier Ireland Ltd. All rights reserved.

PRMT5 as a druggable target for glioblastoma therapy.

PubMed

Banasavadi-Siddegowda, Yeshavanth Kumar; Welker, Alessandra M; An, Min; Yang, Xiaozhi; Zhou, Wei; Shi, Guqin; Imitola, Jaime; Li, Chenglong; Hsu, Sigmund; Wang, Jiang; Phelps, Mitch; Zhang, Jianying; Beattie, Christine E; Baiocchi, Robert; Kaur, Balveen

2018-05-18

In spite of standard multimodal therapy consisting of surgical resection followed by radiation and concurrent chemotherapy, prognosis for glioblastoma (GBM) patients remains poor. The identification of both differentiated and undifferentiated "stem cell like" populations in the tumor highlights the significance of finding novel targets that affect the heterogeneous tumor cell population. Protein arginine methyltransferase 5 (PRMT5) is one such candidate gene whose nuclear expression correlates with poor survival and has been reported to be required for survival of differentiated GBM cells and self-renewal of undifferentiated GBM cells. In the current study we screened the specificity and efficacy of 4 novel PRMT5 inhibitors in the treatment of GBM. Efficacies of these inhibitors were screened using an in vitro GBM neurosphere model and an in vivo intracranial zebrafish model of glioma. Standard molecular biology methods were employed to investigate changes in cell cycle, growth, and senescence. In vitro and in vivo studies revealed that among the 4 PRMT5 inhibitors, treatment of GBM cells with compound 5 (CMP5) mirrored the effects of PRMT5 knockdown wherein it led to apoptosis of differentiated GBM cells and drove undifferentiated primary patient derived GBM cells into a nonreplicative senescent state. In vivo antitumor efficacy combined with the specificity of CMP5 underscores the importance of developing it for translation.

Lentiviral gene transfer regenerates hematopoietic stem cells in a mouse model for Mpl-deficient aplastic anemia.

PubMed

Heckl, Dirk; Wicke, Daniel C; Brugman, Martijn H; Meyer, Johann; Schambach, Axel; Büsche, Guntram; Ballmaier, Matthias; Baum, Christopher; Modlich, Ute

2011-04-07

Thpo/Mpl signaling plays an important role in the maintenance of hematopoietic stem cells (HSCs) in addition to its role in megakaryopoiesis. Patients with inactivating mutations in Mpl develop thrombocytopenia and aplastic anemia because of progressive loss of HSCs. Yet, it is unknown whether this loss of HSCs is an irreversible process. In this study, we used the Mpl knockout (Mpl(-/-)) mouse model and expressed Mpl from newly developed lentiviral vectors specifically in the physiologic Mpl target populations, namely, HSCs and megakaryocytes. After validating lineage-specific expression in vivo using lentiviral eGFP reporter vectors, we performed bone marrow transplantation of transduced Mpl(-/-) bone marrow cells into Mpl(-/-) mice. We show that restoration of Mpl expression from transcriptionally targeted vectors prevents lethal adverse reactions of ectopic Mpl expression, replenishes the HSC pool, restores stem cell properties, and corrects platelet production. In some mice, megakaryocyte counts were atypically high, accompanied by bone neo-formation and marrow fibrosis. Gene-corrected Mpl(-/-) cells had increased long-term repopulating potential, with a marked increase in lineage(-)Sca1(+)cKit(+) cells and early progenitor populations in reconstituted mice. Transcriptome analysis of lineage(-)Sca1(+)cKit(+) cells in Mpl-corrected mice showed functional adjustment of genes involved in HSC self-renewal.

MicroRNA-451 regulates stemness of side population cells via PI3K/Akt/mTOR signaling pathway in multiple myeloma.

PubMed

Du, Juan; Liu, Shuyan; He, Jie; Liu, Xi; Qu, Ying; Yan, Wenqing; Fan, Jianling; Li, Rong; Xi, Hao; Fu, Weijun; Zhang, Chunyang; Yang, Jing; Hou, Jian

2015-06-20

Side population (SP) cells are an enriched source of cancer-initiating cells with stemness characteristics, generated by increased ABC transporter activity, which has served as a unique hallmark for multiple myeloma (MM) stem cell studies. Here we isolated and identified MM SP cells via Hoechst 33342 staining. Furthermore, we demonstrate that SP cells possess abnormal cell cycle, clonogenicity, and high drug efflux characteristics-all of which are features commonly seen in stem cells. Interestingly, we found that bortezomib, As2O3, and melphalan all affected apoptosis and clonogenicity in SP cells. We followed by characterizing the miRNA signature of MM SP cells and validated the specific miR-451 target tuberous sclerosis 1 (TSC1) gene to reveal that it activates the PI3K/Akt/mTOR signaling in MM SP cells. Inhibition of miR-451 enhanced anti-myeloma novel agents' effectiveness, through increasing cells apoptosis, decreasing clonogenicity, and reducing MDR1 mRNA expression. Moreover, the novel specific PI3K/Akt/mTOR signaling inhibitor S14161 displayed its prowess as a potential therapeutic agent by targeting MM SP cells. Our findings offer insights into the mechanisms regulating MM SP cells and provide a novel strategy to overcome resistance to existing therapies against myeloma.

Exploring the Gaps in Practical Ethical Guidance for Animal Welfare Considerations of Field Interventions and Innovations Targeting Dogs and Cats.

PubMed

Tasker, Louisa; Getty, Susan F; Briggs, Joyce R; Benka, Valerie A W

2018-01-27

Domestic dogs ( Canis lupus familiaris ) and cats ( Felis silvestris catus ) are common species targeted by nongovernmental or intergovernmental organizations, veterinarians and government agencies worldwide, for field interventions (e.g., population management, rabies vaccination programs) or innovations (e.g., development of technologies or pharmaceuticals to improve animal welfare). We have a moral responsibility to ensure that the conduct of this work is humane for dogs or cats, and to consider the human communities in which the animals live. Ethical review is widely accepted as being integral to responsible practice, and it is fundamental to good science that underpins innovation. Despite the necessity of field interventions or innovations to advance the welfare of individuals or populations of animals, we found a lack of specific guidance and review processes to help navigate ethical dilemmas surrounding the conduct of such work. This can be detrimental to the wellbeing of animals and their human communities. Here we identify the gaps in existing ethical frameworks (specifically application of Reduction and Refinement principles, challenges of obtaining meaningful informed consent with variations in the quality of human-animal relationships, and limited resources regarding considerations of local stakeholders), and outline the need for additional tools to promote ethical conduct in the field.

T cells bearing a chimeric antigen receptor against prostate-specific membrane antigen mediate vascular disruption and result in tumor regression

PubMed Central

Santoro, Stephen P.; Kim, Soorin; Motz, Gregory T.; Alatzoglou, Dimitrios; Li, Chunsheng; Irving, Melita; Powell, Daniel J.; Coukos, George

2014-01-01

Aberrant blood vessels enable tumor growth, provide a barrier to immune infiltration, and serve as a source of pro-tumorigenic signals. Targeting tumor blood vessels for destruction, or tumor vascular disruption therapy, can therefore provide significant therapeutic benefit. Here we describe the ability of chimeric antigen receptor (CAR)-bearing T cells to recognize human prostate-specific membrane antigen (hPSMA) on endothelial targets in vitro as well as in vivo. CAR T cells were generated using the anti-PSMA scFv, J591, and the intracellular signaling domains: CD3ζ, CD28, and/or CD137/4-1BB. We found that all anti-hPSMA CAR T cells recognized and eliminated PSMA+ endothelial targets in vitro, regardless of the signaling domain. T cells bearing the 3rd generation anti-hPSMA CAR, P28BBζ, were able to recognize and kill primary human endothelial cells isolated from gynecologic cancers. In addition, the P28BBζ CAR T cells mediated regression of hPSMA-expressing vascular neoplasms in mice. Finally, in murine models of ovarian cancers populated by murine vessels expressing hPSMA, the P28BBζ CAR T cells were able to ablate PSMA+ vessels, cause secondary depletion of tumor cells, and reduce tumor burden. Taken together, these results provide strong rationale for the use of CAR T cells as agents of tumor vascular disruption, specifically those targeting PSMA. PMID:25358763

PD-L1 Expression on Retrovirus-Infected Cells Mediates Immune Escape from CD8+ T Cell Killing.

PubMed

Akhmetzyanova, Ilseyar; Drabczyk, Malgorzata; Neff, C Preston; Gibbert, Kathrin; Dietze, Kirsten K; Werner, Tanja; Liu, Jia; Chen, Lieping; Lang, Karl S; Palmer, Brent E; Dittmer, Ulf; Zelinskyy, Gennadiy

2015-10-01

Cytotoxic CD8+ T Lymphocytes (CTL) efficiently control acute virus infections but can become exhausted when a chronic infection develops. Signaling of the inhibitory receptor PD-1 is an important mechanism for the development of virus-specific CD8+ T cell dysfunction. However, it has recently been shown that during the initial phase of infection virus-specific CD8+ T cells express high levels of PD-1, but are fully competent in producing cytokines and killing virus-infected target cells. To better understand the role of the PD-1 signaling pathway in CD8+ T cell cytotoxicity during acute viral infections we analyzed the expression of the ligand on retrovirus-infected cells targeted by CTLs. We observed increased levels of PD-L1 expression after infection of cells with the murine Friend retrovirus (FV) or with HIV. In FV infected mice, virus-specific CTLs efficiently eliminated infected target cells that expressed low levels of PD-L1 or that were deficient for PD-L1 but the population of PD-L1high cells escaped elimination and formed a reservoir for chronic FV replication. Infected cells with high PD-L1 expression mediated a negative feedback on CD8+ T cells and inhibited their expansion and cytotoxic functions. These findings provide evidence for a novel immune escape mechanism during acute retroviral infection based on PD-L1 expression levels on virus infected target cells.

Cell type specificity of GABA(A) receptor mediated signaling in the hippocampus.

PubMed

Semyanov, A

2003-08-01

Inhibitory signaling mediated by ionotropic GABA(1) receptors generally acts as a major brake against excessive excitability in the brain. This is especially relevant in epilepsy-prone structures such as the hippocampus, in which GABA(A) receptor mediated inhibition is critical in suppressing epileptiform activity. Indeed, potentiating GABA(A) receptor mediated signaling is an important target for antiepileptic drug therapy. GABA(A) receptor mediated inhibition has different roles in the network dependent on the target neuron. Inhibiting principal cells will thus reduce network excitability, whilst inhibiting interneurons will increase network excitability; GABAergic therapeutic agents do not distinguish between these two alternatives, which may explain why, on occasion, GABAergic antiepileptic drugs can be proconvulsant. The importance of the target-cell for the effect of neuroactive drugs has emerged from a number of recent studies. Immunocytochemical data have suggested non-uniform distribution of GABA(A) receptor subunits among hippocampal interneurons and pyramidal cells. This has been confirmed by subsequent electropharmacological data. These have demonstrated that compounds which act on GABA(A) receptors or the extracellular GABA concentration can have distinct effects in different neuronal populations. Recently, it has also been discovered that presynaptic glutamate heteroreceptors can modulate GABA release in the hippocampus in a postsynaptic cell-specific manner. Since systemically administrated drugs may act on different neuronal subtypes, they can exhibit paradoxical effects. Distinguishing compounds that have target specific effects on GABAergic signaling may lead to novel and more effective treatments against epilepsy.

WE-H-BRA-03: Development of a Model to Include the Evolution of Resistant Tumor Subpopulations Into the Treatment Optimization Process for Schedules Involving Targeted Agents in Chemoradiation Therapy

DOE Office of Scientific and Technical Information (OSTI.GOV)

Grassberger, C; Paganetti, H

Purpose: To develop a model that includes the process of resistance development into the treatment optimization process for schedules that include targeted therapies. Further, to validate the approach using clinical data and to apply the model to assess the optimal induction period with targeted agents before curative treatment with chemo-radiation in stage III lung cancer. Methods: Growth of the tumor and its subpopulations is modeled by Gompertzian growth dynamics, resistance induction as a stochastic process. Chemotherapy induced cell kill is modeled by log-cell kill dynamics, targeted agents similarly but restricted to the sensitive population. Radiation induced cell kill is assumedmore » to follow the linear-quadratic model. The validation patient data consist of a cohort of lung cancer patients treated with tyrosine kinase inhibitors that had longitudinal imaging data available. Results: The resistance induction model was successfully validated using clinical trial data from 49 patients treated with targeted agents. The observed recurrence kinetics, with tumors progressing from 1.4–63 months, result in tumor growth equaling a median volume doubling time of 92 days [34–248] and a median fraction of pre-existing resistance of 0.035 [0–0.22], in agreement with previous clinical studies. The model revealed widely varying optimal time points for the use of curative therapy, reaching from ∼1m to >6m depending on the patient’s growth rate and amount of pre-existing resistance. This demonstrates the importance of patient-specific treatment schedules when targeted agents are incorporated into the treatment. Conclusion: We developed a model including evolutionary dynamics of resistant sub-populations with traditional chemotherapy and radiation cell kill models. Fitting to clinical data yielded patient specific growth rates and resistant fraction in agreement with previous studies. Further application of the model demonstrated how proper timing of chemo-radiation could minimize the probability of resistance, increasing tumor control significantly.« less

Health promotion communications system: a model for a dispersed population.

PubMed

Foran, M; Campanelli, L C

1995-11-01

1. Corporations with geographically dispersed populations need to provide flexible health promotion programs tailored to meet specific employee interests and needs. 2. Bell Atlantic developed a dispersed model approach based on the transtheoretical model of behavior change. The key to this model is to identify at which stage the individual is operating and provide appropriate information and behavior change programs. 3. Components of the program include: health risk appraisal; exercise/activity tracking system; on line nurse health information service; network of fitness facilities; employee assistance programs; health library available by fax; health film library; network of health promotion volunteers; and targeted health and marketing messaged via corporate media.

Identifying Reservoirs of Infection: A Conceptual and Practical Challenge

PubMed Central

2002-01-01

Many infectious agents, especially those that cause emerging diseases, infect more than one host species. Managing reservoirs of multihost pathogens often plays a crucial role in effective disease control. However, reservoirs remain variously and loosely defined. We propose that reservoirs can only be understood with reference to defined target populations. Therefore, we define a reservoir as one or more epidemiologically connected populations or environments in which the pathogen can be permanently maintained and from which infection is transmitted to the defined target population. Existence of a reservoir is confirmed when infection within the target population cannot be sustained after all transmission between target and nontarget populations has been eliminated. When disease can be controlled solely by interventions within target populations, little knowledge of potentially complex reservoir infection dynamics is necessary for effective control. We discuss the practical value of different approaches that may be used to identify reservoirs in the field. PMID:12498665

CD8 down-regulation and functional impairment of SIV-specific cytotoxic T lymphocytes in lymphoid and mucosal tissues during SIV infection.

PubMed

Xu, Huanbin; Wang, Xiaolei; Lackner, Andrew A; Veazey, Ronald S

2013-06-01

Functional impairment of virus-specific T cells is a hallmark of HIV/SIV infection, but the underlying mechanisms of this dysfunction are not well understood. To address this, we simultaneously analyzed the expression and intensity of CD8 and inhibitory PD-1 on CTL in blood and lymphoid tissues in SIV-infected rhesus macaques. The intensity (mean channel fluorescence) of CD8 expression was transiently down-regulated in early SIV infection (10-14 dpi), despite an increase in CD8(+) T cell proliferation. In chronic infection, CD8 expression was maintained at low levels on CD8(+) T cells in all tissues. Interestingly, Gag-specific CTLs were clearly divided into CD8high- and CD8low-expressing populations in SIV-infected macaques, and CD8low Gag-specific cells increased with disease progression, especially in lymphoid tissues when compared with peripheral blood or in Gag-vaccinated controls. Moreover, the CD8low CTL population secreted lower levels of cytokines upon SIV antigen stimulation and exhibited lower proliferative capacity during infection compared with the CD8high CTL population. Meanwhile, intensity of PD-1 expression on Gag-specific CTL in chronic infection was significantly higher than in acute SIV infection, although the frequencies of PD-1+ Gag-specific cells were similar in acute and chronic stages. In summary, down-regulation of CD8 expression and higher expression of PD-1 on SIV-specific CTLs could coordinately attenuate SIV-specific CTL responses and their ability to recognize virus-infected target cells, especially in lymphoid tissues, resulting in failure to contain viremia, and continued persistence and replication of HIV in lymphoid tissue reservoirs.

Novel method for in vitro depletion of T cells by monoclonal antibody-targeted photosensitization.

PubMed

Berki, T; Németh, P

1998-02-01

An immunotargeting method (called photo-immunotargeting) has been developed for selective in vitro cell destruction. The procedure combines the photosensitizing (toxic) effect of light-induced dye-molecules, e.g., hematoporphyrin (HP) and the selective binding ability of monoclonal antibodies (mAb) to cell surface molecules. The photosensitizer HP molecules were covalently attached to monoclonal antibodies (a-Thy-1) recognizing an antigen on the surface of T lymphocytes, and used for T cell destruction. To increase the selectivity of the conventional targeting methods, a physical activation step (local light irradiation) as a second degree of specificity was employed. The HP in conjugated form was sufficient to induce T cell (thymocytes, EL-4 cell line) death after irradiation at 400 nm, at tenfold lower concentration compared to the photosensitizing effect of unbound HP. The selective killing of T lymphocytes (bearing the Thy-1 antigen) in a mixed cell population was demonstrated after a treatment with the phototoxic conjugate and light irradiation. This method can be useful for selective destruction of one population (target cell) in an in vitro heterogeneous cell mixture, e.g., in bone marrow transplants for T cell depletion to avoid graft vs. host reaction.

Targeted stock identification using multilocus genotype 'familyprinting'

USGS Publications Warehouse

Letcher, B.H.; King, T.L.

1999-01-01

We present an approach to stock identification of small, targeted populations that uses multilocus microsatellite genotypes of individual mating adults to uniquely identify first- and second-generation offspring in a mixture. We call the approach 'familyprinting'; unlike DNA fingerprinting where tissue samples of individuals are matched, offspring from various families are assigned to pairs of parents or sets of four grandparents with known genotypes. The basic unit of identification is the family, but families can be nested within a variety of stock units ranging from naturally reproducing groups of fish in a small tributary or pond from which mating adults can be sampled to large or small collections of families produced in hatcheries and stocked in specific locations. We show that, with as few as seven alleles per locus using four loci without error, first-generation offspring can be uniquely assigned to the correct family. For second-generation applications in a hatchery more alleles per locus (10) and loci (10) are required for correct assignment of all offspring to the correct set of grandparents. Using microsatellite DNA variation from an Atlantic salmon (Salmo solar) restoration river (Connecticut River, USA), we also show that this population contains sufficient genetic diversity in sea-run returns for 100% correct first, generation assignment and 97% correct second-generation assignment using 14 loci. We are currently using first- and second-generation familyprinting in this population with the ultimate goal of identifying stocking tributary. In addition to within-river familyprinting, there also appears to be sufficient genetic diversity within and between Atlantic salmon populations for identification of 'familyprinted' fish in a mixture of multiple populations. We also suggest that second-generation familyprinting with multiple populations may also provide a tool for examining stock structure. Familyprinting with microsatellite DNA markers is a viable method for identification of offspring of randomly mating adults from small, targeted stocks and should provide a useful addition to current mixed stock analyses with genetic markers.

Mapping insecticide resistance and characterization of resistance mechanisms in Anopheles arabiensis (Diptera: Culicidae) in Ethiopia.

PubMed

Alemayehu, Eba; Asale, Abebe; Eba, Kasahun; Getahun, Kefelegn; Tushune, Kora; Bryon, Astrid; Morou, Evangelia; Vontas, John; Van Leeuwen, Thomas; Duchateau, Luc; Yewhalaw, Delenasaw

2017-09-02

The emergence and spread of insecticide resistance in the major African malaria vectors Anopheles gambiae (s.s.) and An. arabiensis may compromise the current vector control interventions and threatens the global malaria control and elimination efforts. Insecticide resistance was monitored in several study sites in Ethiopia from 2013 to 2015 using papers impregnated with discriminating concentrations of DDT, deltamethrin, bendiocarb, propoxur, malathion, fenitrothion and pirimiphos-methyl, following the WHO insecticide susceptibility test procedure. Mosquitoes sampled from different localities for WHO bioassay were morphologically identified as An. gambiae (s.l.) using standard taxonomic keys. Samples were identified to species using species-specific polymerase chain reaction (PCR) and screened for the presence of target site mutations L1014F, L1014S and N1575Y in the voltage gated sodium channel (VGSC) gene and G119S in the acethylcholinesterase (AChE) gene using allele-specific PCR. Biochemical assays were performed to assess elevated levels of acetylcholinesterases, carboxylcholinesterases, glutathione-S-transferases (GSTs) and cytochrome P450s monooxygenases in wild populations of An. arabiensis, compared to the fully susceptible Sekoru An. arabiensis laboratory strain. Populations of An. arabiensis were resistant to DDT and deltamethrin but were susceptible to fenitrothion in all the study sites. Reduced susceptibility to malathion, pirimiphos-methyl, propoxur and bendiocarb was observed in some of the study sites. Knockdown resistance (kdr L1014F) was detected in all mosquito populations with allele frequency ranging from 42 to 91%. Elevated levels of glutathione-S-transferases (GSTs) were detected in some of the mosquito populations. However, no elevated levels of monooxygenases and esterases were detected in any of the populations assessed. Anopheles arabiensis populations from all surveyed sites in Ethiopia exhibited resistance against DDT and pyrethroids. Moreover, some mosquito populations exhibited resistance to propoxur and possible resistance to bendiocarb. Target site mutation kdr L1014F was detected in all mosquito populations while elevated levels of glutathione-S-transferases (GSTs) was detected in some mosquito populations. The reduced susceptibility of An. arabiensis to propoxur and bendiocarb, which are currently used for indoor residual spraying (IRS) in Ethiopia, calls for continuous resistance monitoring, in order to plan and implement evidence based insecticide resistance management.

Assessment of infant exposure to food chemicals: the French Total Diet Study design.

PubMed

Hulin, M; Bemrah, N; Nougadère, A; Volatier, J L; Sirot, V; Leblanc, J C

2014-01-01

As part of the previous French Total Diet Studies (TDS) focusing on exposure to food chemicals in the population aged 3 years and older, the French Agency for Food, Environmental and Occupational Health & Safety (ANSES) launched a specific TDS on infants to complete its overall chemical food safety programme for the general population. More than 500 chemical substances were analysed in food products consumed by children under 3 years old, including nutrients, several endocrine disruptors resulting from human activities (polychlorinated biphenyls, dioxins and furans, brominated flame retardants, perfluoroalkyl acids, pesticide residues, etc.) or migrating from food contact materials such as bisphenol A or phthalates, but also natural substances such as mycotoxins, phytoestrogens and steroids. To obtain a representative and general view of infant food consumption, food items were selected based on results of a national consumption survey conducted specifically on this population. Moreover, a specific study on food was conducted on 429 households to determine which home-cooking practices are employed to prepare food consumed by infants. Overall, the targeted chemical substances were analysed in more than 450 food samples, representing the purchase and home-cooking practices of over 5500 food products. Foods included common foods such as vegetables, fruit or cakes as well as specific infant foods such as infant formula or jarred baby food. The sampling plan covered over 80% of the total diet. Specificities in infant food consumption and habits were therefore considered to define this first infant TDS. This study, conducted on a large scale and focusing on a particularly sensitive population, will provide accurate information on the dietary exposure of children under 3 years to food chemicals, especially endocrine disruptors, and will be particularly useful for risk assessment analysis under the remit of ANSES' expert committees.

An Improved Compressive Sensing and Received Signal Strength-Based Target Localization Algorithm with Unknown Target Population for Wireless Local Area Networks.

PubMed

Yan, Jun; Yu, Kegen; Chen, Ruizhi; Chen, Liang

2017-05-30

In this paper a two-phase compressive sensing (CS) and received signal strength (RSS)-based target localization approach is proposed to improve position accuracy by dealing with the unknown target population and the effect of grid dimensions on position error. In the coarse localization phase, by formulating target localization as a sparse signal recovery problem, grids with recovery vector components greater than a threshold are chosen as the candidate target grids. In the fine localization phase, by partitioning each candidate grid, the target position in a grid is iteratively refined by using the minimum residual error rule and the least-squares technique. When all the candidate target grids are iteratively partitioned and the measurement matrix is updated, the recovery vector is re-estimated. Threshold-based detection is employed again to determine the target grids and hence the target population. As a consequence, both the target population and the position estimation accuracy can be significantly improved. Simulation results demonstrate that the proposed approach achieves the best accuracy among all the algorithms compared.

Observed-Score Equating with a Heterogeneous Target Population

ERIC Educational Resources Information Center

Duong, Minh Q.; von Davier, Alina A.

2012-01-01

Test equating is a statistical procedure for adjusting for test form differences in difficulty in a standardized assessment. Equating results are supposed to hold for a specified target population (Kolen & Brennan, 2004; von Davier, Holland, & Thayer, 2004) and to be (relatively) independent of the subpopulations from the target population (see…

A comprehensive review of available epidemiologic and HIV service data for female sex workers, men who have sex with men, and people who inject drugs in select West and Central African countries.

PubMed

MacAllister, Jack; Sherwood, Jennifer; Galjour, Joshua; Robbins, Sarah; Zhao, Jinkou; Dam, Kim; Grosso, Ashley; Baral, Stefan D

2015-03-01

To identify gaps in epidemiologic and HIV service coverage data for key populations (KP), including men who have sex with men (MSM), female sex workers (FSW), people who inject drugs (PWID), and transgender persons, in 8 West and Central Africa countries: Cameroon, Chad, Cote d'Ivoire, Democratic Republic of Congo, Ghana, Guinea-Bissau, Niger, and Nigeria. A comprehensive search of peer-reviewed literature was conducted using PubMed and MEDLINE. This search was supplemented by an additional search of relevant non-peer-reviewed, or gray, literature. Available data on HIV prevalence, KP size estimates, HIV prevention service targets, and HIV prevention service coverage, including the availability of population-specific minimum packages of services, were included in the review. No data for transgender persons were found. HIV prevalence data and size estimates were more frequently available for FSW, followed by MSM. Only 2 countries (Ghana and Nigeria) had both KP size estimates and HIV prevalence data for PWID. The degree to which HIV prevention service targets were adopted was highly variable across the selected countries, and the collection of relevant HIV prevention service coverage data for those targets that were identified was inconsistent. Population-specific minimum packages of services were identified in 3 countries (Cote d'Ivoire, Ghana, and Nigeria), although only Ghana and Nigeria included services for PWID. Epidemiologic and HIV prevention service data for FSW, MSM, PWID, and transgender persons remain sparse, and these KP are inconsistently accounted for in-service delivery and nationally endorsed minimum packages of HIV services in West and Central Africa. The strengthening of data collection and reporting to consistently include KP and the inclusion of that data in national planning is imperative for effectively addressing the HIV epidemic.

Order of events matter: comparing discrete models for optimal control of species augmentation.

PubMed

Bodine, Erin N; Gross, Louis J; Lenhart, Suzanne

2012-01-01

We investigate optimal timing of augmentation of an endangered/threatened species population in a target region by moving individuals from a reserve or captive population. This is formulated as a discrete-time optimal control problem in which augmentation occurs once per time period over a fixed number of time periods. The population model assumes the Allee effect growth functions in both target and reserve populations and the control objective is to maximize the target and reserve population sizes over the time horizon while accounting for costs of augmentation. Two possible orders of events are considered for different life histories of the species relative to augmentation time: move individuals either before or after population growth occurs. The control variable is the proportion of the reserve population to be moved to the target population. We develop solutions and illustrate numerical results which indicate circumstances for which optimal augmentation strategies depend upon the order of events.

Transcriptomic profiling of curcumin treated human breast stem cells identifies a role for stearoyl coa-desaturase in breast cancer prevention

PubMed Central

Colacino, Justin A.; McDermott, Sean P.; Sartor, Maureen A.; Wicha, Max S.; Rozek, Laura S.

2017-01-01

Curcumin is a potential agent for both the prevention and treatment of cancers. Curcumin treatment alone, or in combination with piperine, limits breast stem cell self-renewal while remaining non-toxic to normal differentiated cells. We paired fluorescence activated cell sorting with RNA sequencing to characterize the genome-wide changes induced specifically in normal breast stem cells following treatment with these compounds. We generated genome-wide maps of the transcriptional changes that occur in epithelial-like (ALDH+) and mesenchymal-like (ALDH−/CD44+/CD24−) normal breast stem/progenitor cells following treatment with curcumin and piperine. We show that curcumin targets both stem cell populations by down-regulating expression of breast stem cell genes including ALDH1A3, CD49f, PROM1, and TP63. We also identified novel genes and pathways targeted by curcumin, including downregulation of SCD. Transient siRNA knockdown of SCD in MCF10A cells significantly inhibited mammosphere formation and the mean proportion of CD44+/CD24− cells, suggesting that SCD is a regulator of breast stemness and a target of curcumin in breast stem cells. These findings extend previous reports of curcumin targeting stem cells, here in two phenotypically distinct stem/progenitor populations isolated from normal human breast tissue. We identified novel mechanisms by which curcumin and piperine target breast stem cell self-renewal, such as by targeting lipid metabolism, providing a mechanistic link between curcumin treatment and stem cell self renewal. These results elucidate the mechanisms by which curcumin may act as a cancer preventive compound and provide novel targets for cancer prevention and treatment. PMID:27306423

Transcriptomic profiling of curcumin-treated human breast stem cells identifies a role for stearoyl-coa desaturase in breast cancer prevention.

PubMed

Colacino, Justin A; McDermott, Sean P; Sartor, Maureen A; Wicha, Max S; Rozek, Laura S

2016-07-01

Curcumin is a potential agent for both the prevention and treatment of cancers. Curcumin treatment alone, or in combination with piperine, limits breast stem cell self-renewal, while remaining non-toxic to normal differentiated cells. We paired fluorescence-activated cell sorting with RNA sequencing to characterize the genome-wide changes induced specifically in normal breast stem cells following treatment with these compounds. We generated genome-wide maps of the transcriptional changes that occur in epithelial-like (ALDH+) and mesenchymal-like (ALDH-/CD44+/CD24-) normal breast stem/progenitor cells following treatment with curcumin and piperine. We show that curcumin targets both stem cell populations by down-regulating expression of breast stem cell genes including ALDH1A3, CD49f, PROM1, and TP63. We also identified novel genes and pathways targeted by curcumin, including downregulation of SCD. Transient siRNA knockdown of SCD in MCF10A cells significantly inhibited mammosphere formation and the mean proportion of CD44+/CD24- cells, suggesting that SCD is a regulator of breast stemness and a target of curcumin in breast stem cells. These findings extend previous reports of curcumin targeting stem cells, here in two phenotypically distinct stem/progenitor populations isolated from normal human breast tissue. We identified novel mechanisms by which curcumin and piperine target breast stem cell self-renewal, such as by targeting lipid metabolism, providing a mechanistic link between curcumin treatment and stem cell self-renewal. These results elucidate the mechanisms by which curcumin may act as a cancer-preventive compound and provide novel targets for cancer prevention and treatment.

Sexual Health Behavior Interventions for U.S. Latino Adolescents: A Systematic Review of the Literature

PubMed Central

Cardoza, Vicky J.; Documét, Patricia I.; Fryer, Craig S.; Gold, Melanie A.; Butler, James

2012-01-01

Study Objective To identify sexual health behavior interventions targeting U.S. Latino adolescents. Design A systematic literature review. Setting Peer-reviewed articles published between 1993 and 2011, conducted in any type of setting. Participants Male and female Latino adolescents ages 11–21 years. Interventions Interventions promoting sexual abstinence, pregnancy prevention, sexually transmitted infection (STI) prevention, and/or HIV/AIDS prevention. Main Outcome Measures Changes in knowledge, attitudes, engagement in risky sexual behaviors, rates of STIs, and/or pregnancy. Results Sixty-eight articles were identified. Fifteen were included in this review that specifically addressed Latino adolescent sexual health behavior. Among the reviewed interventions, most aimed to prevent or reduce STI and HIV/AIDS incidence by focusing on behavior change at two levels of the social ecological model: individual and interpersonal. Major strengths of the articles included addressing the most critical issues of sexual health; using social ecological approaches; employing different strategies to deliver sexual health messages; and employing different intervention designs in diverse geographical locations with the largest population of Latino communities. Most of the interventions targeted female adolescents, stressing the need for additional interventions that target Latino adolescent males. Conclusions Latino adolescent sexual health is a new research field with gaps that need to be addressed in reducing negative sexual health outcomes among this population. More research is needed to produce new or validate existing, age-specific, and culturally-sensitive sexual health interventions for Latino male and female adolescents. Further, this research should also be conducted in areas of the U.S. with the newest Latino migration (e.g., North Carolina). PMID:22206687

The development of a population of 4D pediatric XCAT phantoms for CT imaging research and optimization

NASA Astrophysics Data System (ADS)

Norris, Hannah; Zhang, Yakun; Frush, Jack; Sturgeon, Gregory M.; Minhas, Anum; Tward, Daniel J.; Ratnanather, J. Tilak; Miller, M. I.; Frush, Donald; Samei, Ehsan; Segars, W. Paul

2014-03-01

With the increased use of CT examinations, the associated radiation dose has become a large concern, especially for pediatrics. Much research has focused on reducing radiation dose through new scanning and reconstruction methods. Computational phantoms provide an effective and efficient means for evaluating image quality, patient-specific dose, and organ-specific dose in CT. We previously developed a set of highly-detailed 4D reference pediatric XCAT phantoms at ages of newborn, 1, 5, 10, and 15 years with organ and tissues masses matched to ICRP Publication 89 values. We now extend this reference set to a series of 64 pediatric phantoms of a variety of ages and height and weight percentiles, representative of the public at large. High resolution PET-CT data was reviewed by a practicing experienced radiologist for anatomic regularity and was then segmented with manual and semi-automatic methods to form a target model. A Multi-Channel Large Deformation Diffeomorphic Metric Mapping (MC-LDDMM) algorithm was used to calculate the transform from the best age matching pediatric reference phantom to the patient target. The transform was used to complete the target, filling in the non-segmented structures and defining models for the cardiac and respiratory motions. The complete phantoms, consisting of thousands of structures, were then manually inspected for anatomical accuracy. 3D CT data was simulated from the phantoms to demonstrate their ability to generate realistic, patient quality imaging data. The population of pediatric phantoms developed in this work provides a vital tool to investigate dose reduction techniques in 3D and 4D pediatric CT.

Self-focusing therapeutic gene delivery with intelligent gene vector swarms: intra-swarm signalling through receptor transgene expression in targeted cells.

PubMed

Tolmachov, Oleg E

2015-01-01

Gene delivery in vivo that is tightly focused on the intended target cells is essential to maximize the benefits of gene therapy and to reduce unwanted side-effects. Cell surface markers are immediately available for probing by therapeutic gene vectors and are often used to direct gene transfer with these vectors to specific target cell populations. However, it is not unusual for the choice of available extra-cellular markers to be too scarce to provide a reliable definition of the desired therapeutically relevant set of target cells. Therefore, interrogation of intra-cellular determinants of cell-specificity, such as tissue-specific transcription factors, can be vital in order to provide detailed cell-guiding information to gene vector particles. An important improvement in cell-specific gene delivery can be achieved through auto-buildup in vector homing efficiency using intelligent 'self-focusing' of swarms of vector particles on target cells. Vector self-focusing was previously suggested to rely on the release of diffusible chemo-attractants after a successful target-specific hit by 'scout' vector particles. I hypothesize that intelligent self-focusing behaviour of swarms of cell-targeted therapeutic gene vectors can be accomplished without the employment of difficult-to-use diffusible chemo-attractants, instead relying on the intra-swarm signalling through cells expressing a non-diffusible extra-cellular receptor for the gene vectors. In the proposed model, cell-guiding information is gathered by the 'scout' gene vector particles, which: (1) attach to a variety of cells via a weakly binding (low affinity) receptor; (2) successfully facilitate gene transfer into these cells; (3) query intra-cellular determinants of cell-specificity with their transgene expression control elements and (4) direct the cell-specific biosynthesis of a vector-encoded strongly binding (high affinity) cell-surface receptor. Free members of the vector swarm loaded with therapeutic cargo are then attracted to and internalized into the intended target cells via the expressed cognate strongly binding extra-cellular receptor, causing escalation of gene transfer into these cells and increasing the copy number of the therapeutic gene expression modules. Such self-focusing swarms of gene vectors can be either homogeneous, with 'scout' and 'therapeutic' members of the swarm being structurally identical, or, alternatively, heterogeneous (split), with 'scout' and 'therapeutic' members of the swarm being structurally specialized. It is hoped that the proposed self-focusing cell-targeted gene vector swarms with receptor-mediated intra-swarm signalling could be particularly effective in 'top-up' gene delivery scenarios, achieving high-level and sustained expression of therapeutic transgenes that are prone to shut-down through degradation and silencing. Crucially, in contrast to low-precision 'general location' vector guidance by diffusible chemo-attractants, ear-marking non-diffusible receptors can provide high-accuracy targeting of therapeutic vector particles to the specific cell, which has undergone a 'successful cell-specific hit' by a 'scout' vector particle. Opportunities for cell targeting could be expanded, since in the proposed model of self-focusing it could be possible to probe a broad selection of intra-cellular determinants of cell-specificity and not just to rely exclusively on extra-cellular markers of cell-specificity. By employing such self-focusing gene vectors for the improvement of cell-targeted delivery of therapeutic genes, e.g., in cancer therapy or gene addition therapy of recessive genetic diseases, it could be possible to broaden a leeway for the reduction of the vector load and, consequently, to minimize undesired vector cytotoxicity, immune reactions, and the risk of inadvertent genetic modification of germline cells in genetic treatment in vivo. Copyright © 2014 Elsevier B.V. All rights reserved.

Vaccine herd effect

PubMed Central

Kim, Tae Hyong; Johnstone, Jennie; Loeb, Mark

2011-01-01

Vaccination ideally protects susceptible populations at high risk for complications of the infection. However, vaccines for these subgroups do not always provide sufficient effectiveness. The herd effect or herd immunity is an attractive way to extend vaccine benefits beyond the directly targeted population. It refers to the indirect protection of unvaccinated persons, whereby an increase in the prevalence of immunity by the vaccine prevents circulation of infectious agents in susceptible populations. The herd effect has had a major impact in the eradication of smallpox, has reduced transmission of pertussis, and protects against influenza and pneumococcal disease. A high uptake of vaccines is generally needed for success. In this paper we aim to provide an update review on the herd effect, focusing on the clinical benefit, by reviewing data for specific vaccines. PMID:21604922

A safety assessment of biological therapies targeting the IL-23/IL-17 axis in inflammatory bowel diseases.

PubMed

Verstockt, Bram; Deleenheer, Barbara; Van Assche, Gert; Vermeire, Séverine; Ferrante, Marc

2017-07-01

Many different compounds targeting the interleukin 23/17 axis have been developed and successfully studied in several autoimmune diseases, including inflammatory bowel diseases. Nevertheless, interfering with key immunological pathways raises potential safety concerns. This review focuses on the safety profile of these novel biological therapies. Areas covered: A literature search until March 2017 was performed to collect safety data on different compounds targeting this pathway, with emphasis on ustekinumab and secukinumab. Firstly, the authors discuss briefly how genetics can inform about potential safety issues. Secondly, they extensively describe safety issues (common adverse events, infections, malignancies…), immunogenicity, exposure to ustekinumab in specific populations and provide advice for vaccination. Finally, they address safety profiles of secukinumab and other biological targeting the IL-23/17 axis in IBD. Expert opinion: Current evidence suggests that ustekinumab therapy overweigh the potential drug-related risks. Additional safety data beyond randomized-controlled trials, derived from statistically powered, large prospective studies with long-term follow-up are urgently needed to assess the real-life ustekinumab-related risks and to establish the correct position of these novel class of biologicals in IBD treatment. Combining immunomodulators with ustekinumab seems to be safe, though prospective data specifically addressing this topic are currently missing. Similarly, the combination of different biological therapies still has to be studied.

Systematic approach identifies RHOA as a potential biomarker therapeutic target for Asian gastric cancer.

PubMed

Chang, Hae Ryung; Nam, Seungyoon; Lee, Jinhyuk; Kim, Jin-Hee; Jung, Hae Rim; Park, Hee Seo; Park, Sungjin; Ahn, Young Zoo; Huh, Iksoo; Balch, Curt; Ku, Ja-Lok; Powis, Garth; Park, Taesung; Jeong, Jin-Hyun; Kim, Yon Hui

2016-12-06

Gastric cancer (GC) is a highly heterogeneous disease, in dire need of specific, biomarker-driven cancer therapies. While the accumulation of cancer "Big Data" has propelled the search for novel molecular targets for GC, its specific subpathway and cellular functions vary from patient to patient. In particular, mutations in the small GTPase gene RHOA have been identified in recent genome-wide sequencing of GC tumors. Moreover, protein overexpression of RHOA was reported in Chinese populations, while RHOA mutations were found in Caucasian GC tumors. To develop evidence-based precision medicine for heterogeneous cancers, we established a systematic approach to integrate transcriptomic and genomic data. Predicted signaling subpathways were then laboratory-validated both in vitro and in vivo, resulting in the identification of new candidate therapeutic targets. Here, we show: i) differences in RHOA expression patterns, and its pathway activity, between Asian and Caucasian GC tumors; ii) in vitro and in vivo perturbed RHOA expression inhibits GC cell growth in high RHOA-expressing cell lines; iii) inverse correlation between RHOA and RHOB expression; and iv) an innovative small molecule design strategy for RHOA inhibitors. In summary, RHOA, and its oncogenic signaling pathway, represent a strong biomarker-driven therapeutic target for Asian GC. This comprehensive strategy represents a promising approach for the development of "hit" compounds.

Therapies targeting cancer stem cells: Current trends and future challenges

PubMed Central

Dragu, Denisa L; Necula, Laura G; Bleotu, Coralia; Diaconu, Carmen C; Chivu-Economescu, Mihaela

2015-01-01

Traditional therapies against cancer, chemo- and radiotherapy, have multiple limitations that lead to treatment failure and cancer recurrence. These limitations are related to systemic and local toxicity, while treatment failure and cancer relapse are due to drug resistance and self-renewal, properties of a small population of tumor cells called cancer stem cells (CSCs). These cells are involved in cancer initiation, maintenance, metastasis and recurrence. Therefore, in order to develop efficient treatments that can induce a long-lasting clinical response preventing tumor relapse it is important to develop drugs that can specifically target and eliminate CSCs. Recent identification of surface markers and understanding of molecular feature associated with CSC phenotype helped with the design of effective treatments. In this review we discuss targeting surface biomarkers, signaling pathways that regulate CSCs self-renewal and differentiation, drug-efflux pumps involved in apoptosis resistance, microenvironmental signals that sustain CSCs growth, manipulation of miRNA expression, and induction of CSCs apoptosis and differentiation, with specific aim to hamper CSCs regeneration and cancer relapse. Some of these agents are under evaluation in preclinical and clinical studies, most of them for using in combination with traditional therapies. The combined therapy using conventional anticancer drugs with CSCs-targeting agents, may offer a promising strategy for management and eradication of different types of cancers. PMID:26516409

Sexual Behavior Among Persons With Cognitive Impairments.

PubMed

Thom, Robyn P; Grudzinskas, Albert J; Saleh, Fabian M

2017-05-01

Although the cognitively impaired are frequently included in heterogeneous studies of problematic sexual behavior, the epidemiology, etiology, and approach to assessment and treatment of persons with dementia and intellectual disability are distinct from those of the general population. The incidence of inappropriate sexual behavior among the intellectually disabled is 15-33%; however, the nature tends to be more socially inappropriate than with violative intent. Limited sociosexual education is a large contributor, and better addressing this area offers a target for prevention and treatment. A thorough clinical assessment of problematic sexual behaviors in the cognitively impaired requires understanding the patient's internal experience, which can be challenging. Assessment tools validated for the general population have not been validated for this population. Very few studies have assessed treatment approaches specifically among the cognitively impaired; however, research does suggest utility in habilitative, psychotherapeutic, and pharmacologic approaches which have been validated among the general population.

Rapid estimation of microbial populations in fish samples by using terminal restriction fragment length polymorphism analysis of 16S rDNA.

PubMed

Tanaka, Yuichiro; Takahashi, Hajime; Kitazawa, Nao; Kimura, Bon

2010-01-01

A rapid system using terminal restriction fragment length polymorphism (T-RFLP) analysis targeting 16S rDNA is described for microbial population analysis in edible fish samples. The defined terminal restriction fragment database was constructed by collecting 102 strains of bacteria representing 53 genera that are associated with fish. Digestion of these 102 strains with two restriction enzymes, HhaI and MspI, formed 54 pattern groups with discrimination to the genus level. This T-RFLP system produced results comparable to those from a culture-based method in six natural fish samples with a qualitative correspondence of 71.4 to 92.3%. Using the T-RFLP system allowed an estimation of the microbial population within 7 h. Rapid assay of the microbial population is advantageous for food manufacturers and testing laboratories; moreover, the strategy presented here allows adaptation to specific testing applications.

A systematic review of interventions to increase breast and cervical cancer screening uptake among Asian women

PubMed Central

2012-01-01

Background The Asian population is one of the fastest growing ethnic minority groups in western countries. However, cancer screening uptake is consistently lower in this group than in the native-born populations. As a first step towards developing an effective cancer screening intervention program targeting Asian women, we conducted a comprehensive systematic review, without geographic, language or date limitations, to update current knowledge on the effectiveness of existing intervention strategies to enhance breast and cervical screening uptake in Asian women. Methods This study systematically reviewed studies published as of January 2010 to synthesize knowledge about effectiveness of cancer screening interventions targeting Asian women. Fifteen multidisciplinary peer-reviewed and grey literature databases were searched to identify relevant studies. Results The results of our systematic review were reported in accordance with the PRISMA Statement. Of 37 selected intervention studies, only 18 studies included valid outcome measures (i.e. self-reported or recorded receipt of mammograms or Pap smear). 11 of the 18 intervention studies with valid outcome measures used multiple intervention strategies to target individuals in a specific Asian ethnic group. This observed pattern of intervention design supports the hypothesis that employing a combination of multiple strategies is more likely to be successful than single interventions. The effectiveness of community-based or workplace-based group education programs increases when additional supports, such as assistance in scheduling/attending screening and mobile screening services are provided. Combining cultural awareness training for health care professionals with outreach workers who can help healthcare professionals overcome language and cultural barriers is likely to improve cancer screening uptake. Media campaigns and mailed culturally sensitive print materials alone may be ineffective in increasing screening uptake. Intervention effectiveness appears to vary with ethnic population, methods of program delivery, and study setting. Conclusions Despite some limitations, our review has demonstrated that the effectiveness of existing interventions to promote breast and cervical cancer screening uptake in Asian women may hinge on a variety of factors, such as type of intervention and study population characteristics. While some studies demonstrated the effectiveness of certain intervention programs, the cost effectiveness and long-term sustainability of these programs remain questionable. When adopting an intervention program, it is important to consider the impacts of social-and cultural factors specific to the Asian population on cancer screening uptake. Future research is needed to develop new interventions and tools, and adopt vigorous study design and evaluation methodologies to increase cancer screening among Asian women to promote population health and health equity. PMID:22676147

A systematic review of interventions to increase breast and cervical cancer screening uptake among Asian women.

PubMed

Lu, Mingshan; Moritz, Sabina; Lorenzetti, Diane; Sykes, Lindsay; Straus, Sharon; Quan, Hude

2012-06-07

The Asian population is one of the fastest growing ethnic minority groups in western countries. However, cancer screening uptake is consistently lower in this group than in the native-born populations. As a first step towards developing an effective cancer screening intervention program targeting Asian women, we conducted a comprehensive systematic review, without geographic, language or date limitations, to update current knowledge on the effectiveness of existing intervention strategies to enhance breast and cervical screening uptake in Asian women. This study systematically reviewed studies published as of January 2010 to synthesize knowledge about effectiveness of cancer screening interventions targeting Asian women. Fifteen multidisciplinary peer-reviewed and grey literature databases were searched to identify relevant studies. The results of our systematic review were reported in accordance with the PRISMA Statement. Of 37 selected intervention studies, only 18 studies included valid outcome measures (i.e. self-reported or recorded receipt of mammograms or Pap smear). 11 of the 18 intervention studies with valid outcome measures used multiple intervention strategies to target individuals in a specific Asian ethnic group. This observed pattern of intervention design supports the hypothesis that employing a combination of multiple strategies is more likely to be successful than single interventions. The effectiveness of community-based or workplace-based group education programs increases when additional supports, such as assistance in scheduling/attending screening and mobile screening services are provided. Combining cultural awareness training for health care professionals with outreach workers who can help healthcare professionals overcome language and cultural barriers is likely to improve cancer screening uptake. Media campaigns and mailed culturally sensitive print materials alone may be ineffective in increasing screening uptake. Intervention effectiveness appears to vary with ethnic population, methods of program delivery, and study setting. Despite some limitations, our review has demonstrated that the effectiveness of existing interventions to promote breast and cervical cancer screening uptake in Asian women may hinge on a variety of factors, such as type of intervention and study population characteristics. While some studies demonstrated the effectiveness of certain intervention programs, the cost effectiveness and long-term sustainability of these programs remain questionable. When adopting an intervention program, it is important to consider the impacts of social-and cultural factors specific to the Asian population on cancer screening uptake. Future research is needed to develop new interventions and tools, and adopt vigorous study design and evaluation methodologies to increase cancer screening among Asian women to promote population health and health equity.

Targeting a Dark Excited State of HIV-1 Nucleocapsid by Antiretroviral Thioesters Revealed by NMR Spectroscopy.

PubMed

Deshmukh, Lalit; Tugarinov, Vitali; Appella, Daniel H; Clore, G Marius

2018-03-01

HIV-1 nucleocapsid (NCp7) is a two Cys 2 HisCys zinc knuckle (N-Zn and C-Zn) protein that plays a key role in viral replication. NCp7 conformational dynamics is characterized by NMR relaxation dispersion and chemical exchange saturation transfer measurements. While the N-Zn knuckle is conformationally stable, the C-Zn knuckle interconverts on the millisecond timescale between the major state, in which the zinc is coordinated by three cysteines and a histidine, and two folded minor species (with populations around 1 %) in which one of the coordination bonds (Cys413-Sγ-Zn or His421-Nϵ2-Zn) is hydrolyzed. These findings explain why antiretroviral thioesters specifically disrupt the C-Zn knuckle by initial acylation of Cys413, and show that transient, sparsely-populated ("dark"), excited states of proteins can present effective targets for rational drug design. © 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

Tobacco, Marijuana, and Alcohol Use in University Students: A Cluster Analysis

PubMed Central

Primack, Brian A.; Kim, Kevin H.; Shensa, Ariel; Sidani, Jaime E.; Barnett, Tracey E.; Switzer, Galen E.

2012-01-01

Objective Segmentation of populations may facilitate development of targeted substance abuse prevention programs. We aimed to partition a national sample of university students according to profiles based on substance use. Participants We used 2008–2009 data from the National College Health Assessment from the American College Health Association. Our sample consisted of 111,245 individuals from 158 institutions. Method We partitioned the sample using cluster analysis according to current substance use behaviors. We examined the association of cluster membership with individual and institutional characteristics. Results Cluster analysis yielded six distinct clusters. Three individual factors—gender, year in school, and fraternity/sorority membership—were the most strongly associated with cluster membership. Conclusions In a large sample of university students, we were able to identify six distinct patterns of substance abuse. It may be valuable to target specific populations of college-aged substance users based on individual factors. However, comprehensive intervention will require a multifaceted approach. PMID:22686360

Population-based HPV vaccination programmes are safe and effective: 2017 update and the impetus for achieving better global coverage.

PubMed

Brotherton, Julia M L; Bloem, Paul N

2018-02-01

Persistent oncogenic human papillomavirus (HPV) is the cause of cervical cancer, as well as cancers of the anus, penis, vulva, vagina and oropharynx. There is good evidence that prophylactic HPV vaccines are immunogenic and effective against targeted-type HPV infections and type-specific genital lesions, including high-grade cervical intraepithelial neoplasia (CIN), when administered prior to HPV infection. There is good evidence that HPV vaccines are safe in population usage, with the most frequent adverse event being injection-site reactions. There is evidence to support some cross-protection against non-targeted types occurring following the administration of HPV vaccines. There is limited evidence suggesting that HPV vaccines may be beneficial in preventing future disease in women treated for high-grade CIN. This chapter focuses on the accumulated evidence regarding the global use of the three licensed HPV vaccines including safety, immunogenicity, duration of protection, effectiveness, coverage to date and barriers to higher coverage. Copyright © 2018 Elsevier Ltd. All rights reserved.

Managing Cardiovascular Disease Risk in Rheumatoid Arthritis: Clinical Updates and Three Strategic Approaches.

PubMed

Chodara, Ann M; Wattiaux, Aimée; Bartels, Christie M

2017-04-01

ᅟ: The increase in cardiovascular disease (CVD) risk in rheumatoid arthritis (RA) is well known; however, appropriate management of this elevated risk in rheumatology clinics is less clear. By critically reviewing literature published within the past 5 years, we aim to clarify current knowledge and gaps regarding CVD risk management in RA. We examine recent guidelines, recommendations, and evidence and discuss three approaches: (1) RA-specific management including treat-to-target and medication management, (2) assessment of comprehensive individual risk, and (3) targeting traditional CVD risk factors (hypertension, smoking, hyperlipidemia, diabetes, obesity, and physical inactivity) at a population level. Considering that 75% of US RA visits occur in specialty clinics, further research is needed regarding evidence-based strategies to manage and reduce CVD risk in RA. This review highlights clinical updates including US cardiology and international professional society guidelines, successful evidence-based population approaches from primary care, and novel opportunities in rheumatology care to reduce CVD risk in RA.

Avoiding 40% of the premature deaths in each country, 2010-30: review of national mortality trends to help quantify the UN sustainable development goal for health.

PubMed

Norheim, Ole F; Jha, Prabhat; Admasu, Kesetebirhan; Godal, Tore; Hum, Ryan J; Kruk, Margaret E; Gómez-Dantés, Octavio; Mathers, Colin D; Pan, Hongchao; Sepúlveda, Jaime; Suraweera, Wilson; Verguet, Stéphane; Woldemariam, Addis T; Yamey, Gavin; Jamison, Dean T; Peto, Richard

2015-01-17

The UN will formulate ambitious Sustainable Development Goals for 2030, including one for health. Feasible goals with some quantifiable, measurable targets can influence governments. We propose, as a quatitative health target, "Avoid in each country 40% of premature deaths (under-70 deaths that would be seen in the 2030 population at 2010 death rates), and improve health care at all ages". Targeting overall mortality and improved health care ignores no modifiable cause of death, nor any cause of disability that is treatable (or also causes many deaths). 40% fewer premature deaths would be important in all countries, but implies very different priorities in different populations. Reinforcing this target for overall mortality in each country are four global subtargets for 2030: avoid two-thirds of child and maternal deaths; two-thirds of tuberculosis, HIV, and malaria deaths; a third of premature deaths from non-communicable diseases (NCDs); and a third of those from other causes (other communicable diseases, undernutrition, and injuries). These challenging subtargets would halve under-50 deaths, avoid a third of the (mainly NCD) deaths at ages 50-69 years, and so avoid 40% of under-70 deaths. To help assess feasibility, we review mortality rates and trends in the 25 most populous countries, in four country income groupings, and worldwide. UN sources yielded overall 1970-2010 mortality trends. WHO sources yielded cause-specific 2000-10 trends, standardised to country-specific 2030 populations; decreases per decade of 42% or 18% would yield 20-year reductions of two-thirds or a third. Throughout the world, except in countries where the effects of HIV or political disturbances predominated, mortality decreased substantially from 1970-2010, particularly in childhood. From 2000-10, under-70 age-standardised mortality rates decreased 19% (with the low-income and lower-middle-income countries having the greatest absolute gains). The proportional decreases per decade (2000-10) were: 34% at ages 0-4 years; 17% at ages 5-49 years; 15% at ages 50-69 years; 30% for communicable, perinatal, maternal, or nutritional causes; 14% for NCDs; and 13% for injuries (accident, suicide, or homicide). Moderate acceleration of the 2000-10 proportional decreases in mortality could be feasible, achieving the targeted 2030 disease-specific reductions of two-thirds or a third. If achieved, these reductions avoid about 10 million of the 20 million deaths at ages 0-49 years that would be seen in 2030 at 2010 death rates, and about 17 million of the 41 million such deaths at ages 0-69 years. Such changes could be achievable by 2030, or soon afterwards, at least in areas free of war, other major effects of political disruption, or a major new epidemic. UK Medical Research Council, Norwegian Agency for Development Cooperation, Centre for Global Health Research, and Bill & Melinda Gates Foundation. Copyright © 2015 Norheim et al. Open Access article distributed under the terms of CC BY-NC-SA. Published by Elsevier Ltd. All rights reserved.

Advances in plant virus evolution: translating evolutionary insights into better disease management.

PubMed

Acosta-Leal, R; Duffy, S; Xiong, Z; Hammond, R W; Elena, S F

2011-10-01

Recent studies in plant virus evolution are revealing that genetic structure and behavior of virus and viroid populations can explain important pathogenic properties of these agents, such as host resistance breakdown, disease severity, and host shifting, among others. Genetic variation is essential for the survival of organisms. The exploration of how these subcellular parasites generate and maintain a certain frequency of mutations at the intra- and inter-host levels is revealing novel molecular virus-plant interactions. They emphasize the role of host environment in the dynamic genetic composition of virus populations. Functional genomics has identified host factors that are transcriptionally altered after virus infections. The analyses of these data by means of systems biology approaches are uncovering critical plant genes specifically targeted by viruses during host adaptation. Also, a next-generation resequencing approach of a whole virus genome is opening new avenues to study virus recombination and the relationships between intra-host virus composition and pathogenesis. Altogether, the analyzed data indicate that systematic disruption of some specific parameters of evolving virus populations could lead to more efficient ways of disease prevention, eradication, or tolerable virus-plant coexistence.

Progress towards the child mortality millennium development goal in urban sub-Saharan Africa: the dynamics of population growth, immunization, and access to clean water.

PubMed

Fotso, Jean-Christophe; Ezeh, Alex Chika; Madise, Nyovani Janet; Ciera, James

2007-08-28

Improvements in child survival have been very poor in sub-Saharan Africa (SSA). Since the 1990 s, declines in child mortality have reversed in many countries in the region, while in others, they have either slowed or stalled, making it improbable that the target of reducing child mortality by two thirds by 2015 will be reached. This paper highlights the implications of urban population growth and access to health and social services on progress in achieving MDG 4. Specifically, it examines trends in childhood mortality in SSA in relation to urban population growth, vaccination coverage and access to safe drinking water. Correlation methods are used to analyze national-level data from the Demographic and Health Surveys and from the United Nations. The analysis is complemented by case studies on intra-urban health differences in Kenya and Zambia. Only five of the 22 countries included in the study have recorded declines in urban child mortality that are in line with the MDG target of about 4% per year; five others have recorded an increase; and the 12 remaining countries witnessed only minimal decline. More rapid rate of urban population growth is associated with negative trend in access to safe drinking water and in vaccination coverage, and ultimately to increasing or timid declines in child mortality. There is evidence of intra-urban disparities in child health in some countries like Kenya and Zambia. Failing to appropriately target the growing sub-group of the urban poor and improve their living conditions and health status - which is an MDG target itself - may result in lack of improvement on national indicators of health. Sustained expansion of potable water supplies and vaccination coverage among the disadvantaged urban dwellers should be given priority in the efforts to achieve the child mortality MDG in SSA.

The economic dimensions of malnutrition in young children.

PubMed

Reutlinger, S; Selowsky, M

1979-06-01

1 billion people - 1/3 of them children under the age of 10 - live on diets that are deficient in essential calories. Focus in this discussion is on the magnitude of the problem. The economic implications of specific intervention programs designed to solve the problem are reviewed. Caloric intake is closely associated with per capita income, and malnutrition characterizes the poorest segments of the population. Since the lowest-income groups have larger families, the incidence of malnutrition among children is certain to be higher than the incidence among adults. 3 factors will determine whether, on the basis of current trends, caloric malnutrition can be expected to be eliminated among the poorest segments of the population of the development countries: 1) the future income growth of the malnourished groups; 2) their propensity to use additional income to increase their caloric consumption; and 3) the future changes in the relative price of the main staples, basically cereals. The problem of malnutrition cannot be resolved quickly enough without explicit measures to raise the level of caloric consumption. Governments can initiate a wide range of programs and policies in an effort to augment the caloric consumption of children in the target population - transfer of cash to target households, target group oriented food programs, and food stamps for certain groups. In order for a food program to have more of an effect on consumption than would an equivalent transfer of income, 2 conditions need to be met: 1) the food must be made available at lower prices and in larger quantities than that previously consumed; and 2) reselling of the food must be precluded. In sum, the only effective solution for dealing with the problem of malnutrition among children of developing countries is either a more equitable distribution of income or supplying the food to the target population at a price far below its normally supply price.

Shark Attack: high affinity binding proteins derived from shark vNAR domains by stepwise in vitro affinity maturation.

PubMed

Zielonka, Stefan; Weber, Niklas; Becker, Stefan; Doerner, Achim; Christmann, Andreas; Christmann, Christine; Uth, Christina; Fritz, Janine; Schäfer, Elena; Steinmann, Björn; Empting, Martin; Ockelmann, Pia; Lierz, Michael; Kolmar, Harald

2014-12-10

A novel method for stepwise in vitro affinity maturation of antigen-specific shark vNAR domains is described that exclusively relies on semi-synthetic repertoires derived from non-immunized sharks. Target-specific molecules were selected from a CDR3-randomized bamboo shark (Chiloscyllium plagiosum) vNAR library using yeast surface display as platform technology. Various antigen-binding vNAR domains were easily isolated by screening against several therapeutically relevant antigens, including the epithelial cell adhesion molecule (EpCAM), the Ephrin type-A receptor 2 (EphA2), and the human serine protease HTRA1. Affinity maturation was demonstrated for EpCAM and HTRA1 by diversifying CDR1 of target-enriched populations which allowed for the rapid selection of nanomolar binders. EpCAM-specific vNAR molecules were produced as soluble proteins and more extensively characterized via thermal shift assays and biolayer interferometry. Essentially, we demonstrate that high-affinity binders can be generated in vitro without largely compromising the desirable high thermostability of the vNAR scaffold. Copyright © 2014 Elsevier B.V. All rights reserved.

Cost effectiveness of a government supported policy strategy to decrease sodium intake: global analysis across 183 nations.

PubMed

Webb, Michael; Fahimi, Saman; Singh, Gitanjali M; Khatibzadeh, Shahab; Micha, Renata; Powles, John; Mozaffarian, Dariush

2017-01-10

 To quantify the cost effectiveness of a government policy combining targeted industry agreements and public education to reduce sodium intake in 183 countries worldwide.  Global modeling study.  183 countries.  Full adult population in each country.  A "soft regulation" national policy that combines targeted industry agreements, government monitoring, and public education to reduce population sodium intake, modeled on the recent successful UK program. To account for heterogeneity in efficacy across countries, a range of scenarios were evaluated, including 10%, 30%, 0.5 g/day, and 1.5 g/day sodium reductions achieved over 10 years. We characterized global sodium intakes, blood pressure levels, effects of sodium on blood pressure and of blood pressure on cardiovascular disease, and cardiovascular disease rates in 2010, each by age and sex, in 183 countries. Country specific costs of a sodium reduction policy were estimated using the World Health Organization Noncommunicable Disease Costing Tool. Country specific impacts on mortality and disability adjusted life years (DALYs) were modeled using comparative risk assessment. We only evaluated program costs, without incorporating potential healthcare savings from prevented events, to provide conservative estimates of cost effectiveness MAIN OUTCOME MEASURE:  Cost effectiveness ratio, evaluated as purchasing power parity adjusted international dollars (equivalent to the country specific purchasing power of US$) per DALY saved over 10 years.  Worldwide, a 10% reduction in sodium consumption over 10 years within each country was projected to avert approximately 5.8 million DALYs/year related to cardiovascular diseases, at a population weighted mean cost of I$1.13 per capita over the 10 year intervention. The population weighted mean cost effectiveness ratio was approximately I$204/DALY. Across nine world regions, estimated cost effectiveness of sodium reduction was best in South Asia (I$116/DALY); across the world's 30 most populous countries, best in Uzbekistan (I$26.08/DALY) and Myanmar (I$33.30/DALY). Cost effectiveness was lowest in Australia/New Zealand (I$880/DALY, or 0.02×gross domestic product (GDP) per capita), although still substantially better than standard thresholds for cost effective (<3.0×GDP per capita) or highly cost effective (<1.0×GDP per capita) interventions. Most (96.0%) of the world's adult population lived in countries in which this intervention had a cost effectiveness ratio <0.1×GDP per capita, and 99.6% in countries with a cost effectiveness ratio <1.0×GDP per capita.  A government "soft regulation" strategy combining targeted industry agreements and public education to reduce dietary sodium is projected to be highly cost effective worldwide, even without accounting for potential healthcare savings. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.

RNA therapeutics targeting osteoclast-mediated excessive bone resorption

PubMed Central

Wang, Yuwei; Grainger, David W

2011-01-01

RNA interference (RNAi) is a sequence-specific post-transcriptional gene silencing technique developed with dramatically increasing utility for both scientific and therapeutic purposes. Short interfering RNA (siRNA) is currently exploited to regulate protein expression relevant to many therapeutic applications, and commonly used as a tool for elucidating disease-associated genes. Osteoporosis and their associated osteoporotic fragility fractures in both men and women are rapidly becoming a global healthcare crisis as average life expectancy increases worldwide. New therapeutics are needed for this increasing patient population. This review describes the diversity of molecular targets suitable for RNAi-based gene knock-down in osteoclasts to control osteoclast-mediated excessive bone resorption. We identify strategies for developing targeted siRNA delivery and efficient gene silencing, and describe opportunities and challenges of introducing siRNA as a therapeutic approach to hard and connective tissue disorders. PMID:21945356

Cystic Fibrosis and Its Management Through Established and Emerging Therapies.

PubMed

Spielberg, David R; Clancy, John P

2016-08-31

Cystic fibrosis (CF) is the most common life-shortening autosomal recessive disorder in the Caucasian population and occurs in many other ethnicities worldwide. The daily treatment burden is substantial for CF patients even when they are well, with numerous pharmacologic and physical therapies targeting lung disease requiring the greatest time commitment. CF treatments continue to advance with greater understanding of factors influencing long-term morbidity and mortality. In recent years, in-depth understanding of genetic and protein structure-function relationships has led to the introduction of targeted therapies for patients with specific CF genotypes. With these advances, CF has become a model of personalized or precision medicine. The near future will see greater access to targeted therapies for most patients carrying common mutations, which will mandate individualized bench-to-bedside methodologies for those with rare genotypes.

Using experimental evolution to identify druggable targets that could inhibit the evolution of antimicrobial resistance

PubMed Central

Mehta, Heer H.; Prater, Amy G.; Shamoo, Yousif

2017-01-01

With multi-drug and pan-drug resistant bacteria becoming increasingly common in hospitals, antibiotic resistance has threatened to return us to a pre-antibiotic era that would completely undermine modern medicine. There is an urgent need to develop new antibiotics and strategies to combat resistance that are substantially different from earlier drug discovery efforts. One such strategy that would complement current and future antibiotics would be a class of co-drugs that target the evolution of resistance and thereby extend the efficacy of specific classes of antibiotics. A critical step in the development of such strategies lies in understanding the critical evolutionary trajectories responsible for resistance and which proteins or biochemical pathways within those trajectories would be good candidates for co-drug discovery. We identify the most important steps in the evolution of resistance for a specific pathogen and antibiotic combination by evolving highly polymorphic populations of pathogens to resistance in a novel bioreactor that favors biofilm development. As the populations evolve to increasing drug concentrations, we use deep sequencing to elucidate the network of genetic changes responsible for resistance and subsequent in vitro biochemistry and often structure determination to determine how the adaptive mutations produce resistance. Importantly, the identification of the molecular steps, their frequency within the populations and their chronology within the evolutionary trajectory toward resistance is critical to assessing their relative importance. In this work, we discuss findings from the evolution of the ESKAPE pathogen, Pseudomonas aeruginosa to the drug of last resort, colistin to illustrate the power of this approach. PMID:28928474

Culturally Targeted Strategies for Diabetes Prevention in Minority Population.

PubMed

Lagisetty, Pooja A; Priyadarshini, Shubadra; Terrell, Stephanie; Hamati, Mary; Landgraf, Jessica; Chopra, Vineet; Heisler, Michele

2017-02-01

Purpose The purpose of this study is to (a) assess the effectiveness of culturally tailored diabetes prevention interventions in minority populations and (b) develop a novel framework to characterize 4 key domains of culturally tailored interventions. Prevention strategies specifically tailored to the culture of ethnic minority patients may help reduce the incidence of diabetes. Methods We searched PubMed, EMBASE, and CINAHL for English-language, randomized controlled trials (RCTs) or quasi-experimental (QE) trials testing culturally tailored interventions to prevent diabetes in minority populations. Two reviewers independently extracted data and assessed risk of bias. Inductive thematic analysis was used to develop a framework with 4 domains (FiLLM: Facilitating [ie, delivering] Interventions Through Language, Location, and Message). The framework was used to assess the overall effectiveness of culturally tailored interventions. Results Thirty-four trials met eligibility criteria. Twelve studies were RCTs, and 22 were QE trials. Twenty-five out of 34 studies (74%) that used cultural tailoring demonstrated significantly improved A1C, fasting glucose, and/or weight loss. Of the 25 successful interventions, 21 (84%) incorporated at least 3 culturally targeted domains. Seven studies used all 4 domains and were all successful. The least utilized domain was delivery (4/34) of the intervention's key educational message. Conclusions Culturally tailoring interventions across the 4 domains of facilitators, language, location, and messaging can be effective in improving risk factors for progression to diabetes among ethnic minority groups. Future studies should evaluate how specific tailoring approaches work compared to usual care as well as comparative effectiveness of each tailoring domain.

Building the Infrastructure for Value at UCLA: Engaging Clinicians and Developing Patient-Centric Measurement.

PubMed

Clarke, Robin; Hackbarth, Andrew S; Saigal, Christopher; Skootsky, Samuel A

2015-10-01

Evolving payer and patient expectations have challenged academic health centers (AHCs) to improve the value of clinical care. Traditional quality approaches may be unable to meet this challenge. One AHC, UCLA Health, has implemented a systematic approach to delivery system redesign that emphasizes clinician engagement, a patient-centric scope, and condition-specific, clinician-guided measurement. A physician champion serves as quality officer (QO) for each clinical department/division. Each QO, with support from a central measurement team, has developed customized analytics that use clinical data to define targeted populations and measure care across the full treatment episode. From October 2012 through June 2015, the approach developed rapidly. Forty-three QOs are actively redesigning care delivery protocols within their specialties, and 95% of the departments/divisions have received a customized measure report for at least one patient population. As an example of how these analytics promote systematic redesign, the authors discuss how Department of Urology physicians have used these new measures, first, to better understand the relationship between clinical practice and outcomes for patients with benign prostatic hyperplasia and, then, to work toward reducing unwarranted variation. Physicians have received these efforts positively. Early outcome data are encouraging. This infrastructure of engaged physicians and targeted measurement is being used to implement systematic care redesign that reliably achieves outcomes that are meaningful to patients and clinicians-incorporating both clinical and cost considerations. QOs are using an approach, for multiple newly launched projects, to identify, test, and implement value-oriented interventions tailored to specific patient populations.

Prostate-specific antigen screening in a high-risk population: lessons from the community and how they relate to large-scale population-based studies.

PubMed

Shelton, Jeremy B; Barocas, Daniel A; Conway, Frances; Hart, Kathleen; Nelson, Kinloch; Richstone, Lee; Gonzalez, Ricardo R; Raman, Jay D; Scherr, Douglas S

2005-05-01

To estimate the incidence of prostate cancer among African-American men and Caribbean immigrants to the United States, to assess the applicability of large-scale prostate screening trials to a community screening program, and to recruit unscreened men. African-American and Caribbean-American men were targeted with a community-based prostate cancer screening program in Jamaica, New York. Serum prostate-specific antigen determination and digital rectal examination were used to determine abnormal findings. The incidence of an abnormal screening examination was used to project the incidence of prostate cancer, which was compared with that in other reported trials. The projected incidence of prostate cancer among African-Americans and Caribbean-Americans older than 50 years was 8% and 7%, respectively, similar to that reported in other trials of African-American men. The projected incidence of prostate cancer in Caribbean-American men aged 40 to 49 years was 1%, the same as the high rate reported among Caribbean men. As in other trials, a family history of prostate cancer and age were strong predictors of abnormal findings. Of the recruited men older than 50 years, 58% had never been screened compared with 42% nationally. Large population-based screening trials have identified ethnic groups at high risk of prostate cancer. This trial detected high rates of abnormal screening findings by targeting ethnicity. The incidence of an abnormal examination was high in Caribbean-American men younger than 50 years old. Finally, this trial successfully recruited underscreened men.

Efficient genome editing by FACS enrichment of paired D10A Cas9 nickases coupled with fluorescent proteins.

PubMed

Gopalappa, Ramu; Song, Myungjae; Chandrasekaran, Arun Pandian; Das, Soumyadip; Haq, Saba; Koh, Hyun Chul; Ramakrishna, Suresh

2018-05-31

Targeted genome editing by clustered regularly interspaced short palindromic repeats (CRISPR-Cas9) raised concerns over off-target effects. The use of double-nicking strategy using paired Cas9 nickase has been developed to minimize off-target effects. However, it was reported that the efficiency of paired nickases were comparable or lower than that of either corresponding nuclease alone. Recently, we conducted a systematic comparison of the efficiencies of several paired Cas9 with their corresponding Cas9 nucleases and showed that paired D10A Cas9 nickases are sometimes more efficient than individual nucleases for gene disruption. However, sometimes the designed paired Cas9 nickases exhibited significantly lower mutation frequencies than nucleases, hampering the generation of cells containing paired Cas9 nickase-induced mutations. Here we implemented IRES peptide-conjugation of fluorescent protein to Cas9 nickase and subjected for fluorescence-activated cell sorting. The sorted cell populations are highly enriched with cells containing paired Cas9 nickase-induced mutations, by a factor of up to 40-fold as compared with the unsorted population. Furthermore, gene-disrupted single cell clones using paired nickases followed by FACS sorting strategy were generated highly efficiently, without compromising with its low off-target effects. We envision that our fluorescent protein coupled paired nickase-mediated gene disruption, facilitating efficient and highly specific genome editing in medical research.

[Prevention among migrants: Participation, migrant sensitive strategies and programme characteristics].

PubMed

Brand, T; Kleer, D; Samkange-Zeeb, F; Zeeb, Hajo

2015-06-01

Health promotion and prevention can contribute to a long, healthy life in populations both with and without migrant background. This paper provides an overview on migrant participation in prevention programmes in Germany. Furthermore, we describe migrant sensitive prevention strategies and characteristics of prevention programmes for migrants in Germany. With regard to participation in prevention programmes, lower vaccination rates are found among children and adolescents who migrated to Germany after birth. Among adults with a migrant background, we found lower participation in general health check-ups, oral health check-ups, cancer screening programs and influenza vaccination. Migrant sensitive prevention strategies address the visual style of the material, a target group specific risk communication, language requirements, a systematic involvement of the target group, and the recognition of deeply rooted sociocultural practices and beliefs. On analyzing a large database on prevention programs in Germany, we found only a few programmes that were exclusively targeted to migrant groups (0.6%). In 16.6% of the programs migrants were addressed as the target group among others. Compared to general population programs, programs for migrants were more often exclusively directed towards girls or women. Moreover, programs for migrants used community-based approaches more often and addressed different age groups. Although information on migrant participation in prevention programs and utilization of migrant sensitive strategies is still incomplete, we can assume that there is a need for diversity-oriented, migrant sensitive prevention.

CD33 monoclonal antibody conjugated Au cluster nano-bioprobe for targeted flow-cytometric detection of acute myeloid leukaemia

NASA Astrophysics Data System (ADS)

Retnakumari, Archana; Jayasimhan, Jasusri; Chandran, Parwathy; Menon, Deepthy; Nair, Shantikumar; Mony, Ullas; Koyakutty, Manzoor

2011-07-01

Protein stabilized gold nanoclusters (Au-NCs) are biocompatible, near-infrared (NIR) emitting nanosystems having a wide range of biomedical applications. Here, we report the development of a Au-NC based targeted fluorescent nano-bioprobe for the flow-cytometric detection of acute myeloid leukaemia (AML) cells. Au-NCs with ~ 25-28 atoms showing bright red-NIR fluorescence (600-750 nm) and average size of ~ 0.8 nm were prepared by bovine serum albumin assisted reduction-cum-stabilization in aqueous phase. The protein protected clusters were conjugated with monoclonal antibody against CD33 myeloid antigen, which is overexpressed in ~ 99.2% of the primitive population of AML cells, as confirmed by immunophenotyping using flow cytometry. Au-NC-CD33 conjugates having average size of ~ 12 nm retained bright fluorescence over an extended duration of ~ a year, as the albumin protein protects Au-NCs against degradation. Nanotoxicity studies revealed excellent biocompatibility of Au-NC conjugates, as they showed no adverse effect on the cell viability and inflammatory response. Target specificity of the conjugates for detecting CD33 expressing AML cells (KG1a) in flow cytometry showed specific staining of ~ 95.4% of leukaemia cells within 1-2 h compared to a non-specific uptake of ~ 8.2% in human peripheral blood cells (PBMCs) which are CD33low. The confocal imaging also demonstrated the targeted uptake of CD33 conjugated Au-NCs by leukaemia cells, thus confirming the flow cytometry results. This study demonstrates that novel nano-bioprobes can be developed using protein protected fluorescent nanoclusters of Au for the molecular receptor targeted flow cytometry based detection and imaging of cancer cells.

Geographic Distribution of Disaster-Specific Emergency Department Use After Hurricane Sandy in New York City.

PubMed

Lee, David C; Smith, Silas W; Carr, Brendan G; Doran, Kelly M; Portelli, Ian; Grudzen, Corita R; Goldfrank, Lewis R

2016-06-01

We aimed to characterize the geographic distribution of post-Hurricane Sandy emergency department use in administrative flood evacuation zones of New York City. Using emergency claims data, we identified significant deviations in emergency department use after Hurricane Sandy. Using time-series analysis, we analyzed the frequency of visits for specific conditions and comorbidities to identify medically vulnerable populations who developed acute postdisaster medical needs. We found statistically significant decreases in overall post-Sandy emergency department use in New York City but increased utilization in the most vulnerable evacuation zone. In addition to dialysis- and ventilator-dependent patients, we identified that patients who were elderly or homeless or who had diabetes, dementia, cardiac conditions, limitations in mobility, or drug dependence were more likely to visit emergency departments after Hurricane Sandy. Furthermore, patients were more likely to develop drug-resistant infections, require isolation, and present for hypothermia, environmental exposures, or administrative reasons. Our study identified high-risk populations who developed acute medical and social needs in specific geographic areas after Hurricane Sandy. Our findings can inform coherent and targeted responses to disasters. Early identification of medically vulnerable populations can help to map "hot spots" requiring additional medical and social attention and prioritize resources for areas most impacted by disasters. (Disaster Med Public Health Preparedness. 2016;10:351-361).

Comparison of liver fibrosis blood tests developed for HCV with new specific tests in HIV/HCV co-infection.

PubMed

Calès, Paul; Halfon, Philippe; Batisse, Dominique; Carrat, Fabrice; Perré, Philippe; Penaranda, Guillaume; Guyader, Dominique; d'Alteroche, Louis; Fouchard-Hubert, Isabelle; Michelet, Christian; Veillon, Pascal; Lambert, Jérôme; Weiss, Laurence; Salmon, Dominique; Cacoub, Patrice

2010-08-01

We compared 5 non-specific and 2 specific blood tests for liver fibrosis in HCV/HIV co-infection. Four hundred and sixty-seven patients were included into derivation (n=183) or validation (n=284) populations. Within these populations, the diagnostic target, significant fibrosis (Metavir F > or = 2), was found in 66% and 72% of the patients, respectively. Two new fibrosis tests, FibroMeter HICV and HICV test, were constructed in the derivation population. Unadjusted AUROCs in the derivation population were: APRI: 0.716, Fib-4: 0.722, Fibrotest: 0.778, Hepascore: 0.779, FibroMeter: 0.783, HICV test: 0.822, FibroMeter HICV: 0.828. AUROCs adjusted on classification and distribution of fibrosis stages in a reference population showed similar values in both populations. FibroMeter, FibroMeter HICV and HICV test had the highest correct classification rates in F0/1 and F3/4 (which account for high predictive values): 77-79% vs. 70-72% in the other tests (p=0.002). Reliable individual diagnosis based on predictive values > or = 90% distinguished three test categories: poorly reliable: Fib-4 (2.4% of patients), APRI (8.9%); moderately reliable: Fibrotest (25.4%), FibroMeter (26.6%), Hepascore (30.2%); acceptably reliable: HICV test (40.2%), FibroMeter HICV (45.6%) (p<10(-3) between tests). FibroMeter HICV classified all patients into four reliable diagnosis intervals (< or =F1, F1+/-1, > or =F1, > or =F2) with an overall accuracy of 93% vs. 79% (p<10(-3)) for a binary diagnosis of significant fibrosis. Tests designed for HCV infections are less effective in HIV/HCV infections. A specific test, like FibroMeter HICV, was the most interesting test for diagnostic accuracy, correct classification profile, and a reliable diagnosis. With reliable diagnosis intervals, liver biopsy can therefore be avoided in all patients. Copyright 2010 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

Informing Investment to Reduce Inequalities: A Modelling Approach.

PubMed

McAuley, Andrew; Denny, Cheryl; Taulbut, Martin; Mitchell, Rory; Fischbacher, Colin; Graham, Barbara; Grant, Ian; O'Hagan, Paul; McAllister, David; McCartney, Gerry

2016-01-01

Reducing health inequalities is an important policy objective but there is limited quantitative information about the impact of specific interventions. To provide estimates of the impact of a range of interventions on health and health inequalities. Literature reviews were conducted to identify the best evidence linking interventions to mortality and hospital admissions. We examined interventions across the determinants of health: a 'living wage'; changes to benefits, taxation and employment; active travel; tobacco taxation; smoking cessation, alcohol brief interventions, and weight management services. A model was developed to estimate mortality and years of life lost (YLL) in intervention and comparison populations over a 20-year time period following interventions delivered only in the first year. We estimated changes in inequalities using the relative index of inequality (RII). Introduction of a 'living wage' generated the largest beneficial health impact, with modest reductions in health inequalities. Benefits increases had modest positive impacts on health and health inequalities. Income tax increases had negative impacts on population health but reduced inequalities, while council tax increases worsened both health and health inequalities. Active travel increases had minimally positive effects on population health but widened health inequalities. Increases in employment reduced inequalities only when targeted to the most deprived groups. Tobacco taxation had modestly positive impacts on health but little impact on health inequalities. Alcohol brief interventions had modestly positive impacts on health and health inequalities only when strongly socially targeted, while smoking cessation and weight-reduction programmes had minimal impacts on health and health inequalities even when socially targeted. Interventions have markedly different effects on mortality, hospitalisations and inequalities. The most effective (and likely cost-effective) interventions for reducing inequalities were regulatory and tax options. Interventions focused on individual agency were much less likely to impact on inequalities, even when targeted at the most deprived communities.

A novel W1999S mutation and non-target site resistance impact on acetyl-CoA carboxylase inhibiting herbicides to varying degrees in a UK Lolium multiflorum population.

PubMed

Kaundun, Shiv Shankhar; Bailly, Geraldine C; Dale, Richard P; Hutchings, Sarah-Jane; McIndoe, Eddie

2013-01-01

Acetyl-CoA carboxylase (ACCase) inhibiting herbicides are important products for the post-emergence control of grass weed species in small grain cereal crops. However, the appearance of resistance to ACCase herbicides over time has resulted in limited options for effective weed control of key species such as Lolium spp. In this study, we have used an integrated biological and molecular biology approach to investigate the mechanism of resistance to ACCase herbicides in a Lolium multiflorum Lam. from the UK (UK21). The study revealed a novel tryptophan to serine mutation at ACCase codon position 1999 impacting on ACCase inhibiting herbicides to varying degrees. The W1999S mutation confers dominant resistance to pinoxaden and partially recessive resistance to cycloxydim and sethoxydim. On the other hand, plants containing the W1999S mutation were sensitive to clethodim and tepraloxydim. Additionally population UK21 is characterised by other resistance mechanisms, very likely non non-target site based, affecting several aryloxyphenoxyproprionate (FOP) herbicides but not the practical field rate of pinoxaden. The positive identification of wild type tryptophan and mutant serine alleles at ACCase position 1999 could be readily achieved with an original DNA based derived cleaved amplified polymorphic sequence (dCAPS) assay that uses the same PCR product but two different enzymes for positively identifying the wild type tryptophan and mutant serine alleles identified here. This paper highlights intrinsic differences between ACCase inhibiting herbicides that could be exploited for controlling ryegrass populations such as UK21 characterised by compound-specific target site and non-target site resistance.

Interventions to Reduce Harm from Smoking with Families in Infancy and Early Childhood: A Systematic Review

PubMed Central

Brown, Nicola; Luckett, Tim; Davidson, Patricia M.; Di Giacomo, Michelle

2015-01-01

Exposure to adult smoking can have deleterious effects on children. Interventions that assist families with smoking cessation/reduction and environmental tobacco smoke (ETS) avoidance can improve child health outcomes and reduce the risk of smoking initiation. The purpose of this review was to describe the state of the science of interventions with families to promote smoke-free home environments for infants and young children, including parent smoking reduction and cessation interventions, ETS reduction, and anti-smoking socialisation interventions, using the socio-ecological framework as a guide. A systematic review of peer-reviewed articles identified from journal databases from 2000 to 2014 was undertaken. Of 921 articles identified, 28 were included in the review. Considerable heterogeneity characterised target populations, intervention types, complexity and intensity, precluding meta-analysis. Few studies used socio-ecological approaches, such as family theories or concepts. Studies in early parenthood (child age newborn to one year) tended to focus on parent smoking cessation, where studies of families with children aged 1–5 years were more likely to target household SHSe reduction. Results suggest that interventions for reduction in ETS may be more successful than for smoking cessation and relapse prevention in families of children aged less than 5 years. There is a need for a range of interventions to support families in creating a smoke free home environment that are both tailored and targeted to specific populations. Interventions that target the social and psychodynamics of the family should be considered further, particularly in reaching vulnerable populations. Consideration is also required for approaches to interventions that may further stigmatise families containing smokers. Further research is required to identify successful elements of interventions and the contexts in which they are most effective. PMID:25785496

A Novel W1999S Mutation and Non-Target Site Resistance Impact on Acetyl-CoA Carboxylase Inhibiting Herbicides to Varying Degrees in a UK Lolium multiflorum Population

PubMed Central

Kaundun, Shiv Shankhar; Bailly, Geraldine C.; Dale, Richard P.; Hutchings, Sarah-Jane; McIndoe, Eddie

2013-01-01

Background Acetyl-CoA carboxylase (ACCase) inhibiting herbicides are important products for the post-emergence control of grass weed species in small grain cereal crops. However, the appearance of resistance to ACCase herbicides over time has resulted in limited options for effective weed control of key species such as Lolium spp. In this study, we have used an integrated biological and molecular biology approach to investigate the mechanism of resistance to ACCase herbicides in a Lolium multiflorum Lam. from the UK (UK21). Methodology/Principal Findings The study revealed a novel tryptophan to serine mutation at ACCase codon position 1999 impacting on ACCase inhibiting herbicides to varying degrees. The W1999S mutation confers dominant resistance to pinoxaden and partially recessive resistance to cycloxydim and sethoxydim. On the other hand, plants containing the W1999S mutation were sensitive to clethodim and tepraloxydim. Additionally population UK21 is characterised by other resistance mechanisms, very likely non non-target site based, affecting several aryloxyphenoxyproprionate (FOP) herbicides but not the practical field rate of pinoxaden. The positive identification of wild type tryptophan and mutant serine alleles at ACCase position 1999 could be readily achieved with an original DNA based derived cleaved amplified polymorphic sequence (dCAPS) assay that uses the same PCR product but two different enzymes for positively identifying the wild type tryptophan and mutant serine alleles identified here. Conclusion/Significance This paper highlights intrinsic differences between ACCase inhibiting herbicides that could be exploited for controlling ryegrass populations such as UK21 characterised by compound-specific target site and non-target site resistance. PMID:23469130

Building New Bridges between In Vitro and In Vivo in Early Drug Discovery: Where Molecular Modeling Meets Systems Biology.

PubMed

Pearlstein, Robert A; McKay, Daniel J J; Hornak, Viktor; Dickson, Callum; Golosov, Andrei; Harrison, Tyler; Velez-Vega, Camilo; Duca, José

2017-01-01

Cellular drug targets exist within networked function-generating systems whose constituent molecular species undergo dynamic interdependent non-equilibrium state transitions in response to specific perturbations (i.e.. inputs). Cellular phenotypic behaviors are manifested through the integrated behaviors of such networks. However, in vitro data are frequently measured and/or interpreted with empirical equilibrium or steady state models (e.g. Hill, Michaelis-Menten, Briggs-Haldane) relevant to isolated target populations. We propose that cells act as analog computers, "solving" sets of coupled "molecular differential equations" (i.e. represented by populations of interacting species)via "integration" of the dynamic state probability distributions among those populations. Disconnects between biochemical and functional/phenotypic assays (cellular/in vivo) may arise with targetcontaining systems that operate far from equilibrium, and/or when coupled contributions (including target-cognate partner binding and drug pharmacokinetics) are neglected in the analysis of biochemical results. The transformation of drug discovery from a trial-and-error endeavor to one based on reliable design criteria depends on improved understanding of the dynamic mechanisms powering cellular function/dysfunction at the systems level. Here, we address the general mechanisms of molecular and cellular function and pharmacological modulation thereof. We outline a first principles theory on the mechanisms by which free energy is stored and transduced into biological function, and by which biological function is modulated by drug-target binding. We propose that cellular function depends on dynamic counter-balanced molecular systems necessitated by the exponential behavior of molecular state transitions under non-equilibrium conditions, including positive versus negative mass action kinetics and solute-induced perturbations to the hydrogen bonds of solvating water versus kT. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Canonical Wnt Signaling as a Specific Marker of Normal and Tumorigenic Mammary Stem Cells

DTIC Science & Technology

2010-02-01

for mammary stem cells and be a target for transformation that results in the formation of aggressive mammary tumors. Breast cancer stem cells, Wnt...tumorigenesis, and human breast cancer. In addition, increasing evidence suggests that tumors arise from either normal stem or progenitor cells...population of mammary tumor cells that are CD24+/CD49++. Since Wnt pathway activation occurs in human breast cancer and is required for

Training needs assessment of service providers: targeted intervention for HIV/AIDS in Jharkhand, India.

PubMed

Kumar, Anant; Kumar, Prakash

2013-01-01

Training needs assessments are pivotal for any capacity building program. Building capacity of service providers and staff involved in HIV/AIDS intervention programs is crucial because of the distinct nature of such programs. It requires specific knowledge, skills, and attitudes that are of utmost importance, influencing the reach of the program and its impact in halting and reversing the epidemic. This study was conducted to identify the training needs assessment of personnel involved in targeted intervention for high risk populations vulnerable to HIV infection in Jharkhand, India. Through the study the authors critically examine the existing training needs and gaps and suggest strategies to address them.

Comprehensive HIV Prevention for Transgender Persons.

PubMed

Neumann, Mary Spink; Finlayson, Teresa J; Pitts, Nicole L; Keatley, JoAnne

2017-02-01

Transgender persons are at high risk for HIV infection, but prevention efforts specifically targeting these people have been minimal. Part of the challenge of HIV prevention for transgender populations is that numerous individual, interpersonal, social, and structural factors contribute to their risk. By combining HIV prevention services with complementary medical, legal, and psychosocial services, transgender persons' HIV risk behaviors, risk determinants, and overall health can be affected simultaneously. For maximum health impact, comprehensive HIV prevention for transgender persons warrants efforts targeted to various impact levels-socioeconomic factors, decision-making contexts, long-lasting protections, clinical interventions, and counseling and education. We present current HIV prevention efforts that reach transgender persons and present others for future consideration.

Comprehensive HIV Prevention for Transgender Persons

PubMed Central

Neumann, Mary Spink; Finlayson, Teresa J.; Pitts, Nicole L.; Keatley, JoAnne

2017-01-01

Transgender persons are at high risk for HIV infection, but prevention efforts specifically targeting these people have been minimal. Part of the challenge of HIV prevention for transgender populations is that numerous individual, interpersonal, social, and structural factors contribute to their risk. By combining HIV prevention services with complementary medical, legal, and psychosocial services, transgender persons’ HIV risk behaviors, risk determinants, and overall health can be affected simultaneously. For maximum health impact, comprehensive HIV prevention for transgender persons warrants efforts targeted to various impact levels—socioeconomic factors, decision-making contexts, long-lasting protections, clinical interventions, and counseling and education. We present current HIV prevention efforts that reach transgender persons and present others for future consideration. PMID:27997228

Approaches to Recruiting 'Hard-To-Reach' Populations into Re-search: A Review of the Literature.

PubMed

Shaghaghi, Abdolreza; Bhopal, Raj S; Sheikh, Aziz

2011-01-01

'Hard-to-reach' is a term used to describe those sub-groups of the population that may be difficult to reach or involve in research or public health programmes. Application of a single term to call these sub-sections of populations implies a homogeneity within distinct groups, which does not necessarily exist. Different sampling techniques were introduced so far to recruit hard-to-reach populations. In this article, we have reviewed a range of ap-proaches that have been used to widen participation in studies. We performed a Pubmed and Google search for relevant English language articles using the keywords and phrases: (hard-to-reach AND population* OR sampl*), (hidden AND population* OR sample*) and ("hard to reach" AND population* OR sample*) and a consul-tation of the retrieved articles' bibliographies to extract empirical evidence from publications that discussed or examined the use of sampling techniques to recruit hidden or hard-to-reach populations in health studies. Reviewing the literature has identified a range of techniques to recruit hard-to-reach populations, including snowball sampling, respondent-driven sampling (RDS), indigenous field worker sampling (IFWS), facility-based sampling (FBS), targeted sampling (TS), time-location (space) sampling (TLS), conventional cluster sampling (CCS) and capture re-capture sampling (CR). The degree of compliance with a study by a certain 'hard-to-reach' group de-pends on the characteristics of that group, recruitment technique used and the subject of inter-est. Irrespective of potential advantages or limitations of the recruitment techniques reviewed, their successful use depends mainly upon our knowledge about specific characteristics of the target populations. Thus in line with attempts to expand the current boundaries of our know-ledge about recruitment techniques in health studies and their applications in varying situa-tions, we should also focus on possibly all contributing factors which may have an impact on participation rate within a defined population group.

Detecting Signatures of Positive Selection along Defined Branches of a Population Tree Using LSD.

PubMed

Librado, Pablo; Orlando, Ludovic

2018-06-01

Identifying the genomic basis underlying local adaptation is paramount to evolutionary biology, and bears many applications in the fields of conservation biology, crop, and animal breeding, as well as personalized medicine. Although many approaches have been developed to detect signatures of positive selection within single populations and population pairs, the increasing wealth of high-throughput sequencing data requires improved methods capable of handling multiple, and ideally large number of, populations in a single analysis. In this study, we introduce LSD (levels of exclusively shared differences), a fast and flexible framework to perform genome-wide selection scans, along the internal and external branches of a given population tree. We use forward simulations to demonstrate that LSD can identify branches targeted by positive selection with remarkable sensitivity and specificity. We illustrate a range of potential applications by analyzing data from the 1000 Genomes Project and uncover a list of adaptive candidates accompanying the expansion of anatomically modern humans out of Africa and their spread to Europe.

Targeting of Asian Americans and Pacific Islanders by the tobacco industry: results from the Minnesota Tobacco Document Depository

PubMed Central

Muggli, M; Pollay, R; Lew, R; Joseph, A

2002-01-01

Objective: The study objective was to review internal tobacco industry documents written between 1985 and 1995 regarding the Asian American and Pacific Islander (AAPI) population in the USA. These documents detail opportunities and barriers to promotion of tobacco products, as viewed by the tobacco industry and its market research firms. Data sources/methods: Researchers reviewed tobacco industry documents from the document depository in Minneapolis, Minnesota and the tobacco industry's website, The Tobacco Archive, in a systematic fashion. A combined technique was employed using title keywords, dates, and names to search the 4(b) index. Findings: A review of internal tobacco company documents reveal that during the late 1980s, the industry and its market research firms recognised the importance of the AAPI community as a potential business market. Documents describe the population growth in this community, the high prevalence of smoking in countries of origin, high purchasing power of AAPI immigrants, cultural predisposition to smoking, opportunities afforded by the high proportion of retail businesses under AAPI ownership, barriers to developing the AAPI market, comprehensive campaigns, and political and lobbying efforts. Comprehensive campaigns were designed to integrate promotion efforts in AAPI consumer, retail, and business communities. Conclusions: The documents show that the tobacco industry developed specific promotion strategies to target the AAPI population. Tobacco control initiatives in the AAPI group have been slower to develop than in other targeted ethnic groups, and may benefit by increased awareness of industry methods to promote tobacco use. PMID:12198269

Targeting of Asian Americans and Pacific Islanders by the tobacco industry: results from the Minnesota Tobacco Document Depository.

PubMed

Muggli, M E; Pollay, R W; Lew, R; Joseph, A M

2002-09-01

The study objective was to review internal tobacco industry documents written between 1985 and 1995 regarding the Asian American and Pacific Islander (AAPI) population in the USA. These documents detail opportunities and barriers to promotion of tobacco products, as viewed by the tobacco industry and its market research firms. /methods: Researchers reviewed tobacco industry documents from the document depository in Minneapolis, Minnesota and the tobacco industry's website, The Tobacco Archive, in a systematic fashion. A combined technique was employed using title keywords, dates, and names to search the 4(b) index. A review of internal tobacco company documents reveal that during the late 1980s, the industry and its market research firms recognised the importance of the AAPI community as a potential business market. Documents describe the population growth in this community, the high prevalence of smoking in countries of origin, high purchasing power of AAPI immigrants, cultural predisposition to smoking, opportunities afforded by the high proportion of retail businesses under AAPI ownership, barriers to developing the AAPI market, comprehensive campaigns, and political and lobbying efforts. Comprehensive campaigns were designed to integrate promotion efforts in AAPI consumer, retail, and business communities. The documents show that the tobacco industry developed specific promotion strategies to target the AAPI population. Tobacco control initiatives in the AAPI group have been slower to develop than in other targeted ethnic groups, and may benefit by increased awareness of industry methods to promote tobacco use.

Adaptive evolution and functional innovation of Populus-specific recently evolved microRNAs.

PubMed

Xie, Jianbo; Yang, Xiaohui; Song, Yuepeng; Du, Qingzhang; Li, Ying; Chen, Jinhui; Zhang, Deqiang

2017-01-01

Lineage-specific microRNAs (miRNAs) undergo rapid turnover during evolution; however, their origin and functional importance have remained controversial. Here, we examine the origin, evolution, and potential roles in local adaptation of Populus-specific miRNAs, which originated after the recent salicoid-specific, whole-genome duplication. RNA sequencing was used to generate extensive, comparable miRNA and gene expression data for six tissues. A natural population of Populus trichocarpa and closely related species were used to study the divergence rates, evolution, and adaptive variation of miRNAs. MiRNAs that originated in 5' untranslated regions had higher expression levels and their expression showed high correlation with their host genes. Compared with conserved miRNAs, a significantly higher proportion of Populus-specific miRNAs appear to target genes that were duplicated in salicoids. Examination of single nucleotide polymorphisms in Populus-specific miRNA precursors showed high amounts of population differentiation. We also characterized the newly emerged MIR6445 family, which could trigger the production of phased small interfering RNAs from NAC mRNAs, which encode a transcription factor with primary roles in a variety of plant developmental processes. Together, these observations provide evolutionary insights into the birth and potential roles of Populus-specific miRNAs in genome maintenance, local adaptation, and functional innovation. © 2016 The Authors. New Phytologist © 2016 New Phytologist Trust.

[Population study of seroprevalence of antibodies against hepatitis A virus in the Community of Madrid, 2008-2009].

PubMed

García-Comas, Luis; Ordobás, María; Sanz, Juan Carlos; Ramos, Belén; Arce, Araceli; Barranco, Dolores

2016-01-01

Seroprevalence surveys enable the level of endemicity of hepatitis A (HAV) to be assessed. The aim of this study was to estimate the seroprevalence (SP) antibody against HAV by age group, and compare it with those obtained in previous surveys. Observational cross-sectional study. The target population consists of residents from 2 to 60 years old in the Community of Madrid. Two-stage cluster sampling was performed with stratification of first stage units. After signing the informed consent, a serum sample was extracted from each participant and sociodemographic data were collected by a questionnaire. SP antibodies to hepatitis A is 46.8% (95% CI 44.6 to 49.0). The SP increases with age. It is higher in the population from more endemic countries and people with less education and lower social class. In relation to the previous survey, SP increased in the population under 30 years old, and a decline after that age is observed. If only the autochthonous population and from countries with very low endemicity is observed, the increase is statistically significant in the 2-5 years age group. Our region has a very low level of endemicity thus, following the recommendations of WHO, vaccination should be targeted at specific risk groups. Copyright © 2015 Elsevier España, S.L.U. y Sociedad Española de Enfermedades Infecciosas y Microbiología Clínica. All rights reserved.

Study design and implementation for population pharmacokinetics of Chinese medicine: An expert consensus.

PubMed

Jiang, Jun-jie; Zhang, Wen; Xie, Yan-ming; Wang, Jian-nong; He, Fu-yuan; Xiong, Xin

2016-02-01

Although many population pharmacokinetics (PPK) researches have been conducted on chemical drugs, few have been in the field of Chinese medicine (CM). Each ingredient in CMs possesses different pharmacokinetic characteristics, therefore, it is important to develop methods of PPK studies on them to identify the differences in CM drug safety and efficacy among the population subgroups and to conduct quantitative studies on the determinants of CM drug concentrations. To develop an expert consensus on study design and implementation for PPK of CM, in August 2013, 6 experts in the field of PPK, CMs pharmacology, and statistics discussed problems on the PPK research protocol of CMs, and a consensus was reached. The medicines with toxicity and narrow therapeutic windows and with wide range of target population or with frequent adverse reactions were selected. The compositions with definite therapeutic effects were selected as indices, and specific time points and sample sizes were designed according to standard PPK design methods. Target components were tested through various chromatography methods. Total quantity statistical moment analysis was used to estimate PPK parameters of each component and PPK models reflecting the trend of CMs (which assists in reasonable adjustments on clinical dosage). This consensus specifies the study design and implementation process of PPK. It provides guidance for the following: post-marketing clinical studies, in vivo investigations related to the metabolism in different populations, and development and clinical adjustment of dosages of CMs.

Epidemiology of ischemic heart disease in HIV.

PubMed

Triant, Virginia A; Grinspoon, Steven K

2017-11-01

The purpose of this review is to summarize and synthesize recent data on the risk of ischemic heart disease (IHD) in HIV-infected individuals. Recent studies in the field demonstrate an increasing impact of cardiovascular disease (CVD) on morbidity and mortality in HIV relative to AIDS-related diagnoses. Studies continue to support an approximately 1.5 to two-fold increased risk of IHD conferred by HIV, with specific risk varying by sex and virologic/immunologic status. Risk factors include both traditional CVD risk factors and novel, HIV-specific factors including inflammation and immune activation. Specific antiretroviral therapy (ART) drugs may increase CVD risk, yet the net effect of ART with viral suppression is beneficial with regard to CVD risk. Management of cardiovascular risk and prevention of CVD is complex, because current general population strategies target traditional CVD risk factors only. Extensive investigation is being directed at developing tailored CVD risk prediction algorithms and interventions to reduce CVD risk in HIV. Increased IHD risk is a significant clinical and public health challenge in HIV. The development and application of HIV-specific interventions to manage CVD risk factors and reduce CVD risk will improve the long-term health of this ageing population.

Physiological and Molecular Characterization of Hydroxyphenylpyruvate Dioxygenase (HPPD)-inhibitor Resistance in Palmer Amaranth (Amaranthus palmeri S.Wats.)

PubMed Central

Nakka, Sridevi; Godar, Amar S.; Wani, Prashant S.; Thompson, Curtis R.; Peterson, Dallas E.; Roelofs, Jeroen; Jugulam, Mithila

2017-01-01

Herbicides that inhibit hydroxyphenylpyruvate dioxygenase (HPPD) such as mesotrione are widely used to control a broad spectrum of weeds in agriculture. Amaranthus palmeri is an economically troublesome weed throughout the United States. The first case of evolution of resistance to HPPD-inhibiting herbicides in A. palmeri was documented in Kansas (KS) and later in Nebraska (NE). The objective of this study was to investigate the mechansim of HPPD-inhibitor (mesotrione) resistance in A. palmeri. Dose response analysis revealed that this population (KSR) was 10–18 times more resistant than their sensitive counterparts (MSS or KSS). Absorbtion and translocation analysis of [14C] mesotrione suggested that these mechanisms were not involved in the resistance in A. palmeri. Importantly, mesotrione (>90%) was detoxified markedly faster in the resistant populations (KSR and NER), within 24 hours after treatment (HAT) compared to sensitive plants (MSS, KSS, or NER). However, at 48 HAT all populations metabolized the mesotrione, suggesting additional factors may contribute to this resistance. Further evaluation of mesotrione-resistant A. palmeri did not reveal any specific resistance-conferring mutations nor amplification of HPPD gene, the molecular target of mesotrione. However, the resistant populations showed 4- to 12-fold increase in HPPD gene expression. This increase in HPPD transcript levels was accompanied by increased HPPD protein expression. The significant aspects of this research include: the mesotrione resistance in A. palmeri is conferred primarily by rapid detoxification (non-target-site based) of mesotrione; additionally, increased HPPD gene expression (target-site based) also contributes to the resistance mechanism in the evolution of herbicide resistance in this naturally occurring weed species. PMID:28443128

Vulnerability of dynamic genetic conservation units of forest trees in Europe to climate change.

PubMed

Schueler, Silvio; Falk, Wolfgang; Koskela, Jarkko; Lefèvre, François; Bozzano, Michele; Hubert, Jason; Kraigher, Hojka; Longauer, Roman; Olrik, Ditte C

2014-05-01

A transnational network of genetic conservation units for forest trees was recently documented in Europe aiming at the conservation of evolutionary processes and the adaptive potential of natural or man-made tree populations. In this study, we quantified the vulnerability of individual conservation units and the whole network to climate change using climate favourability models and the estimated velocity of climate change. Compared to the overall climate niche of the analysed target species populations at the warm and dry end of the species niche are underrepresented in the network. However, by 2100, target species in 33-65 % of conservation units, mostly located in southern Europe, will be at the limit or outside the species' current climatic niche as demonstrated by favourabilities below required model sensitivities of 95%. The highest average decrease in favourabilities throughout the network can be expected for coniferous trees although they are mainly occurring within units in mountainous landscapes for which we estimated lower velocities of change. Generally, the species-specific estimates of favourabilities showed only low correlations to the velocity of climate change in individual units, indicating that both vulnerability measures should be considered for climate risk analysis. The variation in favourabilities among target species within the same conservation units is expected to increase with climate change and will likely require a prioritization among co-occurring species. The present results suggest that there is a strong need to intensify monitoring efforts and to develop additional conservation measures for populations in the most vulnerable units. Also, our results call for continued transnational actions for genetic conservation of European forest trees, including the establishment of dynamic conservation populations outside the current species distribution ranges within European assisted migration schemes. © 2013 John Wiley & Sons Ltd.

Utilizing Social Media for Community Consultation and Public Disclosure in Exception from Informed Consent Trials

PubMed Central

Stephens, Shannon W.; Williams, Carolyn; Gray, Randal; Kerby, Jeffrey D.; Wang, Henry E.; Bosarge, Patrick L.

2016-01-01

Background The U.S. Food and Drug Administration and Department of Health and Human Services outline regulations allowing an Exception From Informed Consent (EFIC) for research conducted in an emergency settings. Acute care clinical trials utilizing EFIC must include community consultation and public disclosure (CC/PD) activities. We describe our experience using social media to facilitate the CC/PD process in two trauma resuscitation clinical trials. Methods We conducted local CC/PD activities for two multicenter trauma clinical trials, Pragmatic, Randomized Optimal Platelet and Plasma Ratios (PROPPR) and Prehospital Tranexamic Acid Use for Traumatic Brain Injury (ROC TXA). As part of the CC/PD process, we developed research study advertisements using the social media website Facebook. The Facebook advertisements directed users to a regional study website that contained trial information. We targeted the advertisements to specific demographic users, in specific geographic areas. We analyzed the data using descriptive statistics. Results During the study periods, the PROPPR Facebook advertisement was displayed 5,001,520 times, (12 displays per target population) with 374 individuals selected the advertisement. The ROC-TXA Facebook advertisement was displayed 3,806,448 times (8 per target population) with 790 individuals selecting the advertisement. Respondents to both Facebook advertisements were mostly male (52.6%), with the highest proportion between the ages 15-24 (28.2%). Collectively, 26.9% of individuals that clicked on the Facebook advertisement, spent > 3 minutes on the study website [3min – 49 min]. Commonly accessed webpages were “Contact Us” (PROPPR 5.5%, TXA 7.7%), “Study-specific FAQs” (PROPPR 2.4%), ROC-TXA 6.7%) and “Opt-Out of Research” (PROPPR 2.5%, ROC-TXA 3.8%). Of 51 total individuals viewing the opt-out of research information (PROPPR 19, ROC-TXA 32), Time spent on that specific page was modest (PROPPR 62 seconds, ROC-TXA 55 seconds), with no individuals requesting to opt-out of either study participation. Conclusion In clinical trauma trials, using EFIC, social media may provide a viable option for facilitating the CC/PD process. Level Of Evidence Descriptive Study, Level IV. PMID:26998781

Using social media for community consultation and public disclosure in exception from informed consent trials.

PubMed

Stephens, Shannon W; Williams, Carolyn; Gray, Randal; Kerby, Jeffrey D; Wang, Henry E; Bosarge, Patrick L

2016-06-01

The US Food and Drug Administration and the Department of Health and Human Services outline regulations allowing an exception from informed consent (EFIC) for research conducted in an emergency setting. Acute care clinical trials using EFIC must include community consultation and public disclosure (CC/PD) activities. We describe our experience using social media to facilitate the CC/PD process in two trauma resuscitation clinical trials. We conducted local CC/PD activities for two multicenter trauma clinical trials, Pragmatic, Randomized Optimal Platelet and Plasma Ratios (PROPPR) and Prehospital Tranexamic Acid Use for Traumatic Brain Injury (ROC-TXA). As part of the CC/PD process, we developed research study advertisements using the social media Web site Facebook. The Facebook advertisements directed users to a regional study Web site that contained trial information. We targeted the advertisements to specific demographic users, in specific geographic areas. We analyzed the data using descriptive statistics. During the study periods, the PROPPR Facebook advertisement was displayed 5,001,520 times (12 displays per target population) with 374 individuals selecting the advertisement. The ROC-TXA Facebook advertisement was displayed 3,806,448 times (8 per target population) with 790 individuals selecting the advertisement. Respondents to both Facebook advertisements were mostly male (52.6%), with the highest proportion between the ages 15 years and 24 years (28.2%). Collectively, 26.9% of individuals that clicked on the Facebook advertisement spent more than 3 minutes on the study Web site (3-49 minutes). Commonly accessed Web pages were "contact us" (PROPPR, 5.5%; ROC-TXA, 7.7%), "study-specific FAQs" (PROPPR, 2.4%; ROC-TXA, 6.7%), and "opt out of research" (PROPPR, 2.5%; ROC-TXA, 3.8%). Of 51 total individuals viewing the opt out of research information (PROPPR, 19; ROC-TXA, 32), time spent on that specific page was modest (PROPPR, 62 seconds; ROC-TXA, 55 seconds), with no individuals requesting to opt out of either study participation. In clinical trauma trials using EFIC, social media may provide a viable option for facilitating the CC/PD process.

High-Performance Multiplex SNP Analysis of Three Hemochromatosis-Related Mutations With Capillary Array Electrophoresis Microplates

PubMed Central

Medintz, Igor; Wong, Wendy W.; Berti, Lorenzo; Shiow, Lawrence; Tom, Jennifer; Scherer, James; Sensabaugh, George; Mathies, Richard A.

2001-01-01

An assay is described for high-throughput single nucleotide polymorphism (SNP) genotyping on a microfabricated capillary array electrophoresis (CAE) microchip. The assay targets the three common variants at the HFE locus associated with the genetic disease hereditary hemochromatosis (HHC). The assay employs allele-specific PCR (ASPCR) for the C282Y (845g->a), H63D (187c->g), and S65C (193a->t) variants using fluorescently-labeled energy-transfer (ET) allele-specific primers. Using a 96-channel radial CAE microplate, the labeled ASPCR products generated from 96 samples in a reference Caucasian population are simultaneously separated with single-base-pair resolution and genotyped in under 10 min. Detection is accomplished with a laser-excited rotary four-color fluorescence scanner. The allele-specific amplicons are differentiated on the basis of both their size and the color of the label emission. This study is the first demonstration of the combined use of ASPCR with ET primers and microfabricated radial CAE microplates to perform multiplex SNP analyses in a clinically relevant population. PMID:11230165

Lentiviral diseases of sheep and goats: chronic pneumonia leukoencephalomyelitis and arthritis.

PubMed

Narayan, O; Cork, L C

1985-01-01

This review describes the pathogenesis of a slowly progressive disease complex caused by naturally occurring nononcogenic retroviruses in sheep and goats. In nature, infections are usually clinically silent, but disease may manifest itself after prolonged incubation periods. Clinically, this is seen as dyspnea, progressive paralysis, and/or progressive arthritis. In all organs the basic lesion is inflammatory with infiltration and proliferation of lymphocytes, plasma cells, and macrophages. Other organ-specific pathologic changes such as primary demyelination in the central nervous system and degeneration of cartilaginous structures in joints accompany inflammation. The viruses infect tissue-specific macrophage populations in vivo. Viral replication in these cells is restricted to minimal levels but continues indefinitely in the animal as a result of either failure to induce specific neutralizing antibodies or antigenic drift when neutralizing antibodies develop. Consistent low-grade viral replication sets the pace for disease by providing continuous antigenic stimulation for the inflammatory cellular immune response or antibodies that localize in the target tissues. These cells and immune complexes may have adverse effects on indigenous cell populations.

Predicting the impacts of bioenergy production on farmland birds.

PubMed

Rivas Casado, Monica; Mead, Andrew; Burgess, Paul J; Howard, David C; Butler, Simon J

2014-04-01

Meeting European renewable energy production targets is expected to cause significant changes in land use patterns. With an EU target of obtaining 20% of energy consumption from renewable sources by 2020, national and local policy makers need guidance on the impact of potential delivery strategies on ecosystem goods and services to ensure the targets are met in a sustainable manner. Within agroecosystems, models are available to explore consequences of such policy decisions for food, fuel and fibre production but few can describe the effect on biodiversity. This paper describes the integration and application of a farmland bird population model within a geographical information system (GIS) to explore the consequences of land use changes arising from different strategies to meet renewable energy production targets. Within a 16,000 ha arable dominated case study area in England, the population growth rates of 19 farmland bird species were predicted under baseline land cover, a scenario maximising wheat production for bioethanol, and a scenario focused on mix of bioenergy sources. Both scenarios delivered renewable energy production targets for the region (>12 kWh per person per day) but, despite differences in resultant landscape composition, the response of the farmland bird community as a whole to each scenario was small and broadly similar. However, this similarity in overall response masked significant intra- and inter-specific variations across the study area and between scenarios suggesting contrasting mechanisms of impact and highlighting the need for context dependent, species-level assessment of land use change impacts. This framework provides one of the first systematic attempts to spatially model the effect of policy driven land use change on the population dynamics of a suite of farmland birds. The GIS framework also facilitates its integration with other ecosystem service models to explore wider synergies and trade offs arising from national or local policy interventions. Copyright © 2013 Elsevier B.V. All rights reserved.

When can efforts to control nuisance and invasive species backfire?

USGS Publications Warehouse

Zipkin, E.F.; Kraft, C.E.; Cooch, E.G.; Sullivan, P.J.

2009-01-01

Population control through harvest has the potential to reduce the abundance of nuisance and invasive species. However, demographic structure and density-dependent processes can confound removal efforts and lead to undesirable consequences, such as overcompensation (an increase in abundance in response to harvest) and instability (population cycling or chaos). Recent empirical studies have demonstrated the potential for increased mortality (such as that caused by harvest) to lead to overcompensation and instability in plant, insect, and fish populations. We developed a general population model with juvenile and adult stages to help determine the conditions under which control harvest efforts can produce unintended outcomes. Analytical and simulation analyses of the model demonstrated that the potential for overcompensation as a result of harvest was significant for species with high fecundity, even when annual stage-specific survivorship values were fairly low. Population instability as a result of harvest occurred less frequently and was only possible with harvest strategies that targeted adults when both fecundity and adult survivorship were high. We considered these results in conjunction with current literature on nuisance and invasive species to propose general guidelines for assessing the risks associated with control harvest based on life history characteristics of target populations. Our results suggest that species with high per capita fecundity (over discrete breeding periods), short juvenile stages, and fairly constant survivorship rates are most likely to respond undesirably to harvest. It is difficult to determine the extent to which overcompensation and instability could occur during real-world removal efforts, and more empirical removal studies should be undertaken to evaluate population-level responses to control harvests. Nevertheless, our results identify key issues that have been seldom acknowledged and are potentially generic across taxa. ?? 2009 by the Ecological Society ot America.

When can efforts to control nuisance and invasive species backfire?

PubMed

Zipkin, Elise F; Kraft, Clifford E; Cooch, Evan G; Sullivan, Patrick J

2009-09-01

Population control through harvest has the potential to reduce the abundance of nuisance and invasive species. However, demographic structure and density-dependent processes can confound removal efforts and lead to undesirable consequences, such as overcompensation (an increase in abundance in response to harvest) and instability (population cycling or chaos). Recent empirical studies have demonstrated the potential for increased mortality (such as that caused by harvest) to lead to overcompensation and instability in plant, insect, and fish populations. We developed a general population model with juvenile and adult stages to help determine the conditions under which control harvest efforts can produce unintended outcomes. Analytical and simulation analyses of the model demonstrated that the potential for overcompensation as a result of harvest was significant for species with high fecundity, even when annual stage-specific survivorship values were fairly low. Population instability as a result of harvest occurred less frequently and was only possible with harvest strategies that targeted adults when both fecundity and adult survivorship were high. We considered these results in conjunction with current literature on nuisance and invasive species to propose general guidelines for assessing the risks associated with control harvest based on life history characteristics of target populations. Our results suggest that species with high per capita fecundity (over discrete breeding periods), short juvenile stages, and fairly constant survivorship rates are most likely to respond undesirably to harvest. It is difficult to determine the extent to which overcompensation and instability could occur during real-world removal efforts, and more empirical removal studies should be undertaken to evaluate population-level responses to control harvests. Nevertheless, our results identify key issues that have been seldom acknowledged and are potentially generic across taxa.

Population pharmacokinetics of busulfan in pediatric and young adult patients undergoing hematopoietic cell transplant: a model-based dosing algorithm for personalized therapy and implementation into routine clinical use.

PubMed

Long-Boyle, Janel R; Savic, Rada; Yan, Shirley; Bartelink, Imke; Musick, Lisa; French, Deborah; Law, Jason; Horn, Biljana; Cowan, Morton J; Dvorak, Christopher C

2015-04-01

Population pharmacokinetic (PK) studies of busulfan in children have shown that individualized model-based algorithms provide improved targeted busulfan therapy when compared with conventional dose guidelines. The adoption of population PK models into routine clinical practice has been hampered by the tendency of pharmacologists to develop complex models too impractical for clinicians to use. The authors aimed to develop a population PK model for busulfan in children that can reliably achieve therapeutic exposure (concentration at steady state) and implement a simple model-based tool for the initial dosing of busulfan in children undergoing hematopoietic cell transplantation. Model development was conducted using retrospective data available in 90 pediatric and young adult patients who had undergone hematopoietic cell transplantation with busulfan conditioning. Busulfan drug levels and potential covariates influencing drug exposure were analyzed using the nonlinear mixed effects modeling software, NONMEM. The final population PK model was implemented into a clinician-friendly Microsoft Excel-based tool and used to recommend initial doses of busulfan in a group of 21 pediatric patients prospectively dosed based on the population PK model. Modeling of busulfan time-concentration data indicates that busulfan clearance displays nonlinearity in children, decreasing up to approximately 20% between the concentrations of 250-2000 ng/mL. Important patient-specific covariates found to significantly impact busulfan clearance were actual body weight and age. The percentage of individuals achieving a therapeutic concentration at steady state was significantly higher in subjects receiving initial doses based on the population PK model (81%) than in historical controls dosed on conventional guidelines (52%) (P = 0.02). When compared with the conventional dosing guidelines, the model-based algorithm demonstrates significant improvement for providing targeted busulfan therapy in children and young adults.

Leveraging Online Learning Resources to Teach Core Research Skills to Undergraduates at a Diverse Research University.

PubMed

McFARLIN, Brian K; Breslin, Whitney L; Carpenter, Katie C; Strohacker, Kelley; Weintraub, Randi J

2010-01-01

Today's students have unique learning needs and lack knowledge of core research skills. In this program report, we describe an online approach that we developed to teach core research skills to freshman and sophomore undergraduates. Specifically, we used two undergraduate kinesiology (KIN) courses designed to target students throughout campus (KIN1304: Public Health Issues in Physical Activity and Obesity) and specifically kinesiology majors (KIN1252: Foundations of Kinesiology). Our program was developed and validated at the 2 nd largest ethnically diverse research university in the United States, thus we believe that it would be effective in a variety of student populations.

Improving diet and physical activity to reduce population prevalence of overweight and obesity: an overview of current evidence.

PubMed

Stephens, Samantha K; Cobiac, Linda J; Veerman, J Lennert

2014-05-01

The aim of this study is to provide an overview of interventions to reduce or prevent overweight or obesity and improve diet or physical activity. A review of meta-analyses and/or systematic reviews of these interventions in any setting or age group were conducted. Narrative systematic reviews were included for intervention categories with limited meta-analyses available. Summary measures including weighted mean difference, standardised mean difference, and I-squared, were examined. A total of 60 meta-analyses and 23 systematic reviews met the inclusion criteria. Dietary interventions and multi-component interventions targeting overweight and obesity appeared to have the greatest effects, particularly in comparison with workplace or technology or internet-based interventions. Pharmaceutical and surgical interventions produced favourable results for specific population sub-groups (i.e. morbidly obese). Population-wide strategies such as policy interventions have not been widely analysed. The effectiveness of the interventions to assist in maintaining behaviour or weight change remains unclear. Various individually targeted interventions were shown to reduce body weight, although effect sizes were typically modest, and the durability of effects has been questioned. New approaches to evaluating population-based interventions, such as taxes and regulation, are recommended. Future research modelling the long-term effects of interventions across the lifespan would also be beneficial. Copyright © 2014 Elsevier Inc. All rights reserved.

National surveys of military personnel, nursing students, and the public: drivers of military nursing careers.

PubMed

Donelan, Karen; Romano, Carol; Buerhaus, Peter; DesRoches, Catherine; Applebaum, Sandra; Ward, Johanna Rm; Schoneboom, Bruce A; Hinshaw, Ada Sue

2014-05-01

The U.S. health care system is facing a projected nursing shortage of unprecedented magnitude. Although military nursing services recently have been able to meet their nursing recruitment quotas, national studies have predicted a long-term nursing shortage that may affect future recruitment for the Nurse Corps of the three military services. Data are needed to plan for recruitment incentives and the impact of those incentives on targeted populations of likely future nurses. Data are drawn from three online surveys conducted in 2011-2012, including surveys of 1,302 Army, Navy, and Air Force personnel serving on major military bases, 914 nursing students at colleges with entry Bachelor of Science in Nursing programs located nearby major military bases, and a qualitative survey of 1,200 young adults, age 18-39, in the general public. The three populations are different in several demographic characteristics. We explored perceptions of military careers, nursing careers and barriers, and incentives to pursue military nursing careers in all populations. Perceptions differ among the groups. The results of this study may help to inform strategies for reaching out to specific populations with targeted messages that focus on barriers and facilitators relevant to each to successfully recruit a diverse Nurse Corps for the future. Reprint & Copyright © 2014 Association of Military Surgeons of the U.S.

The effect of targeted wide age range SIAs in reducing measles incidence in the African Region.

PubMed

Masresha, Balcha; Luce, Richard; Katsande, Regis; Fall, Amadou; Eshetu, Meseret; Mihigo, Richard

2017-01-01

Periodic measles supplemental immunisation activities (SIAs) increase population immunity and thereby reduce the pool of accumulated susceptible children. They are typically conducted every 2 - 4 years, and most often target children up to five years of age. Between 2012 and 2015, after surveillance data indicated a shift in the epidemiological profile of measles towards older age groups, 11 countries were supported to conduct wide age range SIAs based on their local epidemiological patterns. Six other countries conducted SIAs with measles-rubella vaccines targeting ages 9 months to 14 years as an initial step of introducing rubella vaccine into the immunization program. In subsequent years, the incidence of confirmed measles dropped significantly in 13 of the 17 countries reviewed. The findings emphasize the importance of well-functioning surveillance systems, and the benefits of using of surveillance data to determine the specific target age-range for periodic SIAs to accelerate progress towards measles elimination.

The effect of targeted wide age range SIAs in reducing measles incidence in the African Region

PubMed Central

Masresha, Balcha; Luce, Richard; Katsande, Regis; Fall, Amadou; Eshetu, Meseret; Mihigo, Richard

2017-01-01

Periodic measles supplemental immunisation activities (SIAs) increase population immunity and thereby reduce the pool of accumulated susceptible children. They are typically conducted every 2 – 4 years, and most often target children up to five years of age. Between 2012 and 2015, after surveillance data indicated a shift in the epidemiological profile of measles towards older age groups, 11 countries were supported to conduct wide age range SIAs based on their local epidemiological patterns. Six other countries conducted SIAs with measles-rubella vaccines targeting ages 9 months to 14 years as an initial step of introducing rubella vaccine into the immunization program. In subsequent years, the incidence of confirmed measles dropped significantly in 13 of the 17 countries reviewed. The findings emphasize the importance of well-functioning surveillance systems, and the benefits of using of surveillance data to determine the specific target age-range for periodic SIAs to accelerate progress towards measles elimination. PMID:29296148

A Medium-Throughput Single Cell CRISPR-Cas9 Assay to Assess Gene Essentiality.

PubMed

Grassian, A R; Scales, T M E; Knutson, S K; Kuntz, K W; McCarthy, N J; Lowe, C E; Moore, J D; Copeland, R A; Keilhack, H; Smith, J J; Wickenden, J A; Ribich, S

2015-01-01

Target selection for oncology is a crucial step in the successful development of therapeutics. Clustered regularly interspaced short palindromic repeats (CRISPR)-Cas9 editing of specific loci offers an alternative method to RNA interference and small molecule inhibitors for determining whether a cell line is dependent on a specific gene product for proliferation or survival. In our initial studies using CRISPR-Cas9 to verify the dependence on EZH2 activity for proliferation of a SMARCB1/SNF5/INI1 mutant malignant rhabdoid tumor (MRT) cell line, we noted that the initial reduction in proliferation was lost over time. We hypothesized that in the few cells that retain proliferative capacity, at least one allele of EZH2 remains functional. To verify this, we developed an assay to analyze 10s-100s of clonal cell populations for target gene disruption using restriction digest and fluorescent fragment length analyses. Our results clearly show that in cell lines in which EZH2 is essential for proliferation, at least one potentially functional allele of EZH2 is retained in the clones that survive. This assay clearly indicates whether or not a specific gene is essential for survival and/or proliferation in a given cell line. Such data can aid the development of more robust therapeutics by increasing confidence in target selection.

Regulatory Myeloid Cells in Transplantation

PubMed Central

Rosborough, Brian R.; Raïch-Regué, Dàlia; Turnquist, Heth R.; Thomson, Angus W.

2013-01-01

Regulatory myeloid cells (RMC) are emerging as novel targets for immunosuppressive (IS) agents and hold considerable promise as cellular therapeutic agents. Herein, we discuss the ability of regulatory macrophages (Mreg), regulatory dendritic cells (DCreg) and myeloid-derived suppressor cells (MDSC) to regulate alloimmunity, their potential as cellular therapeutic agents and the IS agents that target their function. We consider protocols for the generation of RMC and the selection of donor- or recipient-derived cells for adoptive cell therapy. Additionally, the issues of cell trafficking and antigen (Ag) specificity following RMC transfer are discussed. Improved understanding of the immunobiology of these cells has increased the possibility of moving RMC into the clinic to reduce the burden of current IS agents and promote Ag-specific tolerance. In the second half of this review, we discuss the influence of established and experimental IS agents on myeloid cell populations. IS agents believed historically to act primarily on T cell activation and proliferation are emerging as important regulators of RMC function. Better insights into the influence of IS agents on RMC will enhance our ability to develop cell therapy protocols to promote the function of these cells. Moreover, novel IS agents may be designed to target RMC in situ to promote Ag-specific immune regulation in transplantation and usher in a new era of immune modulation exploiting cells of myeloid origin. PMID:24092382

Engineering antigens for in situ erythrocyte binding induces T-cell deletion.

PubMed

Kontos, Stephan; Kourtis, Iraklis C; Dane, Karen Y; Hubbell, Jeffrey A

2013-01-02

Antigens derived from apoptotic cell debris can drive clonal T-cell deletion or anergy, and antigens chemically coupled ex vivo to apoptotic cell surfaces have been shown correspondingly to induce tolerance on infusion. Reasoning that a large number of erythrocytes become apoptotic (eryptotic) and are cleared each day, we engineered two different antigen constructs to target the antigen to erythrocyte cell surfaces after i.v. injection, one using a conjugate with an erythrocyte-binding peptide and another using a fusion with an antibody fragment, both targeting the erythrocyte-specific cell surface marker glycophorin A. Here, we show that erythrocyte-binding antigen is collected much more efficiently than free antigen by splenic and hepatic immune cell populations and hepatocytes, and that it induces antigen-specific deletional responses in CD4(+) and CD8(+) T cells. We further validated T-cell deletion driven by erythrocyte-binding antigens using a transgenic islet β cell-reactive CD4(+) T-cell adoptive transfer model of autoimmune type 1 diabetes: Treatment with the peptide antigen fused to an erythrocyte-binding antibody fragment completely prevented diabetes onset induced by the activated, autoreactive CD4(+) T cells. Thus, we report a translatable modular biomolecular approach with which to engineer antigens for targeted binding to erythrocyte cell surfaces to induce antigen-specific CD4(+) and CD8(+) T-cell deletion toward exogenous antigens and autoantigens.

Widespread occurrence of both metabolic and target-site herbicide resistance mechanisms in Lolium rigidum populations.

PubMed

Han, Heping; Yu, Qin; Owen, Mechelle J; Cawthray, Gregory R; Powles, Stephen B

2016-02-01

Lolium rigidum populations in Australia and globally have demonstrated rapid and widespread evolution of resistance to acetyl coenzyme A carboxylase (ACCase)-inhibiting and acetolactate synthase (ALS)-inhibiting herbicides. Thirty-three resistant L. rigidum populations, randomly collected from crop fields in a most recent resistance survey, were analysed for non-target-site diclofop metabolism and all known target-site ACCase gene resistance-endowing mutations. The HPLC profile of [(14) C]-diclofop-methyl in vivo metabolism revealed that 79% of these resistant L. rigidum populations showed enhanced capacity for diclofop acid metabolism (metabolic resistance). ACCase gene sequencing identified that 91% of the populations contain plants with ACCase resistance mutation(s). Importantly, 70% of the populations exhibit both non-target-site metabolic resistance and target-site ACCase mutations. This work demonstrates that metabolic herbicide resistance is commonly occurring in L. rigidum, and coevolution of both metabolic resistance and target-site resistance is an evolutionary reality. Metabolic herbicide resistance can potentially endow resistance to many herbicides and poses a threat to herbicide sustainability and thus crop production, calling for major research and management efforts. © 2015 Society of Chemical Industry.

Cancer stem cell-targeted therapeutics and delivery strategies.

PubMed

Ahmad, Gulzar; Amiji, Mansoor M

2017-08-01

Cancer initiating or stem cells (CSCs) are a small population of cells in the tumor mass, which have been reported to be present in different types of cancers. CSCs usually reside within the tumor and are responsible for reoccurrence of cancer. The imprecise, inaccessible nature and increased efflux of conventional therapeutic drugs make these cells resistant to drugs. We discuss the specific markers for identification of these cells, role of CSCs in chemotherapy resistance and use of different therapeutic means to target them, including elucidation of specific cell markers, exploitation of different signaling pathways and use of nanotechnology. Area covered: This review covers cancer stem cell signaling which are used by these cells to maintain their quiescence, stemness and resistant phenotype, distinct cell surface markers, contribution of these cells in drug resistance, inevitability to cure cancer and use of nanotechnology to overcome this hurdle. Expert opinion: Cancer stem cells are the main culprit of our failure to cure cancer. In order to cure cancer along with other cells types in cancer, cancer stem cells need to be targeted in the tumor bed. Nanotechnology solutions can facilitate clinical translation of the therapeutics along with other emerging technologies to cure cancer.

Mathematical model for HIV dynamics in HIV-specific helper cells

NASA Astrophysics Data System (ADS)

Pinto, Carla M. A.; Carvalho, Ana

2014-03-01

In this paper we study a delay mathematical model for the dynamics of HIV in HIV-specific CD4 + T helper cells. We modify the model presented by Roy and Wodarz in 2012, where the HIV dynamics is studied, considering a single CD4 + T cell population. Non-specific helper cells are included as alternative target cell population, to account for macrophages and dendritic cells. In this paper, we include two types of delay: (1) a latent period between the time target cells are contacted by the virus particles and the time the virions enter the cells and; (2) virus production period for new virions to be produced within and released from the infected cells. We compute the reproduction number of the model, R0, and the local stability of the disease free equilibrium and of the endemic equilibrium. We find that for values of R0<1, the model approaches asymptotically the disease free equilibrium. For values of R0>1, the model approximates asymptotically the endemic equilibrium. We observe numerically the phenomenon of backward bifurcation for values of R0⪅1. This statement will be proved in future work. We also vary the values of the latent period and the production period of infected cells and free virus. We conclude that increasing these values translates in a decrease of the reproduction number. Thus, a good strategy to control the HIV virus should focus on drugs to prolong the latent period and/or slow down the virus production. These results suggest that the model is mathematically and epidemiologically well-posed.

Nature and impact of European anti-stigma depression programmes.

PubMed

Quinn, Neil; Knifton, Lee; Goldie, Isabella; van Bortel, Tine; Dowds, Julie; Lasalvia, Antonio; Scheerder, Gert; Boumans, Jenny; Svab, Vesna; Lanfredi, Mariangela; Wahlbeck, Kristian; Thornicroft, Graham

2014-09-01

Stigma associated with depression is a major public health issue in the EU, with over 20 million people experiencing depression and its associated personal distress each year. While most programmes against stigma related to mental health problems are of a general nature, the knowledge about programmes tackling stigma against people with depression is limited. This study therefore aims to assess the nature and impact of depression-specific programmes in EU countries. Using a web-based tool, 26 programmes were identified across the 18 EU countries taking part in the study. Most were universal and targeted the whole population, while many also targeted specific population groups or settings, such as young people or health professionals. The most common programme aim was improving literacy, although reducing stigmatizing attitudes and discriminatory behaviour and promoting help-seeking were also common. Most programmes originated from professional bodies, or as grassroots initiatives from service user groups/NGOs, rather than as part of national and local policy. The approaches used were primarily different forms of education/information, with some, but very limited, use of positive personal contact. Overall, the quality and extent of impact of the programmes was limited, with few leading to peer-reviewed publications. Specific programmes were identified with evidence of positive impact, and we drew on these examples to develop a framework to be used for future programmes against stigma and discrimination associated with depression. These findings are provided in full in the Anti-Stigma Partnership European Network Toolkit available at www.antistigma.eu. © The Author (2013). Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Imaging and Screening of Cancer of the Small Bowel.

PubMed

Kim, Jin Sil; Park, Seong Ho; Hansel, Stephanie; Fletcher, Joel G

2017-11-01

Delayed diagnosis of small bowel cancers frequently occurs and may arise because of many factors, including low incidence of disease, difficult endoscopic access, lack of mucosal mass or abnormality, subtle radiologic features, and low index of clinical suspicion. As small bowel cancers are rare and their causes are largely unknown, routine population-based screening of asymptomatic patients to find precursor lesions or early cancers is ineffective. However, targeted screening/surveillance strategies are used in specific at-risk and symptomatic patient populations. This article reviews issues regarding early diagnosis of small bowel cancers, with focus on state-of-the-art cross-sectional imaging techniques. Copyright © 2017 Elsevier Inc. All rights reserved.

Targeting solid tumors with non-pathogenic obligate anaerobic bacteria.

PubMed

Taniguchi, Shun'ichiro; Fujimori, Minoru; Sasaki, Takayuki; Tsutsui, Hiroko; Shimatani, Yuko; Seki, Keiichi; Amano, Jun

2010-09-01

Molecular-targeting drugs with fewer severe adverse effects are attracting great attention as the next wave of cancer treatment. There exist, however, populations of cancer cells resistant to these drugs that stem from the instability of tumor cells and/or the existence of cancer stem cells, and thus specific toxicity is required to destroy them. If such selectivity is not available, these targets may be sought out not by the cancer cell types themselves, but rather in their adjacent cancer microenvironments by means of hypoxia, low pH, and so on. The anaerobic conditions present in malignant tumor tissues have previously been regarded as a source of resistance in cancer cells against conventional therapy. However, there now appears to be a way to make use of these limiting factors as a selective target. In this review, we will refer to several trials, including our own, to direct attention to the utilizable anaerobic conditions present in malignant tumor tissues and the use of bacteria as carriers to target them. Specifically, we have been developing a method to attack solid cancers using the non-pathogenic obligate anaerobic bacterium Bifidobacterium longum as a vehicle to selectively recognize and target the anaerobic conditions in solid cancer tissues. We will also discuss the existence of low oxygen pressure in tumor masses in spite of generally enhanced angiogenesis, overview current cancer therapies, especially the history and present situation of bacterial utility to treat solid tumors, and discuss the rationality and future possibilities of this novel mode of cancer treatment. © 2010 Japanese Cancer Association.

Targeted health department expenditures benefit birth outcomes at the county level.

PubMed

Bekemeier, Betty; Yang, Youngran; Dunbar, Matthew D; Pantazis, Athena; Grembowski, David E

2014-06-01

Public health leaders lack evidence for making decisions about the optimal allocation of resources across local health department (LHD) services, even as limited funding has forced cuts to public health services while local needs grow. A lack of data has also limited examination of the outcomes of targeted LHD investments in specific service areas. This study used unique, detailed LHD expenditure data gathered from state health departments to examine the influence of maternal and child health (MCH) service investments by LHDs on health outcomes. A multivariate panel time-series design was used in 2013 to estimate ecologic relationships between 2000-2010 LHD expenditures on MCH and county-level rates of low birth weight and infant mortality. The unit of analysis was 102 LHD jurisdictions in Washington and Florida. Results indicate that LHD expenditures on MCH services have a beneficial relationship with county-level low birth weight rates, particularly in counties with high concentrations of poverty. This relationship is stronger for more targeted expenditure categories, with expenditures in each of the three specific examined MCH service areas demonstrating the strongest effects. Findings indicate that specific LHD investments in MCH have an important effect on related health outcomes for populations in poverty and likely help reduce the costly burden of poor birth outcomes for families and communities. These findings underscore the importance of monitoring the impact of these evolving investments and ensuring that targeted, beneficial investments are not lost but expanded upon across care delivery systems. Copyright © 2014 American Journal of Preventive Medicine. Published by Elsevier Inc. All rights reserved.

Use of a leukocyte-targeted peptide probe as a potential tracer for imaging the tuberculosis granuloma.

PubMed

Locke, Landon W; Kothandaraman, Shankaran; Tweedle, Michael; Chaney, Sarah; Wozniak, Daniel J; Schlesinger, Larry S

2018-01-01

Granulomas are the histopathologic hallmark of tuberculosis (TB), both in latency and active disease. Diagnostic and therapeutic strategies that specifically target granulomas have not been developed. Our objective is to develop a probe for imaging relevant immune cell populations infiltrating the granuloma. We report the binding specificity of Cyanine 3 (Cy3)-labeled cFLFLFK-PEG 12 to human leukocytes and cellular constituents within a human in vitro granuloma model. We also report use of the probe in in vivo studies using a mouse model of lung granulomatous inflammation. We found that the probe preferentially binds human neutrophils and macrophages in human granuloma structures. Inhibition studies showed that peptide binding to human neutrophils is mediated by the receptor formyl peptide receptor 1 (FPR1). Imaging the distribution of intravenously administered cFLFLFK-PEG 12 -Cy3 in the mouse model revealed probe accumulation within granulomatous inflammatory responses in the lung. Further characterization revealed that the probe preferentially associated with neutrophils and cells of the monocyte/macrophage lineage. As there is no current clinical diagnostic imaging tool that specifically targets granulomas, the use of this probe in the context of latent and active TB may provide a unique advantage over current clinical imaging probes. We anticipate that utilizing a FPR1-targeted radiopharmaceutical analog of cFLFLFK in preclinical imaging studies may greatly contribute to our understanding of granuloma influx patterns and the biological roles and consequences of FPR1-expressing cells in contributing to disease pathogenesis. Copyright © 2018 Elsevier Ltd. All rights reserved.

Targeted Facebook Advertising is a Novel and Effective Method of Recruiting Participants into a Human Papillomavirus Vaccine Effectiveness Study

PubMed Central

Wark, John D; Tabrizi, Sepehr N; Garland, Suzanne M

2016-01-01

Background Targeted advertising using social networking sites (SNS) as a recruitment strategy in health research is in its infancy. Objective The aim of this study was to determine the feasibility of targeted Facebook advertisements to increase recruitment of unvaccinated women into a human papillomavirus (HPV) vaccine effectiveness study. Methods Between September 2011 and November 2013, females aged 18 to 25 years, residing in Victoria, Australia, were recruited through Facebook advertisements relating to general women’s health. From November 2013 to June 2015, targeted advertising campaigns were implemented to specifically recruit women who had not received the HPV vaccine. Consenting participants were invited to complete an online questionnaire and those who had ever had sexual intercourse were asked to provide a self-collected vaginal swab. The HPV vaccination status of participants was confirmed from the National HPV Vaccination Program Register (NHVPR). Results The campaign comprised 10 advertisements shown between September 2011 and June 2015 which generated 55,381,637 impressions, yielding 23,714 clicks, at an overall cost of AUD $22,078.85. A total of 919 participants were recruited. A greater proportion of unvaccinated women (50.4%, 131/260) were recruited into the study following targeted advertising, compared with those recruited (19.3%, 127/659) prior to showing the modified advertisement (P<.001). A greater proportion of the total sample completed tertiary education and resided in inner regional Victoria, compared with National population census data (P<.001), but was otherwise representative of the general population. Conclusions Targeted Facebook advertising is a rapid and cost-effective way of recruiting young unvaccinated women into a HPV vaccine effectiveness study. PMID:27450586

Targeted Facebook Advertising is a Novel and Effective Method of Recruiting Participants into a Human Papillomavirus Vaccine Effectiveness Study.

PubMed

Subasinghe, Asvini K; Nguyen, Margaret; Wark, John D; Tabrizi, Sepehr N; Garland, Suzanne M

2016-07-22

Targeted advertising using social networking sites (SNS) as a recruitment strategy in health research is in its infancy. The aim of this study was to determine the feasibility of targeted Facebook advertisements to increase recruitment of unvaccinated women into a human papillomavirus (HPV) vaccine effectiveness study. Between September 2011 and November 2013, females aged 18 to 25 years, residing in Victoria, Australia, were recruited through Facebook advertisements relating to general women's health. From November 2013 to June 2015, targeted advertising campaigns were implemented to specifically recruit women who had not received the HPV vaccine. Consenting participants were invited to complete an online questionnaire and those who had ever had sexual intercourse were asked to provide a self-collected vaginal swab. The HPV vaccination status of participants was confirmed from the National HPV Vaccination Program Register (NHVPR). The campaign comprised 10 advertisements shown between September 2011 and June 2015 which generated 55,381,637 impressions, yielding 23,714 clicks, at an overall cost of AUD $22,078.85. A total of 919 participants were recruited. A greater proportion of unvaccinated women (50.4%, 131/260) were recruited into the study following targeted advertising, compared with those recruited (19.3%, 127/659) prior to showing the modified advertisement (P<.001). A greater proportion of the total sample completed tertiary education and resided in inner regional Victoria, compared with National population census data (P<.001), but was otherwise representative of the general population. Targeted Facebook advertising is a rapid and cost-effective way of recruiting young unvaccinated women into a HPV vaccine effectiveness study.

siRNA as a tool to improve the treatment of brain diseases: Mechanism, targets and delivery.

PubMed

Gomes, Maria João; Martins, Susana; Sarmento, Bruno

2015-05-01

As the population ages, brain pathologies such as neurodegenerative diseases and brain cancer increase their incidence, being the need to find successful treatments of upmost importance. Drug delivery to the central nervous system (CNS) is required in order to reach diseases causes and treat them. However, biological barriers, mainly blood-brain barrier (BBB), are the key obstacles that prevent the effectiveness of possible treatments due to their ability to strongly limit the perfusion of compounds into the brain. Over the past decades, new approaches towards overcoming BBB and its efflux transporters had been proposed. One of these approaches here reviewed is through small interfering RNA (siRNA), which is capable to specifically target one gene and silence it in a post-transcriptional way. There are different possible functional proteins at the BBB, as the ones responsible for transport or just for its tightness, which could be a siRNA target. As important as the effective silence is the way to delivery siRNA to its anatomical site of action. This is where nanotechnology-based systems may help, by protecting siRNA circulation and providing cell/tissue-targeting and intracellular siRNA delivery. After an initial overview on incidence of brain diseases and basic features of the CNS, BBB and its efflux pumps, this review focuses on recent strategies to reach brain based on siRNA, and how to specifically target these approaches in order to treat brain diseases. Copyright © 2015 Elsevier B.V. All rights reserved.

Identification of Reprogrammed Myeloid Cell Transcriptomes in NSCLC

PubMed Central

Gupta, Ravi; Fischer, Kari R.; Choi, Hyejin; El Rayes, Tina; Ryu, Seongho; Nasar, Abu; Spinelli, Cathy F.; Andrews, Weston; Elemento, Olivier; Nolan, Daniel; Stiles, Brendon; Rafii, Shahin; Narula, Navneet; Davuluri, Ramana; Altorki, Nasser K.; Mittal, Vivek

2015-01-01

Lung cancer is the leading cause of cancer related mortality worldwide, with non-small cell lung cancer (NSCLC) as the most prevalent form. Despite advances in treatment options including minimally invasive surgery, CT-guided radiation, novel chemotherapeutic regimens, and targeted therapeutics, prognosis remains dismal. Therefore, further molecular analysis of NSCLC is necessary to identify novel molecular targets that impact prognosis and the design of new-targeted therapies. In recent years, tumor “activated/reprogrammed” stromal cells that promote carcinogenesis have emerged as potential therapeutic targets. However, the contribution of stromal cells to NSCLC is poorly understood. Here, we show increased numbers of bone marrow (BM)-derived hematopoietic cells in the tumor parenchyma of NSCLC patients compared with matched adjacent non-neoplastic lung tissue. By sorting specific cellular fractions from lung cancer patients, we compared the transcriptomes of intratumoral myeloid compartments within the tumor bed with their counterparts within adjacent non-neoplastic tissue from NSCLC patients. The RNA sequencing of specific myeloid compartments (immature monocytic myeloid cells and polymorphonuclear neutrophils) identified differentially regulated genes and mRNA isoforms, which were inconspicuous in whole tumor analysis. Genes encoding secreted factors, including osteopontin (OPN), chemokine (C-C motif) ligand 7 (CCL7) and thrombospondin 1 (TSP1) were identified, which enhanced tumorigenic properties of lung cancer cells indicative of their potential as targets for therapy. This study demonstrates that analysis of homogeneous stromal populations isolated directly from fresh clinical specimens can detect important stromal genes of therapeutic value. PMID:26046767

Communication and marketing as climate change-intervention assets a public health perspective.

PubMed

Maibach, Edward W; Roser-Renouf, Connie; Leiserowitz, Anthony

2008-11-01

The understanding that global climate change represents a profound threat to the health and well-being of human and nonhuman species worldwide is growing. This article examines the potential of communication and marketing interventions to influence population behavior in ways consistent with climate change prevention and adaptation objectives. Specifically, using a framework based on an ecologic model of public health, the paper examines: (1) the potential of communication and marketing interventions to influence population behaviors of concern, including support for appropriate public policies; (2) potential target audiences for such programs; and (3) the attributes of effective climate change messages. Communication and marketing interventions appear to have considerable potential to promote important population behavior change objectives, but there is an urgent need for additional translational research to effectively harvest this potential to combat climate change.

Genomically Encoded Analog Memory with Precise In vivo DNA Writing in Living Cell Populations

PubMed Central

Farzadfard, Fahim; Lu, Timothy K.

2014-01-01

Cellular memory is crucial to many natural biological processes and for sophisticated synthetic-biology applications. Existing cellular memories rely on epigenetic switches or recombinases, which are limited in scalability and recording capacity. Here, we use the DNA of living cell populations as genomic ‘tape recorders’ for the analog and distributed recording of long-term event histories. We describe a platform for generating single-stranded DNA (ssDNA) in vivo in response to arbitrary transcriptional signals. When co-expressed with a recombinase, these intracellularly expressed ssDNAs target specific genomic DNA addresses, resulting in precise mutations that accumulate in cell populations as a function of the magnitude and duration of the inputs. This platform could enable long-term cellular recorders for environmental and biomedical applications, biological state machines, and enhanced genome engineering strategies. PMID:25395541

Impact of Climate Change on Heat-Related Mortality in Jiangsu Province, China

NASA Technical Reports Server (NTRS)

Chen, Kai; Horton, Radley M.; Bader, Daniel A.; Lesk, Corey; Jiang, Leiwen; Jones, Bryan; Zhou, Lian; Chen, Xiaodong; Bi, Jun; Kinney, Patrick L.

2017-01-01

A warming climate is anticipated to increase the future heat-related total mortality in urban areas. However, little evidence has been reported for cause-specific mortality or nonurban areas. Here we assessed the impact of climate change on heat-related total and cause-specific mortality in both urban and rural counties of Jiangsu Province, China, in the next five decades. To address the potential uncertainty in projecting future heat-related mortality, we applied localized urban- and nonurban-specific exposure response functions, six population projections including a no population change scenario and five Shared Socioeconomic Pathways (SSPs), and 42 temperature projections from 21 global-scale general circulation models and two Representative Concentration Pathways (RCPs). Results showed that projected warmer temperatures in 2016-2040 and 2041-2065 will lead to higher heat-related mortality for total non-accidental, cardiovascular, respiratory, stroke, ischemic heart disease (IHD), and chronic obstructive pulmonary disease (COPD) causes occurring annually during May to September in Jiangsu Province, China. Nonurban residents in Jiangsu will suffer from more excess heat-related cause-specific mortality in 2016-2065 than urban residents. Variations across climate models and RCPs dominated the uncertainty of heat-related mortality estimation whereas population size change only had limited influence. Our findings suggest that targeted climate change mitigation and adaptation measures should be taken in both urban and nonurban areas of Jiangsu Province. Specific public health interventions should be focused on the leading causes of death (stroke, IHD, and COPD), whose health burden will be amplified by a warming climate.

Impact of climate change on heat-related mortality in Jiangsu Province, China.

PubMed

Chen, Kai; Horton, Radley M; Bader, Daniel A; Lesk, Corey; Jiang, Leiwen; Jones, Bryan; Zhou, Lian; Chen, Xiaodong; Bi, Jun; Kinney, Patrick L

2017-05-01

A warming climate is anticipated to increase the future heat-related total mortality in urban areas. However, little evidence has been reported for cause-specific mortality or nonurban areas. Here we assessed the impact of climate change on heat-related total and cause-specific mortality in both urban and rural counties of Jiangsu Province, China, in the next five decades. To address the potential uncertainty in projecting future heat-related mortality, we applied localized urban- and nonurban-specific exposure response functions, six population projections including a no population change scenario and five Shared Socioeconomic Pathways (SSPs), and 42 temperature projections from 21 global-scale general circulation models and two Representative Concentration Pathways (RCPs). Results showed that projected warmer temperatures in 2016-2040 and 2041-2065 will lead to higher heat-related mortality for total non-accidental, cardiovascular, respiratory, stroke, ischemic heart disease (IHD), and chronic obstructive pulmonary disease (COPD) causes occurring annually during May to September in Jiangsu Province, China. Nonurban residents in Jiangsu will suffer from more excess heat-related cause-specific mortality in 2016-2065 than urban residents. Variations across climate models and RCPs dominated the uncertainty of heat-related mortality estimation whereas population size change only had limited influence. Our findings suggest that targeted climate change mitigation and adaptation measures should be taken in both urban and nonurban areas of Jiangsu Province. Specific public health interventions should be focused on the leading causes of death (stroke, IHD, and COPD), whose health burden will be amplified by a warming climate. Copyright © 2017 Elsevier Ltd. All rights reserved.

Efficient priming of CD4 T cells by Langerin-expressing dendritic cells targeted with porcine epidemic diarrhea virus spike protein domains in pigs.

PubMed

Subramaniam, Sakthivel; Cao, Dianjun; Tian, Debin; Cao, Qian M; Overend, Christopher; Yugo, Danielle M; Matzinger, Shannon R; Rogers, Adam J; Heffron, C Lynn; Catanzaro, Nicholas; Kenney, Scott P; Opriessnig, Tanja; Huang, Yao-Wei; Labarque, Geoffrey; Wu, Stephen Q; Meng, Xiang-Jin

2017-01-02

Porcine epidemic diarrhea virus (PEDV) first emerged in the United States in 2013 causing high mortality and morbidity in neonatal piglets with immense economic losses to the swine industry. PEDV is an alpha-coronavirus replicating primarily in porcine intestinal cells. PEDV vaccines are available in Asia and Europe, and conditionally-licensed vaccines recently became available in the United States but the efficacies of these vaccines in eliminating PEDV from swine populations are questionable. In this study, the immunogenicity of a subunit vaccine based on the spike protein of PEDV, which was directly targeted to porcine dendritic cells (DCs) expressing Langerin, was assessed. The PEDV S antigen was delivered to the dendritic cells through a single-chain antibody specific to Langerin and the targeted cells were stimulated with cholera toxin adjuvant. This approach, known as "dendritic cell targeting," greatly improved PEDV S antigen-specific T cell interferon-γ responses in the CD4 pos CD8 pos T cell compartment in pigs as early as 7days upon transdermal administration. When the vaccine protein was targeted to Langerin pos DCs systemically through intramuscular vaccination, it induced higher serum IgG and IgA responses in pigs, though these responses require a booster dose, and the magnitude of T cell responses were lower as compared to transdermal vaccination. We conclude that PEDV spike protein domains targeting Langerin-expressing dendritic cells significantly increased CD4 T cell immune responses in pigs. The results indicate that the immunogenicity of protein subunit vaccines can be greatly enhanced by direct targeting of the vaccine antigens to desirable dendritic cell subsets in pigs. Copyright © 2016 Elsevier B.V. All rights reserved.

Targeted microbubbles: a novel application for the treatment of kidney stones.

PubMed

Ramaswamy, Krishna; Marx, Vanessa; Laser, Daniel; Kenny, Thomas; Chi, Thomas; Bailey, Michael; Sorensen, Mathew D; Grubbs, Robert H; Stoller, Marshall L

2015-07-01

Kidney stone disease is endemic. Extracorporeal shockwave lithotripsy was the first major technological breakthrough where focused shockwaves were used to fragment stones in the kidney or ureter. The shockwaves induced the formation of cavitation bubbles, whose collapse released energy at the stone, and the energy fragmented the kidney stones into pieces small enough to be passed spontaneously. Can the concept of microbubbles be used without the bulky machine? The logical progression was to manufacture these powerful microbubbles ex vivo and inject these bubbles directly into the collecting system. An external source can be used to induce cavitation once the microbubbles are at their target; the key is targeting these microbubbles to specifically bind to kidney stones. Two important observations have been established: (i) bisphosphonates attach to hydroxyapatite crystals with high affinity; and (ii) there is substantial hydroxyapatite in most kidney stones. The microbubbles can be equipped with bisphosphonate tags to specifically target kidney stones. These bubbles will preferentially bind to the stone and not surrounding tissue, reducing collateral damage. Ultrasound or another suitable form of energy is then applied causing the microbubbles to induce cavitation and fragment the stones. This can be used as an adjunct to ureteroscopy or percutaneous lithotripsy to aid in fragmentation. Randall's plaques, which also contain hydroxyapatite crystals, can also be targeted to pre-emptively destroy these stone precursors. Additionally, targeted microbubbles can aid in kidney stone diagnostics by virtue of being used as an adjunct to traditional imaging methods, especially useful in high-risk patient populations. This novel application of targeted microbubble technology not only represents the next frontier in minimally invasive stone surgery, but a platform technology for other areas of medicine. © 2014 The Authors BJU International © 2014 BJU International Published by John Wiley & Sons Ltd.

Stem cells in the canine pituitary gland and in pituitary adenomas.

PubMed

van Rijn, Sarah J; Tryfonidou, Marianna A; Hanson, Jeanette M; Penning, Louis C; Meij, Björn P

2013-12-01

Cushing's disease (CD) or pituitary-dependent hypercortisolism is a common endocrinopathy in dogs, with an estimated prevalence of 1 or 2 in 1000 dogs per year. It is caused by an adrenocorticotropic hormone secreting adenoma in the pars distalis or pars intermedia of the pituitary gland. The pituitary gland is a small endocrine gland located in the pituitary fossa. In the postnatal individual, the hypothalamus-pituitary axis plays a central role in maintaining homeostatic functions, like control of metabolism, reproduction, and growth. Stem cells are suggested to play a role in the homeostatic adaptations of the adult pituitary gland, such as the rapid specific cell-type expansion in response to pregnancy or lactation. Several cell populations have been suggested as pituitary stem cells, such as Side Population cells and cells expressing Sox2 or Nestin. These cell populations are discussed in this review. Also, stem and progenitor cells are thought to play a role in pituitary tumorigenesis, such as the development of pituitary adenomas in dogs. There are limited reports on the role of stem cells in pituitary adenomas, especially in dogs. Further studies are needed to identify and characterize this cell population and to develop specific cell targeting therapeutic strategies as a new way of treating canine CD.

A Unique Opportunity to Test Whether Cell Fusion is a Mechanism of Breast Cancer Metastasis

DTIC Science & Technology

2012-07-01

tetraploid with numerous structural rearrangements. The observations that a majority of cancer cell lines in the NCI-60 drug screening panel99 and...optimized electroporation conditions for T47D and human mesenchymal stem cell populations. As a result we have been able to conduct our first co...specific receptor-ligand interactions necessary for cell fusion, to produce a target for drug therapy. Post-fusion events might also be investigated

Securing the Borders: Creation of the Border Patrol Auxiliary

DTIC Science & Technology

2007-05-05

auxiliary members will be the elite members of the BPA who will attend training at the Border Patrol Academy to gain the knowledge and skills required to...recruits and greatly reducing start-up costs for the Border Patrol. It would appeal directly to ideal candidates for the elite tier-two service: new...program, which is a small, elite , and highly selective service. Tier-two members will have to be recruited from specific target populations. Based on the

Lipid nanocarriers and molecular targets for malaria chemotherapy.

PubMed

Jain, Kunal; Sood, Sumeet; Gowthamarajan, Kuppusamy

2014-03-01

Malaria is the most serious tropical disease of humankind and a cause of much debilitation and morbidity throughout the world especially in endemic areas like India and Africa. The development of drug resistance may be due to insufficient drug concentration in presence of high parasite load. In addition, the present pharmaceutical dosage forms are ineffective thereby necessitating the development of novel dosage forms which are effective, safe and affordable to underprivileged population of the developing world. The rapid advancement of nanotechnology has raised the possibility of using lipid nanocarriers that interact within biological environment for treatment of infectious diseases. Thus, lipid based nano-delivery systems offer a platform to formulate old and toxic antimalarial drugs thereby modifying their pharmacokinetic profile, biodistribution and targetability. Further, there is a need to develop new chemotherapy based approaches for inhibiting the parasite-specific metabolic pathways. The present review highlights the advances in lipid nanocarriers and putative molecular targets for antimalarial chemotherapy.

Hepatic stellate cells: fibrogenic, regenerative or both? Heterogeneity and context are key.

PubMed

Bansal, Meena B

2016-11-01

Since their original identification, our understanding of the role of hepatic stellate cells in both health and disease continues to grow. Numerous studies have delineated the role of stellate cell activation in contributing to the pool of myofibroblasts responsible for liver fibrosis, and these have resulted in the development of a number of anti-fibrotic strategies targeting this cell. However, their potential role in liver regeneration, both initiation and termination, is also emerging and needs to be contemplated when considering targeted therapy. Perhaps what is most striking is the increasing recognition that this is not just one cell, but rather, a heterogenous population made up of a number of different subsets of cells, each with differentiated and specific functions. The tools are emerging for this dissection and are greatly needed to truly develop targeted therapies that will inhibit fibrosis while promoting liver regeneration and repair.

Pre-fusion RSV F strongly boosts pre-fusion specific neutralizing responses in cattle pre-exposed to bovine RSV.

PubMed

Steff, Ann-Muriel; Monroe, James; Friedrich, Kristian; Chandramouli, Sumana; Nguyen, Thi Lien-Anh; Tian, Sai; Vandepaer, Sarah; Toussaint, Jean-François; Carfi, Andrea

2017-10-20

Human respiratory syncytial virus (hRSV) is responsible for serious lower respiratory tract disease in infants and in older adults, and remains an important vaccine need. RSV fusion (F) glycoprotein is a key target for neutralizing antibodies. RSV F stabilized in its pre-fusion conformation (DS-Cav1 F) induces high neutralizing antibody titers in naïve animals, but it remains unknown to what extent pre-fusion F can boost pre-existing neutralizing responses in RSV seropositive adults. We here assess DS-Cav1 F immunogenicity in seropositive cattle pre-exposed to bovine RSV, a virus closely related to hRSV. A single immunization with non-adjuvanted DS-Cav1 F strongly boosts RSV neutralizing responses, directed towards pre-fusion F-specific epitopes, whereas a post-fusion F is unable to do so. Vaccination with pre-fusion F thus represents a promising strategy for maternal immunization and for other RSV vaccine target populations such as older adults.

Sensitizing pathogens to antibiotics using the CRISPR-Cas system.

PubMed

Goren, Moran; Yosef, Ido; Qimron, Udi

2017-01-01

The extensive use of antibiotics over the last century has resulted in a significant artificial selection pressure for antibiotic-resistant pathogens to evolve. Various strategies to fight these pathogens have been introduced including new antibiotics, naturally-derived enzymes/peptides that specifically target pathogens and bacteriophages that lyse these pathogens. A new tool has recently been introduced in the fight against drug-resistant pathogens-the prokaryotic defense mechanism-clustered regularly interspaced short palindromic repeats-CRISPR associated (CRISPR-Cas) system. The CRISPR-Cas system acts as a nuclease that can be guided to cleave any target DNA, allowing sophisticated, yet feasible, manipulations of pathogens. Here, we review pioneering studies that use the CRISPR-Cas system to specifically edit bacterial populations, eliminate their resistance genes and combine these two strategies in order to produce an artificial selection pressure for antibiotic-sensitive pathogens. We suggest that intelligent design of this system, along with efficient delivery tools into pathogens, may significantly reduce the threat of antibiotic-resistant pathogens. Copyright © 2016 Elsevier Ltd. All rights reserved.