Gatekeeping Strategies Research Articles

A gender-focused analysis of structural and social precipitators to child institutionalization in Azerbaijan: A qualitative study

Deinstitutionalization reforms in the post-Soviet region—the region with the highest rate of institutional care worldwide—are aimed at reducing the number of children in institutions. To develop context-specific gatekeeping strategies and prevent new cohorts of children from entering institutions, it is crucial to understand the local factors that contribute to institutional placement. Using a phenomenological approach, this qualitative study explores the contexts of institutional placement of children in Azerbaijan from their caregivers' perspectives. We conducted semi-structured qualitative interviews of the parents and primary caregivers (N = 26) of children placed in the institutional care system in Azerbaijan. Using systematic thematic analysis with inductive coding, we identified caregivers' reasons for placing children in the system, and inferred the life circumstances that led parents—women in particular—to be more likely to place their children in institutions. Our findings reveal multiple, gendered pathways that contribute to such placement. The majority of caregivers were single mothers, many of whom had divorced their husbands in response to domestic violence (often attributed to the husband's substance addiction). The strong stigma against divorce led women to be ostracized by close family members, often leaving them without economic and social support. Because of the limitations of public benefits available in the region, publicly-funded child institutions are often the only remaining way to provide education and care for their children. This qualitative study shows the importance of addressing the social and economic needs of parents, single mothers in particular, to prevent child institutional placement in the post-Soviet Caucasus region.

Applications of general multistage gatekeeping and graphical multiple testing strategies in a clinical trial setting

Multiplicity adjustment plays a critical role for testing multiple endpoints and/or multiple doses in clinical trials. Under the clinical trial setting, multiple hypotheses are usually grouped into primary and secondary families and hierarchically ordered between and within families. The determination of the order and grouping of the hypotheses depends on the objectives of the trial. In such scenarios, strong control of the family-wise error rate (FWER) can be achieved via either gatekeeping procedures or the graphical approach to sequential testing procedures. The aforementioned two types of procedures are related but are not completely overlapping. Both approaches are assessed in this manuscript, with a focus on the comparison and relationship between the two. In addition, the performance of various constructions of gatekeeping and graphical multiple comparison procedures (MCPs) under a typical clinical trial setting with multiple doses and multiple endpoints is studied.

Book Review: Race and upward mobility: Seeking, gatekeeping, and other class strategies in postwar America

Book Review: Race and upward mobility: Seeking, gatekeeping, and other class strategies in postwar America

Gatekeeping in the Field: Strategies and Practices

Though counseling graduate programs often rely heavily on field site supervisors for help remediating interns with professional competence problems, there is little published research on the remediation and gatekeeping strategies used by field site supervisors. This article presents the results of a descriptive study of 103 field site supervisors on perspectives and strategies for gatekeeping and remediating counselors-in-training. The most common gatekeeping and remediation strategies reported by participants were consulting with other professionals, discussing the issue directly with the supervisee, and increasing live supervision. Only 35% reported discussing the student with counselor education faculty.

A randomized, double-blind, placebo-controlled phase III study of cisplatin plus a fluoropyrimidine with or without ramucirumab as first-line therapy in patients with metastatic gastric or gastroesophageal junction (GEJ) adenocarcinoma (RAINFALL, NCT02314117).

TPS178 Background: Ramucirumab, a human IgG1 monoclonal antibody directed to the ectodomain of VEGFR-2, prevents ligand binding to the receptor, blocking activation of downstream receptor-mediated pathways. Ramucirumab has demonstrated significant improvement in overall survival (OS) and progression-free survival (PFS) in 2 phase III registration studies (REGARD, RAINBOW) in patients in second-line treatment of gastric cancer. This global phase III trial will compare PFS in patients with HER2-negative, metastatic gastric or GEJ adenocarcinoma receiving ramucirumab with cisplatin/capecitabine (or 5-FU) versus placebo with cisplatin/capecitabine (or 5-FU) as first-line treatment. The trial is conducted in 137 sites in the Americas, Europe and Japan and is currently open to enrollment. Methods: Eligible patients will be randomized to receive ramucirumab (8mg/kg on days 1 and 8, based upon population pharmacokinetic modelling) or placebo with cisplatin/capecitabine every 21-day cycle until disease progression, unacceptable toxicity, or other withdrawal criteria are met. The primary endpoint is PFS; OS is the key secondary endpoint. Efficacy will be considered at 3 analysis points: futility analysis for PFS, primary analysis of PFS & final analysis of OS. A gatekeeping strategy will be used to assess PFS and OS. The OS endpoint will only be tested if the PFS test is significant to control Type I error at 5% across both endpoints. An exposure/safety analysis will be done after 60 patients have started the 3rd cycle. The study has 90% power to demonstrate a PFS advantage assuming HR = 0.70 and 80% power to demonstrate an OS advantage assuming HR = 0.77. Other secondary endpoints include PFS2 (the time from randomization to disease progression after the start of additional systemic anticancer treatment, or death from any cause, whichever occurs first), objective response rate, safety and quality of life. As of 9/11/2015, 128 patients have been enrolled in 19 countries. The 1st exposure/safety analysis is underway. Clinical trial information: NCT02314117.

Gatekeepers in Russian High-Tech: A Study of Heads of Leading Research Centers

The paper proposes one of the first attempts to conceptualize the “human capital” in science and technology gatekeeping in Russia, based on obtaining sociological data on real active subjects. The study strives to provide analytical information on the specific characteristics and stances of individuals making a decisive contribution to the development of strategic areas in science and technology. In Russia, the most perceptible impact on changing the situation of new scientific knowledge production and, in particular, high-tech development comes from heads of “advanced” research laboratories. Capable of forming and carrying out their own research programmes, in the majority of instances they act as “gatekeepers” of the high-tech sector.In the first stage a quantitative questionnaire survey was carried out by means of a formalized interview (312 respondents). In the second stage qualitative information was collected using in-depth semi-structured individual interviews with the managers of leading laboratories in their field (31 interviews). The information on the gatekeeping strategies in the six science and technology priority areas was obtained.Research on the expert community associated with high-tech projects logically fits into the “cluster” of foresight studies, supplementing it with “human capital”.

Adaptive designs for clinical trials with multiple endpoints

Rationale for adaptive designs with multiple endpoints In clinical trials, the efficacy of a new treatment is usually assessed by a single primary endpoint [1,2]. Other important aspects concerning the new treatment, such as adverse events or quality of life, are taken into account by the definition of secondary endpoints. Usually, only the primary endpoint is analyzed confirmatorily with a statistical test whereas the secondary endpoints are evaluated with descriptive statistical methods. A descriptive analysis, however, does not result in a definite proof and therefore provides only limited additional information. The current research on multiple testing strategies offers many opportunities to incorporate secondary endpoints in the confirmatory analysis of a trial, for example, by a predefined hierarchical testing procedure or enhanced gatekeeping strategies [3–6]. While the nature of secondary endpoints is that they are only of subordinate clinical importance, there also exist many clinical trial applications where the efficacy of a new treatment cannot be adequately described by only one primary endpoint. The EMEA Guideline Points to Consider on Multiplicity Issues states that ‘If, however, a single variable is not sufficient to capture the range of clinically relevant treatment benefits, the use of more than one primary variable may become necessary’ [2]. In some situations, the efficacy claim is therefore based on the significance of several primary endpoints, also referred to as coprimary endpoints. However, even if several primary endpoints are considered, it is not always necessary to demonstrate a significant and relevant effect in all primary endpoints under investigation. Another option is to base the efficacy claim of the new intervention on the significance of at least one endpoint out of a predefined set of primary endpoints considered as clinically relevant. Whenever several endpoints are included in the confirmatory analysis of a clinical trial, a multiple testing problem arises. In order to control the probability to falsely reject at least one of the null hypotheses under investigation at a predefined global significance level α, the local significance levels corresponding to the individual test hypotheses have to be adjusted by an adequate multiple testing procedure. There exist a variety of multiple testing procedures in the statistical literature for many different possible applications [3–8]. When several endpoints are assessed within a multiple test problem, the power of the trial depends on the expected effects of all endpoints and on the correlations between them. The calculation of an adequate sample size therefore is a particular challenge, as the number of required parameter assumptions to be estimated in the planning stage is much larger as compared with a single endpoint test problem. For this reason, adaptive study designs which allow reacting flexibly to these uncertainties in the planning stage play a major role for clinical trials with multiple endpoints.

Incremental cost-effectiveness of dobutamine stress cardiac magnetic resonance imaging in patients at intermediate risk for coronary artery disease.

AimsThe effectiveness of stress cardiac magnetic resonance (CMR) as a gatekeeper for coronary angiography (CA) has been established. Level five HTA studies according to the hierarchical model of diagnostic test evaluation are not available.MethodsThis cohort study included 1,158 consecutive patients (mean age 63 ± 11 years, 42 % women) presenting at our institution between January 1, 2003 and December 31, 2004 with suspected coronary artery disease (CAD) for an elective CA. The patients were assessed for eligibility and propensity score matching was applied to address selection bias regarding the patients’ allocation to CMR or direct CA. Median patient follow-up was 7.9 years (95 % CI 7.8–8.0 years). The primary effect was calculated as relative survival difference. The cost unit calculation (per patient) at our institute was the source of costs.ResultsSurvival was similar in CMR and CA (p = 0.139). Catheterizations ruling out CAD were significantly reduced by the CMR gate-keeper strategy. Patients with prior CMR had significantly lower costs at the initial hospital stay and at follow-up (CMR vs. CA, initial: 2,904€ vs. 3,421€, p = 0.018; follow-up: 2,045€ vs. 3,318€, p = 0.037). CMR was cost-effective in terms of a contribution of 12,466€ per life year to cover a part of the CMR costs.ConclusionStress CMR prior to CA was saving 12,466€ of hospital costs per life year. Lower costs at follow-up suggest sustained cost-effectiveness of the CMR-guided strategy.Electronic supplementary materialThe online version of this article (doi:10.1007/s00392-014-0793-0) contains supplementary material, which is available to authorized users.

Novel Inorganic Gatekeeper Strategy for Obtaining Controlled Release in Mesoporous Silica Nanoparticles

Abstract A relatively facile and adjustable approach was investigated to synthesize mesoporous silica nanoparticles (MSNs) with a thin controllable solid silica-cap (sSiO2) outer layer that prevented unwanted degradation for controlled drug release because the sSiO2 turned out to degrade gradually. Ibuprofen (IBU) and calcium ions were loaded to evaluate the efficiency of this system. This sSiO2-capped degradation strategy for controlled release could easily be extended to other pH- or temperature-responsive MSN systems and applications.

Multi-levelling and externalizing migration and asylum: lessons from the southern European islands

Southern European countries have come to constitute the most vulnerable external border of the European Union (EU) over the last decade. Irregular migration pressures have been acutely felt on the EU’s southern sea borders, and particularly on four sets of islands: Canary Islands (Spain), Lampedusa and Linosa (Italy), Malta, and Aegean Islands (Greece). This quartet is, to a large extent, used as stepping stones by irregular migrants and asylum seekers to reach the European continent. This paper studies the role of these islands as ‘outposts’ of a framework of externalization. It starts by discussing the notion of externalization and its different facets. It considers how externalization is linked to both fencing and gate-keeping strategies of migration and asylum control. The second part of the paper focuses on the special role of the island quartet with respect to the externalization web cast by national and EU-wide migration policies. It concludes with a critical reflection on the multi-level character of externalization policies and practices that occur both within the EU and between the EU and third countries.

Assessment of strategies for male involvement in the prevention of mother-to-child transmission of HIV services in Blantyre, Malawi

BackgroundDespite the documented benefits of prevention of mother-to-child transmission (PMTCT) of human immunodeficiency virus (HIV) services, the uptake remains low in sub-Saharan Africa. The lack of male involvement (MI) may be one of the reasons for this. However, there are limited data on strategies for MI in PMTCT.ObjectiveThe objective of this study was to identify strategies that may promote MI in PMTCT services in antenatal care (ANC) services in Blantyre, Malawi.Study designAn exploratory qualitative study was conducted from December 2012 to January 2013 at South Lunzu Health Centre (SLHC) in Blantyre, Malawi. It consisted of six face-to-face key informant interviews (KIIs) with healthcare workers and four focus group discussions (FGDs) with 18 men and 17 pregnant women attending ANC at SLHC. The FGDs were divided according to sex and age. All FGDs and KIIs were digitally recorded and simultaneously transcribed and translated verbatim into English. Data were analyzed using thematic content analysis.ResultsThree major themes with several subcategories emerged. Theme 1 was a gatekeeping strategy with two subcategories: (1) healthcare workers refusing service provision to women accessing antenatal clinic without their partners and (2) women refusing ANC attention in the absence of a partner. Theme 2 comprised extending invitations and had six subcategories: (1) word of mouth, (2) card invites, (3) woman's health passport book invites, (4) telephonic invites, (5) use of influential people, and (6) home visits. Theme 3 was information education and communication, such as health education forums and advertisements. Of all the strategies, an invitation card addressed to the male partner was most preferred by study participants.ConclusionsThere are several strategies by which men may be involved in PMTCT. Healthcare workers should offer a pregnant woman all strategies available for MI for her to select the appropriate one. Further research and consultations with men should continue to achieve higher levels of MI.

Readers Comments on Zimbabwean Newspaper Websites

Using qualitative data drawn from in-depth interviews with journalists, this study investigates how leading print newsrooms in Zimbabwe are adapting to the wave of changes spawned by readers’ comments on their websites. It specifically examines how newspaper journalists are handling the “new” context in which strangers contribute and respond directly to something they alone once controlled. The paper further explores the professional and ethical dilemmas emerging with the volumes of user-generated content posted on the websites and the approaches taken by newsrooms in managing and “gatekeeping” the content. The study generally observes that while newsrooms are still broadly adjusting to the influx of readers’ voices in their territory, the comments are increasingly shaping and contributing to the dynamics of newsmaking in ways that point to an emerging ecological reconfiguration and recasting of dimensions of news production. In the same way, the comment forums embody spaces for public deliberation. However, the lack of clear gatekeeping strategies has opened floodgates of abuses and extremist views that pose serious threats to the core values of news as well as the normative ideals of traditional journalism.

Remapping the Border: Geospatial Technologies and Border Activism

This paper analyzes the politics of mapping along the US–Mexico border to explore how humanitarian activists wield geospatial technologies in challenging border securitization. In addition to ‘bounding’ societies within delimited territorial zones, mapping technologies have recently been elevated to encompass observing, locating, and tracking mobile bodies—outcomes that, in the context of immigration control, have heightened the risk of clandestine border crossings and produced a sharp rise in migrant fatalities. As geospatial tools have been integrated into official gatekeeping strategies, activists have deployed them to protect migrants, promote mobility rights, and disrupt borders and the spatial, legal, and technical orders underpinning their materialization and enforcement. This case study considers the political implications of these interventions, and highlights how technologies traditionally aligned with state security and surveillance have been reappropriated in the service of transnational solidarity, recognition, and hospitality.

From Border Control to Border Care: The Political and Ethical Potential of Surveillance.

This paper analyzes the use of surveillance by activist groups opposed to the extensive securitization of the US-Mexico border and examines the implications of their activities for scholarship on borders, surveillance, and empowerment. The work of three organizations—the American Civil Liberties Union (ACLU), No More Deaths, and Humane Borders—is covered. While there is some overlap in their practices, these three organizations, respectively, have concentrated on (1) the use of digital photography and video recording equipment to monitor state agents and vigilante organizations; (2) the coordination of citizen-organized foot patrols to locate and assist migrants in danger; and (3) the use of Geographic Information Systems (GIS) to support the provision of water and high-resolution border maps to migrants. In documenting the practical use and symbolic framing of surveillance by secular and faith-based activists, this article adds necessary complexity to prevailing conceptualizations of observational strategies and practices. It demonstrates that, while they may enhance and extend state control over bounded territories and populations, watching, monitoring, and rendering visible are not inherently exclusionary or repressive acts and can, in fact, be used in the service of undermining borders and their attendant consequences. The groups examined herein have applied surveillance towards contesting official gatekeeping strategies and creating alternative moral geographies where the imperatives of sovereignty and national security are subordinated to social justice and global hospitality.

Treatment Rationale and Study Design for a Randomized Trial of Pemetrexed/Carboplatin Followed by Maintenance Pemetrexed Versus Paclitaxel/Carboplatin/Bevacizumab Followed by Maintenance Bevacizumab in Patients With Advanced Non–Small-Cell Lung Cancer of Nonsquamous Histology

Herein we describe a companion ongoing randomized phase III study in patients with advanced nonsquamous non–small-cell lung cancer (NSCLC). Patients with chemotherapy-naive advanced disease will be randomized to receive either pemetrexed 500 mg/m2 plus carboplatin area under the curve (AUC) 6 for 4 cycles followed by maintenance pemetrexed (arm A) or paclitaxel 200 mg/m2 plus carboplatin AUC 6 plus bevacizumab 15 mg/kg for 4 cycles followed by maintenance bevacizumab (arm B). Cycles are 3 weeks. The primary endpoint is progression-free survival (PFS)without grade 4 toxicity (G4PFS) and will test the hypothesis that G4PFS is superior for the pemetrexed-containing combination. This type of endpoint has been used previously in clinical trials in which survival outcomes have been shown to be similar between treatment regimens; thus, a regimen that reduces the risk of toxicity is clinically relevant, particularly in the palliative setting. The study will enroll approximately 360 patients (180 per arm), allowing for a 10% drop-out. Assuming a hazard ratio (HR) of 0.75, this study will have an 80% statistical power to detect superiority of arm A over arm B with the use of a 1-sided log-rank test and a type I error of 0.05. If the true median G4PFS for arm B is 3 months, then the HR of 0.75 equals approximately 1 month of improvement in median G4PFS for arm A. A gatekeeper strategy will be used to sequentially test PFS. This strategy will preserve the overall type I error rate when conducting statistical tests on both G4PFS and PFS.

Teriparatide for acceleration of fracture repair in humans: A prospective, randomized, double-blind study of 102 postmenopausal women with distal radial fractures

Animal experiments show a dramatic improvement in skeletal repair by teriparatide. We tested the hypothesis that recombinant teriparatide, at the 20 microg dose normally used for osteoporosis treatment or higher, would accelerate fracture repair in humans. Postmenopausal women (45 to 85 years of age) who had sustained a dorsally angulated distal radial fracture in need of closed reduction but no surgery were randomly assigned to 8 weeks of once-daily injections of placebo (n = 34) or teriparatide 20 microg (n = 34) or teriparatide 40 microg (n = 34) within 10 days of fracture. Hypotheses were tested sequentially, beginning with the teriparatide 40 microg versus placebo comparison, using a gatekeeping strategy. The estimated median time from fracture to first radiographic evidence of complete cortical bridging in three of four cortices was 9.1, 7.4, and 8.8 weeks for placebo and teriparatide 20 microg and 40 microg, respectively (overall p = .015). There was no significant difference between the teriparatide 40 microg versus placebo groups (p = .523). In post hoc analyses, there was no significant difference between teriparatide 40 microg versus 20 microg (p = .053); however, the time to healing was shorter in teriparatide 20 microg than placebo (p = .006). The primary hypothesis that teriparatide 40 microg would shorten the time to cortical bridging was not supported. The shortened time to healing for teriparatide 20 microg compared with placebo still may suggest that fracture repair can be accelerated by teriparatide, but this result should be interpreted with caution and warrants further study.

A Dunnett–Bonferroni‐based parallel gatekeeping procedure for dose–response clinical trials with multiple endpoints

This paper proposes a Dunnett-Bonferroni-based parallel gatekeeping procedure in a setting of dose-response clinical trials with multiple endpoints. It follows the Dunnett-based parallel gatekeeping strategy of Dmitrienko et al. (Pharm. Stat. 2006; 5:19-28), but differs in the calculation of the critical values. The implementation of the Dunnett-based parallel gatekeeping procedure relies on assumptions difficult to justify in typical clinical trials, namely (a) that the joint distribution of the test statistics from different endpoints can be approximated by a multivariate-t distribution and (b) that the true correlation between multiple endpoints can be well estimated using observed data. The proposed Dunnett-Bonferroni-based parallel gatekeeping procedure relaxes the preceding assumptions by splitting type I error rate among families using the Bonferroni inequality. While it is potentially less powerful than a Dunnett-based procedure when both procedures are applicable, the power loss is very minimal. Our proposed method avoids assumptions that might be challenged by regulatory agencies and does so with virtually no cost. Moreover, in most cases this method is easier to implement compared with the Dunnett-based procedure.

A graphical approach to sequentially rejective multiple test procedures

For clinical trials with multiple treatment arms or endpoints a variety of sequentially rejective, weighted Bonferroni-type tests have been proposed, such as gatekeeping procedures, fixed sequence tests, and fallback procedures. They allow to map the difference in importance as well as the relationship between the various research questions onto an adequate multiple test procedure. Since these procedures rely on the closed test principle, they usually require the explicit specification of a large number of intersection hypotheses tests. The underlying test strategy may therefore be difficult to communicate. We propose a simple iterative graphical approach to construct and perform such Bonferroni-type tests. The resulting multiple test procedures are represented by directed, weighted graphs, where each node corresponds to an elementary hypothesis, together with a simple algorithm to generate such graphs while sequentially testing the individual hypotheses. The approach is illustrated with the visualization of several common gatekeeping strategies. A case study is used to illustrate how the methods from this article can be used to tailor a multiple test procedure to given study objectives.

A two-step nucleotide-flipping mechanism enables kinetic discrimination of DNA lesions by AGT

O(6)-alkylguanine-DNA alkyltransferase (AGT) repairs damage to the human genome by flipping guanine and thymine bases into its active site for irreversible transfer of alkyl lesions to Cys-145, but how the protein identifies its targets has remained unknown. Understanding molecular recognition in this system, which can serve as a paradigm for the many nucleotide-flipping proteins that regulate genes and repair DNA in all kingdoms of life, is particularly important given that inhibitors are in clinical trials as anticancer therapeutics. Computational approaches introduced recently for harvesting and statistically characterizing trajectories of molecularly rare events now enable us to elucidate a pathway for nucleotide flipping by AGT and the forces that promote it. In contrast to previously proposed flipping mechanisms, we observe a two-step process that promotes a kinetic, rather than a thermodynamic, gate-keeping strategy for lesion discrimination. Connection is made to recent single-molecule studies of DNA-repair proteins sliding on DNA to understand how they sense subtle chemical differences between bases efficiently.

Structure of a repair enzyme interrogating undamaged DNA elucidates recognition of damaged DNA

How DNA repair proteins distinguish between the rare sites of damage and the vast expanse of normal DNA is poorly understood. Recognizing the mutagenic lesion 8-oxoguanine (oxoG) represents an especially formidable challenge, because this oxidized nucleobase differs by only two atoms from its normal counterpart, guanine (G). Here we report the use of a covalent trapping strategy to capture a human oxoG repair protein, 8-oxoguanine DNA glycosylase I (hOGG1), in the act of interrogating normal DNA. The X-ray structure of the trapped complex features a target G nucleobase extruded from the DNA helix but denied insertion into the lesion recognition pocket of the enzyme. Free energy difference calculations show that both attractive and repulsive interactions have an important role in the preferential binding of oxoG compared with G to the active site. The structure reveals a remarkably effective gate-keeping strategy for lesion discrimination and suggests a mechanism for oxoG insertion into the hOGG1 active site.