A single harmonised pharmacy process to improve clinical trial set-up times.

The UK has fallen from fourth to 10th place in the global ranking for clinical trial activities in the past 6 years. Due to the limited capacity of the clinical trial pharmacy workforce and delays in providing pharmacy approvals, pharmacy has been identified as one of the constraining services that delays the set-up and delivery of clinical trials. To tackle this problem, we developed a single pharmacy review process for multicentre trials across Greater Manchester (GM) and tested its feasibility and implementation in our region. A survey completed by each GM Trust suggests that this harmonised pharmacy review process for multicentre studies would expedite trial set-up time at each pharmacy site and standardise the pharmacy review process in GM. We therefore believe that this harmonised review process could potentially reduce pharmacy set-up time and reposition the UK in the global market for clinical trials.

Enhancing Human-Centered Design With Youth-Led Participatory Action Research Approaches for Adolescent Sexual and Reproductive Health Programming.

Existing participatory research approaches have failed to identify innovative methods that overcome the persistent barriers to adolescent sexual and reproductive health service demand and access. Increasingly, programmers have turned to human-centered design (HCD), a problem-solving process that centers the needs, perspectives, and experiences of people, when developing solutions to complex SRH challenges. This article describes the application of a youth-engaged version of HCD as part of Adolescents 360, a transdisciplinary initiative to increase 15- to 19-year-old girls' use of modern contraception in Nigeria, Ethiopia, and Tanzania. Youth-adult design teams (including 111 "youth designers" trained in HCD methods) undertook formative research to inform the design and implementation of interventions. We reflect on the practical implications of using instrumental strategies of HCD with a youth-led participatory approach. Our experience indicates that (1) engaging youth as project partners in transdisciplinary teams requires planned and dedicated financial and human resources; (2) involving youth as action researchers can help identify opportunities to improve program empathy and responsiveness; (3) it is difficult to recruit "extreme users" as project partners because of the high competencies needed in HCD; (4) centering empathy and employing design standards during prototyping can drive decision-making and resolve questions raised by conflicting evidence claims in existing bodies of literature; and (5) testing tangible services and products in real-world settings continues long after the intervention design phase. Youth-adult partnership should continue throughout this iterative and adaptive phase to ensure that the adolescent experience of the intervention remains at the core of intervention delivery.

A Package of Sexual and Reproductive Health and Rights Interventions-What Does It Mean for Adolescents?

This article analyzes the relevance of the comprehensive definition of sexual and reproductive health and rights (SRHR) to adolescents and identifies adolescent-specific implications for the implementation of an essential package of SRHR interventions. The delivery of a comprehensive approach to SRHR targeting adolescents is underpinned by five principles-equity, quality, accountability, multisectorality, and meaningful engagement. All SRHR interventions included in the package are relevant to adolescents, given the diversity of adolescents' SRHR needs and considering their specific attributes, circumstances, and experiences. Ensuring that this package is available, accessible, and acceptable to adolescents requires an approach that looks at adolescents as being biologically and socially distinct from other age groups and acknowledges that they face some specific barriers when accessing SRHR services. This article provides cross-cutting strategies for the implementation of a comprehensive approach to SRHR for adolescents and specific considerations in delivering each intervention in the package of essential SRHR interventions. To further implement the International Conference on Population and Development Programme of Action, a prerequisite for achieving the Sustainable Development Goals, SRHR interventions must be adolescent responsive, delivered through multiple platforms, leveraging multisectoral collaboration, and strengthening accountability and participation.

Forward, Together: A Collaborative Path to Comprehensive Adolescent Sexual and Reproductive Health and Rights in Our Time.

The 1994 International Conference on Population and Development established a basis for the advancement of adolescent sexual and reproductive health and rights (ASRHR) that endures today. Twenty-five years later, our vision for the future warrants reflection based on a clear understanding of the opportunities and challenges before us. Inclusion of adolescents on global, regional, and national agendas; increased investment in ASRHR policies and programs; renewed commitments to universal health coverage; increased school enrollment; and advances in technology are all critical opportunities we can and must leverage to catalyze progress for adolescents. At the same time, a range of significant challenges remain, have newly emerged, or can be seen on the horizon, including persistent denial of adolescent sexuality; entrenched gender inequality; resistance to meaningfully engaging adolescents and young people in political and programmatic processes; weak systems, integration, and multisectoral coordination; changes in population dynamics; humanitarian and climate crises; and changes in family and community structures. To achieve as much progress toward our vision for ASRHR as possible, the global ASRHR community must take strategic and specific steps in the next 10 years within five areas for action: (1) mobilize and make full use of political and social support for ASRHR policies and programs; (2) increase and make effective use of external and domestic funding for ASRHR; (3) develop, communicate, apply, and monitor enabling and protective laws and policies for ASRHR; (4) use and improve available ASRHR data and evidence to strengthen advocacy, policies, and programs; and (5) manage the implementation of ASRHR strategies at scale with quality and equity.

Get Smart: Learning and partnership with Ethiopia's Health Extension Programme to re-envision contraceptive service delivery to young couples.

Background: Adolescents 360 (A360) implements the Smart Start (SS) programme through Ethiopia's Health Extension Programme (HEP). SS is premised on financial planning as an entry point to discuss family planning (FP) with newly married couples and central to its delivery are the health extension workers (HEW). This article evaluates the A360 experience and learning from the process evaluation implemented by Itad to understand contextual barriers and enablers from the perspective of the HEW. Methods: A purposive sampling strategy was employed whereby 27 key stakeholders were identified from Oromia, Addis Ababa and Amhara, based on exposure to the SS programme. Findings from the action research were shared with A360 through a one day sounding workshop. Results: Findings revealed that many local government and communal respondents do not view adolescent pregnancy as a problem, unless out of wedlock, and adolescent pregnancy is closely linked to early marriage. As a result, some providers, including HEWs, acknowledged that married adolescent girls were previously 'neglected' by them, while husbands indicated that they had not previously been included in FP counselling. Findings also revealed some challenges with SS implementation as HEWs were 'deprioritizing' the intervention and many HEWs had been in situ for several years and were overworked and frustrated. Against this backdrop, A360 was viewed as adding to the HEW workload. While the programme design was focused on adolescent users, there was increasing recognition that HEWs also needed to be at the centre of solution design. Conclusions: Despite challenges associated with the HEP, Ethiopia FP2020 plans to support the 'next generation' of HEWs, including a focus on adolescents and youth. To gain deeper insight and put the HEW at the centre of design, A360 will continue to work with the process evaluation to understand contextual barriers and enablers from the perspective of the HEW.

Toward communities as systems: a sequential mixed methods study to understand factors enabling implementation of a skilled birth attendance intervention in Nampula Province, Mozambique.

BACKGROUND: Skilled birth attendance, institutional deliveries, and provision of quality, respectful care are key practices to improve maternal and neonatal health outcomes. In Mozambique, the government has prioritized improved service delivery and demand for these practices, alongside "humanization of the birth process." An intervention implemented in Nampula province beginning in 2009 saw marked improvement in institutional delivery rates. This study uses a sequential explanatory mixed methods case study design to explore the contextual factors that may have contributed to the observed increase in institutional deliveries. METHODS: A descriptive time series analysis was conducted using clinic register data from 2009 to 2014 to assess institutional delivery coverage rates in two primary health care facilities, in two districts of Nampula province. Site selection was based on facilities exhibiting an initial increase in institutional deliveries from 2009 to 2011, similarity of health system attributes, and accessibility for study participation. Using a modified Delphi technique, two expert panels-each composed of ten stakeholders familiar with maternal health implementation at facility, district, provincial, and national levels-were convened to formulate the "story" of the implementation and to identify contextual factors to use in developing semi-structured interview guides. Thirty-four key informant interviews with facility MCH nurses, facility managers, traditional birth attendants, community leaders, and beneficiaries were then conducted and analyzed using the Consolidated Framework for Implementation Research through inductive and deductive coding. RESULTS: The two sites' skilled birth attendance coverage of estimated live births reached 80 and 100%, respectively. Eight contextual and human factors were found as dominant themes. Though both sites achieved increases, implementation context differed significantly with compelling examples of both respectful and disrespectful care. In one site, facility and community actors worked together as complementary systems to sustain improved care and institutional deliveries. In the other, community actors sustained implementation and institutional deliveries largely in absence of health system counterparts. CONCLUSION: Findings support global health recommendations for combined health system and community interventions for improved MNH outcomes including delivery of respectful care, and further suggest the capacity of communities to act as systems both in partnership to and independent of the formal health system.

Synthetic Site-Selectively Mono-6-O-Sulfated Heparan Sulfate Dodecasaccharide Shows Anti-Angiogenic Properties In Vitro and Sensitizes Tumors to Cisplatin In Vivo.

Heparan sulphate (HS), a ubiquitously expressed glycosaminoglycan (GAG), regulates multiple cellular functions by mediating interactions between numerous growth factors and their cell surface cognate receptors. However, the structural specificity of HS in these interactions remains largely undefined. Here, we used completely synthetic, structurally defined, alternating N-sulfated glucosamine (NS) and 2-O-sulfated iduronate (IS) residues to generate dodecasaccharides ([NSIS]6) that contained no, one or six glucosamine 6-O-sulfates (6S). The aim was to address how 6S contributes to the potential of defined HS dodecasaccharides to inhibit the angiogenic growth factors FGF2 and VEGF165, in vitro and in vivo. We show that the addition of a single 6S at the non-reducing end of [NSIS]6, i.e. [NSIS6S]-[NSIS]5, significantly augments the inhibition of FGF2-dependent endothelial cell proliferation, migration and sprouting in vitro when compared to the non-6S variant. In contrast, the fully 6-O-sulfated dodecasaccharide, [NSIS6S]6, is not a potent inhibitor of FGF2. Addition of a single 6S did not significantly improve inhibitory properties of [NSIS]6 when tested against VEGF165-dependent endothelial cell functions.In vivo, [NSIS6S]-[NSIS]5 blocked FGF2-dependent blood vessel formation without affecting tumor growth. Reduction of non-FGF2-dependent ovarian tumor growth occurred when [NSIS6S]-[NSIS]5 was combined with cisplatin. The degree of inhibition by [NSIS6S]-[NSIS]5 in combination with cisplatin in vivo equated with that induced by bevacizumab and sunitinib when administered with cisplatin. Evaluation of post-treatment vasculature revealed that [NSIS6S]-[NSIS]5 treatment had the greatest impact on tumor blood vessel size and lumen formation. Our data for the first time demonstrate that synthetic, structurally defined oligosaccharides have potential to be developed as active anti-angiogenic agents that sensitize tumors to chemotherapeutic agents.

Impact of attention biases to threat and effortful control on individual variations in negative affect and social withdrawal in very young children.

Early temperamental sensitivity may form the basis for the later development of socioemotional maladjustment. In particular, temperamental negative affect places children at risk for the development of anxiety. However, not all children who show negative affect go on to develop anxiety or extreme social withdrawal. Recent research indicates that reactive control, in the form of attention to threat, may serve as a bridge between early temperament and the development of later social difficulties. In addition, variation in effortful control may also modulate this trajectory. Children (mean age=5.57 years) were assessed for attention bias to threatening and pleasant faces using a dot-probe paradigm. Attention bias to threatening (but not happy) faces moderated the direct positive relation between negative affect and social withdrawal. Children with threat biases showed a significant link between negative affect and social withdrawal, whereas children who avoided threat did not. In contrast, effortful control did not moderate the relation between negative affect and social withdrawal. Rather, there was a direct negative relation between effortful control and social withdrawal. The findings from this short report indicate that the relations among temperament, attention bias, and social withdrawal appears early in life and point to early emerging specificity in reactive and regulatory functioning.

Synthetic heparan sulfate dodecasaccharides reveal single sulfation site interconverts CXCL8 and CXCL12 chemokine biology.

The multigram-scale synthesis of a sulfation-site programmed heparin-like dodecasaccharide is described. Evaluation alongside dodecasaccharides lacking this single glucosamine O6-sulfation, or having per-O6-sulfation, shows that site-specific modification of the terminal glucosamine dramatically interconverts regulation of in vitro and in vivo biology mediated by the two important chemokines, CXCL12 (SDF1α) or CXCL8 (IL-8).

Segregation of late outgrowth endothelial cells into functional endothelial CD34- and progenitor-like CD34+ cell populations.

Late outgrowth endothelial cells (OECs) that originate from peripheral blood mononuclear cells ex vivo have phenotypic and functional properties of mature endothelial cells. Given the potential therapeutic applications of OECs, understanding their biology is crucial. We have identified two distinct OEC populations based on differential expression of the cell surface marker CD34. OEC colonies lacked CD34 expression (CD34-), expressed CD34 in the majority of cells (CD34+), or showed a mixed expression pattern within a colony (CD34+/-). CD34+ and CD34- OECs were negative for hematopoietic cell marker CD45 and expressed the endothelial cell surface markers CD31, CD146, CD105, and VEGFR-2. Functionally CD34- and CD34+ OECs exhibited strikingly distinct behaviors. CD34- OECs, unlike CD34+ OECs, were capable of sprouting, formed tubes, and responded to angiogenic growth factors in vitro. In vivo, CD34- OECs formed endothelial tubes, while CD34+ OECs, despite being unable to form tubes, promoted infiltration of murine vasculature. Global gene expression profiling in CD34- and CD34+ OECs identified functional importance of the MMP-1/PAR-1 pathway in CD34- OECs. MMP-1 stimulated the expression of VEGFR-2, neuropilin-1, neuropilin-2, and CXCR4 and activated ERK1/2, whereas down-regulation of PAR-1 in CD34- OECs resulted in impaired angiogenic responses in vitro and reduced VEGFR-2 levels. In contrast, the CD34+ OEC colonies expressed high levels of the progenitor cell marker ALDH, which was absent in CD34- OECs. In summary, we show that OECs can be classified into functionally mature endothelial cells (CD34- OECs) that depend on the MMP-1/PAR-1 pathway and progenitor-like angiogenesis-promoting cells (CD34+ OECs).

Can't stop believing: inhibitory control and resistance to misleading testimony.

Why are some young children consistently willing to believe what they are told even when it conflicts with first-hand experience? In this study, we investigated the possibility that this deference reflects an inability to inhibit a prepotent response. Over the course of several trials, 2.5- to 3.5-year-olds (N = 58) heard an adult contradict their report of a simple event they had both witnessed, and children were asked to resolve this discrepancy. Those who repeatedly deferred to the adult's misleading testimony had more difficulty on an inhibitory control task involving spatial conflict than those who responded more skeptically. These results suggest that responding skeptically to testimony that conflicts with first-hand experience may be challenging for some young children because it requires inhibiting a normally appropriate bias to believe testimony.

Ovarian cancer cell heparan sulfate 6-O-sulfotransferases regulate an angiogenic program induced by heparin-binding epidermal growth factor (EGF)-like growth factor/EGF receptor signaling.

Heparan sulfate (HS) is a component of cell surface and extracellular matrix proteoglycans that regulates numerous signaling pathways by binding and activating multiple growth factors and chemokines. The amount and pattern of HS sulfation are key determinants for the assembly of the trimolecular, HS-growth factor-receptor, signaling complex. Here we demonstrate that HS 6-O-sulfotransferases 1 and 2 (HS6ST-1 and HS6ST-2), which perform sulfation at 6-O position in glucosamine in HS, impact ovarian cancer angiogenesis through the HS-dependent HB-EGF/EGFR axis that subsequently modulates the expression of multiple angiogenic cytokines. Down-regulation of HS6ST-1 or HS6ST-2 in human ovarian cancer cell lines results in 30-50% reduction in glucosamine 6-O-sulfate levels in HS, impairing HB-EGF-dependent EGFR signaling and diminishing FGF2, IL-6, and IL-8 mRNA and protein levels in cancer cells. These cancer cell-related changes reduce endothelial cell signaling and tubule formation in vitro. In vivo, the development of subcutaneous tumor nodules with reduced 6-O-sulfation is significantly delayed at the initial stages of tumor establishment with further reduction in angiogenesis occurring throughout tumor growth. Our results show that in addition to the critical role that 6-O-sulfate moieties play in angiogenic cytokine activation, HS 6-O-sulfation level, determined by the expression of HS6ST isoforms in ovarian cancer cells, is a major regulator of angiogenic program in ovarian cancer cells impacting HB-EGF signaling and subsequent expression of angiogenic cytokines by cancer cells.

A school based study of psychological disturbance in children following the Omagh bomb.

OBJECTIVE: To assess the extent and nature of psychiatric morbidity among children (aged 8 to 13 years) 15 months after a car bomb explosion in the town of Omagh, Northern Ireland. METHOD: A survey was conducted of 1945 school children attending 13 schools in the Omagh district. Questionnaires included demographic details, measures of exposure, the Horowitz Impact of Events Scale, the Birleson Self-Rating Depression Scale, and the Spence Children's Anxiety Scale. RESULTS: Children directly exposed to the bomb reported higher levels of probable PTSD (70%), and psychological distress than those not exposed. Direct exposure was more closely associated with an increase in PTSD symptoms than in general psychiatric distress. Significant predictors of increased IES scores included being male, witnessing people injured and reporting a perceived life threat but when co-morbid anxiety and depression are included as potential predictors anxiety remains the only significant predictor of PTSD scores. CONCLUSIONS: School-based studies are a potentially valuable means of screening and assessing for PTSD in children after large-scale tragedies. Assessment should consider type of exposure, perceived life threat and other co-morbid anxiety as risk factors for PTSD.

Tetrasaccharide iteration synthesis of a heparin-like dodecasaccharide and radiolabelling for in vivo tissue distribution studies.

Heparin-like oligosaccharides mediate numerous important biological interactions, of which many are implicated in various diseases. Synthetic improvements are central to the development of such oligosaccharides as therapeutics and, in addition, there are no methods to elucidate the pharmacokinetics of structurally defined heparin-like oligosaccharides. Here we report an efficient two-cycle [4+4+4] tetrasaccharide-iteration-based approach for rapid chemical synthesis of a structurally defined heparin-related dodecasaccharide, combined with the incorporation of a latent aldehyde tag, unmasked in the final step of chemical synthesis, providing a generic end group for labelling/conjugation. We exploit this latent aldehyde tag for (3)H radiolabelling to provide the first example of this kind of agent for monitoring in vivo tissue distribution and in vivo stability of a biologically active, structurally defined heparin related dodecasaccharide. Such studies are critical for the development of related saccharide therapeutics, and the data here establish that a biologically active, synthetic, heparin-like dodecasaccharide provides good organ distribution, and serum lifetimes relevant to developing future oligosaccharide therapeutics.

The relation between electroencephalogram asymmetry and attention biases to threat at baseline and under stress.

Electroencephalogram (EEG) asymmetry in the alpha frequency band has been implicated in emotion processing and broad approach-withdrawal motivation systems. Questions remain regarding the cognitive mechanisms that may help elucidate the observed links between EEG asymmetry and patterns of socioemotional functioning. The current study observed frontal EEG asymmetry patterns at rest and under social threat among young adults (N=45, M=21.1 years). Asymmetries were, in turn, associated with performance on an emotion-face dot-probe attention bias task. Attention biases to threat have been implicated as potential causal mechanisms in anxiety and social withdrawal. Frontal EEG asymmetry at baseline did not predict attention bias patterns to angry or happy faces. However, increases in right frontal alpha asymmetry from baseline to the stressful speech condition were associated with vigilance to angry faces and avoidance of happy faces. The findings may reflect individual differences in the pattern of response (approach or withdrawal) with the introduction of a mild stressor. Comparison analyses with frontal beta asymmetry and parietal alpha asymmetry did not find similar patterns. Thus, the data may reflect the unique role of frontal regions, particularly the dorsolateral prefrontal cortex, in cognitive control and threat detection, coupled with ruminative processes associated with alpha activity.

Defense-like behaviors evoked by pharmacological disinhibition of the superior colliculus in the primate.

Stimulation of the intermediate and deep layers of superior colliculus (DLSC) in rodents evokes both orienting/pursuit (approach) and avoidance/flight (defense) responses (Dean et al., 1989). These two classes of response are subserved by distinct output projections associated with lateral (approach) and medial (defense) DLSC (Comoli et al., 2012). In non-human primates, DLSC has been examined only with respect to orienting/approach behaviors, especially eye movements, and defense-like behaviors have not been reported. Here we examined the profile of behavioral responses evoked by activation of DLSC by unilateral intracerebral infusions of the GABA(A) receptor antagonist, bicuculline methiodide (BIC), in nine freely moving macaques. Across animals, the most consistently evoked behavior was cowering (all animals), followed by increased vocalization and escape-like behaviors (seven animals), and attack of objects (three animals). The effects of BIC were dose-dependent within the range 2.5-14 nmol (threshold dose of 4.6 nmol). The behaviors and their latencies to onset did not vary across different infusion sites within DLSC. Cowering and escape-like behaviors resembled the defense-like responses reported after DLSC stimulation in rats, but in the macaques these responses were evoked from both medial and lateral sites within DLSC. Our findings are unexpected in the context of an earlier theoretical perspective (Dean et al., 1989) that emphasized a preferential role of the primate DLSC for approach rather than defensive responses. Our data provide the first evidence for induction of defense-like behaviors by activation of DLSC in monkeys, suggesting that the role of DLSC in responding to threats is conserved across species.

Endothelial heparan sulfate 6-O-sulfation levels regulate angiogenic responses of endothelial cells to fibroblast growth factor 2 and vascular endothelial growth factor.

Fibroblast growth factor 2 (FGF2) and vascular endothelial growth factor 165 (VEGF(165)) are potent pro-angiogenic growth factors that play a pivotal role in tumor angiogenesis. The activity of these growth factors is regulated by heparan sulfate (HS), which is essential for the formation of FGF2/FGF receptor (FGFR) and VEGF(165)/VEGF receptor signaling complexes. However, the structural characteristics of HS that determine activation or inhibition of such complexes are only partially defined. Here we show that ovarian tumor endothelium displays high levels of HS sequences that harbor glucosamine 6-O-sulfates when compared with normal ovarian vasculature where these sequences are also detected in perivascular area. Reduced HS 6-O-sulfotransferase 1 (HS6ST-1) or 6-O-sulfotransferase 2 (HS6ST-2) expression in endothelial cells impacts upon the prevalence of HS 6-O-sulfate moieties in HS sequences, which consist of repeating short, highly sulfated S domains interspersed by transitional N-acetylated/N-sulfated domains. 1-40% reduction in 6-O-sulfates significantly compromises FGF2- and VEGF(165)-induced endothelial cell sprouting and tube formation in vitro and FGF2-dependent angiogenesis in vivo. Moreover, HS on wild-type neighboring endothelial or smooth muscle cells fails to restore endothelial cell sprouting and tube formation. The affinity of FGF2 for HS with reduced 6-O-sulfation is preserved, although FGFR1 activation is inhibited correlating with reduced receptor internalization. These data show that 6-O-sulfate moieties in endothelial HS are of major importance in regulating FGF2- and VEGF(165)-dependent endothelial cell functions in vitro and in vivo and highlight HS6ST-1 and HS6ST-2 as potential targets of novel antiangiogenic agents.

Speech presentation cues moderate frontal EEG asymmetry in socially withdrawn young adults.

Socially withdrawn individuals display solitary behavior across wide contexts with both unfamiliar and familiar peers. This tendency to withdraw may be driven by either past or anticipated negative social encounters. In addition, socially withdrawn individuals often exhibit right frontal electroencephalogram (EEG) asymmetry at baseline and when under stress. In the current study we examined shifts in frontal EEG activity in young adults (N=41) at baseline, as they viewed either an anxiety-provoking or a benign speech video, and as they subsequently prepared for their own speech. Results indicated that right frontal EEG activity increased, relative to the left, only for socially withdrawn participants exposed to the anxious video. These results suggest that contextual affective cues may prime an individual's response to stress, particularly if they illustrate or substantiate an anticipated negative event.