Range Of Potential Indicators Research Articles

Tinzaparin for venous thromboembolism in patients with renal impairment: a single-centre, prospective pilot study.

Low molecular weight heparins (LMWH) are used extensively for prophylaxis and treatment of venous thromboembolism (VTE), bridging therapy for warfarin and standard of care in cancer-associated VTE (CA-VTE). Tinzaparin has the highest molecular weight of all LMWH and relies least on renal clearance to Cockcroft-Gault creatinine clearance (CrCl) of 20 mL/min. Previous pharmacological studies have demonstrated safety and effectiveness in elderly patients. Prospective clinical trials have confirmed these findings to CrCl 20 mL/min and in CA-VTE. We describe the pilot program developed at Concord Repatriation General Hospital for tinzaparin. We aim to confirm the deliverability of tinzaparin in patients with renal insufficiency. Twenty patients were established on tinzaparin as therapeutic anticoagulation with CrCl or CKD-EPI estimated glomerular filtration rate (eGFR) 20-50 mL/min with an indication for anticoagulation. Tinzaparin was given as a subcutaneous injection at 175 units/kg as a single daily dose, rounded to the nearest vial size. Tinzaparin anti-Xa levels were tested at Days 2, 7 and 14 (±1 day) and transition to oral anticoagulants were allowed at clinician discretion. No accumulation of tinzaparin was seen into Day 14. Two patients required dose-adjustment, five patients had bleeding complications (two major, three minor) and four patients died during follow-up, all attributable to patients' comorbidities. CrCl and body surface area-standardised CrCl were significantly correlated with tinzaparin anti-Xa level only on Day 2, and this effect was lost when patients with CrCl >50 mL/min were excluded. Data from our cohort confirm the deliverability of therapeutic tinzaparin in patients with CrCl or CKD-EPI eGFR 20-50 mL/min. Bleeding and death outcomes were also comparable to other trials using tinzaparin in CA-VTE. For patients with renal insufficiency, tinzaparin represents an attractive alternative anticoagulant with once-daily administration in a range of potential indications.

In Transition – Patterns of Development and Change Among Vulnerable Young People

This paper seeks to contribute to current debates about the nature of youth transitions. Transitions research seeks to account for more than just individual-level maturational processes, recognising that the pathway from childhood to adulthood is heterogenous and subject to the influence of macro-level factors such as political, social and economic environments. Within these larger debates this paper has a particular concern with three things. First, responding to calls for research to gather a diverse suite of indicators when examining youth transitions, it examines a range of potential indicators in terms of how they might help us understand better the transition experiences of a group of vulnerable young people. Here improvements in individual-level and neighbourhood-level indicators are observed alongside increasing educational risks and high levels of family risk that remain stable over time. Second, building on the work of others, who have argued that we need to be concerned about the experience of transition as a process as much with the various destinations at which youth may arrive, it explores the ways these indicators change over time. Third, by focusing specifically on the in-transition experiences of a group of youth who face more than the ‘normal’ range of challenges during adolescence it seeks to add to the corpus of knowledge concerning the heterogeneity of youth transitions.

Abstract 2476: Bispecific redirected T-cell immunotherapy targeting P-cadherin expressing tumors

Abstract Introduction: Strong evidence exists supporting the important role T-cells play in the immune response against tumors. Still, the ability to initiate tumor specific immune responses remains a challenge. We have developed a Dual-Affinity Re-Targeting (DART®) protein engineered with enhanced pharmacokinetic properties to extend in vivo half-life, and designed to engage and activate endogenous polyclonal T cell populations via the CD3 complex in the presence of P-cadherin expressing tumors. We designate this bispecific redirecting T-cell molecule as P-cadherin LP-DART. P-cadherin up-regulation has been reported in various tumors, including breast, gastric, endometrial, colorectal and pancreatic cancers, and is correlated with poor survival of patients. Methods: The P-cadherin LP-DART was stably expressed by CHO cells and purified to homogeneity via standard antibody-purification methods. Functional in vitro studies were performed with a panel of human cancer cell lines and human T cells isolated from healthy donors. In vivo tumor growth inhibition studies were performed in immunodeficient athymic nude or NOD-scid IL2Rgammanull (NSG) mice bearing human tumor cell line- or patient derived-xenografts and human T-cells, and treated with P-cadherin LP-DART. Results: P-cadherin LP-DART exhibited binding to a broad panel of cancer cell lines expressing various levels of endogenous cell surface P-cadherin, and comparable binding to a number of human donor derived T-cells expressing CD3. In the presence of T-cells, this bispecific molecule elicited P-cadherin expression level dependent cytotoxic T-lymphocyte (CTL) responses against the different tumor cell lines, and induced antigen dependent T-cell activation and cytokine release. P-cadherin LP-DART also demonstrated potent in vivo anti-tumor activity against implanted tumor xenografts. Significant tumor growth inhibition was observed across a range of potential indications that express P-cadherin. Measurement of in vivo pharmacodynamic markers support P-cadherin LP-DART mediated CTL infiltration and killing as the mechanism of tumor inhibition. Conclusions: P-cadherin LP-DART displays potent in vitro and in vivo redirected T-cell activity against a broad panel of cancer cell lines expressing a range of cell surface P-cadherin levels. These data support further investigation of P-cadherin LP-DART as a potential novel therapeutic treatment for cancers expressing P-cadherin. Citation Format: Timothy S. Fisher, Adam Root, Bryan Peano, Allison Rohner, Justin Lucas, Mark Elliott, Konstantinos Tsaparikos, Hui Wang, Jonathan Golas, Maria Gavriil, Susan Benard, Tao He, Tracey Clark, Nahor Haddish-Berhane, Ralph Alderson, Yinhua Yang, Syd Johnson, Paul Moore, Lioudmila Tchistiakova, Hans-Peter Gerber, Chad May. Bispecific redirected T-cell immunotherapy targeting P-cadherin expressing tumors. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2476. doi:10.1158/1538-7445.AM2015-2476

BAY 1002670: a novel, highly potent and selective progesterone receptor modulator for gynaecological therapies

Does the novel progesterone receptor (PR) modulator BAY 1002670, based on its preclinical pharmacological profile, offer a potential novel treatment option for uterine fibroids? The newly synthesized BAY1002670 has proved to be a very potent, highly selective PR modulator in all in vitro and in vivo pharmacodynamics assays performed: it exhibits marked efficacy in an innovative humanized fibroid disease model, suggesting BAY 1002670 to be a very promising treatment option for uterine fibroids. PR inhibiting ligands have shown clinical utility in a range of potential indications and applications. Despite the emergence of the first PR antagonist >30 years ago, no agent of this compound class has been authorized in any indication for long-term application. Among other reasons, suboptimal selectivity and safety profiles of previous candidates have led to discontinuation and modification of development programmes. The preclinical studies include relevant in vitro and in vivo assays to clarify the properties of the PR modulator BAY 1002670 as well as a fibroid xenograft study to show directly the efficacy of BAY 1002670 on the human target tissue. BAY 1002670 was tested for binding and transactivational activity towards different human steroid receptors. Activity of the compound in the corresponding in vivo models (rat, rabbit) was assessed. Furthermore, BAY 1002670 was tested in a disease model for uterine fibroids utilizing primary human tumour tissues as xenograft in immunodeficient mice treated with estradiol (E2) and progesterone (P). BAY1002670 in subnanomolar concentrations exhibits a highly selective binding profile and antagonistic activity for the PR. These properties are also reflected in its action in two progesterone-dependent animal models that assess the termination of pregnancy and endometrial transformation. Favourable selectivity towards other nuclear hormone receptors was demonstrated. No in vivo activity was found at the glucocorticoid, estrogenic and mineralocorticoid receptors with only weak anti-androgenic activity. In a human fibroid xenograft model BAY 1002670 showed a marked dose-dependent reduction of fibroid tumour weight gain of 95% at a dose of 3 mg/kg/day (P < 0.005). Selectivity and potency of BAY 1002670 have only been determined in vitro and in animal models so far. The PR modulator BAY 1002670 might offer a treatment option not only for uterine fibroids but also for other gynaecological indications. The studies took place at Bayer Pharma AG. All authors are employees of Bayer Pharma AG. No external funding declared.

Conceptualising research performance

In a context of increasing emphasis on academic performance and accountability, data from a structured survey in which academics elaborated on eight different attributes of high‐performing researchers were used to build a conceptual model of research performance. Research performance was seen to comprise two basic components, with six secondary level dimensions and a range of potential indicators. Four essential (necessary and sufficient) dimensions, relating to the research activity component of research performance, were: engagement, task orientation, research practice and intellectual processes. Two alternative dimensions (of which at least one is necessary) relating to the performance, or making research visible, component of research performance were dissemination and collegial engagement. Research performance was seen to occur within conditions provided by an institutional context (education and training; opportunity and resources), and to bring about a range of outcomes (product, impact and reputation).

WorkChoices and Family-Friendly Working Hours: An Assessment of Data Sources

ABSTRACT When the Australian Federal Government introduced the WorkChoices legislation in 2006, one of its stated aims was to facilitate the negotiation of ‘family-friendly’ employment arrangements. This article assesses our capacity to achieve an accurate picture of’ family-friendly’ arrangements in the new regulatory regime and examines the adequacy of publicly available indicators of women's employment status. We focus specifically on the capacity of current data to monitor ‘family-friendly’ employment arrangements in the form of flexible working hours and find that while there are a range of potential indicators, few will give a complete assessment of how women are faring. We conclude that there is ample capacity to reduce the fragmentation of currently available information and to increase the regularity with which it is collected. There is also a need for additional research to determine the indicators that might be most relevant to women in vulnerable positions in the workforce.

Hazards of percutaneous PFO closure

Please see the article by Christen et al. (doi: 10.1016/j.euje.2005.08.002 ) to which this editorial pertains. In 2004, an estimated 2000–3000 patients underwent percutaneous closure of a patent foramen ovale (PFO). Given the range of potential indications (such as prevention of cryptogenic stroke, decompression illness in divers, platypnea–orthodeoxia syndrome, and migraine headaches) and the perception of PFO closure being an easy and safe procedure,1 the number of patients with percutaneously implanted PFO closure devices will continue to grow. The first attempt to percutaneously close an interatrial defect was undertaken in 1974 and reported by King and colleagues in 1976.2 In the following years, several different devices were developed and re-modified to facilitate this technique. It began with the Clamshell occluder from Rashkind,3 later modified into the CardioSEAL and then the StarFLEX device. Other models soon followed including the Buttoned device,4 the ASDOS device,5 the Monodisk,6 the Angel-Wings device,7 the Amplatzer ASD occluder8 and the Helex device.9 Although these devices were initially intended for atrial septal defect closure, they could also be used for closure of PFO, an idea first evoked by Bridges in 1992.10 Soon thereafter, devices dedicated exclusively for percutaneous PFO closure entered the market, namely the Amplatzer PFO occluder and the PFOStar (now Cardiastar) device. Part of the reasoning to favour percutaneous PFO closure over open heart surgery promises a safer and of course, less …

Indicators of adolescent health: expanding the framework for assessing health status among young people.

Determination of indicators to measure adolescent health status is guided by the purpose and use of the research. For example the research can facilitate 1) health service planning and management 2) health promotion and disease prevention 3) health protection or 4) research and theory development and each of these perspectives entails use of a substantial range of potential indicators. This paper 1) distinguishes between different types of health indicators 2) illustrates the interrelationship among health indicators and 3) illustrates how indicators can be linked to health services and health promotion interventions. Thus an outcome model for health promotion is offered that identifies which types of indicators can be used for three broad types of outcome. For health and social outcomes the proposed indicators are quality of life functional independence equity mortality morbidity and disability. For intermediate health outcomes the indicators are health lifestyles effective health services and healthy environments. For health promotion outcomes the indicators are health literacy social influence and action and healthy public policy as well as organizational practice. The model highlights complexities between health promotion action and eventual health outcomes and offers an expanded view of health promotion.