Manufacturing and use of human placenta-derived mesenchymal stromal cells for phase I clinical trials: Establishment and evaluation of a protocol

Background/Aim. Mesenchymal stromal cells (MSCs) have been utilised in many clinical trials as an experimental treatment in numerous clinical settings. Bone marrow remains the traditional source tissue for MSCs but is relatively hard to access in large volumes. Alternatively, MSCs may be derived from other tissues including the placenta and adipose tissue. In an initial study no obvious differences in parameters such as cell surface phenotype, chemokine receptor display, mesodermal differentiation capacity or immunosuppressive ability, were detected when we compared human marrow derived- MSCs to human placenta-derived MSCs. The aim of this study was to establish and evaluate a protocol and related processes for preparation placenta-derived MSCs for early phase clinical trials. Methods. A full-term placenta was taken after delivery of the baby as a source of MSCs. Isolation, seeding, incubation, cryopreservation of human placentaderived MSCs and used production release criteria were in accordance with the complex regulatory requirements applicable to Code of Good Manufacturing Practice manufacturing of ex vivo expanded cells. Results. We established and evaluated instructions for MSCs preparation protocol and gave an overview of the three clinical areas application. In the first trial, MSCs were co-transplanted iv to patient receiving an allogeneic cord blood transplant as therapy for treatmentrefractory acute myeloid leukemia. In the second trial, MSCs were administered iv in the treatment of idiopathic pulmonary fibrosis and without serious adverse effects. In the third trial, MSCs were injected directly into the site of tendon damage using ultrasound guidance in the treatment of chronic refractory tendinopathy. Conclusion. Clinical trials using both allogeneic and autologous cells demonstrated MSCs to be safe. A described protocol for human placenta-derived MSCs is appropriate for use in a clinical setting, relatively inexpensive and can be relatively easily adjusted to a different set of regulatory requirements, as applicable to early phase clinical trials.

Improving SEA procedures within Italian regions: Towards a more effective evaluation of urban sustainability

Sustainable urban development, a major issue at global scale, will become more relevant according to population growth predictions in developed and developing countries. Societal and international recognition of sustainability concerns led to the development of specific tools and procedures, known as sustainability assessments/appraisals (SA). Their effectiveness however, considering that global quality life indicators have worsened since their introduction, has promoted a re-thinking of SA instruments. More precisely, Strategic Environmental Assessment (SEA), – a tool introduced in the European context to evaluate policies, plans, and programmes (PPPs), – is being reconsidered because of several features that seem to limit its effectiveness. Over time, SEA has evolved in response to external and internal factors dealing with technical, procedural, planning and governance systems thus involving a shift of paradigm from EIA-based SEAs (first generation protocols) towards more integrated approaches (second generation ones). Changes affecting SEA are formalised through legislation in each Member State, to guide institutions at regional and local level. Defining SEA effectiveness is quite difficult. Its’ capacity-building process appears quite far from its conclusion, even if any definitive version can be conceptualized. In this paper, we consider some European nations with different planning systems and SA traditions. After the identification of some analytical criteria, a multi-dimensional cluster analysis is developed on some case studies, to outline current weaknesses.

Improving SEA prodedures within Italian regions: Towards a more effective evaluation of urban sustainability

Sustainable urban development, a major issue at global scale, will become more relevant according to population growth predictions in developed and developing countries. Societal and international recognition of sustainability concerns led to the development of specific tools and procedures, known as sustainability assessments/appraisals (SA). Their effectiveness however, considering that global quality life indicators have worsened since their introduction, has promoted a re-thinking of SA instruments. More precisely, Strategic Environmental Assessment (SEA), – a tool introduced in the European context to evaluate policies, plans, and programmes (PPPs), – is being reconsidered because of several features that seem to limit its effectiveness. Over time, SEA has evolved in response to external and internal factors dealing with technical, procedural, planning and governance systems thus involving a shift of paradigm from EIA-based SEAs (first generation protocols) towards more integrated approaches (second generation ones). Changes affecting SEA are formalised through legislation in each Member State, to guide institutions at regional and local level. Defining SEA effectiveness is quite difficult. Its’ capacity-building process appears quite far from its conclusion, even if any definitive version can be conceptualized. In this paper, we consider some European nations with different planning systems and SA traditions. After the identification of some analytical criteria, a multi-dimensional cluster analysis is developed on some case studies, to outline current weaknesses.

“It puts a human face on the researched”: A qualitative evaluation of an Indigenous research governance model

Objective This study aimed to describe the Inala Aboriginal and Torres Strait Islander Community Jury for Health Research, and evaluate its usefulness as a model of Indigenous research governance within an urban Indigenous primary health care service from the perspectives of Jury members and researchers. Methods Informed by a phenomenological approach and using narrative inquiry, a focus group was conducted with Jury members and key informant interviews were undertaken with researchers who had presented to the Community Jury in its first year of operation. Results The Jury was a site of identity work for researchers and Jury members, providing an opportunity to observe and affirm community cultural protocols. Although researchers and Jury members had differing levels of research literacy, the Jury processes enabled respectful communication and relationships to form which positively influenced research practice, community aspirations and clinical care. Discussion The Jury processes facilitated transformative research practice among researchers, and resulted in transference of power from researchers to the Jury members to the mutual benefit of both. Conclusion Ethical Indigenous health research practice requires an engagement with Indigenous peoples and knowledges at the research governance level, not simply as subjects or objects of research.

Evaluation of an intervention for patients with alcohol-related injuries: results of a mixed methods study

Objective: To explore the effect of education and training on the delivery of alcohol screening and brief intervention and referral to high-risk patients in a hospital setting. Main outcome measures included; delivery of training; practice change in relation to staff performing alcohol screening, brief intervention and referrals. Methods: Observational study design using mixed methods set in a tertiary referral hospital. Pre-post assessment of medical records and semi-structured interviews with key informants. Results: Routine screening for substance misuse (9% pre / 71.4% post) and wellbeing concerns (6.6% pre / 15 % post) was more frequent following the introduction of resources and staff participation in educational workshops. There was no evidence of a concomitant increase in delivery of brief intervention or referrals to services. Implementation challenges, including time constraints and staff attitudes, and enablers such as collaboration and visible pathways, were identified. Conclusion: Rates of patient screening increased, however barriers to delivery of brief intervention and referrals remained. Implementation strategies targeting specific barriers and enablers to introducing interventions are both required to improve the application of secondary prevention for patients in acute settings. Implications: Educational training, formalised liaison between services, systematised early intervention protocols, and continuous quality improvement processes will progress service delivery in this area.

Evaluation of regional and distant metastases in head and neck squamous cell carcinoma patients with special reference to the assessment of regional lymph nodes in oral cancer

For optimal treatment planning, a thorough assessment of the metastatic status of mucosal squamous cell carcinoma of the head and neck (HNSCC) is required. Current imaging methods do not allow the recognition of all patients with metastatic disease. Therefore, elective treatment of the cervical lymph nodes is usually given to patients in whom the risk of subclinical metastasis is estimated to exceed 15-20%. The objective of this study was to improve the pre-treatment evaluation of patients diagnosed with HNSCC. Particularly, we aimed at improving the identification of patients who will benefit from elective neck treatment. Computed tomography (CT) of the chest and abdomen was performed prospectively for 100 patients diagnosed with HNSCC. The findings were analysed to clarify the indications for this examination in this patient group. CT of the chest influenced the treatment approach in 3% of patients, while CT of the abdomen did not reveal any significant findings. Our results suggest that CT of the chest and abdomen is not indicated routinely for patients with newly diagnosed HNSCC but can be considered in selected cases. Retrospective analysis of 80 patients treated for early stage squamous cell carcinoma of the oral tongue was performed to investigate the potential benefits of elective neck treatment and to examine whether histopathological features of the primary tumour could be used in the prediction of occult metastases, local recurrence, or/and poor survival. Patients who had received elective neck treatment had significantly fewer cervical recurrences during the follow-up when compared to those who only had close observation of the cervical lymph nodes. Elective neck treatment did not result in survival benefit, however. Of the histopathological parameters examined, depth of infiltration and pT-category (representing tumour diameter) predicted occult cervical metastasis, but only the pT-category predicted local recurrence. Depth of infiltration can be used in the identification of at risk patients but no clear cut-off value separating high-risk and low-risk patients was found. None of the histopathological parameters examined predicted survival. Sentinel lymph node (SLN) biopsy was studied as a means of diagnosing patients with subclinical cervical metastases. SLN biopsy was applied to 46 patients who underwent elective neck dissection for oral squamous cell carcinoma. In addition, SLN biopsy was applied to 13 patients with small oral cavity tumours who were not intended to undergo elective neck dissection because of low risk of occult metastasis. The sensitivity of SLN biopsy for finding subclinical cervical metastases was found to be 67%, when SLN status was compared to the metastatic status of the rest of the neck dissection specimen. Of the patients not planned to have elective neck dissection, SLN biopsy revealed cervical metastasis in 15% of the patients. Our results suggest that SLN biopsy can not yet entirely replace elective neck dissection in the treatment of oral cancer, but it seems beneficial for patients with low risk of metastasis who are not intended for elective neck treatment according to current treatment protocols.

Microbiological characterisation of soils : Evaluation of some critical steps in data collection and experimental design

The study of soil microbiota and their activities is central to the understanding of many ecosystem processes such as decomposition and nutrient cycling. The collection of microbiological data from soils generally involves several sequential steps of sampling, pretreatment and laboratory measurements. The reliability of results is dependent on reliable methods in every step. The aim of this thesis was to critically evaluate some central methods and procedures used in soil microbiological studies in order to increase our understanding of the factors that affect the measurement results and to provide guidance and new approaches for the design of experiments. The thesis focuses on four major themes: 1) soil microbiological heterogeneity and sampling, 2) storage of soil samples, 3) DNA extraction from soil, and 4) quantification of specific microbial groups by the most-probable-number (MPN) procedure. Soil heterogeneity and sampling are discussed as a single theme because knowledge on spatial (horizontal and vertical) and temporal variation is crucial when designing sampling procedures. Comparison of adjacent forest, meadow and cropped field plots showed that land use has a strong impact on the degree of horizontal variation of soil enzyme activities and bacterial community structure. However, regardless of the land use, the variation of microbiological characteristics appeared not to have predictable spatial structure at 0.5-10 m. Temporal and soil depth-related patterns were studied in relation to plant growth in cropped soil. The results showed that most enzyme activities and microbial biomass have a clear decreasing trend in the top 40 cm soil profile and a temporal pattern during the growing season. A new procedure for sampling of soil microbiological characteristics based on stratified sampling and pre-characterisation of samples was developed. A practical example demonstrated the potential of the new procedure to reduce the analysis efforts involved in laborious microbiological measurements without loss of precision. The investigation of storage of soil samples revealed that freezing (-20 °C) of small sample aliquots retains the activity of hydrolytic enzymes and the structure of the bacterial community in different soil matrices relatively well whereas air-drying cannot be recommended as a storage method for soil microbiological properties due to large reductions in activity. Freezing below -70 °C was the preferred method of storage for samples with high organic matter content. Comparison of different direct DNA extraction methods showed that the cell lysis treatment has a strong impact on the molecular size of DNA obtained and on the bacterial community structure detected. An improved MPN method for the enumeration of soil naphthalene degraders was introduced as an alternative to more complex MPN protocols or the DNA-based quantification approach. The main advantage of the new method is the simple protocol and the possibility to analyse a large number of samples and replicates simultaneously.

Analytical efficiency evaluation of a network mobility management protocol for Intelligent Transportation Systems

One of the major concerns in an Intelligent Transportation System (ITS) scenario, such as that which may be found on a long-distance train service, is the provision of efficient communication services, satisfying users' expectations, and fulfilling even highly demanding application requirements, such as safety-oriented services. In an ITS scenario, it is common to have a significant amount of onboard devices that comprise a cluster of nodes (a mobile network) that demand connectivity to the outside networks. This demand has to be satisfied without service disruption. Consequently, the mobility of the mobile network has to be managed. Due to the nature of mobile networks, efficient and lightweight protocols are desired in the ITS context to ensure adequate service performance. However, the security is also a key factor in this scenario. Since the management of the mobility is essential for providing communications, the protocol for managing this mobility has to be protected. Furthermore, there are safety-oriented services in this scenario, so user application data should also be protected. Nevertheless, providing security is expensive in terms of efficiency. Based on this considerations, we have developed a solution for managing the network mobility for ITS scenarios: the NeMHIP protocol. This approach provides a secure management of network mobility in an efficient manner. In this article, we present this protocol and the strategy developed to maintain its security and efficiency in satisfactory levels. We also present the developed analytical models to analyze quantitatively the efficiency of the protocol. More specifically, we have developed models for assessing it in terms of signaling cost, which demonstrates that NeMHIP generates up to 73.47% less signaling compared to other relevant approaches. Therefore, the results obtained demonstrate that NeMHIP is the most efficient and secure solution for providing communications in mobile network scenarios such as in an ITS context.

NHS Wales e-library portal evaluation (For Informing Healthcare Strategy implementation programme)

Thomas, R. & Urquhart, C. NHS Wales e-library portal evaluation. (For Informing Healthcare Strategy implementation programme). Aberystwyth: Department of Information Studies, University of Wales Aberystwyth Follow-on to NHS Wales User Needs study Sponsorship: Informing Healthcare, NHS Wales

Comparative evaluation of serologic tests for celiac disease: a European initiative toward standardization.

BACKGROUND: Serologic methods have been used widely to test for celiac disease and have gained importance in diagnostic definition and in new epidemiologic findings. However, there is no standardization, and there are no reference protocols and materials. METHODS: The European working group on Serological Screening for Celiac Disease has defined robust noncommercial test protocols for immunoglobulin (Ig)G and IgA gliadin antibodies and for IgA autoantibodies against endomysium and tissue transglutaminase. Standard curves were linear in the decisive range, and intra-assay variation coefficients were less than 5% to 10%. Calibration was performed with a group reference serum. Joint cutoff limits were used. Seven laboratories took part in the final collaborative study on 252 randomized sera classified by histology (103 pediatric and adult patients with active celiac disease, 89 disease control subjects, and 60 blood donors). RESULTS: IgA autoantibodies against endomysium and tissue transglutaminase rendered superior sensitivity (90% and 93%, respectively) and specificity (99% and 95%, respectively) over IgA and IgG gliadin antibodies. Tissue transglutaminase antibody testing showed superior receiver operating characteristic performance compared with gliadin antibodies. The K values for interlaboratory reproducibility showed superiority for IgA endomysium (0.93) in comparison with tissue transglutaminase antibodies (0.83) and gliadin antibodies (0.82 for IgG, 0.62 for IgA). CONCLUSIONS: Basic criteria of standardization and quality assessment must be fulfilled by any given test protocol proposed for serologic investigation of celiac disease. The working group has produced robust test protocols and reference materials available for standardization to further improve reliability of serologic testing for celiac disease.

Evaluation of tumor response, disease control, progression-free survival, and time to progression as potential surrogate end points in metastatic breast cancer.

PURPOSE: Overall survival (OS) can be observed only after prolonged follow-up, and any potential effect of first-line therapies on OS may be confounded by the effects of subsequent therapy. We investigated whether tumor response, disease control, progression-free survival (PFS), or time to progression (TTP) could be considered a valid surrogate for OS to assess the benefits of first-line therapies for patients with metastatic breast cancer. PATIENTS AND METHODS: Individual patient data were collected on 3,953 patients in 11 randomized trials that compared an anthracycline (alone or in combination) with a taxane (alone or in combination with an anthracycline). Surrogacy was assessed through the correlation between the end points as well as through the correlation between the treatment effects on the end points. RESULTS: Tumor response (survival odds ratio [OR], 6.2; 95% CI, 5.3 to 7.0) and disease control (survival OR, 5.5; 95% CI, 4.8 to 6.3) were strongly associated with OS. PFS (rank correlation coefficient, 0.688; 95% CI, 0.686 to 0.690) and TTP (rank correlation coefficient, 0.682; 95% CI, 0.680 to 0.684) were moderately associated with OS. Response log ORs were strongly correlated with PFS log hazard ratios (linear coefficient [rho], 0.96; 95% CI, 0.73 to 1.19). Response and disease control log ORs and PFS and TTP log hazard ratios were poorly correlated with log hazard ratios for OS, but the confidence limits of rho were too wide to be informative. CONCLUSION: No end point could be demonstrated as a good surrogate for OS in these trials. Tumor response may be an acceptable surrogate for PFS.

Performance evaluation of the register insertion protocol for voice-data integration

The performance of the register insertion protocol for mixed voice-data traffic is investigated by simulation. The simulation model incorporates a common insertion buffer for station and ring packets. Bandwidth allocation is achieved by imposing a queue limit at each node. A simple priority scheme is introduced by allowing the queue limit to vary from node to node. This enables voice traffic to be given priority over data. The effect on performance of various operational and design parameters such as ratio of voice to data traffic, queue limit and voice packet size is investigated. Comparisons are made where possible with related work on other protocols proposed for voice-data integration. The main conclusions are: (a) there is a general degradation of performance as the ratio of voice traffic to data traffic increases, (b) substantial improvement in performance can be achieved by restricting the queue length at data nodes and (c) for a given ring utilisation, smaller voice packets result in lower delays for both voice and data traffic.

The evaluation of time series: their scientific value and contribution to policy needs. Occasional Publication of the Marine Biological Association 22

In 2000 a Review of Current Marine Observations in relation to present and future needs was undertaken by the Inter-Agency Committee for Marine Science and Technology (IACMST). The Marine Environmental Change Network (MECN) was initiated in 2002 as a direct response to the recommendations of the report. A key part of the current phase of the MECN is to ensure that information from the network is provided to policy makers and other end-users to enable them to produce more accurate assessments of ecosystem state and gain a clearer understanding of factors influencing change in marine ecosystems. The MECN holds workshops on an annual basis, bringing together partners maintaining time-series and long-term datasets as well as end-users interested in outputs from the network. It was decided that the first workshop of the MECN continuation phase should consist of an evaluation of the time series and data sets maintained by partners in the MECN with regard to their ‘fit for purpose’ for answering key science questions and informing policy development. This report is based on the outcomes of the workshop. Section one of the report contains a brief introduction to monitoring, time series and long-term datasets. The various terms are defined and the need for MECN type data to complement compliance monitoring programmes is discussed. Outlines are also given of initiatives such as the United Kingdom Marine Monitoring and Assessment Strategy (UKMMAS) and Oceans 2025. Section two contains detailed information for each of the MECN time series / long-term datasets including information on scientific outputs and current objectives. This information is mainly based on the presentations given at the workshop and therefore follows a format whereby the following headings are addressed: Origin of time series including original objectives; current objectives; policy relevance; products (advice, publications, science and society). Section three consists of comments made by the review panel concerning all the time series and the network. Needs or issues highlighted by the panel with regard to the future of long-term datasets and time-series in the UK are shown along with advice and potential solutions where offered. The recommendations are divided into 4 categories; ‘The MECN and end-user requirements’; ‘Procedures & protocols’; ‘Securing data series’ and ‘Future developments’. Ever since marine environmental protection issues really came to the fore in the 1960s, it has been recognised that there is a requirement for a suitable evidence base on environmental change in order to support policy and management for UK waters. Section four gives a brief summary of the development of marine policy in the UK along with comments on the availability and necessity of long-term marine observations for the implementation of this policy. Policy relating to three main areas is discussed; Marine Conservation (protecting biodiversity and marine ecosystems); Marine Pollution and Fisheries. The conclusion of this section is that there has always been a specific requirement for information on long-term change in marine ecosystems around the UK in order to address concerns over pollution, fishing and general conservation. It is now imperative that this need is addressed in order for the UK to be able to fulfil its policy commitments and manage marine ecosystems in the light of climate change and other factors.

On the Problems of Mixing RCTs with Qualitative Research: The Case of the MRC Framework for the Evaluation of Complex Healthcare Interventions

In the perceived hierarchy of research designs, the results from randomized controlled trials are considered to provide the highest level of evidence. Indeed these trials have been upheld as the gold standard in research. The benefits and limitations of the randomized controlled trial as a method of evaluating the effectiveness of healthcare interventions are presented. The article then examines the different levels of complexity within healthcare interventions and the problems this poses in determining effectiveness. In an effort to provide a solution to this problem, the Medical Research Council produced a framework to assist investigators to develop and evaluate complex healthcare interventions. The framework is described with reference to an example of implementing and evaluating protocols for weaning patients in the intensive care unit. The framework is critiqued on the basis that it involves an ambiguous or contradictory ontology, which fails to articulate the relationship between the positivism of randomized controlled trials with the relativism of qualitative approaches. It is concluded that the use of realist strategies in combination with randomized controlled trials provides the most coherent solution to this quandary

An evaluation of an adapted United States model of pharmaceutical care to improve psychoactive prescribing for nursing home residents in Northern Ireland (Fleetwood NI Study).

OBJECTIVES: To test the effect of an adapted U.S. model of pharmaceutical care on prescribing of inappropriate psychoactive (anxiolytic, hypnotic, and antipsychotic) medications and falls in nursing homes for older people in Northern Ireland (NI).

DESIGN: Cluster randomized controlled trial.

SETTING: Nursing homes randomized to intervention (receipt of the adapted model of care; n=11) or control (usual care continued; n=11).

PARTICIPANTS: Residents aged 65 and older who provided informed consent (N=334; 173 intervention, 161 control).

INTERVENTION: Specially trained pharmacists visited intervention homes monthly for 12 months and reviewed residents' clinical and prescribing information, applied an algorithm that guided them in assessing the appropriateness of psychoactive medication, and worked with prescribers (general practitioners) to improve the prescribing of these drugs. The control homes received usual care.

MEASUREMENTS: The primary end point was the proportion of residents prescribed one or more inappropriate psychoactive medicine according to standardized protocols; falls were evaluated using routinely collected falls data mandated by the regulatory body for nursing homes in NI.

RESULTS: The proportion of residents taking inappropriate psychoactive medications at 12 months in the intervention homes (25/128, 19.5%) was much lower than in the control homes (62/124, 50.0%) (odds ratio=0.26, 95% confidence interval=0.14–0.49) after adjustment for clustering within homes. No differences were observed at 12 months in the falls rate between the intervention and control groups.

CONCLUSION: Marked reductions in inappropriate psychoactive medication prescribing in residents resulted from pharmacist review of targeted medications, but there was no effect on falls.