Reasons for ineligibility in phase 1 and 2A HIV vaccine clinical trials at Kenya AIDS vaccine initiative (KAVI), Kenya

Background

With the persistent challenges towards controlling the HIV epidemic, there is an ongoing need for research into HIV vaccines and drugs. Sub-Saharan African countries - worst affected by the HIV pandemic - have participated in the conduct of clinical trials for HIV vaccines. In Kenya, the Kenya AIDS Vaccine Initiative (KAVI) at the University of Nairobi has conducted HIV vaccine clinical trials since 2001.

Methodology

Participants were recruited after an extensive informed consent process followed by screening to determine eligibility. Screening included an assessment of risk behavior, medical history and physical examination, and if clinically healthy, laboratory testing. In the absence of locally derived laboratory reference ranges, the ranges used in these trials were derived from populations in the West.

Principal findings

Two hundred eighty-one participants were screened between 2003 and 2006 for two clinical trials. Of these, 167 (59.4%) met the inclusion/exclusion criteria. Overall, laboratory abnormalities based on the non-indigenous laboratory references used were the most frequent reasons (61.4%) for ineligibility. Medical abnormalities contributed 30.7% of the total reasons for ineligibility. Based on the laboratory reference intervals now developed from East and Southern Africa, those ineligible due to laboratory abnormalities would have been 46.3%. Of the eligible participants, 18.6% declined enrolment.

Conclusions

Participant recruitment for HIV vaccine clinical trials is a rigorous and time-consuming exercise. Over 61% of the screening exclusions in clinically healthy people were due to laboratory abnormalities. It is essential that laboratory reference ranges generated from local populations for laboratory values be used in the conduct of clinical trials to avoid unnecessary exclusion of willing participants and to avoid over-reporting of adverse events for enrolled participants.

Trial registration

Protocol IAVI VRC V001 [1]. ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT00124007","term_id":"NCT00124007"}}NCT00124007 Protocol IAVI 010 [2] (registration with ClincalTrials.gov is in progress) Protocols IAVI 002 and IAVI 004 are Phase 1 trials only mentioned in introductory paragraphs; details will not be reported. Registration was not required when they were conducted.     

A Critical Role of Fatty Acid Binding Protein 4 and 5 (FABP4/5) in the Systemic Response to Fasting

During prolonged fasting, fatty acid (FA) released from adipose tissue is a major energy source for peripheral tissues, including the heart, skeletal muscle and liver. We recently showed that FA binding protein 4 (FABP4) and FABP5, which are abundantly expressed in adipocytes and macrophages, are prominently expressed in capillary endothelial cells in the heart and skeletal muscle. In addition, mice deficient for both FABP4 and FABP5 (FABP4/5 DKO mice) exhibited defective uptake of FA with compensatory up-regulation of glucose consumption in these tissues during fasting. Here we showed that deletion of FABP4/5 resulted in a marked perturbation of metabolism in response to prolonged fasting, including hyperketotic hypoglycemia and hepatic steatosis. Blood glucose levels were reduced, whereas the levels of non-esterified FA (NEFA) and ketone bodies were markedly increased during fasting. In addition, the uptake of the ¹²⁵I-BMIPP FA analogue in the DKO livers was markedly increased after fasting. Consistent with an increased influx of NEFA into the liver, DKO mice showed marked hepatic steatosis after a 48-hr fast. Although gluconeogenesis was observed shortly after fasting, the substrates for gluconeogenesis were reduced during prolonged fasting, resulting in insufficient gluconeogenesis and enhanced hypoglycemia. These metabolic responses to prolonged fasting in DKO mice were readily reversed by re-feeding. Taken together, these data strongly suggested that a maladaptive response to fasting in DKO mice occurred as a result of an increased influx of NEFA into the liver and pronounced hypoglycemia. Together with our previous study, the metabolic consequence found in the present study is likely to be attributed to an impairment of FA uptake in the heart and skeletal muscle. Thus, our data provided evidence that peripheral uptake of FA via capillary endothelial FABP4/5 is crucial for systemic metabolism and may establish FABP4/5 as potentially novel targets for the modulation of energy homeostasis.     

Cost-effectiveness and budget impact analyses of dengue vaccination in Indonesia

Despite the fact that the incidence and mortality rates due to dengue virus (DENV) infection in Indonesia are relatively high, dengue vaccination has not yet been introduced. This study aimed to analyse the cost-effectiveness and the budget impact of dengue vaccination in Indonesia by taking the potential of pre-vaccination screening into account. An age-structured decision tree model was developed to assess the cost-effectiveness value by applying a single cohort of 4,710,100 children that was followed-up in a 10-year time horizon within a 1-year analytical cycle. The budget impact was analysed in a 5-year period (2020–2024) by considering provinces’ readiness to introduce dengue vaccine and their incidence rate of DENV infection in the last 10 years. Vaccination that was coupled with pre-vaccination screening would reduce dengue fever (DF), dengue haemorrhagic fever (DHF) and dengue shock syndrome (DSS) by 188,142, 148,089 and 426 cases, respectively. It would save treatment cost at $23,433,695 and $14,091,642 from the healthcare and payer perspective, respectively. The incremental cost-effectiveness ratios (ICERs) would be $5,733 and $5,791 per quality-adjusted-life-year (QALY) gained from both perspectives. The most influential parameters affecting the ICERs were probability of DENV infection, vaccine efficacy, under-reporting factor, vaccine price, case fatality rate and screening cost. It can be concluded that dengue vaccination and pre-vaccination screening would be cost-effective to be implemented in Indonesia. Nevertheless, it seems unaffordable to be implemented since the total required cost for the nationwide vaccination would be 94.44% of routine immunization budget.     

Correction to: Reduced Serum Selenium Concentration in Miscarriage Incidence of Indonesian Subjects

Biological Trace Element Research - The original version of this article unfortunately contained a mistake. The name of “Herlambang herlambang” is now corrected in the author group of...     

10-year experience with the Thai national LCI database: case study of “refinery products”

Purpose

Due to various environmental pressures such as climate change and scarcity of natural resources, as well as nontariff barriers from trade partners, Thailand has established the Thai national life cycle inventory (LCI) database in 2006. In the 1st phase (2006–2007), three working groups were developed for natural gas, refinery, and petrochemical products. Another seven working groups were established in the 2nd phase (2007–2010) for ferrous and non-ferrous metals, utilities and transportation, construction materials, agricultural materials and products, basic chemicals, recycling and waste management, and others. In the 3rd phase (2010 to present), expansion of the number of data sets from the previous phases has been carried out. The purpose of this paper is to present the experiences on national database development in emerging countries with the example of Thailand on both strategic and technical levels using refinery products as the case study.

Methods

Data sets were developed according to ISO 14044:2006. The LCI data were managed and archived at the central facility known as the “central LCI database”. The Life Cycle Assessment lab (LCA lab) at MTEC, NSTDA, has been responsible for the central LCI database management. From 2008 to 2010, the “Thai national LCI database and its applications” project was granted a 3-year funding of over 50 million THB, and was operated under supervision of a steering committee set up by the Ministry of Industry (MoI). For this case study, to illustrate the development process, primary data of the refinery products were collected by Petroleum Institute of Thailand in the year 2005 from seven refineries covering more than 70 % of the production in the country. Attributional modelling has been used, with energy content as an allocation criterion.

Results and discussion

During the initial phase of the “Thai National LCI Database Development Project”, two key barriers have been faced. One was the lack of awareness from stakeholders as LCI and LCA were quite new tools for most people in Thailand. This problem was tackled by collaborating with the right strategic partners to drive the LCI national project and educating stakeholders with the training supports from Japan. The other hindrance was the lack of expertise of local experts on LCA. It took several years to continually build the capacity through seminars and workshops in Thailand and Japan, including “on the job training” on some pilot projects. As of May 2016, there were more than 700 data sets in the Thai national LCI database, considering only the data that MTEC acted as the project commissioner. However, only 515 data were certified as the national database. The other 211 data were qualified merely as the data from pilot projects. More details of the database list and how to access the data can be viewed in Thai language at the URL: http://www.thailcidatabase.net. Because the Thai national LCI data were mostly primary data from a core set of products for the Thai economy with a very high representativeness (>60 %) of the actual Thai productions, the data have been treated carefully. Only C-to-G data and G-to-G data from literature were allowed to disclose to Thai delegates with some signing agreements. However, G-to-G data from the actual Thai productions were sometimes provided, only with the signing confidentiality contracts. For refinery products, seven average data sets were established as national LCI data sets, i.e. liquefied petroleum gas, sulfur, gasoline, kerosene/jet oil, naphtha, fuel oil and diesel, with the year 2005 as the reference year. The data representativeness was very high covering more than 70 % of the production in Thailand. Due to the positive feedback and engagement from industries, several LCI projects have been started after this initial phase. The national LCI data sets have been used in various national applications and policies such as sustainable biofuels, government green public procurement, green GDP, Thai carbon footprint, etc. However, some relevant limitations of the Thai LCI database were listed as follows. Similar to most surveyed national LCI database worldwide, the climate change impact category has been chosen as the main focus for these data sets. Nevertheless, there is a more growing demand to use the data for other applications. As a result, more data sets that cover other impact categories will be required in the near future. Regarding the nomenclature and format, the Thai data sets were technically unique and not fully compatible with any other database.

Conclusions

The Thai national LCI database could be considered as the pioneer case for other countries in the South East Asia region. Thailand has further progressed in its LCI database development. Since 2009, the Thai national LCI database has been used as one of the key infrastructures of Thailand to support public policies and applications related to green growth. Many Thai stakeholders are well aware on LCI, LCA, and EcoDesign. Expertise of local experts has been increasingly improved. However, there are still more challenges to be faced to harvest the value of the Thai database in its full potential for better decision making in industry and policy, and for better positioning of Thai products on the global markets. From our experience, the following issues could be identified as “lessons learned”. At the onset of the project, it was crucial to get in expert advices from LCA-experienced countries to establish local expertise. Also, industry experts from abroad could help in clarifying the concept and addressing confidentiality concerns, as well as building awareness on LCA to Thai industries. Searching for some supporting programmes for capacity building, such as the GPP from Japan in our case, could provide great benefits to any emerging economies for national LCI initiatives. However, sustaining the trained human resources was also vital. Continual funding supports for LCI development and its applications were necessary to keep the momentum of active people in the field. Multiplying effect of the LCI knowledge to related organizations in the three main groups, i.e. government, academia, and industries, could help sustain the knowhow. Also, effective knowledge management through media such as books, guidelines, training courses, etc. would relief the turnover problem of trained staffs. Although it took a lot of time to develop local expertise, it was an essential step to have sufficient number of local experts to sustain the national database project. Moreover, a strong network of experts and researchers locally and internationally also strengthened the technical capacity to deal with any challenges during the project implementation. Furthermore, collaboration with the right strategic partners to drive the project was also very important in order to elevate it to the national level. It should be noted for any emerging economies aiming to initiate national LCI, the work plan for LCI database development (including the database management system) and its applications should be well balanced. Also, a well-designed database management system would enhance the database usage in the long run, especially when dealing with various impact categories like those in PEF.

     

Compatibility of toluidine blue with laser microdissection and saturation labeling DIGE

Tissue fixation and staining protocols for laser microdissection are frequently not fully compatible with subsequent proteomic analysis. We compared the effect of three common histological stains (toluidine blue (TB), hemotoxylin, and hematoxylin and eosin (HE)) on tissue visualization, protein recovery, the saturation labeling reaction, and 2‐D electrophoresis. TB provided the best visualization of colorectal tumor tissue during laser microdissection (LMD) and had a comparable effect on protein recovery and the saturation labeling reaction with hematoxylin, provided a modified 2‐D clean‐up protocol was used. Eosin inhibited both protein recovery and the saturation labeling reaction.     

Key issues and options in accounting for carbon sequestration and temporary storage in life cycle assessment and carbon footprinting

The International Journal of Life Cycle Assessment - Biological sequestration can increase the carbon stocks of non-atmospheric reservoirs (e.g. land and land-based products). Since this contained...     

Rapid and direct determination of selenium, copper, and zinc in blood plasma by flow injection-inductively coupled plasma-mass spectrometry

A flow injection-inductively coupled plasma-mass spectrometry (FI-ICP-MS) with a simple sample preparation procedure was developed for the determination of selenium, copper, and zinc in blood serum/plasma. A serum/plasma sample was filtered through a 0.45-μm membrane filter and diluted with a mixture of trace elements in a standard solution (9∶1, v/v). Measurement of the reference serum sample confirmed the accuracy of our method for selenium, copper, and zinc concentration. In the case of blood plasma samples obtained from six healthy adult males, the selenium, copper, and zinc concentrations were similar to those of a typical healthy male in Japan. These results suggest that the sample prepartive procedure coupled with FI-ICP-MS can be used for the routine determination of selenium, copper, and zinc in human blood serum/plasma.