Multi-Study Assessment of Vaginal Cytokines and Microflora in the Safety Evaluation of Intravaginal Rings in Pig-Tailed Macaques

BACKGROUND: HIV microbicide trials have emphasized the need to evaluate the safety of topical microbicides and delivery platforms in an animal model prior to conducting clinical efficacy trials. An ideal delivery device should provide sustainable and sufficient concentrations of effective products to prevent HIV transmission while not increasing transmission risk by either local mucosal inflammation and/or disruption of the normal vaginal microflora.

METHODS: Safety analyses of macaque-sized elastomeric silicone and polyurethane intravaginal rings (IVRs) loaded with candidate antiretroviral (ARV) drugs were tested in four studies ranging in duration from 49 to 73 days with retention of the IVR being 28 days in each study. Macaques were assigned to 3 groups; blank IVR, ARV-loaded IVR, and naïve. In sequential studies, the same macaques were used but rotated into different groups. Mucosal and systemic levels of cytokines were measured from vaginal fluids and plasma, respectively, using multiplex technology. Changes in vaginal microflora were also monitored. Statistical analysis (Mann-Whitney test) was used to compare data between two groups of unpaired samples (with and without IVR, and IVR with and without ARV) for the groups collectively, and also for individual macaques.

RESULTS: There were few statistically significant differences in mucosal and systemic cytokine levels measured longitudinally when the ring was present or absent, with or without ARVs. Of the 8 proinflammatory cytokines assayed a significant increase (p = 0.015) was only observed for IL8 in plasma with the blank and ARV loaded IVR (median of 9.2 vs. 5.7 pg/ml in the absence of IVR). There were no significant differences in the prevalence of H2O2-producing lactobacilli or viridans streptococci, or other microorganisms indicative of healthy vaginal microflora. However, there was an increase in the number of anaerobic gram negative rods in the presence of the IVR (p= < 0.0001).

CONCLUSIONS: IVRs with or without ARVs neither significantly induce the majority of potentially harmful proinflammatory cytokines locally or systemically, nor alter the lactobacillus or G. vaginalis levels. The increase in anaerobic gram negative rods alone suggests minimal disruption of normal vaginal microflora. The use of IVRs as a long-term sustained delivery device for ARVs is promising and preclinical studies to demonstrate the prevention of transmission in the HIV/SHIV nonhuman primate model should continue.

Microneedle-based drug delivery systems: Microfabrication, drug delivery, and safety

Many promising therapeutic agents are limited by their inability to reach the systemic circulation, due to the excellent barrier properties of biological membranes, such as the stratum corneum (SC) of the skin or the sclera/cornea of the eye and others. The outermost layer of the skin, the SC, is the principal barrier to topically-applied medications. The intact SC thus provides the main barrier to exogenous substances, including drugs. Only drugs with very specific physicochemical properties (molecular weight <500 Da, adequate lipophilicity, and low melting point) can be successfully administered transdermally. Transdermal delivery of hydrophilic drugs and macromolecular agents of interest, including peptides, DNA, and small interfering RNA is problematic. Therefore, facilitation of drug penetration through the SC may involve by-pass or reversible disruption of SC molecular architecture. Microneedles (MNs), when used to puncture skin, will by-pass the SC and create transient aqueous transport pathways of micron dimensions and enhance the transdermal permeability. These micropores are orders of magnitude larger than molecular dimensions, and, therefore, should readily permit the transport of hydrophilic macromolecules. Various strategies have been employed by many research groups and pharmaceutical companies worldwide, for the fabrication of MNs. This review details various types of MNs, fabrication methods and, importantly, investigations of clinical safety of MN.

Experiences with mephedrone pre- and post-legislative controls: Perceptions of safety and sources of supply

Background: Drug scenes within several countries have changed in recent years to incorporate a range of licit psychoactive products, collectively known as “legal highs.” Hundreds of different legal high products have been described in the literature. Many of these products contain synthetic stimulants that allegedly
“mirror” the effects of some illicit drugs. In 2009–2010, growing concern by the UK and Irish governments focused on mephedrone, a synthetic stimulant that had become embedded within several drug scenes in Britain and Ireland. In April 2010, mephedrone and related cathinone derivatives were banned under
the UK’s Misuse of Drugs Act 1971. Setting aside “worse case scenarios” that have been portrayed by UK and Irish media, little is known about mephedrone use from the consumer’s perspective. The purpose of this paper was to (1) explore respondents’ experiences with mephedrone, (2) examine users’ perceptions
about the safety of mephedrone, and primarily to (3) examine sources of mephedrone supply during the pre- and post-ban periods.
Methods: Semi-structured interviews were conducted with 23 adults who had used mephedrone during 2009–2010. Data collection occurred in May and June 2010, following the ban on mephedrone. A total of 20/23 respondents had used mephedrone during the post-ban period, and the vast majority had prior
experience with ecstasy or cocaine. Respondents’ ages ranged from 19 to 51, approximately half of the sample were female and the majority (19 of 23) were employed in full- or part-time work.
Results: Most respondents reported positive experiences with mephedrone, and for some, the substance emerged as a drug of choice. None of the respondents reported that the once-legal status of mephedrone implied that it was safe to use. Very few respondents reported purchasing mephedrone from street-based
or on-line headshops during the pre-ban period, and these decisions were guided in part by respondents’ attempts to avoid “drug user” identities. Most respondents purchased or obtained mephedrone from friends or dealers, and mephedrone was widely available during the 10-week period following the ban. Respondents reported a greater reliance on dealers and a change in mephedrone packaging following the criminalisation of mephedrone.
Conclusion: The findings are discussed in the context of what appears to be a rapidly changing mephedrone market. We discuss the possible implications of criminalising mephedrone, including the potential displacement effects and the development of an illicit market.

Confined Site Construction: Issues Regarding Implementation of Health and Safety

The objective of this paper is to identify the various managerial constraints, difficulties and issues encountered and resulting strategies adopted, to aid in the management of the various and often complex health and safety concerns, which occur within a confined construction site. This is achieved through classifying the various managerial burdens encountered with the numerous strategies adopted, to ensure the successful management of such confined environments within the realm of health and safety. Through an extensive literature review and detailed interviews, a comprehensive insight into the health and safety concerns within a confined construction site environment is portrayed. The leading managerial strategies to the management of health and safety on confined construction sites may be listed as follows; (1) Traffic Management Plan, (2) Effective Resource Management Plan, (3) Temporary Facilities Management Plan, (4) Safe System of Work Plan, (5) Site Safety Plan, (6) Design Site Layout, (7) Space Management Plan, (8) Effective Program Management, and (9) Space Scheduling. Based on the research, it can be concluded, that through effective management of these issues identified coupled with implementing the various strategies highlighted; successful management of health and safety within a confined construction site environment is attainable.

Micro-environmental change as a trigger for granite decay in offshore Irish lighthouses: implications for the long-term preservation of operational historic buildings.

Following automation of lighthouses around the coastline of Ireland, reports of accelerated deterioration of interior granite stonework have increased significantly with an associated deterioration in the historic structure and rise in related maintenance costs. Decay of granite stone- work primarily occurs through granular disintegration with the effective grusification of granite surfaces. A decay gradient exists within the towers whereby the condition of granite in the lower levels is much worse than elsewhere. The lower tower levels are also regions with highest rela- tive humidity values and greatest salt concentrations. Data indicate that post-automation decay may have been trig- gered by a change in micro-environmental conditions within the towers associated with increased episodes of condensation on stone surfaces. This in turn appears to have facilitated deposition and accumulation of hygro- scopic salts (e.g. NaCl) giving rise to widespread evidence of deliquescence in the lower tower levels. Evidence indicates that the main factors contributing to accelerated deterioration of interior granite stonework are changes in micro-environmental conditions, salt weathering, chemical weathering through the corrosive effect of strongly alkaline conditions on alumino-silicate minerals within the granite and finally, the mica-rich characteristics of the granite itself which increases its structural and chemical susceptibility to subaerial weathering processes by creating points of weakness within the granite. This case study demonstrates how seemingly minor changes in micro-environmental conditions can unintentionally trigger the rapid and extensive deterioration of a previously stable rock type and threaten the long-term future of nationally iconic opera- tional historic structures.

A work-based research assessment of the impact of 'lean manufacturing' on health and safety education within an SME

Globalisation has had a major impact on the engineering industry as pacific Rim countries undercut manufacturing costs and provide a more cost-effective location for many businesses. Engineering in Nortehrn Ireland has mostly declined owing to increased competition from these countries. Engineering companies are now forced to streamline their production processes and employ cost-reducing practices in order to meet customer demands at reduced prices. This article aims to analyse the effects of one such streamlining endeavour which was first introduced after World War II in Japan- 'lean manufacturing' . 'Lean manufacturing' aims to reduce all wasteful activities within the production process in order to improve productivity, while reducing manufacturing costs. The work-based project under consideration was concerned with the impact 'lean manufacturing' may have on health and safety performance and education within an engineering company. The focus of the project was to determine through work-based research, and quantitative analysis, the employee perception on health and safety: has it changed (either positively or negatively), as a consequence of implementing 'lean manufacturing'.

Impact of gate-source/drain channel architecture on the performance of an operational transconductance amplifier (OTA)

In this work, we report on the significance of gate-source/drain extension region (also known as underlap design) optimization in double gate (DG) FETs to improve the performance of an operational transconductance amplifier (OTA). It is demonstrated that high values of intrinsic voltage gain (A(VO_OTA)) > 55 dB and unity gain frequency (f(T_OTA)) similar to 57 GHz in a folded cascode OTA can be achieved with gate-underlap channel design in 60 nm DG MOSFETs. These values correspond to 15 dB improvement in A(VO_OTA) and three fold enhancement in f(T_OTA) over a conventional non-underlap design. OTA performance based on underlap single gate SOI MOSFETs realized in ultra-thin body (UTB) and ultra-thin body BOX (UTBB) technologies is also evaluated. A(VO_OTA) values exhibited by a DG MOSFET-based OTA are 1.3-1.6 times higher as compared to a conventional UTB/UTBB single gate OTA. f(T_OTA) values for DG OTA are 10 GHz higher for UTB OTAs whereas a twofold improvement is observed with respect to UTBB OTAs. The simultaneous improvement in A(VO_OTA) and f(T_OTA) highlights the usefulness of underlap channel architecture in improving gain-bandwidth trade-off in analog circuit design. Underlap channel OTAs demonstrate high degree of tolerance to misalignment/oversize between front and back gates without compromising the performance, thus relaxing crucial process/technology-dependent parameters to achieve 'idealized' DG MOSFETs. Results show that underlap OTAs designed with a spacer-to-straggle (s/sigma) ratio of 3.2 and operated below a bias current (IBIAS) of 80 mu A demonstrate optimum performance. The present work provides new opportunities for realizing future ultra-wide band OTA design with underlap DG MOSFETs.