Clinical use of HIV integrase inhibitors : a systematic review and meta-analysis

Background: Optimal regimen choice of antiretroviral therapy is essential to achieve long-term clinical success. Integrase inhibitors have swiftly been adopted as part of current antiretroviral regimens. The purpose of this study was to review the evidence for integrase inhibitor use in clinical settings. Methods: MEDLINE and Web-of-Science were screened from April 2006 until November 2012, as were hand-searched scientific meeting proceedings. Multiple reviewers independently screened 1323 citations in duplicate to identify randomized controlled trials, nonrandomized controlled trials and cohort studies on integrase inhibitor use in clinical practice. Independent, duplicate data extraction and quality assessment were conducted. Results: 48 unique studies were included on the use of integrase inhibitors in antiretroviral therapy-naive patients and treatment-experienced patients with either virological failure or switching to integrase inhibitors while virologically suppressed. On the selected studies with comparable outcome measures and indication (n = 16), a meta-analysis was performed based on modified intention-to-treat (mITT), on-treatment (OT) and as-treated (AT) virological outcome data. In therapy-naive patients, favorable odds ratios (OR) for integrase inhibitor-based regimens were observed, (mITT OR 0.71, 95% CI 0.59-0.86). However, integrase inhibitors combined with protease inhibitors only did not result in a significant better virological outcome. Evidence further supported integrase inhibitor use following virological failure (mITT OR 0.27; 95% CI 0.11-0.66), but switching to integrase inhibitors from a high genetic barrier drug during successful treatment was not supported (mITT OR 1.43; 95% CI 0.89-2.31). Integrase inhibitor-based regimens result in similar immunological responses compared to other regimens. A low genetic barrier to drug-resistance development was observed for raltegravir and elvitegravir, but not for dolutegravir. Conclusion: In first-line therapy, integrase inhibitors are superior to other regimens. Integrase inhibitor use after virological failure is supported as well by the meta-analysis. Careful use is however warranted when replacing a high genetic barrier drug in treatment-experienced patients switching successful treatment

Increased charcoal yield & production of lighter oils from the slow pyrolysis of biomass

In an effort to reduce CO2 emissions from solid fuels, a considerable amount of research is going into how improve the manufacturing processes and product properties of the products from pyrolysis. One aspect that is often overlooked is the production of charcoal for cooking and soil remediation, which is an inefficient conversion process. There is considerable interest into using additives to increase charcoal yields, and based on the observation from fast pyrolysis work that certain catalyst tar cracking pathways can deposit considerable amounts of coke on the surface of the catalyst, there is a potential application to slow pyrolysis processes producing charcoal. Alumino-silicate catalysts have been shown to have a relatively high tendency to do this. This work hypothesises that this catalysation can be applied to slow pyrolysis, with low cost alumino-silicate minerals, specially bentonite clay, which has been added to pine pyrolysis in concentrations up to 60% wt (against input biomass) at temperatures 300–700 °C. This study has shown that the use of bentonite clay minerals can be beneficial to the process, as there is an increase in the charcoal yield from biomass, whilst the proximate analysis of the charcoal shows little change from levels expected from biomass only pyrolysis. The conversion of oil to charcoal was more effective at high temperatures due to higher levels of oil cracking. At 700 °C with 60% clay loading, charcoal yield increased 16%wt (dry ash free basis) was seen, while at the same time 19% extra gas was produced at the expense of 35% of the oil from raw pine pyrolysis. This indicates fuel properties of the charcoal are predictable, and changes in yield considerable. At the same time, the abundance of lower molecular weight oils is increased (relative to 4-methyl phenol). It is though that pyrolysis oil reacts with the clay, causing the heavier tars to disproportionate into charcoal and gas

Coastal ecosystems: A critical element of risk reduction

The conservation of coastal ecosystems can provide considerable coastal protection benefits, but this role has not been sufficiently accounted for in coastal planning and engineering. Substantial evidence now exists showing how, and under what conditions, ecosystems can play a valuable function in wave and storm surge attenuation, erosion reduction, and in the longer term maintenance of the coastal profile. Both through their capacity for self repair and recovery, and through the often considerable cobenefits they provide, ecosystems can offer notable advantages over traditional engineering approaches in some settings. They can also be combined in "hybrid" engineering designs. We make 10 recommendations to encourage the utilization of existing knowledge and to improve the incorporation of ecosystems into policy, planning and funding for coastal hazard risk reduction

Subsidence reveals potential impacts of future sea level rise on inhabited mangrove coasts

Human-induced land subsidence causes many coastal areas to sink centimetres per year, exacerbating relative sea level rise (RSLR). While cities combat this problem through investment in coastal infrastructure, rural areas are highly dependent on the persistence of protective coastal ecosystems, such as mangroves and marshes. To shed light on the future of low-lying rural areas in the face of RSLR, we here studied a 20-km-long rural coastline neighbouring a sinking city in Indonesia, reportedly sinking with 8–20 cm per year. By measuring water levels in mangroves and quantifying floor raisings of village houses, we show that, while villages experienced rapidly rising water levels, their protective mangroves experience less rapid changes in RSLR. Individual trees were able to cope with RSLR rates of 4.3 (95% confidence interval 2.3–6.3) cm per year through various root adaptations when sediment was available locally. However, lateral retreat of the forest proved inevitable, with RSLR rates up to four times higher than foreshore accretion, forcing people from coastal communities to migrate as the shoreline retreated. Whereas local RSLR may be effectively reduced by better management of groundwater resources, the effects of RSLR described here predict a gloomy prospect for rural communities that are facing globally induced sea level rise beyond the control of local or regional government

Bone Microenvironment Specific Roles of ITAM Adapter Signaling during Bone Remodeling Induced by Acute Estrogen-Deficiency

Immunoreceptor tyrosine-based activation motif (ITAM) signaling mediated by DAP12 or Fcε receptor Iγ chain (FcRγ) have been shown to be critical for osteoclast differentiation and maturation under normal physiological conditions. Their function in pathological conditions is unknown. We studied the role of ITAM signaling during rapid bone remodeling induced by acute estrogen-deficiency in wild-type (WT), DAP12-deficient (DAP12-/-), FcRγ-deficient (FcRγ-/-) and double-deficient (DAP12-/-FcRγ-/-) mice. Six weeks after ovariectomy (OVX), DAP12-/-FcRγ-/- mice showed resistance to lumbar vertebral body (LVB) trabecular bone loss, while WT, DAP12-/- and FcRγ-/- mice had significant LVB bone loss. In contrast, all ITAM adapter-deficient mice responded to OVX with bone loss in both femur and tibia of approximately 40%, relative to basal bone volumes. Only WT mice developed significant cortical bone loss after OVX. In vitro studies showed microenvironmental changes induced by OVX are indispensable for enhanced osteoclast formation and function. Cytokine changes, including TGFβ and TNFα, were able to induce osteoclastogenesis independent of RANKL in BMMs from WT but not DAP12-/- and DAP12-/-FcRγ-/- mice. FSH stimulated RANKL-induced osteoclast differentiation from BMMs in WT, but not DAP12-/- and DAP12-/-FcRγ-/- mice. Our study demonstrates that although ITAM adapter signaling is critical for normal bone remodeling, estrogen-deficiency induces an ITAM adapter-independent bypass mechanism allowing for enhanced osteoclastogenesis and activation in specific bony microenvironments