The IDvIP Trial: A two-centre randomised double-blind controlled trial comparing intramuscular diamorphine and intramuscular pethidine for labour analgesia

<p>Abstract</p> <p>Background</p> <p>Intramuscular pethidine is routinely used throughout the UK for labour analgesia. Studies have suggested that pethidine provides little pain relief in labour and has a number of side effects affecting mother and neonate. It can cause nausea, vomiting and dysphoria in mothers and can cause reduced fetal heart rate variability and accelerations. Neonatal effects include respiratory depression and impaired feeding. There are few large studies comparing the relative side effects and efficacy of different opioids in labour. A small trial comparing intramuscular pethidine with diamorphine, showed diamorphine to have some benefits over pethidine when used for labour analgesia but the study did not investigate the adverse effects of either opioid.</p> <p>Methods</p> <p>The Intramuscular Diamorphine versus Intramuscular Pethidine (IDvIP) trial is a randomised double-blind two centre controlled trial comparing intramuscular diamorphine and pethidine regarding their analgesic efficacy in labour and their side effects in mother, fetus and neonate. Information about the trial will be provided to women in the antenatal period or in early labour. Consent and recruitment to the trial will be obtained when the mother requests opioid analgesia. The sample size requirement is 406 women with data on primary outcomes. The maternal primary outcomes are pain relief during the first 3 hours after trial analgesia and specifically pain relief after 60 minutes. The neonatal primary outcomes are need for resuscitation and Apgar Score <7 at 1 minute. The secondary outcomes are an additional measure of pain relief, maternal sedation, nausea and vomiting, maternal oxygen saturation, satisfaction with analgesia, whether method of analgesia would be used again, use of Entonox, umbilical arterial and venous pH, fetal heart rate, meconium staining, time from delivery to first breath, Apgar scores at 5 mins, naloxone requirement, transfer to neonatal intensive care unit, neonatal haemoglobin oxygen saturation at 30, 60, 90, and 120 mins after delivery, and neonatal sedation and feeding behaviour during first 2 hours.</p> <p>Discussion</p> <p>If the trial demonstrates that diamorphine provides better analgesia with fewer side effects in mother and neonate this could lead to a change in national practice and result in diamorphine becoming the preferred intramuscular opioid for analgesia in labour.</p> <p>Trial Registration</p> <p><a href="http://www.controlled-trials.com/ISRCTN14898678">ISRCTN14898678</a></p> <p>Eudra No: 2006-003250-18, REC Reference No: 06/Q1702/95, MHRA Authorisation No: 1443/0001/001-0001, NIHR UKCRN reference 6895, RfPB grant PB-PG-0407-13170_IR5</p

Structural and functional responses of macroinvertebrate assemblages to long‐term flow variability at perennial and nonperennial sites

Temporary streams constitute a significant proportion of rivers globally and are common in wet, cool, temperate regions. These heterogeneous ecosystems harbour high biodiversity associated with the dynamic turnover of taxa. Despite flow permanence being widely recognised as an important environmental control, few studies have characterised biotic responses to long‐term hydrological variability in temporary streams. We examined taxonomic and functional macroinvertebrate communities of perennial and nonperennial river reaches over a 26‐year period. Flow permanence resulted in spatial variation in taxonomic and functional macroinvertebrate communities. Nonperennial river reaches, which were characterised by dynamic habitat provision (lotic, lentic, and dry states) over the study period, supported more heterogeneous communities than perennial river reaches. Hydrological variables, in particular wetted width, water depth, and zero‐flow states, were instrumental in structuring taxonomic and functional communities, although the importance of substrate conditions increased in autumn. Hydrological conditions resulted in separation of perennial and nonperennial taxonomic communities regardless of season, whereas functional communities differed only in spring. Our results emphasise that understanding of community responses to hydrological variability is enhanced by analyses that concurrently explore taxonomic and functional responses to long‐term intraannual and interannual hydrological variability. Moreover, functional responses represent a robust method to test ecological responses to hydrological drivers. Further research that builds on our work is needed to inform the protection of both perennial and nonperennial streams as they adapt to ongoing environmental change

Exploring the Trypanosoma brucei Hsp83 Potential as a Target for Structure Guided Drug Design

Human African trypanosomiasis is a neglected parasitic disease that is fatal if untreated. The current drugs available to eliminate the causative agent Trypanosoma brucei have multiple liabilities, including toxicity, increasing problems due to treatment failure and limited efficacy. There are two approaches to discover novel antimicrobial drugs--whole-cell screening and target-based discovery. In the latter case, there is a need to identify and validate novel drug targets in Trypanosoma parasites. The heat shock proteins (Hsp), while best known as cancer targets with a number of drug candidates in clinical development, are a family of emerging targets for infectious diseases. In this paper, we report the exploration of T. brucei Hsp83--a homolog of human Hsp90--as a drug target using multiple biophysical and biochemical techniques. Our approach included the characterization of the chemical sensitivity of the parasitic chaperone against a library of known Hsp90 inhibitors by means of differential scanning fluorimetry (DSF). Several compounds identified by this screening procedure were further studied using isothermal titration calorimetry (ITC) and X-ray crystallography, as well as tested in parasite growth inhibitions assays. These experiments led us to the identification of a benzamide derivative compound capable of interacting with TbHsp83 more strongly than with its human homologs and structural rationalization of this selectivity. The results highlight the opportunities created by subtle structural differences to develop new series of compounds to selectively target the Trypanosoma brucei chaperone and effectively kill the sleeping sickness parasite

The comparative osmoregulatory ability of two water beetle genera whose species span the fresh-hypersaline gradient in inland waters (Coleoptera: Dytiscidae, Hydrophilidae).

A better knowledge of the physiological basis of salinity tolerance is essential to understanding the ecology and evolutionary history of organisms that have colonized inland saline waters. Coleoptera are amongst the most diverse macroinvertebrates in inland waters, including saline habitats; however, the osmoregulatory strategies they employ to deal with osmotic stress remain unexplored. Survival and haemolymph osmotic concentration at different salinities were examined in adults of eight aquatic beetle species which inhabit different parts of the fresh-hypersaline gradient. Studied species belong to two unrelated genera which have invaded saline waters independently from freshwater ancestors; Nebrioporus (Dytiscidae) and Enochrus (Hydrophilidae). Their osmoregulatory strategy (osmoconformity or osmoregulation) was identified and osmotic capacity (the osmotic gradient between the animal's haemolymph and the external medium) was compared between species pairs co-habiting similar salinities in nature. We show that osmoregulatory capacity, rather than osmoconformity, has evolved independently in these different lineages. All species hyperegulated their haemolymph osmotic concentration in diluted waters; those living in fresh or low-salinity waters were unable to hyporegulate and survive in hyperosmotic media (> 340 mosmol kg(-1)). In contrast, the species which inhabit the hypo-hypersaline habitats were effective hyporegulators, maintaining their haemolymph osmolality within narrow limits (ca. 300 mosmol kg(-1)) across a wide range of external concentrations. The hypersaline species N. ceresyi and E. jesusarribasi tolerated conductivities up to 140 and 180 mS cm(-1), respectively, and maintained osmotic gradients over 3500 mosmol kg(-1), comparable to those of the most effective insect osmoregulators known to date. Syntopic species of both genera showed similar osmotic capacities and in general, osmotic responses correlated well with upper salinity levels occupied by individual species in nature. Therefore, osmoregulatory capacity may mediate habitat segregation amongst congeners across the salinity gradient

A multi-component flood risk assessment in the Maresme coast (NW Mediterranean)

Coastal regions are the areas most threatened by natural hazards, with floods being the most frequent and significant threat in terms of their induced impacts, and therefore, any management scheme requires their evaluation. In coastal areas, flooding is a hazard associated with various processes acting at different scales: coastal storms, flash floods, and sea level rise (SLR). In order to address the problem as a whole, this study presents a methodology to undertake a preliminary integrated risk assessment that determines the magnitude of the different flood processes (flash flood, marine storm, SLR) and their associated consequences, taking into account their temporal and spatial scales. The risk is quantified using specific indicators to assess the magnitude of the hazard (for each component) and the consequences in a common scale. This allows for a robust comparison of the spatial risk distribution along the coast in order to identify both the areas at greatest risk and the risk components that have the greatest impact. This methodology is applied on the Maresme coast (NW Mediterranean, Spain), which can be considered representative of developed areas of the Spanish Mediterranean coast. The results obtained characterise this coastline as an area of relatively low overall risk, although some hot spots have been identified with high-risk values, with flash flooding being the principal risk process

Exploiting bacterial DNA gyrase as a drug target: current state and perspectives

DNA gyrase is a type II topoisomerase that can introduce negative supercoils into DNA at the expense of ATP hydrolysis. It is essential in all bacteria but absent from higher eukaryotes, making it an attractive target for antibacterials. The fluoroquinolones are examples of very successful gyrase-targeted drugs, but the rise in bacterial resistance to these agents means that we not only need to seek new compounds, but also new modes of inhibition of this enzyme. We review known gyrase-specific drugs and toxins and assess the prospects for developing new antibacterials targeted to this enzyme