The Medicines Optimisation Innovation Centre: a dedicated centre driving innovation in medicines optimisation-impact and sustainability.

BACKGROUND: Sub-optimal medicines use is a challenge globally, contributing to poorer health outcomes, inefficiencies and waste. The Medicines Optimisation Innovation Centre (MOIC) was established in Northern Ireland by the Department of Health (DH) in 2015 to support implementation of the Medicines Optimisation Quality Framework. AIM: To demonstrate how MOIC informs policy and provides support to commissioners to improve population health and wellbeing. SETTING: MOIC is a regional centre with multidisciplinary and multi-sector clinical expertise across Health and Social Care and patient representation. DEVELOPMENT: Core funded by DH, MOIC has a robust governance structure and oversight programme board. An annual business plan is agreed with DH. Rigorous processes have been developed for project adoption and working collaboratively with industry. IMPLEMENTATION: MOIC has established partnerships with academia, industry, healthcare and representative organisations across Europe, participating in research and development projects and testing integrated technology solutions. A hosting programme has been established and evaluation and dissemination strategies have been developed. EVALUATION: MOIC has established numerous agreements, partnered in three large EU projects and strengthened networks globally with extensive publications and conference presentations. Informing pathway redesign, sustainability and COVID response, MOIC has also assisted in the development of clinical pharmacy services and antimicrobial stewardship in Europe and Africa. Northern Ireland has been recognised as a 4-star European Active and Healthy Ageing Reference Site and the Integrated Medicines Management model as an example of best practice in Central and Eastern Europe. CONCLUSION: MOIC has demonstrated considerable success and sustainability and is applicable to health systems globally.

The chromosomal polymorphism of Drosophila subobscura: a microevolutionary weapon to monitor global change.

The Palaearctic species Drosophila subobscura recently invaded the west coast of Chile and North America. This invasion helped to corroborate the adaptive value of the rich chromosomal polymorphism of the species, as the same clinal patterns than those observed in the original Palaearctic area were reproduced in the colonized areas in a relatively short period of time. The rapid response of this polymorphism to environmental conditions makes it a good candidate to measure the effect of the global rising of temperatures on the genetic composition of populations. Indeed, the long-term variation of this polymorphism shows a general increase in the frequency of those inversions typical of low latitudes, with a corresponding decrease of those typical of populations closer to the poles. Although the mechanisms underlying these changes are not well understood, the system remains a valid tool to monitor the genetic impact of global warming on natural populations.

Potential responses to climate change in organisms with complex life histories: evolution and plasticity in Pacific salmon.

Salmon life histories are finely tuned to local environmental conditions, which are intimately linked to climate. We summarize the likely impacts of climate change on the physical environment of salmon in the Pacific Northwest and discuss the potential evolutionary consequences of these changes, with particular reference to Columbia River Basin spring/summer Chinook (Oncorhynchus tshawytscha) and sockeye (Oncorhynchus nerka) salmon. We discuss the possible evolutionary responses in migration and spawning date egg and juvenile growth and development rates, thermal tolerance, and disease resistance. We know little about ocean migration pathways, so cannot confidently suggest the potential changes in this life stage. Climate change might produce conflicting selection pressures in different life stages, which will interact with plastic (i.e. nongenetic) changes in various ways. To clarify these interactions, we present a conceptual model of how changing environmental conditions shift phenotypic optima and, through plastic responses, phenotype distributions, affecting the force of selection. Our predictions are tentative because we lack data on the strength of selection, heritability, and ecological and genetic linkages among many of the traits discussed here. Despite the challenges involved in experimental manipulation of species with complex life histories, such research is essential for full appreciation of the biological effects of climate change.

Introduction history of Drosophila subobscura in the New World: a microsatellite-based survey using ABC methods.

Drosophila subobscura is a Palearctic species that was first observed in South and North America in the early 1980s, and that rapidly invaded broad latitudinal ranges on both continents. To trace the source and history of this invasion, we obtained genotypic data on nine microsatellite loci from two South American, two North American and five European populations of D. subobscura. We analysed these data with traditional statistics as well as with an approximate Bayesian computation (ABC) framework. ABC methods yielded the strongest support for the scenario involving a serial introduction with founder events from Europe into South America, and then from South America into North America. Stable effective population size of the source population was very large (around one million individuals), and the propagule size was notably smaller for the introduction into South America (i.e. high bottleneck severity index with only a few effective founders) but considerably larger for the subsequent introduction into North America (i.e. low bottleneck severity index with around 100-150 effective founders). Finally, the Mediterranean region of Europe (and most likely Barcelona from the localities so far analysed) is proposed as the source of the New World flies, based on mean individual assignment statistics.

Limits to human performance: elevated risks on high mountains.

In 1950, Maurice Herzog and Louis Lachenal became the first climbers to reach the summit of an 8000m peak (Annapurna, 8091m). In the half century since that pioneering climb, mountaineers have increasingly sought to climb the fourteen '8K peaks' of the Himalayas and Karakoram, with remarkable success; they have made 5085 ascents of those peaks up to the year 2000. While seeking adventure on those great peaks, mountaineers are inevitably exposed to hypoxia, cold and dehydration as well as to the physical hazards of climbing. Those few mountaineers who successfully summit an 8K peak are likely to be at or near their physiological limits and probably confront an elevated probability of dying during their descent. We will briefly review some of the physiological challenges climbers face at extreme elevation and then compare success rates and death rates on mountains of different heights (Rainer, Foraker, Denali, K2, Everest). Success rates decline with summit height, but overall death rates and death rates during descent from the summit increase with summit height. Although these patterns are based on non-experimental and uncontrolled data, our findings are consistent with the hypothesis that increasing altitude is associated with decreased success and with increased risk of death.

Chill-coma temperature in Drosophila: effects of developmental temperature, latitude, and phylogeny.

We modify and apply a nonlethal technique for rapidly quantifying the cold tolerance of large numbers of Drosophila and other small insects. Flies are transferred to individual vials, cooled in groups in progressive 0.5 degrees C steps, and checked for loss of righting response (chill-coma temperature [T(cc)]). Flies recover quickly when transferred to ambient temperature, and thus this technique potentially can be used in selection experiments. We applied this technique in several experiments. First, we examined the sensitivity of T(cc) to developmental temperature. Drosophila melanogaster (Congo, France), Drosophila subobscura (Spain, Denmark), and Drosophila ananassae (India) were reared from egg to adult at 15 degrees, 18 degrees, 25 degrees, or 29 degrees C, transferred to 15 degrees C for several days, and then progressively chilled: T(cc) was positively related to developmental temperature, inversely related to latitude of the population, but independent of sex. The sensitivity of T(cc) to developmental temperature (acclimation flexibility) was marked: T(cc) shifted on average 1 degrees for each 4 degrees C shift in developmental temperature. Among 15 species of the obscura group of Drosophila, T(cc) varied from -0.1 degrees to 4.5 degrees C; T(cc) was inversely related to latitude in both nonphylogenetic and phylogenetically based ANCOVA (standardized independent contrasts) and was unrelated to body size.

Locomotor performance of Drosophila melanogaster: interactions among developmental and adult temperatures, age, and geography.

We explored the extent to which a phenotypic trait (walking speed) of Drosophila melanogaster is influenced by population, developmental temperature, adult temperature, and age. Our goals were to estimate the importance of these factors and to test the beneficial acclimation hypothesis. We measured speed of flies from two populations (the Congo and France) that developed at different temperatures (18, 25, and 29 degrees C) and were tested at different temperatures (18, 25, and 29 degrees C) and ages (2, 7, 13 days). Not surprisingly, speed increased strongly with test temperature. Speed was generally greatest for flies reared at an intermediate developmental temperature, contrary to the beneficial acclimation hypothesis, which predicts that speed would be greatest when influenced by interactions involving population. For example, speed was greatest for flies from France that developed at a low temperature, but for flies from the Congo that developed at a high temperature. The impact of developmental temperature declined with age. Surprisingly, speed actually increased with age for flies raised and maintained at a low temperature, but decreased with age for flies raised and maintained at an intermediate or at a high temperature. Thus, walking performance is highly dynamic phenotypically, complicating potential attempts to predict responses to selection on performance.

Parental and developmental temperature effects on the thermal dependence of fitness in Drosophila melanogaster.

Cross-generational effects refer to nongenetic influences of the parental phenotype or environment on offspring phenotypes. Such effects are commonly observed, but their adaptive significance is largely unresolved. We examined cross-generational effects of parental temperature on offspring fitness (estimated via a serial-transfer assay) at different temperatures in a laboratory population of Drosophila melanogaster. Parents were reared at 18 degrees C, 25 degrees C, or 29 degrees C (Tpar) and then their offspring were reared at 18 degrees C, 25 degrees C, or 29 degrees C (Toff) to evaluate several competing hypotheses (including an adaptive one) involving interaction effects of parental and offspring temperature on offspring fitness. The results clearly show that hotter parents are better; in other words, the higher the temperature of the parents, the higher the fitness of their offspring, independent of offspring thermal environment. These data contradict the adaptive cross-generational hypothesis, which proposes that offspring fitness is maximal when the offspring thermal regime matches the parental one. Flies with hot parents have high fitness seemingly because their own offspring develop relatively quickly, not because they have higher fecundity early in life.

Rapid evolution of wing size clines in Drosophila subobscura.

Parallel latitudinal clines across species and continents provide dramatic evidence of the efficacy of natural selection, however little is known about the dynamics involved in cline formation. For example, several drosophilids and other ectotherms increase in body and wing size at higher latitudes. Here we compare evolution in an ancestral European and a recently introduced (North America) cline in wing size and shape in Drosophila subobscura. We show that clinal variation in wing size, spanning more than 15 degrees of latitude, has evolved in less than two decades. In females from Europe and North America, the clines are statistically indistinguishable however the cline for North American males is significantly shallower than that for European males. We document that while overall patterns of wing size are similar on two continents, the European cline is obtained largely through changing the proximal portion of the wing, whereas the North American cline is largely in the distal portion. We use data from sites collected in 1986/1988 (Pegueroles et al. 1995) and our 1997 collections to compare synchronic (divergence between contemporary populations that share a common ancestor) and allochronic (changes over time within a population) estimates of the rates of evolution. We find that, for these populations, allochronically estimated evolutionary rates within a single population are over 0.02 haldanes (2800 darwins), a value similar in magnitude to the synchronic estimates from the extremes of the cline. This paper represents an expanded analysis of data partially presented in Huey et al. (2000).

Mountaineering in thin air. Patterns of death and of weather at high altitude.

An 8000-m peak bring challenges of extremes of hypoxia and weather as well as the normal hazards of climbing itself. These challenges have taken a severe toll: 604 mountaineers have died on those great peaks since 1950. Little is known about whether mountain height, use of supplemental oxygen, or team size might influence rates of death or of success. However, such information may provide insights not only to our understanding of the limits of human performance, but also to mountaineers in making decisions on these peaks. We present several examples from a research program that is attempting to analyze factors that potentially influence success or death rates on the 8K peaks. (1) Apparent risk of death in the notorious Khumbu Icefall on Mt. Everest has declined dramatically in recent years. This decline could reflect improved route finding and technique, but might also reflect climate warming, which has caused the Khumbu glacier to shrink and slow in recent decades. (2) Risk of death during descent from an 8000-m peak increases with the height of the peak. (3) Risk of death during descent from the summit of Everest or of K2 is elevated for climbers not using supplemental oxygen. (4) We outline some new studies that are exploring how convective heat loss, which influences wind chill, changes with altitude as well as the incidence of storms: both factors will impact the probability success and death of Himalayan mountaineers.

Rapid evolution of a geographic cline in size in an introduced fly.

The introduction and rapid spread of Drosophila subobscura in the New World two decades ago provide an opportunity to determine the predictability and rate of evolution of a geographic cline. In ancestral Old World populations, wing length increases clinally with latitude. In North American populations, no wing length cline was detected one decade after the introduction. After two decades, however, a cline has evolved and largely converged on the ancestral cline. The rate of morphological evolution on a continental scale is very fast, relative even to rates measured within local populations. Nevertheless, different wing sections dominate the New versus Old World clines. Thus, the evolution of geographic variation in wing length has been predictable, but the means by which the cline is achieved is contingent.

The direct response of Drosophila melanogaster to selection on knockdown temperature.

We selected on knockdown temperature, the upper temperature at which insects lose the ability to cling to an inclined surface, in replicate populations of Drosophila melanogaster for 32 generations (46 generations of rearing). Knockdown temperature (Tkd) was initially bimodally distributed in both control and selected lines, and a similar pattern was found in several populations surveyed from two other continents. Within 20 generations of selection, the Up-selected lines (top 25% each generation) had lost the lower mode and the Low-selected lines (selected to fall out at approximately 37 degrees C) had largely lost the upper mode. The realized heritability of Tkd computed over the first 10 selection episodes was approximately 0.12 in the Up-selected and approximately 0.19 in the Low-selected lines. Realized heritability rose dramatically in the Low-selected lines over the first 20 generations of selection. The two modes, plus this rise in heritability, suggest that knockdown temperature is the product of one or two genes of large effect. The global polymorphism for knockdown temperature, coupled with the ease of selective removal of either mode, suggests that genetic variation for knockdown temperature may be maintained by natural selection.

Thermal sensitivity of Drosophila melanogaster: evolutionary responses of adults and eggs to laboratory natural selection at different temperatures.

We compared aspects of the thermal sensitivity of replicated lines of Drosophila melanogaster that had been evolving by laboratory natural selection at three selection temperatures: 16.5 degrees C (10+ yr), 25 degrees C (9+ yr), or 29 degrees C (4+ yr). The 16.5 degrees C and 25 degrees C lines are known to have diverged in fitness at 16.5 degrees C versus 25 degrees C and also in heat tolerance. We designed new experiments to explore further possible shifts in thermal sensitivity of these lines. The optimal temperature for walking speed of adults was positively related to selection temperature, but differences among lines in thermal sensitivity of walking speed were small. Performance breath was inversely related to selection temperature. Tolerance of adults to an acute heat shock was also positively related to selection temperature, but tolerance to a cold shock was not. Thus, fitness at moderately high temperatures is genetically coupled with tolerance of extreme high (but not of low) temperature. Knock-down temperature and walking speed at high temperature, however, were independent of selection temperature. In contrast to adults, eggs from different lines had similar heat and cold tolerance. Thus, long-term natural selection has led to divergence in thermal sensitivity of some (but not of all) traits and may have had more of an impact on adults than on eggs. Attempts to predict evolutionary states in nature are, however, complicated because of the observed genetic correlations and the simple selection scheme.

Distributed automated docking of flexible ligands to proteins: parallel applications of AutoDock 2.4.

AutoDock 2.4 predicts the bound conformations of a small, flexible ligand to a nonflexible macromolecular target of known structure. The technique combines simulated annealing for conformation searching with a rapid grid-based method of energy evaluation based on the AMBER force field. AutoDock has been optimized in performance without sacrificing accuracy; it incorporates many enhancements and additions, including an intuitive interface. We have developed a set of tools for launching and analyzing many independent docking jobs in parallel on a heterogeneous network of UNIX-based workstations. This paper describes the current release, and the results of a suite of diverse test systems. We also present the results of a systematic investigation into the effects of varying simulated-annealing parameters on molecular docking. We show that even for ligands with a large number of degrees of freedom, root-mean-square deviations of less than 1 A from the crystallographic conformation are obtained for the lowest-energy dockings, although fewer dockings find the crystallographic conformation when there are more degrees of freedom.