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Treatment concepts in oncology are becoming increasingly personalized and diverse. Successively, changes in standards of care mandate continuous monitoring of patient pathways and clinical outcomes based on large, representative real-world data. The German Cancer Consortium’s (DKTK) Clinical Communication Platform (CCP) provides such opportunity. Connecting fourteen university hospital-based cancer centers, the CCP relies on a federated IT-infrastructure sourcing data from facility-based cancer registry units and biobanks. Federated analyses resulted in a cohort of 600,915 patients, out of which 232,991 were incident since 2013 and for which a comprehensive documentation is available. Next to demographic data (i.e., age at diagnosis: 2.0% 0–20 years, 8.3% 21–40 years, 30.9% 41–60 years, 50.1% 61–80 years, 8.8% 81 + years; and gender: 45.2% female, 54.7% male, 0.1% other) and diagnoses (five most frequent tumor origins: 22,523 prostate, 18,409 breast, 15,575 lung, 13,964 skin/malignant melanoma, 9,005 brain), the cohort dataset contains information about therapeutic interventions and response assessments and is connected to 287,883 liquid and tissue biosamples. Focusing on diagnoses and therapy-sequences, showcase analyses of diagnosis-specific sub-cohorts (pancreas, larynx, kidney, thyroid gland) demonstrate the analytical opportunities offered by the cohort’s data. Due to its data granularity and size, the cohort is a potential catalyst for translational cancer research. It provides rapid access to comprehensive patient groups and may improve the understanding of the clinical course of various (even rare) malignancies. Therefore, the cohort may serve as a decisions-making tool for clinical trial design and contributes to the evaluation of scientific findings under real-world conditions.

The noble crayfish (Astacus astacus) is an endangered freshwater species in Europe. The main threat is from lethal crayfish plague, caused by the oomycete Aphanomyces astaci that has been spread over Europe by introduced North American crayfish species, acting as chronic carriers of the disease. Most of the remaining noble crayfish populations are found in the Baltic Sea area, and there is an urgent need to implement conservation actions to slow down or halt the extinction rate in this region. However, limited knowledge about the genetic structure of populations in this area has so far precluded the development of conservation strategies that take genetic aspects into consideration. Key objectives of this large-scale genetic study, covering 77 locations mainly from northern Europe, were to describe the contemporary population genetic structure of the noble crayfish in the Fennoscandian peninsula (Sweden, Norway, and Finland), taking postglacial colonization history into account, and to evaluate how human activities such as stocking have affected the genetic structure of the populations. Analyses of 15 microsatellite markers revealed three main genetic clusters corresponding to populations in northern, middle, and southern Fennoscandia, with measures of genetic diversity being markedly higher within populations in the southern cluster. The observed genetic structure probably mirrors two main colonizations of the Baltic Sea basin after the last glaciation period. At the same time, several deviations from this pattern were observed, reflecting past human translocations of noble crayfish. The results are discussed in relation to the conservation and management of this critically endangered species. In particular, we recommend increased efforts to protect the few remaining noble crayfish populations in southern Fennoscandia and the use of genetic information when planning stocking activities, such as reintroductions following local extinctions.

Anadromous salmonid fishes frequently exhibit strong geographic population structuring. However, population genetic differentiation of Atlantic salmon (Salmo salar) at fine geographic scales differs across equivalent spatial extents in different regions. So far, fine-scale genetic differentiation has not been assessed in rivers of the Baltic Sea, a region that contains an evolutionarily distinct Atlantic salmon lineage. Thus, Baltic salmon are currently managed on the river level, without focus on potential genetic structure and diversity within rivers. Here, we used microsatellites to characterize the genetic structure of wild juvenile salmon sampled throughout the interconnected, northern Baltic Tornio and Kalix Rivers. We found genetic differentiation within the two rivers, but not between them: salmon in the upper reaches differed from individuals in the lower reaches, regardless of river system. Further, examining smolts migrating from the river to the sea and adults returning from the sea to spawn, we found an association between the genetic structure and seasonal migration timing. Out-migrating smolts genetically assigned to upper river reaches were older and tended to reach the sea later in the season than smolts from the lower reaches. In contrast, mature adults originating from the upper reaches returned to the river early in the season. Our observation of genetic population structuring between downstream and upstream reaches of the large Tornio and Kalix rivers, and its association with migration timing, implies that careful temporal management of the northern Baltic fisheries would help to preserve the diversity and sustainability of the wild salmon stocks of these rivers.

The relationship between the spawning stock size and subsequent number of recruits is a central concept in fisheries ecology. The influence of habitat selection of spawning individuals on the stock-recruitment relationship is poorly known. Here we explore how each of four different spawner behaviors might influence the stock-recruitment relationship and estimates of its parameters in the two most commonly used stock-recruitment functions (Beverton-Holt and Ricker). Using simulated stock-recruitment data generated by four different spawner behaviors applied to multiple discrete habitats, we show that when spawners were distributed proportionally to local carrying capacities, there was small or no bias in estimated recruitment and stock-recruitment parameters. For an ideal free distribution of spawners, larger bias in the estimates of recruitment and stock-recruitment parameters was obtained, whereas a random and a stepwise spawner behavior introduced the largest bias. Using stock-recruitment data corresponding to a "realistic" range of population densities and adding measurement error (20%-60%) to the simulated stock-recruitment data generated larger variation in the estimation bias than what was introduced by the spawner behavior. Thus, for exploited stocks at low population density and where spawning stock size and recruitment cannot be observed perfectly, partial observation of the possible spawner abundance range and measurement error might be of higher concern for management.

ObjectiveDiverticular disease is a common complex disorder characterised by mucosal outpouchings of the colonic wall that manifests through complications such as diverticulitis, perforation and bleeding. We report the to date largest genome-wide association study (GWAS) to identify genetic risk factors for diverticular disease.DesignDiscovery GWAS analysis was performed on UK Biobank imputed genotypes using 31 964 cases and 419 135 controls of European descent. Associations were replicated in a European sample of 3893 cases and 2829 diverticula-free controls and evaluated for risk contribution to diverticulitis and uncomplicated diverticulosis. Transcripts at top 20 replicating loci were analysed by real-time quatitative PCR in preparations of the mucosal, submucosal and muscular layer of colon. The localisation of expressed protein at selected loci was investigated by immunohistochemistry.ResultsWe discovered 48 risk loci, of which 12 are novel, with genome-wide significance and consistent OR in the replication sample. Nominal replication (pCTAGE1 with a p value of 2.3×10−10 and 0.002 (ORallelic=1.14 (95% CI 1.05 to 1.24)) in the replication analysis. Four loci showed stronger effects for diverticulitis, PHGR1 (OR 1.32, 95% CI 1.12 to 1.56), FAM155A-2 (OR 1.21, 95% CI 1.04 to 1.42), CALCB (OR 1.17, 95% CI 1.03 to 1.33) and S100A10 (OR 1.17, 95% CI 1.03 to 1.33).ConclusionIn silico analyses point to diverticulosis primarily as a disorder of intestinal neuromuscular function and of impaired connective fibre support, while an additional diverticulitis risk might be conferred by epithelial dysfunction.

In the field of oncology, a close integration of cancer research and patient care is indispensable. Although an exchange of data between health care providers and other institutions such as cancer registries has already been established in Germany, it does not take advantage of internationally coordinated health data standards. Translational cancer research would also benefit from such standards in the context of secondary data use. This paper employs use cases from the German Cancer Consortium (DKTK) to show how this gap can be closed using a harmonised FHIR-based data model, and how to apply it to an existing federated data platform.

Background Sympatric speciation along ecological gradients has been studied repeatedly, in particular in freshwater fishes. Rapid post-glacial ecological divergence has resulted in numerous endemic species or ecologically distinct populations in lakes of the temperate zones. Here, we focus on the Baltic cisco (Coregonus albula) complex, to study the genetic similarity among two pairs of sympatric autumn- and spring-spawning populations from post-glacial German Lakes Stechlin and Breiter Luzin. For comparison, we included a similar pair of sympatric populations from the Swedish Lake Fegen. We wanted to explore potential genetic similarities between the three sympatric cisco population pairs in the three lakes, to evaluate whether the pairs may have emerged independently in the three lakes, or whether two different species may have colonized all three lakes independently. Furthermore, we considered allopatric C. albula populations from three Polish, three Finnish, and four Swedish locations, added one Siberian population of the sister species C. sardinella and a Swedish C. maraena (whitefish) population. By genotyping nine microsatellite markers in 655 individuals from these 18 populations, we wanted to elucidate how strongly the cisco populations differ across a larger geographical area within Europe. Finally, we compared the genetic differences between the spring- and autumn-spawning populations of ciscoes in the two German lakes to infer the potentially deteriorating effect of strong anthropogenic pressure on the lakes. Results Dendrogram, Principal Coordinate Analysis and admixture analysis all indicated strong correspondence between population differentiation and geographical location for most cisco populations in Europe, including the Siberian population of C. sardinella. However, populations from some Swedish lakes deviated from this general pattern, by showing a distinct genetic structure. We found evidence for independent evolution of the three sympatric population pairs, because the populations co-occurring in the same lake were always most closely related. However, genetic differentiation was weak in the two German population pairs, but strong in the Swedish Lake Fegen, indicating that the weak differentiation in the German pairs reported earlier has eroded further. Conclusions Our results suggest that the genetic differentiation at neutral genetic markers among populations of the Baltic cisco complex has evolved (and is maintained) by random genetic drift in isolated populations. However, earlier studies on the Swedish populations combining mitochondrial DNA and microsatellite data indicate that also post-glacial immigration from separate glacial refugia has shaped the present genetic population structure. The low neutral differentiation of the German sympatric pairs in contrast to the Swedish pair suggests that recent anthropogenic effects on the lakes in Germany may put the endemic spring-spawners at risk to extinction.

Management and conservation of populations that are harvested simultaneously present a unique set of challenges. Failure to account for differences in productivity and spatio-temporal abundance patterns can lead to over-exploitation of depleted populations and/or loss of potential yield from healthy ones. Mixed-stock fisheries (where a stock may comprise one or more populations of reared or wild origin) harvest multiple stocks, often in unknown proportions, and lack of tools for estimation of stock-specific harvest rates can hamper status evaluations and attainment of management goals. We present a method for evaluating stock-specific impacts of alternative harvest strategies, using coastal trap net fisheries for Atlantic salmon (Salmo salar) in the Baltic Sea as a case study. Our results demonstrate a large variation among stocks in coastal mixed fishery harvest rates, as well as large differences in harvest rates relative to stock-specific maximum sustainable yield (MSY) and recovery levels. Bayesian decision analysis showed that spatio-temporal management actions, such as delayed fishery opening and closed areas may be effective in improving probabilities of meeting management objectives for Baltic salmon. However, stocks did not respond uniformly to different management actions, highlighting the potential for trade-offs in reaching stock-specific targets that must be considered by managers.

In the field of oncology, a close integration of cancer research and patient care is indispensable. Although an exchange of data between health care providers and other institutions such as cancer registries has already been established in Germany, it does not take advantage of internationally coordinated health data standards. Translational cancer research would also benefit from such standards in the context of secondary data use. This paper employs use cases from the German Cancer Consortium (DKTK) to show how this gap can be closed using a harmonised FHIR-based data model, and how to apply it to an existing federated data platform.

The decommissioning of nuclear power plants requires project planning and budgeting both during the project and in advance, as well as the secured provision of financial and human resources. When a facility is free from irradiated fuel, the reactor pressure vessel with the nuclear components and the biological shield determine the activity inventory of the facility, which almost exclusively consists of activated radionuclides located in the respective structures. Knowledge of the activity distribution and nuclide vectors of the involved components is of vital importance for decommissioning planning. In this context, the development of a computation procedure is described coupling the Monte Carlo method for the determination of neutron flux densities and spectra with a procedure to perform activation calculations for the determination of nuclide vectors. For this purpose, detailed knowledge of the material composition, particularly the trace-element concentrations of nitrogen and cobalt in steel an...

Brown trout (Salmo trutta) is composed of numerous geographical forms in the wild and a multitude of stocks reared in hatcheries. Practices impacting this species are domestication and fish farming. Thousands of hatcheries are producing domestic trout which are frequently released in the wild without real knowledge of the origin and genetic composition of the strains and of the receiving populations. The present study contains an analysis of the genetic structure (using twelve microsatellites) of 26 hatchery strains from Europe (Sweden, Poland, Czech Republic, Slovakia, Hungary, France, Italy and Spain) and one from North America (Minnesota). Several new observations improved our knowledge on this domestic part of S. trutta. First, a cross-border commercial strain of the North Atlantic lineage occupies most of European hatcheries and the American one, as a probable consequence of intensive exchanges of broodstock materials over time. In addition to the common Europe-wide commercial Atlantic strain, local strains stemming from domesticated regional wild fish also occur. Second, the level of genetic polymorphism of most hatchery strains is high to very high, likely reflecting genetic admixture counteracting expected losses of diversity through random genetic drift and domestication. This study emphasizes the value of identifying the genetic composition of hatchery stocks used for releases. It further stresses the need for caution when stocking a common stock across the whole geographical range of a species, with risks for reducing the intraspecific genetic diversity and local adaptation.

The survival of Baltic salmon Salmo salar during the first year at sea (post-smolt stage) has declined since the beginning of the 1990s. In this analysis, we complement previous studies on possible causes of this decline by considering a suite of environmental parameters, potential change in predation pressure, and post-smolt growth. Marine survival estimates were found to be negatively correlated with temperature, indicating that warming conditions have not favoured survival. Survival was also found to be positively correlated with dissolved oxygen levels and regionally related to shifts in salinity. These relationships were further studied in context to the potential predation on post-smolts by one of the main piscivores in the Baltic, Eastern Baltic cod (Gadus morhua callarias). Concomitant with changes in environmental conditions, Baltic cod has changed its latitudinal range, moving northward in the Baltic, possibly in response to warming conditions. These changes lead us to hypothesize that predation pressure on salmon may have increased in recent years as cod has now occupied habitats used by salmon post-smolts during their southward feeding migrations. This predation may have been intensified as a result of anoxic conditions in the central basin by concentrating predation interactions in coastal waters and/or the upper water column typically occupied by salmon post-smolts. Indicators of post-smolt growth were applied to test the alternate hypothesis that mortality is growth-mediated; these indicators lacked a time series trend, which supports the contention that shifting predation pressure rather than feeding opportunities is responsible for the decline in post-smolt survival in Baltic salmon.

Determining the origin of individuals in mixed population samples is key in many ecological, conservation and management contexts. Genetic data can be analyzed using genetic stock identification (GSI), where the origin of single individuals is determined using Individual Assignment (IA) and population proportions are estimated with Mixed Stock Analysis (MSA). In such analyses, allele frequencies in a reference baseline are required. Unknown individuals or mixture proportions are assigned to source populations based on the likelihood that their multilocus genotypes occur in a particular baseline sample. Representative sampling of populations included in a baseline is important when designing and performing GSI. Here, we investigate the effects of family sampling on GSI, using both simulated and empirical genotypes for Atlantic salmon (Salmo salar). We show that nonrepresentative sampling leading to inclusion of close relatives in a reference baseline may introduce bias in estimated proportions of contributing populations in a mixed sample, and increases the amount of incorrectly assigned individual fish. Simulated data further show that the induced bias increases with increasing family structure, but that it can be partly mitigated by increased baseline population sample sizes. Results from standard accuracy tests of GSI (using only a reference baseline and/or self‐assignment) gave a false and elevated indication of the baseline power and accuracy to identify stock proportions and individuals. These findings suggest that family structure in baseline population samples should be quantified and its consequences evaluated, before carrying out GSI.

The spatial structure of species is important for their dynamics and evolution, but also for management and conservation. There are numerous ways of inferring spatial structures, and information from multiple methods is becoming more common to examine how different processes shape the spatial structures of species to improve fish management. Here, we investigate the spatial structure of a suite of Baltic Sea fish species based on the following: (i) spatial (presumably neutral) genetic differentiation, reviewed from the literature, and (ii) spatial synchrony in abundance changes from time series of fishery-independent surveys, which we currently find to be underused given the amount of data available. For each of these two methods, species were classified as having a distinct, continuous or no/weak spatial structure. In addition, based on each source of information, we estimated the spatial scale of management units for species. The results show that only among species confined to the coastal zone the two sources of information yielded a congruence of the spatial structure (displaying a continuous spatial structure). In contrast, offshore species show weak spatial genetic structure but stronger spatial structure of synchrony in abundance. Based on this, we suggest that population genetic structure and synchrony in abundance should be used as complementary information as they reflect different spatial processes and suggest that management actions should differ with respect to scale depending on the management targets applied. We propose similar analysis should be applied to areas outside the Baltic Sea, and other stock identification methods, to improve management of fish resources.

The genetic structure of nine wild, seven hatchery-reared, and one presumably mixed, sea trout (Salmo trutta L.) populations sampled from watersheds along the Swedish Baltic Sea coast was analysed using ten microsatellite loci. DNA-information was evaluated as a baseline for mixed stock analysis (MSA) and individual assignment (IA). A clear genetic structure with distinct populations was identified (global F ST = 0.066), with significant regional differentiation. Average gene diversity (H e) was similar among samples of wild and reared trout, whereas levels of heterozygote deficiency differed significantly (wild: H e = 0.70, F IS = 0.075; reared: H e = 0.69, F IS = 0.022). The high F IS found in wild samples indicates presence of within-river sub-structuring. Evaluation with realistic-fishery simulations indicated that the baseline resolution was sufficient for MSA, at least at a regional level. Hierarchical MSA and IA analyses of real catches from two coastal fisheries showed that populations from the northern region contributed about 90 % to the catch. Analysed individually, the two fisheries differed in catch compositions despite a short geographic distance among sites. One fishery mainly caught sea trout from a small wild population whereas the other fishery was dominated by reared sea trout. Stock composition analysis is a valuable tool for refining exploitation rate estimates for individual sea trout populations in mixed coastal fisheries, as well as for investigating migration patterns in the Baltic Sea.

The evolution of life-history traits is characterized by trade-offs between different selection pressures, as well as plasticity across environmental conditions. Yet, studies on local adaptation are often performed under artificial conditions, leaving two issues unexplored: (i) how consistent are laboratory inferred local adaptations under natural conditions and (ii) how much phenotypic variation is attributed to phenotypic plasticity and to adaptive evolution, respectively, across environmental conditions? We reared fish from six locally adapted (domesticated and wild) populations of anadromous brown trout (Salmo trutta) in one semi-natural and three natural streams and recorded a key life-history trait (body size at the end of first growth season). We found that population-specific reaction norms were close to parallel across different streams and Q ST was similar - and larger than F ST - within all streams, indicating a consistency of local adaptation in body size across natural environments. The amount of variation explained by population origin exceeded the variation across stream environments, indicating that genetic effects derived from adaptive processes have a stronger effect on phenotypic variation than plasticity induced by environmental conditions. These results suggest that plasticity does not "swamp" the phenotypic variation, and that selection may thus be efficient in generating genetic change.

There is ample evidence that organisms adapt to their native environment when gene flow is restricted. However, evolution of plastic responses across discrete environments is less well examined. We ...

Mäntyniemi, S., Romakkaniemi, A., Dannewitz, J., Palm, S., Pakarinen, T., Pulkkinen, H., Gårdmark, A., and Karlsson, O. 2012. Both predation and feeding opportunities may explain changes in survival of Baltic salmon post-smolts. – ICES Journal of Marine Science, 69: 1574–1579. The survival of wild and hatchery-reared post-smolts of salmon (Salmo salar) in the Baltic Sea has declined since the 1990s. Direct observations of the processes affecting survival are, however, lacking. Here, the importance of food availability and predation in regulating post-smolt survival is analysed. Based on previous studies, the following explanatory variables were selected: (i) availability of herring (Clupea harengus membras) recruits in the Gulf of Bothnia (Bothnian Sea, Bothnian Bay) in the northern Baltic Sea; (ii) sprat (Sprattus sprattus balticus) and herring abundance in the southern Baltic Sea; and (iii) abundance of grey seal (Halichoerus grypus) along the post-smolt migration route. Bayesian analysis was used to estimate the relative probability of each of the 32 combinations of these variables and revealed that the model including grey seal abundance and herring recruits per post-smolt had the highest posterior probability and a high coefficient of determination. The results suggest that the declining trend in post-smolt survival is explained by the increased number of grey seals, whereas the annual variation in survival coincides with variation in the recruitment of Bothnian Sea herring. However, it remains uncertain whether the observed correlations arise from direct causalities or other mechanisms.

Decreased fitness due to loss of genetic variation is a well recognised issue in conservation biology. Along the Swedish west coast, the endangered natterjack toad (Bufo calamita) occurs on, for the species, highly unusual habitat of rocky islands. Although the toads inhabit a restricted geographical area (maximum distance between the populations is 71 km), the fragmented nature of the landscape makes the genetic properties of the populations of conservation interest. However, lack of genetic variation found using conventional methods (microsatellites) has impeded genetic studies within these peripheral populations so far. In this study we assess population structure and genetic variation among seven of these fringe populations using 105 polymorphic Amplified Fragment Length Polymorphism (AFLP) loci. We found a well-defined population structure without evidence for isolation by distance, implying restricted gene flow between populations. Additionally, the populations differed in their amount of genetic variation, emphasizing the need to monitor genetically impoverished populations for possible declines mediated by inbreeding depression and reduced adaptive potential. Conservation implications for these unique populations are discussed in the light of our results.

Several studies have shown that fish shoals may consist of closely related individuals. It has been found, for example, that released out-migrating salmon smolts tend to aggregate with kin, including when sibling groups have been reared separately. We used genetic microsatellite markers to test whether “shoals” of adult Atlantic salmon ( Salmo salar ) during the marine phase (i.e., aggregations of fish caught in drift nets at offshore feeding areas in the Baltic Sea) consisted of closely related individuals (full-siblings, half-siblings). We found no evidence of kin cohesiveness related to shoals, however. Despite a weak overall tendency for individuals assigned to the same population (river or stock) to occur together, estimates of genetic relatedness in combination with consistent heterozygote deficiencies, and results from mixed-stock analyses and assignment tests collectively indicated that shoals consisted of unrelated fish from multiple populations.

Previous studies have reported higher levels of divergence for microsatellites than for allozymes in several species, suggested to reflect stabilizing selection on the allozymes. We compared the differentiation patterns of 11 allozyme and nine microsatellite loci using 679 spawning Atlantic herring (Clupea harengus) collected in the Baltic and North Seas to test for differential natural selection on these markers. Observed distributions of F statistics for the two types of markers are conspicuously dissimilar, but we show that these differences can largely be explained by sampling phenomena caused by different allele frequency distributions and degrees of variability. The results show consistently low levels of differentiation for both marker types, with the exception of one outlier microsatellite locus with a notably high F(ST). The aberrant pattern at this locus is primarily due to two alleles occurring at markedly high frequencies in the Baltic, suggesting selection at this locus, or a closely linked one. When excluding this locus, the two marker types show similar, weak differentiation patterns with F(ST) values between the Baltic and the North Seas of 0.001 and 0.002 for allozymes and microsatellites, respectively. This small heterogeneity, and weak isolation by distance, is easier to distinguish statistically with microsatellites than with allozymes that have fewer alleles and skewed frequency distributions. The allozymes, however, also detect surprisingly low levels of divergence. Our results support suggestions that previously described differences between marker types are primarily caused by a small number of outlier loci.

The genetic relationships among 337 northern pike (Esox lucius) collected from the coastal zone of the central Baltic region and the Finnish islands of Aland were analysed using five microsatellite loci. Spatial structure was delineated using both traditional F-statistics and individually based approaches including spatial autocorrelation analysis. Our results indicate that the observed genotypic distribution is incompatible with that of a single, panmictic population. Isolation by distance appears important for shaping the genetic structure of pike in this region resulting in a largely continuous genetic change over the study area. Spatial autocorrelation analysis (Moran's I) of individual pairwise genotypic data show significant positive genetic correlation among pike collected within geographical distances of less than c. 100-150 km (genetic patch size). We suggest that the genetic patch size may be used as a preliminary basis for identifying management units for pike in the Baltic Sea.

The pattern for distribution of genetic variation within and between populations is referred to as the genetic population structure of the species. To avoid depletion of genetic resources sustainable management should be based on knowledge of this structure. We discuss key aspects of genetic population structure in the context of identifying biological units for fisheries management, suggesting three basic types of structuring: distinct populations; continuous change; and no differentiation. The type of structure determines how units for genetically sustainable management are to be identified. We also review what is currently known regarding the genetic population structure of fishes exploited in the Swedish part of the Baltic Sea, and conclude that sufficient genetic information is lacking for most of the species. This is a serious problem, particularly considering that populations of several commercially exploited fishes are declining and some exhibit recruitment problems. For six species, Atlantic herring, Atlantic salmon, brown trout, European eel, turbot, and pike, sufficient genetic data are available to provide at least basic information on genetic structure and genetic units for biologically sustainable use. Current management practices do not sufficiently consider these data.

The supportive breeding programme for sea trout (Salmo trutta) in the River Dalälven, Sweden, is based on a sea-ranched hatchery stock of local origin that has been kept 'closed' to the immigration of wild genes since the late 1960s (about seven generations). In spite of an apparent potential for substantial uni directional gene flow from sea-ranched to wild (naturally produced) trout, phenotypic differences with a presumed genetic basis have previously been observed between the two 'stocks'. Likewise, two previous studies of allozyme and mitochondrial DNA variation based on a single year of sampling have indicated genetic differentiation. In the present study we used microsatellite and allozyme data collected over four consecutive years, and tested for the existence of overall genetic stock divergence while accounting for temporal heterogeneity. Statistical analyses of allele frequency variation (F-statistics) and multilocus genotypes (assignment tests) revealed that wild and sea-ranched trout were significantly different in three of four years, whereas no overall genetic divergence could be found when temporal heterogeneity among years within stocks was accounted for. On the basis of estimates of effective population size in the two stocks, and of FST between them, we also assessed the level of gene flow from sea-ranched to wild trout to be approximately 80% per generation (with a lower confidence limit of approximately 20%). The results suggest that the reproductive success of hatchery and naturally produced trout may be quite similar in the wild, and that the genetic characteristics of the wild stock are largely determined by introgressed genes from sea-ranched fish.

Temporal genetic data may be used forestimating effective population size (Ne) and for addressing the `temporal stability' of population structure, two issues of central importance for conservation and management. In this paper we assess the amount of spatio-temporal genetic variation at 17 di-allelic allozyme loci and estimate current Ne in two populations of stream resident brown trout (Salmo trutta) using data collected over 20 years. The amount ofpopulation divergence was found to bereasonably stable over the studied time period.There was significant temporal heterogeneitywithin both populations, however, and Ne was estimated as 19 and 48 for the twopopulations. Empirical estimates of theprobability of detecting statisticallysignificant allele frequency differencesbetween samples from the same populationseparated by different numbers of years wereobtained. This probability was found to befairly small when comparing samples collectedonly a few years apart, even for theseparticular populations that exhibit quiterestricted effective sizes. We discuss someimplications of the present results for browntrout population genetics and conservation, andfor the analysis of temporal genetic change inpopulations with overlapping generations ingeneral.

Hintergrund: Fehler sind in der Medizin allgegenwartig und stellen ein komplexes, multifaktorielles Geschen dar. Sie bedeuten ein erhebliches Risiko fur den Patienten und haben enorme wirtschaftliche Konsequenzen fur die Leistungserbringer. Systembezogener Ansatz: Unerwunschte Ereignisse haben ihre Ursache in der Regel nicht in einem einzelnen vorausgehenden Fehler. Ein effizientes Risk-Management-Konzept, das Bestandteil eines umfassenden Qualitatsmanagements, muss daher einen systembezogenen Ansatz verfolgen, der sich auf die Entdeckung und Analyse von Beinahe-Fehlern stutzt und auf die Entwicklung von Abwehrmechanismen fur die unerwunschten Folgen von Fehlern zielt. Die Frage “Wer ist schuld?” muss in den Hintergrund treten. Beinahe-Fehler (Near Misses) gehorchen den gleichen theoretischen und praktischen Bedingungen wir Indikatoren und bieten hierbei gegenuber der Messung von Fehlern und unerwunschten Ereignissen erhebliche methodische Vorteile.

In a study of the genetic relationships among 879 anadromous brown trout Salmo trutta from 13 streams at the Island of Gotland, Sweden, using RFLP analysis of a mitochondrial DNA segment (NADH dehydrogenase-1 gene), six haplotypes were detected. Significant genetic divergence was observed among streams as well as between cohorts within streams. Approximately 8-9% of the total variation was due to differences between populations, and 4-5% was explained by differences between cohorts within populations. The female effective population size (N ef ) was assessed from temporal haplotype frequency differences between consecutive cohorts; the estimated average N ef over all populations was just below 30, suggesting that these populations were effectively quite small. With such small effective sizes the populations are expected to loose genetic variability quickly, but the observed levels do not appear particularly low. This indicates that female migration between streams occurs. The observed level of differentiation does not support the presumption that a particular pre-smolt migratory behaviour observed in Gotland streams, with large portions of fry leaving for the sea soon after hatching, results in a reduced homing ability. From a conservation management perspective the Gotland brown trout streams should be regarded as a population system where the vitality and survival of brown trout in one stream is dependent on the opportunity of contact and exchange of individuals from other streams.

Presence of sympatric populations may reflect local diversification or secondary contact of already distinct forms. The Baltic cisco (Coregonus albula) normally spawns in late autumn, but in a few lakes in Northern Europe sympatric autumn and spring- or winter-spawners have been described. So far, the evolutionary relationships and taxonomic status of these main life history forms have remained largely unclear. With microsatellites and mtDNA sequences, we analyzed extant and extinct spring- and autumn-spawners from a total of 23 Swedish localities, including sympatric populations. Published sequences from Baltic ciscoes in Germany and Finland, and Coregonus sardinella from North America were also included together with novel mtDNA sequences from Siberian C. sardinella. A clear genetic structure within Sweden was found that included two population assemblages markedly differentiated at microsatellites and apparently fixed for mtDNA haplotypes from two distinct clades. All sympatric Swedish populations belonged to the same assemblage, suggesting parallel evolution of spring-spawning rather than secondary contact. The pattern observed further suggests that postglacial immigration to Northern Europe occurred from at least two different refugia. Previous results showing that mtDNA in Baltic cisco is paraphyletic with respect to North American C. sardinella were confirmed. However, the inclusion of Siberian C. sardinella revealed a more complicated pattern, as these novel haplotypes were found within one of the two main C. albula clades and were clearly distinct from those in North American C. sardinella. The evolutionary history of Northern Hemisphere ciscoes thus seems to be more complex than previously recognized.

Measurement of temporal change in allele frequencies represents an indirect method for estimating the genetically effective size of populations. When allele frequencies are estimated for gene markers that display dominant gene expression, such as, e.g. random amplified polymorphic DNA (RAPD) and amplified fragment length polymorphism (AFLP) markers, the estimates can be seriously biased. We quantify bias for previous allele frequency estimators and present a new expression that is generally less biased and provides a more precise assessment of temporal allele frequency change. We further develop an estimator for effective population size that is appropriate when dealing with dominant gene markers. Comparison with estimates based on codominantly expressed genes, such as allozymes or microsatellites, indicates that about twice as many loci or sampled individuals are required when using dominant markers to achieve the same precision.

Knowledge of statistical power is essential for sampling design and data evaluation when testing for genetic differentiation. Yet, such information is typically missing in studies of conservation and evolutionary genetics, most likely because of complex interactions between the many factors that affect power. powsim is a 32-bit Windows/DOS simulation-based computer program that estimates power (and α error) for chi-square and Fisher's exact tests when evaluating the hypothesis of genetic homogeneity. Optional combinations include the number of samples, sample sizes, number of loci and alleles, allele frequencies, and degree of differentiation (quantified as FST). powsim is available at http://www.zoologi.su.se/~ryman.

There is ample evidence that organisms adapt to their native environment when gene flow is restricted. However, evolution of plastic responses across discrete environments is less well examined. We studied divergence in means and plasticity across wild and hatchery populations of sea-run brown trout (Salmo trutta) in a common garden experiment with two rearing environments (hatchery and a nearly natural experimental stream). Since natural and hatchery environments differ, this arrangement provides an experiment in contemporary adaptation across the two environments. A Q(ST) - F(ST) approach was used to investigate local adaptation in survival and growth over the first summer. We found evidence for divergent selection in survival in 1 year and in body length in both years and rearing environments. In general, the hatchery populations had higher survival and larger body size in both environments. Q(ST) in body size did not differ between the rearing environments, and constitutive divergence in the means was in all cases stronger than divergence in the plastic responses. These results suggest that in this system, constitutive changes in mean trait values are more important for local adaptation than increased plasticity. In addition, ex situ rearing conditions induce changes in trait means that are adaptive in the hatchery, but potentially harmful in the wild, suggesting that hatchery rearing is likely to be a suboptimal management strategy for trout populations facing selection in the stream environment.

Previous studies of genetic structure in the European eel have resulted in seemingly conflicting results, ranging from no detectable heterogeneity to small but statistically significant differences and isolation by distance patterns among eels sampled across the continental range. Differences with respect to sampling design and choice of molecular markers, combined with a lack of power estimates, complicate comparisons of existing results. In this study we have used six microsatellite markers and, for the first time, compared maturing silver eels of known age from southern and northern Europe (Italy and Baltic Sea). In comparison with previous studies, our data may give a better representation of potential spawning stocks because eels were sampled when having begun their migration toward the presumed spawning area in the Sargasso Sea. Despite large sample sizes (404 and 806 individuals) we could not observe any signs of genetic differentiation (average F(ST)=-0.00003, P=0.61), and a power analysis showed that the true level of heterogeneity (if existing) must be exceedingly small to have remained undetected (say, F(ST)0.0004). A tendency for slightly increased genetic differences between cohorts over time could be seen, but the amount of temporal change was minor and not statistically significant. Our findings reiterate the notion that previous reports of continental genetic differentiation in the European eel may be largely explained by uncontrolled temporal variation between juvenile glass eel samples.

Previous studies have reported higher levels of divergence for microsatellites than for allozymes in several species, suggested to reflect stabilizing selection on the allozymes. We compared the differentiation patterns of 11 allozyme and nine microsatellite loci using 679 spawning Atlantic herring (Clupea harengus) collected in the Baltic and North Seas to test for differential natural selection on these markers. Observed distributions of F statistics for the two types of markers are conspicuously dissimilar, but we show that these differences can largely be explained by sampling phenomena caused by different allele frequency distributions and degrees of variability. The results show consistently low levels of differentiation for both marker types, with the exception of one outlier microsatellite locus with a notably high F(ST). The aberrant pattern at this locus is primarily due to two alleles occurring at markedly high frequencies in the Baltic, suggesting selection at this locus, or a closely linked one. When excluding this locus, the two marker types show similar, weak differentiation patterns with F(ST) values between the Baltic and the North Seas of 0.001 and 0.002 for allozymes and microsatellites, respectively. This small heterogeneity, and weak isolation by distance, is easier to distinguish statistically with microsatellites than with allozymes that have fewer alleles and skewed frequency distributions. The allozymes, however, also detect surprisingly low levels of divergence. Our results support suggestions that previously described differences between marker types are primarily caused by a small number of outlier loci.

Information on statistical power is critical when planning investigations and evaluating empirical data, but actual power estimates are rarely presented in population genetic studies. We used computer simulations to assess and evaluate power when testing for genetic differentiation at multiple loci through combining test statistics or P values obtained by four different statistical approaches, viz. Pearson's chi-square, the log-likelihood ratio G-test, Fisher's exact test, and an F(ST)-based permutation test. Factors considered in the comparisons include the number of samples, their size, and the number and type of genetic marker loci. It is shown that power for detecting divergence may be substantial for frequently used sample sizes and sets of markers, also at quite low levels of differentiation. The choice of statistical method may be critical, though. For multi-allelic loci such as microsatellites, combining exact P values using Fisher's method is robust and generally provides a high resolving power. In contrast, for few-allele loci (e.g. allozymes and single nucleotide polymorphisms) and when making pairwise sample comparisons, this approach may yield a remarkably low power. In such situations chi-square typically represents a better alternative. The G-test without Williams's correction frequently tends to provide an unduly high proportion of false significances, and results from this test should be interpreted with great care. Our results are not confined to population genetic analyses but applicable to contingency testing in general.

The genetic relationships among 337 northern pike (Esox lucius) collected from the coastal zone of the central Baltic region and the Finnish islands of Aland were analysed using five microsatellite loci. Spatial structure was delineated using both traditional F-statistics and individually based approaches including spatial autocorrelation analysis. Our results indicate that the observed genotypic distribution is incompatible with that of a single, panmictic population. Isolation by distance appears important for shaping the genetic structure of pike in this region resulting in a largely continuous genetic change over the study area. Spatial autocorrelation analysis (Moran's I) of individual pairwise genotypic data show significant positive genetic correlation among pike collected within geographical distances of less than c. 100-150 km (genetic patch size). We suggest that the genetic patch size may be used as a preliminary basis for identifying management units for pike in the Baltic Sea.

Errors are a common problem in medicine and occur as a result of a complex process involving many contributing factors. Medical errors significantly reduce the safety margin for the patient and contribute additional costs in health care delivery.In most cases adverse events cannot be attributed to a single underlying cause. Therefore an effective risk management strategy must follow a system approach, which is based on counting and analysis of near misses. The development of defenses against the undesired effects of errors should be the main focus rather than asking the question "Who blundered?". Analysis of near misses (which in this context can be compared to indicators) offers several methodological advantages as compared to the analysis of errors and adverse events. Risk management is an integral element of quality management.

Objective Meningospinal and cranial dural adhesions were compared in a canine model, after duraplasty using nonpenetrating clips or penetrating needles and sutures. Methods Fourteen dogs underwent bilateral craniotomies and duraplasties, with implantation of dural prostheses (DuraGuard; Biovascular Corp., Minneapolis, MN), using either 6-0 silk sutures or titanium clips (DuraClose; Surgical Dynamics, Norwalk, CT). Fourteen other dogs underwent L3-L4 laminectomies; three longitudinal dural incisions were closed with 6-0 silk sutures, 6-0 polyglactin 910 (Vicryl) sutures, or clips. Groups of eight dogs (four cranially treated and four spinally treated) were killed 6, 12, 24, and 52 weeks after surgery, and specimens were collected for study after perfusion and fixation (two cranial and two spinal dural reconstructions at 52 wk). Evaluations included assessment of the appearance of approximated dural margins and responses to clips, sutures, and dural prostheses (inflammation, foreign body reaction, fibrosis, and severity of meningospinal/meningocerebral adhesions). Data were evaluated using the Wilcoxon signed-rank and McNemar tests. Results Duraplasties with clips displayed significantly less extensive acute and chronic inflammation, foreign body reaction, and meningoneural adhesions than did repairs with needles and sutures. Conclusion This report is the first long-term experimental study comparing two fundamentally different methods for dural repair in a relevant animal model.