dataesr/scientific-paragraphs-categorization huggingface dataset:
Respondents were asked to record BWL and to provide information on what happened during the study (e. g. dosing was stopped, animals died or required euthanasia), and as a consequence of the study (e. g. dose was reduced in a follow up study). Consensus within the working group was that the MTD was exceeded when dosing either had to be stopped or if animals were lost from the study, through premature death or euthanasia. Where we asked for information on dosing decisions for any subsequent follow up studies, this may have applied to repeat studies of similar duration, as well as those of longer duration. BWL was calculated for each individual animal as the percentage in weight lost from the pre-treatment weight. Data were collected from studies with BWL >10% for rat and >6% for both dog and NHP studies.
BWL data were separated into 3 categories using the maximum BWL recorded for each study; for rat these were 10-15%, 16-20% and >20% BWL, for dog and NHP these were 6-10%, 11-15% and 16-20%. Since studies were identified using the maximum BWL recorded, it is possible that studies categorised in a higher BWL category may also include animals with BWL at lower severity levels. Respondents were also asked to specify whether BWL was associated with any additional clinical signs recorded in each individual animal. The nature of each specific clinical sign was not recorded and therefore 'the presence of additional clinical signs' encompass a range of signs with variable severity. Data on the therapy area of the compound under study were also collected from respondents and whether BWL was linked to an expected pharmacological effect.
For example, compounds with a pharmacological action that interferes with biological processes (such as many compounds in metabolic, endocrine or anti-inflammatory therapy areas) are likely to result in BWL. Additional information that may be useful in the analysis was provided in the comments field e. g. differences or patterns of effect in low, medium and high dose groups, food intake observations, weighing frequency and vehicle effects. Completed questionnaire tables were provided in confidence by individual companies and data were collated and anonymized before analysis by the working group. We specifically examined whether there were any differences between study types or BWL categories. We analysed further those studies where the recorded BWL had no impact on the subsequent study and whether there was a link between the dose selection for subsequent work and the absence or presence of additional clinical signs.
Overall data Data from 151 toxicity studies in rats, dogs and NHPs were collected from 13 of the 15 listed pharmaceutical companies and contract research organisations (Fig. 1 ). The data spanned a wide range of therapeutic areas. In total, data were obtained from 90 rat, 48 dog and 13 NHP studies (Fig. 1A ). Raw data for all studies collected, Table  1  Questionnaire (for rat). for each species, are supplied in the supplementary information (Tables  S1-S3 ). The most highly represented therapy areas were oncology and central nervous system, corresponding to almost a third or a quarter of the studies respectively (Fig. 1B ); this was approximately consistent between the different species (as shown in Fig. 2A , Fig. 3A  and Fig. 4A ). Therapy area was not recorded for a small number of studies (4 rat studies and 1 dog study).
Non-human primate data The dataset for NHPs was limited; data were collected from 13 studies in total where BWL >6% was recorded. Almost one third of the data were from type 2 studies, and only one type 1 study was included. The remaining studies were type 3, where data were derived from the first 7 days of studies of longer duration, up to a maximum of 1 month in duration (Fig. 4B ). NHP studies were a MTD was considered to have been exceeded when dosing either had to be stopped or if animals were lost from the study, through death or euthanasia. b Where a subsequent study was not carried out we asked respondents to comment on whether the same dose that caused the initially observed BWL would have been used again. Therefore, in some cases, this data represents a hypothetical dose reduction in the subsequent study.
General discussion The aim of the NC3Rs working group was to build an evidence base to define an upper limit for BWL that could be used in short term studies (up to 1 week in duration) as part of the criteria for defining the MTD. The consensus was that dosing was deemed too high (i. e. the MTD had been exceeded) if the dosing had to be stopped during the study or if animals died prematurely or required euthanasia throughout the study. We collected data from 13 pharmaceutical companies and contract research organisations for 3 species (rat, dog and NHP) and examined how BWL related to the MTD over a short duration of dosing, and what impact this BWL had on any subsequent studies. Since the data were supplied from a wide range of global pharmaceutical and contract research organisations, it is assumed that the data are representative of general toxicity studies industry-wide.
In our dataset, we have shown that this situation rarely takes place, occurring in only 7 of the 151 studies analysed (less than 5% of the data collected) (Figs. 5 6 7 ). Nevertheless, in accordance with good practise guidelines, animals should be closely monitored for adverse effects, and careful consideration should be given as to whether the observed level of BWL is justified. The recommendations are not intended to overrule study director experience and judgement. It is important to note that our recommendations refer to short term toxicity studies of up to 1 week in duration, and that there may be different criteria for setting BWL in longer term studies. For example, a marked BWL which occurs over a shorter time period is less acceptable than the same BWL over a longer time period. In terms of the data we collected, the study type and duration is likely to have had an influence on the dosing decisions and/or interventions made during the studies.
There are two areas in which there may be an assumption that BWL is more acceptable; where BWL is linked to the expected pharmacology (discussed above) and for therapeutic targets for oncology. Due to the aggressive nature of oncology treatments in Fig. 5. Rat decision tree, with a recommended alert/warning system to trigger when BWL is >10%. The decision tree takes additional considerations such as clinical signs and the expected pharmacology into account to make recommendations for when MTD is near and when dosing should be stopped or reduced in subsequent studies. The decision tree shows how our data currently fits into these recommendations (figures shown in brackets) and the potential for refined MTD studies by uptake of these new recommendations. In our dataset the dose was reduced in 71/90 rat studies with BWL >10%.
Using our new recommendations the dose would have been reduced in 83/90 rat studies with BWL >10%. the clinic, oncology is an area where adverse side effects in humans may be more readily accepted. Therefore, in animal studies for oncology, it is seen necessary to push the severity limit to explore the more severe side effects. As a result, it may be that BWL in animal studies has traditionally been considered more acceptable in this area. Our data challenges these assumptions, as the data collected here includes a large proportion of oncology compounds (accounting for almost one third of the dataset). Therefore, our recommendations apply to all therapy areas, including oncology. With regard to the oncology compounds included in this study, the majority of these were administered by daily dosing, but a small number of studies involved cyclical dosing (9/48 oncology com-pounds).
The decision tree takes additional considerations such as clinical signs and the expected pharmacology into account to make recommendations for when MTD is near and when dosing should be stopped or reduced in subsequent studies. The decision tree shows how our data currently fits into these recommendations (figures shown in brackets) and the potential for refined MTD studies by uptake of these new recommendations. In our dataset the dose was reduced in 36/48 dog studies with BWL >10%. Using our new recommendations the dose would have been reduced in 39/40 dog studies with BWL >10%. Fig. 7. NHP decision tree, with a recommended alert/warning system to trigger when BWL is >6%. The decision tree takes additional considerations such as clinical signs and the expected pharmacology into account to make recommendations for when MTD is near and when dosing should be stopped or reduced in subsequent studies.
The decision tree shows how our data currently fits into these recommendations (figures shown in brackets) and the potential for refined MTD studies by uptake of these new recommendations. In our dataset the dose was reduced in 12/13 NHP studies with BWL >6%. Using our new recommendations the dose would have been reduced in all (13/ 13) NHP studies with BWL >6%. presence of clinical signs and expected pharmacological effect to add value to our practical advice on how to determine an MTD. Our findings are used to make recommendations to refine BWL limits in short term toxicity studies. We also took into account an additional aim of an MTD study, which is to determine the dose for the subsequent studies. Although the dosing was reduced in the majority of subsequent studies overall, there were a number of exceptions, which will be discussed in more detail for each species below.
In the 6 studies where the dose would not have been reduced 4 studies displayed >10% BWL. For 2 of these 4 compounds, BWL was linked to the expected pharmacology. Additional clinical signs were seen in 4 of the 6 studies (67%) where the dose would not have been reduced, compared to 40 of the 42 studies (95%) where the dose was subsequently reduced. Although this is a more limited dataset, these findings are similar to the rat data, where studies in which dosing was not reduced were more likely to be associated with the expected pharmacology, and were less likely to display additional clinical signs. Similarly, if we also look back at our initial MTD definition, the MTD was not exceeded in 5 out of the 6 exceptions, where dosing was not reduced. In some studies an additional intervention occurred; the diet was supplemented in 8 of the 48 dog studies, all of which displayed BWL >10%.
In order to define a threshold for an appropriate BWL limit we analysed the difference between studies where BWL was above or below a 10% BWL limit. MTD was reached more often when BWL was >10% and the dose was also more likely to have been reduced in these studies. The data indicates that there is evidence for regarding 10% BWL as the upper limit for dogs in short term studies of up to 7 days in duration. There is no apparent scientific value in going higher than 10% BWL to validate dose selection for follow up studies when the compound is progressing further into nonclinical development. However, the dataset for the lower BWL category was limited, with only 8 studies displaying a maximum BWL of 6-10%, and if a larger evidence base was collected, it would have been possible to determine whether a lower limit could have been set.
The decision tree in Fig. 6  shows our recommendation for a 10% BWL limit in MTD studies using dogs, as well as additional factors to consider, such as additional clinical signs and expected pharmacology, and shows how data from our existing studies currently fit those recommendations. For BWL that exceeds 10% the dose was reduced, or would have been reduced in 36 of the 40 cases. Using our new recommendations, this would have risen to dose reductions in 39 of the 40 studies with BWL >10% (90% vs. 98%). However, for short term duration we would recommend that BWL of 6% should act as a warning sign that MTD is near, and that BWL should not exceed 10%. 4. 4. Non-human primates -6% BWL limit is sufficient to define the MTD BWL >6% was recorded for NHPs. Although we had a more limited dataset for NHPs, we saw that the MTD was reached in the majority of studies with BWL >6%, and that the dose was reduced (or was predicted to have been reduced) in all but one study.
In our dataset, when BWL was >6%, the dose was reduced, or would have been hypothetically reduced in 12 of the 13 NHP studies. Using our new recommendations, this would have risen to all 13 NHP studies (92% vs. 100%). Physiologically, there are several reasons why NHPs may tolerate BWL less well than the other species tested. Since rats have a very long growth period, BWL is a sensitive parameter for toxicity. However, as rats are generally very robust, they tolerate BWL fairly well over a period of time. Dogs, as carnivores, are physiologically well prepared to deal with periods of feed restriction and subsequent BWL and, since adult animals show only little body weight gain, they tolerate BWL reasonably well over a period of time. In addition, due to their close connection to humans, clinical signs are generally easy to observe in dogs, so that assessment of general toxicity by combining BWL and clinical signs is feasible.
Statistics All values are expressed as median (range). Differences between winter and summer samples were analyzed with paired Wilcoxon signed rank test. Comparative statistical between healthy humans and summer bears were analyzed by non-parametric Wilcoxon signed rank test. Changes in the level of some variables between the hibernation and active periods were calculated and shown as ''D''. Spearman's rank correlation was used to determine correlations between two variables. A p-value ,0. 05 was considered to be statistically significant. The statistical analysis was performed using statistical software SAS version 9. 3 (SAS Campus Drive, Cary, NC, USA).
Secondly, due to limited amount of serum/plasma, some analyses could not be performed in all bears. Three proteinogenic amino acids are missing in our analyses and we did not measure, hematocrit, plasma sodium and osmolality (which could have given information about the hydration status of the animals). It should also be acknowledged that as sampling was performed in February (or March) and June, respectively, our data are not representative of late hibernation or late summer-autumn conditions. Although body weight did not differ between hibernation and the active summer period significant differences in body composition would probably be observed if bears were instead captured at the end of the hibernation period (i. e. leanest) and late autumn (i. e. fattest). As the bear diet changes in the late summer when berries are abundant and start to ripe, it is possible that dietary changes may lead to a different metabolic milieu.
Results and discussion All the animals behaved normally in the cages with only one period of diarrhoea on one pig in the 6th week of experiment. According to the relatively linear increase in faecal digestibility over the successive experimental weeks (Figure  1 ), this missing data were replaced by the mean of the previous and the following week. Average feed intakes increased regularly with BW and age (Table  2 ). However, to ensure equal intakes among pigs, feed intake was restricted and as a result, growth (860 g/day on average) was lower than what would be expected in pigs fed ad libitum on such diets (Le  Bellego et al. , 2002). Finally, over the 2 days between two successive collection periods, feed intake was progressively increased up to the feeding level of the following period on the 2nd day and refusals and spillage were not recorded; therefore, precise feed intake on these 2 days was not available.
The concentration of each gas in the respiration chamber was then calculated from its volume divided by the sum of volumes of O 2 , CO 2 , and N 2. Equations of the model were written in Fortran and compiled in a dynamic linked library that was loaded in R (R Development Core Team, 2010). Package deSolve  (Soetaert et al. , 2010)  was used to solve the ordinary differential equations with an integration step-size of 10 s, after smoothing the data from force sensors, temperature, pressure and outflow to ensure their continuity. Parameters of the model were estimated for each day according to a three-step procedure: parameters directly related to O 2 consumption or CO 2 production were first estimated separately and then together to minimize the sum of squared differences between predicted O 2 or CO 2 concentration and measured O 2 or CO 2 concentrations  (Nelder and Mead, 1965).
STATISTICAL ANALYSES One FHP value was missing for a SC pig in group 2 and it was calculated (kJ/kg BW 0. 60 per day) as the average of the values obtained for the SC in the five other groups. The data (n = 18) were analyzed for the effects of sex (EM, SC, IC) and group using the PROC GLM of SAS  (SAS, 2004). Only the P-values for the effect of sex will be described in details. Pearson correlation coefficients between time spent standing, mean voltage measured from force sensors, ME intake, AHP and AHP/ME ratio were calculated (PROC CORR;  SAS, 2004). The linear relationship between AHP (% of ME intake) and the mean voltage from force sensors (mV/day) was tested and the difference of the slope from zero was tested through a T-test (PROC GLM;  SAS, 2004). The linear relationship between corrected HP c (HP c ) (kJ/kg BW 0.
Opistohaptor Morphometry Morphometry measurements were performed according to  [21]. Briefly, at least 1-3 monogeneans were isolated from the gill arch of a single host, mounted on a slide with 2. 5% sodium dodecyl sulphate to enable a clear visualization of the opisthaptor sclerotized parts. In total, ten monogeneans isolated from farmed fish and five from wild fish sampled in the vicinity of cages were used for measurement of opistohaptor morphometry. The same individuals were further fixed in absolute alcohol and stored at 4uC for phylogenetic analysis. A picture of the opistohaptor of each parasite was taken using a digital camera mounted on an Olympus CX41 light microscope, at 1006 magnification. Images were loaded into DP-Soft software to perform measurements. Measurements were taken using landmarks method by taking distances between two points out of a total of eleven landmarks (Figure  S1 ).
For a specific landmark, minimum and maximum observed values were taken, subtracted and obtain value was divided by the designated number of morphotype classes  (5). Further, for each landmark in respect to its measurement, a 0-4 class was assigned. Morphometry measurements (landmarks) were subjected to statistical multivariate techniques, using the STATISTICA software package (v. 7. 0 for Windows), in order to discriminate morphotypes within F. echeneis individuals. First, to test whether or not the global morphometry of monogenean individuals differs between hosts, a principal component analysis (PCA) was conducted using all variables measured on the haptor. Also, each landmark value was compared between two types of host i. e. wild and reared seabream, using the Mann-Whitney test. Second, to define possible morphotypes, the Euclidian standardized morphometric distance between individuals of F.
Data Analyses Parasite population dynamic. Parasites were counted on each gill arch and prevalence and abundance were calculated according to  [22]. Sterne's exact 95% confidence limits (CL) were calculated for prevalences, bootstrap 95% confidence limits (number of bootstrap replications = 2000) for mean abundances, and exponent of the negative binomial (k) for the parasite skewness, using Quantitative Parasitology 3. 0 software (QP3. 0) [23]. Since parasites typically exhibit an aggregated (right-skewed) distribution within a host population, the negative binomial model represents the observed data following the maximum-likelihood method  [24]. To test whether the mean abundance and intensity of parasites differs among three sea bream categories (wild, +1 year reared, fingerlings), bootstrap t-test was used, while differences among prevalences were tested by unconditional tests, both incorporated within QP3.
Genetic Diversity of the COI and ITS1 Gene Fragments Unambiguous sequences for the mitochondrial COI and nuclear ITS1 genes of three F. echeneis populations from different geographic origins were obtained and deposited in GenBank (JX089988-JX090041 for COI locus and JX090045-JX090099 for ITS1 locus). The length of the COI and ITS1 fragments used in the analysis was 279 bp (n = 66) and 969 bp (n = 55), respectively. In total, 20 variable sites were observed and 17 haplotypes were detected for COI fragment while for ITS1 fragment, 19 variable sites and 9 haplotypes were detected (Results S1, S2). Sequence divergence (Tamura and Nei distance) among COI haplotypes ranged from 0. 05% to 1. 14%, with an average of 0. 26%, while among ITS1 haplotypes (Jukes-Cantor distance) ranged from 0. 05% to 1.
We assessed the distribution and status of six large carnivore species on Namibian commercial farmlands and identified correlates of persistence and landowner tolerance toward those species. These data are used to identify steps required to improve the conservation status of carnivores in Namibia and provide insights that are of relevance to conservation efforts elsewhere in southern and East Africa. Human-carnivore conflict is a globally significant issue  [29] , and our results are likely to be of interest anywhere that carnivore conservation on private lands is being attempted.
Data Collection Approval for our study was obtained from the Namibian Ministry of Environment and Tourism. A structured, pre-tested questionnaire was used to gather data on land use, wildlife, presence/absence of carnivores, whether farmers wished to have carnivores on their property, and estimates of financial losses through depredation by carnivores on livestock. Data on presence/absence and tolerance were collected for cheetahs, brown hyaenas, spotted hyaenas, leopards, lions and wild dogs. Sixty of the 104 commercial farmers unions in Namibia were randomly selected and farmers' contacts requested (following  [15] ). From each union selected, four farmers were randomly sampled and contacted to request an in-person interview. Farmers were asked to provide verbal consent for the interview survey, and records were kept of negative responses to allow calculation of the refusal rate.
Statistical Analyses We first tested for pair-wise correlations between our continuous variables using a Spearman non-parametric test to allow for the removal of redundant variables and ensure that each variable contributed unique insights. Survey data were then analysed using multiple logistic regressions  [34]. When commencing with multiple logistic regressions, all variables expected to influence the dependent variable were included in the models and removed following a backwards stepwise procedure until all remaining variables were statistically significant. Rainfall data (which were obtained from a Namibian government database, http://www. met. gov. na/Pages/DefaultNew. aspx, accessed June 2011) were available in categorical form, and were reorganised into 4 categories (,200 ml/year, 201-300 ml/year, 301-400 ml, and.
Acknowledgments Thanks TRAFFIC East/Southern Africa  and  Tom Milliken , thanks to the  German Federal Ministry for Economic Cooperation and Development and African Wildlife Conservation Fund. Thanks to  Ministry of Environment and Tourism, Namibian Agricultural Union, Namibian Professional Hunters Association, Conservancies Association of Namibia, WWF-Namibia ,  Laurie Marker ,  Danica Shaw ,  Wilfried Pack , and all farmers surveyed.