dataesr/scientific-paragraphs-categorization huggingface dataset:
Dengue hospitalization and severe dengue WHO guidelines stipulate that the clinical evaluation of a candidate live-attenuated dengue tetravalent vaccine should provide evidence that immune response to the vaccine does not predispose vaccinated individuals to develop severe dengue during natural infections in endemic regions  [23, 24, 33]. Suspected symptomatic dengue cases were detected using a passive surveillance method in eight phase I/II non-efficacy trials and using an active surveillance system in the phase IIb and two of the phase III efficacy trials  [7, 9, 10, 15, 16, 19, 21, 28, 34, 35]. Blood samples were taken from individuals with acute febrile illness (see case definition in Table  1 ) occurring from 28 days post-dose 1 for virological testing. In the pooled analysis, the relative risk (RR) of virologically-confirmed dengue (hospitalized and/or severe as assessed by the Independent Data Monitoring Committee (IDMC), see next section) occurring up to 25-months post-dose 1 in the phase IIb and two of the phase III efficacy trials was assessed by age group.
In addition, virologically-confirmed dengue cases were assessed for severity according to the WHO 1997 recommendations (DHF grades 1-4)  [36]. These events occurring in the non-efficacy trials with longer-term follow-up data were summarized using counts and percentages. In addition, a pooled analysis of the RR of dengue hospitalization and severe dengue among those hospitalized during longer-term follow-up the phase IIb (Years 3 and 4 post-dose 1) and two of the phase III trials (CYD14: Years 3 and 4 post-dose 1; CYD15: Year 3 post-dose 1) by age group at enrolment was performed. The RRs for these endpoints were also calculated for the overall follow-up, i. e. from D0.
Independent data monitoring committees WHO guidelines stipulate that an independent data monitoring committee (IDMC) should be set up to ensure the participants' safety and provide an independent assessment of the safety and efficacy data  [23, 24, 33]. Separate IDMCs were set up for each phase I trial whereas a global IDMC was set up for the phase II/IIb and phase III trials to ensure a consistent assessment of the safety profile across all trials in the CYD clinical development program. The IDMC regularly reviewed safety data. Fatal, related SAEs and serious AESIs were reviewed as they occurred. In addition, throughout the CYD-TDV vaccine clinical development program, all dengue cases that were virologically-confirmed were blindly-assessed by the IDMC for disease severity according to pre-defined criteria, as described previously (IDMC severe disease)  [19, 20].
Statistical analysis No formal testing between groups was performed for reactogenicity and all safety parameters, except severe virologically-confirmed dengue disease, although 95% confidence intervals (CIs) were calculated. The analysis set included all participants with available data who had received 1 dose of the dengue vaccine or placebo. Participants were analyzed according to the product received. Sub-group analyzes were performed by age group at enrollment (2-8 years, 9-60 years, 9-17 years and 18-60 years) and for virologically-confirmed dengue from the three efficacy trials, analyses were also performed for those aged 9-16 years. Analyses were also performed by dengue serological status at baseline; individuals with neutralizing antibodies above the low limit of detection (10 (1/dil)) against 1 dengue serotype at baseline were considered as dengue-seropositive and the others were considered as seronegative.
Discussion This pooled analyses included data from 13 main and 5 secondary clinical trials with 77,234 doses of the current formulation of the CYD-TDV vaccine (about 5 log 10 CCID 50 of each of the four live, attenuated dengue vaccine viruses) in individuals aged between 2 and 60 years. The results showed that the overall reactogenicity and safety profile for the CYD-TDV vaccine, including solicited reactions, unsolicited and serious adverse events, viremia and biological parameters was satisfactory and comparable to that for placebo across all age groups (2-8 years; 9-60 years) with similar reported rates and nature of events in the CYD-TDV and placebo groups. The safety profile was not influenced by baseline dengue sero-status or successive doses of the CYD-TDV vaccine. In addition, the reported AEs were transient and mainly mild to moderate.
A WHO vaccine position paper will be published outlining their recommendations in July 2016. In accordance with WHO recommendations, safety and efficacy follow-up will continue for five years after the third dose in the phase IIb efficacy trial and the two phase III efficacy trials in the context of the post-licensure surveillance  [23, 33]. To evaluate the safety and effectiveness including indirect effects of the vaccine in 'real-life' setting, the post-licensure plan, summarized in the pharmacovigilance risk management plan includes post-authorization safety and effectiveness studies, which will be planned in close collaboration with national health authorities, in addition to routine pharmacovigilance surveillance. This surveillance, which will be implemented once the vaccine has been introduced, will provide data for larger-scale reactogenicity and safety assessments of the CYD-TDV vaccine in real-world settings, including in populations excluded from clinical trials.
The pooled safety database was large enough to allow detection of uncommon adverse events occurring in at least 1 per 1,000 individual. As longer-term post-marketing safety data become available the detection of any rare and unexpected events will be also possible. The results from this integrated analysis show that the CYD-TDV vaccine has satisfactory, short-and long-term reactogenicity and safety profiles for up to four years post-dose 1 in participants aged 9-60 years.
From 4-years to 5-years post-dose 3: hospitalized dengue cases Eudra-CT: 2014- Monocentric, Safety, vaccine viremia None Mexico 126 2-45 28-days post- 001706-17 controlled, and immunogenicity dose 3 -Final CYD06 [25] observer-blind (1 st after every injection data available injection: CYD-TDV or YF), open (2 nd and 3 rd injections: CYD-TDV for all) Phase II trials NCT00730288 Phase IIa, Safety, vaccine viremia None Australia 35 18-40 6-months post- CYD10 [13] monocentric, open and immunogenicity dose 3 -Final trial after one injection, data available 6-month post-injection: safety NCT00740155 Phase IIa, Safety, vaccine viremia None Mexico 155 18-45 8. 5-months CYD11 [26] monocentric, and immunogenicity post-dose 1 - randomized open after each injection: Final data trial safety available NCT00617344 Randomized, not Formulation finding None USA 260 18-45 6-months post- CYD12* [8] controlled.
dose 3 -Final data available NCT00993447 Randomized, Safety and Temperature 38°C lasting Columbia, 600 9-16 6-months post- CYD13* [16] placebo and active immunogenicity after 2 days with a suspicion of Honduras, dose 3-Final controlled, each injection; dengue without evidence of Mexico, data available observer-blind Symptomatic dengue local infection Puerto Rico (dose 1 & 2), single blind (dose 3) multicenter trial NCT00875524 Randomized, Safety and Temperature 38°C for 48 Vietnam 180 2-45 4-years post- CYD22* [15] active and placebo immunogenicity after hours with a suspicion of dose 3 -Final controlled each injection: antibody dengue data available observer-blind persistence and safety; Symptomatic dengue (Continued).
e. , least 2 consecutive days) NCT01134263 Randomized, Lot consistency (and None Australia 715 18-60 6-months post- CYD17* [30] placebo-controlled, bridging between phase dose 3-Final observer-blind, II and III lots); Safety; data available multicenter trial Vaccine viremia and virus shedding (subset); Immunogenicity after dose 3 by baseline flavivirus immune status (subset) NCT01373281 Randomized, Vaccine efficacy: Up to 25 months post-dose1: Indonesia, 10,275 2-11 5-years post- CYD14* [19, 22] placebo-controlled, virologically-confirmed Acute febrile illness Malaysia, dose 3 -Data observer-blind, dengue; Safety (temperature 38°C on 2 Thailand, the for up to year 4 multicenter trial throughout the trial; consecutive days); Long-term Philippines, post-dose 1 Reactogenicity (injection follow-up (12-months post- Viet Nam available site and systemic) after dose 3 onwards): as above each dose (subset); and requiring hospitalization Immunity after dose 2 & 3 (subset); 5-year post- dose 3: safety, confirmed-hospitalized dengue (all); antibody persistence (subset) NCT01374516 Randomized, Vaccine efficacy: Up to 25 months post-dose1: Brazil, 20,689 9-16 5-years post- CYD15* [20, 22] placebo-controlled, virologically-confirmed Acute febrile illness Colombia, dose 3 -Data observer-blind, dengue; Safety (temperature 38°C on 2 Honduras, for up to year 3 multicenter trial throughout the trial; consecutive days); Long-term Mexico, post-dose 1 Reactogenicity (injection follow-up (12-months post- Puerto Rico available site and systemic) after dose 3 onwards): as above each dose (subset); and requiring hospitalization Immunity after dose 2 & 3 (subset); 5-year post- dose 3: safety, confirmed-hospitalized dengue (all); antibody persistence (subset) * Main trials, that assessed the current formulation of the CYD-TDV vaccine (containing about 5 log 10 CCID 50 of each of the four live, attenuated vaccine virus) administered at D0, M6 and M12; in the other trials (secondary trials) the same formulation was assessed but with administration at D0, M3.
All the images were collected on a fully customized synchrotron full-field microscope equipped with multispectral detection. The overall data cube results from the mosaicking of 414 tiles collected in three emission bands at three excitation energies, totalling 1. 5 gigapixels. Using the same strategy, we could image structured crystal defects fluctuation within individual ZnO nanowires across populations of hundreds, from their low-yield photoluminescence. The continuous tunability of the synchrotron beam allows excitation down to the shortwave ultraviolet (UVC). We therefore demonstrate the exceptional potential of high spatial dynamics-photoluminescence imaging to study nano-and polycrystalline materials for applications within a variety of fields, ranging from quality control in semiconductor solid-state physics to geophysics, archaeology and environmental sciences.
We have therefore extended our proof of concept to a modern synthetic material by mapping and characterization of crystal defects density within a batch of nanowires. High signal-to-noise ratio images of zinc oxide nanowires of 0. 5-1 mm in diameter and 14 mm in length deposited on a substrate were collected in nine spectral bands ranging from the deep ultraviolet to the near infrared using an excitation wavelength of 275 nm. The images reveal both unexpected spectral-dependent spatially variable emission from crystal defects along the length of individual nanowires and the statistical variability of the distribution of those defects within the entire population where a limited number of typical nanowire behaviours is observed (Fig. 5 ). Deep ultraviolet-optimized multispectral collection strategy allows 'ala carte' adaptation of integration times to each spectral emission range, to collect extremely low-yield responses that would otherwise go undetected through hyperspectral data collection.
For this analysis, the surface was prepared using vibratory polishing (Buehler VibroMet 2, ChemoMET polishing cloth) with 50 nm colloid alumina suspension. A carbon coating a few nanometres was applied (Leica EMACE600). The experiments were performed at 20 kV (70°tilt) and data were processed using the Channel 5 Tango software. Preparation of the ZnO nanowires. ZnO nanowires were grown at 850 °C by metal-organic chemical vapour deposition (MOCVD) on a (0001) sapphire substrate using diethylzinc and nitrous oxide as zinc and oxygen precursors (GEMaC, Versailles, France).
Acknowledgements This article is dedicated to the memory of  Jean-Franc¸ois Jarrige  (1940Jarrige ( -2014)), former director of the musee Guimet in Paris, who discovered Mehrgarh in 1974 and directed the ' Mission Archeologique de l'Indus ' from 1975 to 2014. Claudie Josse  is warmly acknowledged for providing EBSD results (Centre de microcaracterisation  Raimond Castaing ,  CNRS UMS 3623 , Toulouse, France). We acknowledge SOLEIL for provision of synchrotron radiation under projects no 20120848 and 20130920. We thank  Christophe Sandt  at the SMIS beamline for access to Raman microscopy (SOLEIL synchrotron),  Pierre Gueriau  for complementary synchrotron XRF mapping (IPANEMA) and  Frederic Jamme (SOLEIL synchrotron)  for providing support to generate the point spread function (PSF). We thank  Pierre Galtier ,  Alain Lusson  and  Vincent Sallet  ( GEMaC UMR8635 ) for preparing and providing the ZnO nanowires.
, 2012]. Beerling and Royer [2011]  compiled data from a variety of proxies to document the history of CO 2 through the Cenozoic. CO 2 rose from the end Cretaceous into the Eocene, peaked ∼50 Ma (Ma = million years ago), then fell toward the end of the Eocene, following which values stayed rather low. This pattern is the same as that of global mean surface temperature, which rose to a peak ∼50 Ma then fell to the point where the first Antarctic ice sheet formed ∼34 Ma [see also  Anagnostou et al. , 2016]. The ultimate driver for changing global CO 2 in this time frame was volcanic activity driven by plate tectonics, with changes in greenhouse gas forcing changing atmospheric and oceanic temperatures [e. g. , see  Kent and Muttoni, 2008]. However, as we discuss below, this pattern was disrupted briefly by a short-lived carbon injection event that caused a temporary warming at the Paleocene-Eocene boundary 56.
In situ measurements of Earth System processes have also increased dramatically in the last few decades. For example, the uptake of CO 2 by terrestrial ecosystems is directly measured by eddy covariance techniques. The climate is monitored in real time by a global network of stations that observe temperature, precipitation, solar radiation, wind speed, and other parameters. Through systems such as the Argo buoy network, oceanographers routinely measure the temperature, salinity, and chemical state of the ocean from the surface down to 2000 m. The flow of sediments, nitrogen, phosphorus, and other elements down river systems and into the coastal zone can be measured directly, as well as the subsidence of many of the world's large delta areas. Growing databases coupled with satellite observations show how humans have changed the terrestrial hydrological system by engineering the landscape  [Syvitski and Kettner, 2011] , especially by building millions of small impoundments and thousands of large dams  [ICOLD, 2016].
g. ,  Crutzen, 2002; Ruddiman, 2013; Lewis and Maslin, 2015; Zalasiewicz et al. , 2015; Waters et al. , 2016]. In summary, the relationship between stratigraphy and Earth System science is now much closer and more effective than it was just a few decades ago. Earth System science has a wealth of contemporary data to assess changes in the Earth System and to test predictions arising from theoretical grounds. It is this wealth of direct Earth System data that has led to the proposal for the Anthropocene Epoch. The challenge is to turn this rapidly expanding body of data in stratigraphy and Earth System science into a productive partnership that can define a significant change to the state of the planet consistent with both the Geologic Time Scale and Earth System science.
The concept of the Anthropocene has provided a trigger for the Earth System science and stratigraphic communities to integrate their knowledge, tools, skills, and rapidly growing masses of data in unprecedented ways. From both Earth System science and stratigraphic perspectives, the Earth has been pushed out of the pre-industrial Holocene norm by human activities. This has led scientists to ask: How will the Anthropocene evolve? Even with a rapid and decisive shift of contemporary human societies toward sustainable development, the Anthropocene will remain a distinctly different epoch from the Holocene. The current trajectory of human societies would lead to an Anthropocene that is a much warmer and biotically different state of the Earth System, one that is no longer governed by the late Quaternary regime of glacial-interglacial cycles, and with far fewer species.
Hybrid origin of wisent and ancient European bison. To investigate the potential hybrid origins of wisent and CladeX, we used target enrichment and high-throughput methods to sequence B10,000 genome-wide bovine single-nucleotide polymorphisms (SNPs) from nine members of CladeX, an ancient (455 kyr) and a historical (1911 AD) wisent specimen and two steppe bison (30 and 450 kyr). Principal Component Analysis (PCA) and phylogenetic analysis (Fig. 3  and Supplementary Fig. 10 ) of the nuclear data demonstrate that members of CladeX are closely related to the steppe bison. D-statistic  18  analyses confirm a closer affinity of both CladeX and the ancient wisent to steppe bison than to modern wisent (Fig. 3b ), which is explicable because of rapid genetic drift during the severe bottleneck leading to modern wisent.
To examine the extent of genetic isolation maintained through time by the hybrid forms (wisent and CladeX) from steppe bison, we characterized the genomic signals originating from either steppe bison or aurochs in the wisent and CladeX lineages. Calculations of f 4 ratios  23  show the same high proportion of nuclear signal from steppe bison (Z89. 1%) and low proportion from aurochs (r10. 9%) in both wisent and CladeX (Fig. 3d  and Supplementary Table  6 ). Independent calculation of hybridization levels from ABC comparisons with simulated data also shows clear evidence of hybridization, with similar proportions of nuclear signal (97. 2% probability that there is at least 1% aurochs ancestry and a 87. 6% probability that there is at least 5% aurochs ancestry; see Supplementary Note 2 and Supplementary Tables  10  and 11 ).
Methods Ancient DNA samples description and processing. Samples from a total of 87 putative bison bones were collected from three regions across Europe: Urals, Caucasus and Western Europe (Supplementary Data 1). Dating of 45 samples that yielded DNA was performed at the Oxford Radiocarbon Accelerator Unit of the University of Oxford (OxA numbers), and the Ångstro ¨m Laboratory of the University of Uppsala, Sweden, for the Swiss sample (Ua-42583). The calibration of radiocarbon dates was performed using OxCal v4. 1 with the IntCal13 curve  31  (Supplementary Data 1). (a) Maximum-likelihood phylogeny of modern and ancient bison from B10,000 genome-wide nuclear sites, showing the close relationship between CladeX and steppe bison. However, a bifurcating phylogeny is not capable of displaying the complex relationships between these taxa (see Supplementary Fig.
10 ). (d) Proportion of steppe bison and aurochs ancestry in both wisent and CladeX lineages, calculated with f 4 ratios. All ancient DNA work was conducted in clean-room facilities at the University of Adelaide's Australian Centre for Ancient DNA, Australia (ACAD), and at the University of Tuebingen, Germany (UT) following the published guidelines  32. Samples were extracted using either phenol-chloroform  33  or silica-based methods  34, 35  (see Supplementary Data 1). Mitochondrial control region sequences (4400 bp) were successfully amplified from 65 out of 87 analysed samples in one or up to four overlapping fragments, depending on DNA preservation  33. To provide deeper phylogenetic resolution and further examine the apparent close relationship between Bos and wisent mitochondria, whole-mitogenome sequences of 13 CladeX specimens, as well as one ancient wisent, one historical wisent and one steppe bison were generated using hybridization capture with either custom-made  36, 37  (see Supplementary Note 1 for details).
Figure3| Genome-wide data comparison of bison. (a) Maximum-likelihood phylogeny of modern and ancient bison from B10,000 genome-wide nuclear sites, showing the close relationship between CladeX and steppe bison. However, a bifurcating phylogeny is not capable of displaying the complex relationships between these taxa (see Supplementary Fig. 8). Numbers above branches represent bootstrap values. (b) D-statistics from the same B10,000 nuclear sites, using sheep as outgroup. For three bison populations, assuming two bifurcations and no hybridizations, three possible phylogenetic topologies can be evaluated using D-statistics, with the value closest to 0, indicating which topology is the most parsimonious. The topology being tested is shown on the vertical axis. Error bars are three s. e. 's (from block jackknife) either side of the data point.
Data points that are significantly different from zero are shown in grey. The data point representing the topology in a, among a set of three possible topologies, is shown with a black outline. (c) Principal Component Analysis of B10,000 genome-wide nuclear sites (ancient wisent not included due to the sensitivity of PCA to missing data, see Supplementary Fig. 10). (d) Proportion of steppe bison and aurochs ancestry in both wisent and CladeX lineages, calculated with f 4 ratios.
). The coincident morphological and genetic replacement indicate that variation in bison representations in Paleolithic art does not simply represent stylistic evolution, but actually reflects the different forms of bison genotyped in this study (that is, pre and post-hybridization) through time. Data Availability. All newly sequenced mitochondrial control regions are deposited at the European Nucleotide Archive under the following accession numbers (LT599586-645) and all complete mitochondrial genomes at GenBank (KX592174-89). The BEAST input file (XML) is available as Supplementary Data set 2, the MrBayes input file (Nexus), including all whole-mitochondrial genomes, as Supplementary Data set 3 and the nuclear SNPs as Supplementary Data set 4 (VCF format). All other data are included in the Supplementary Material or available upon request to the corresponding authors.
Acknowledgements We are grateful to  A. A. Krotova  ( Institute of Archeology Ukrainian Academy of Sciences ),  K. Wysocka  ( Vinnytsia Regional Local History Museum ),  M. Blant  ( Swiss Institute for Speleology and Karst Studies ),  G. Zazula  and  E. Hall  ( Yukon Palaeontology Program ),  C. Lefe  `vre ( Museum National d'Histoire Naturelle ),  M. Leonardi  ( Natural History Museum of Denmark ),  J. P. Brugal  ( Laboratoire mediterraneen de prehistoire Europe Afrique  and  Musee d'Orgnac) , the  Natural History Museum of Vienna  and the  Paleontological Institute of Moscow  for providing access to samples. We thank  A. Lister ,  K. Helgen  and  J. Tuke  for their comments the study, as well as  A. Vorobiev ,  Y. Cle  ´ment and  M. E. H. Jones  for their help in the project. This research was supported by the  Australian Research Council , the  European Commission  ( PIRSES-GA-2009-247652-BIOGEAST ), the  Polish National Science Centre  ( N N304 301940  and  2013/11/ B/NZ8/00914 ), the  Danish National Research Foundation  ( DNRF94 ), the  Marie Curie International Outgoing Fellowship  (7th  European Community Framework Program-MEDITADNA ,  PIOF-GA-2011-300854 ,  FP7-PEOPLE ) and the  Russian Foundation for Basic Research  ( N 15-04-03882 ).
(Figure 3 | 3 Figure3| Genome-wide data comparison of bison. (a) Maximum-likelihood phylogeny of modern and ancient bison from B10,000 genome-wide nuclear sites, showing the close relationship between CladeX and steppe bison. However, a bifurcating phylogeny is not capable of displaying the complex relationships between these taxa (see Supplementary Fig. 8). Numbers above branches represent bootstrap values. (b) D-statistics from the same B10,000 nuclear sites, using sheep as outgroup. For three bison populations, assuming two bifurcations and no hybridizations, three possible phylogenetic topologies can be evaluated using D-statistics, with the value closest to 0, indicating which topology is the most parsimonious. The topology being tested is shown on the vertical axis. Error bars are three s.