dataesr/scientific-paragraphs-categorization huggingface dataset:
Further information Further information can be obtained from Orphanet, the European portal for rare diseases and orphan drugs, sections on HPP www. orpha. net, www. hypophosphatasia. com, and OMIM (http://www. ncbi. nlm. nih. gov/ omim) numbers 146300, 241510, and 241500. Prof. Etienne Mornet maintains a database of known ALPL gene mutations at http://www. sesep. uvsq. fr/03_hypo_mutations. php. As of 6 October 2015, a total of 300 mutations have been described.
Why this paper is important to paediatric dentists Dentists and dental surgeons can play an active part in initiatives to identify patients with HPP through their participation in a rare disease registry This voluntary action will support efforts to enhance knowledge of and obtain evidence-based data relating to HPP in orodental medicine Early identification of patients can improve access to life-changing therapy I would like to express my sincere thanks to patients and their families as well as the association Hypophosphatasie Europe.
This article was produced with support from my financial partners; in particular, the Rare Diseases Plan through finance for Reference Centres and the INTERREG IV and INTER-REG V Programmes, Science Offensive, Oro-Dental Manifestations of Rare Diseases (www. genosmile. eu). This programme is jointly financed by the European Regional Development Fund (ERDF) of the European Union through the INTERREG IV and V RARENET Programme for the Upper Rhine and the Science Offensive of the Trinational Metropolitan Region of the Upper Rhine (regional partners: R egion Alsace, Ministerium f€ ur Bildung, Wissenschaft, Weiterbildung und Kultur du Land de Rh enanie-Palatinat, Ministerium f€ ur Wissenschaft, Forschung und Kunst du Land de Bade-Wurtemberg). This article was also supported by the grant ANR-10-LABX-0030-INRT, a French State fund managed by the Agence Nationale de la Recherche under the frame programme Investissements d'Avenir labelled ANR-10-IDEX-0002-02.
Treatments received A list of all treatments available for asthma, conjunctivitis and rhinitis is included in the ARIA Allergy Diary, and users select the treatment(s) they are taking. Multiple treatments may be selected, and users can update the information when (or if ) their treatment changes (Fig. 2 ). The list has been customized for all 20 countries in which the ARIA Allergy Diary is available, using data from IMS Health. Information on allergen specific immunotherapy is also requested on the day of first use. A questionnaire on biologics for asthma is under development.
do you receive your treatment? Injection Tablet under the tongue Drops under the tongue Spray under the tongue Other The scaling up strategy The EIP on AHA has proposed a 5-step framework for developing an individual scaling up strategy: (1) what to scale up: (1-a) databases of good practices, (1-b) assessment of viability of the scaling up of good practices, (1-c) classification of good practices for local replication and (2) how to scale up: (2-a) facilitating partnerships for scaling up, (2-b) implementation of key success factors and lessons learnt, including emerging technologies for individualised and predictive medicine. This strategy has.
Type of telemedicine resource Outcome Analysis of lesions on MRI scans using software that runs in a web browser Similar results to those obtained using conventional software  (Luccichenti et al. , 2010)  Remote assessment of disability Clinically valid information and similar total EDSS scores compared with 'in-person assessments' using a videoconference link  (Kane et al. , 2008)  or low-cost webcam  (Wood et al. , 2013)  Home-based rehabilitation programmes Improvements in function, such as walking, balance  (Finkelstein et al. , 2008)  and postural control  (Ortiz-Gutierrez et al. , 2013)  Low-level evidence for reduction in impairments (such as fatigue, pain and insomnia) and improvement in functional activities and participation, based on a systematic review of nine randomized controlled trials  (Khan et al.
lesions that are currently inflamed) rather than no active lesions  (Signori et al. , 2015). Support for early treatment in RRMS is also provided by real-world evidence from databases and registries (Table  B. 3)  (Trojano et al. , 2007; Trojano et al. , 2009). In addition, for people with CIS, an analysis of data from an international registry shows that the greater the length of time spent taking a DMT within 12 months of onset, the lower the risk of a sustained increase of at least 1 point on the EDSS in the same time period  (Jokubaitis et al. , 2015). Furthermore, data from the Swedish registry indicate that earlier treatment with a DMT is associated with slower disability progression (from diagnosis of MS to EDSS score ≥ 4. 0) than later treatment  (Kavaliunas et al. , 2015). Initiating treatment with a DMT "as early as possible in eligible patients" is also recommended in the 2015 guidelines from the Association of British Neurologists (ABN)  (Scolding et al.
Treatment initiation criteria may lag behind diagnostic criteria The revised McDonald (2010) diagnostic criteria enable an MS diagnosis to be made on the basis of one attack (relapse) and MRI evidence from a baseline scan (Section 2. 4. 2). However, in a 2013 global survey of 106 countries, responders from 14 of the 27 countries for which data were provided on criteria for initiating DMT in people diagnosed with RRMS reported that these included the requirement for at least two clinically significant relapses within 2 years (Multiple Sclerosis International Federation, 2013f). This reflects the Poser diagnostic criteria, which have been obsolete for over a decade since the widespread adoption of the McDonald criteria. Prescribing guidelines governing DMT initiation should evolve in parallel with diagnostic criteria in order to prevent unnecessary loss of cognitive reserve, loss of brain tissue, deterioration in brain health and disability progression as a result of waiting for further relapses to occur before starting treatment.
Clinical and subclinical indicators of disease activity should be monitored Historically, the treatment target for MS was to prevent or reduce clinical disease activityrelapses and, especially, disability progression  (Fox and Rhoades, 2012; Stangel et al. , 2015). The need to prevent disability progression is underscored by real-world evidence from a large international database of people with MS, which indicates that the EDSS score 5 years after the onset of MS predicts disability progression, and that once disability has progressed, it worsens more rapidly from EDSS score 4. 0 onwards than from EDSS score 2. 0 onwards  (Hughes et al. , 2012). However, neurological reserve is affected by damage to the CNS even when it does not lead directly to disability progression or a relapse (Section 1.
Indeed, recent international  (Lublin et al. , 2014)  and Canadian  (Traboulsee et al. , 2015)  consensus papers have recommended that disease activity should be assessed at least annually using MRI. Ideally, brain volume should also be monitored, because it is a measurable indicator of brain reserve and because high rates of brain atrophy in some people with MS are likely to predict poor outcome. We acknowledge that routine brain volume monitoring will rely on the incorporation of measurement techniques for this parameter into radiological practice, and that the technology required to do this is not yet widely available. However, quality monitoring of lesion development (counting new lesions) in MRI brain scans is currently feasible and should be routinely carried out in people with MS. Recording the results of monitoring in a database or registry, accessed via a clinical management tool, can facilitate decisions about lifelong care and treatment for each person with MS because it allows MS healthcare professionals to view their full history of disease activity and treatment in one place.
 The global prices of DMTsas for other pharmaceutical productsare generally set based on the conditions in high-income countries, and other countries may have difficulties in granting access to these therapies.  Current financing models focus on the prices of individual DMTs; however, this effectively incentivizes the rationing of individual drugs instead of focusing on finding the optimal therapy for each person with MS. Alternative financing models should, therefore, be investigated.  For people with MS in low-income countries, access to DMTs can be improved by developing financial support programmes and less-expensive DMTs.  Recording the results of monitoring in databases or registries will generate real-world evidence of the effectiveness and safety of individual DMTs and therapeutic strategies.
Real-world evidence should drive regulatory and funding decisions The therapeutic strategy of early treatment, monitoring and switching, with the full range of DMTs available, will change the economic picture of MS and has the potential to reduce the long-term costs of the disease significantly. Regulatory authorities and payers, however, make initial decisions about DMTs based on their efficacy and safety in short-term clinical trialsan environment in which it is not possible to switch to a different DMT if disease activity is inadequately controlled. Consideration of real-world evidence from registries and databases of the long-term effectiveness and safety of DMTs and therapeutic strategies will help regulatory authorities, HTA bodies and payers to ensure that these decisions do not become out of date or rigid, denying people with MS the flexibility to benefit from the most recent evidence.
3). Additionally, we recommend incorporating such results into national and international MS registries and databases in order to generate real-world evidence of the long-term effectiveness and safety of individual DMTs. This would also enable the effectiveness of overarching therapeutic strategies to be evaluated, for example the predictive power of NEDA (by any definition covered by the data set) on clinical outcomes or the effect of variations in practice patterns on disease activity and health outcomes for people with MS. For this to be possible, we further recommend that the curators of databases and registries should ensure accessibility of data to those performing HTAs and economic evaluations.
This is an author's draft of an accepted article submitted and published in Multiple Sclerosis and Related Disorders DOI: http://www. sciencedirect. com/science/article/pii/S221103481630102X 63  approaches that reduce the costs of managing MS and of alternative financing models, to improve access to treatment.  Agree and implement standardized data collection techniques, protocols and data sets, nationally and internationally, to track clinical and subclinical events in routine practice. Incorporate these into national and international MS registries and databases to generate real-world evidence of the long-term effectiveness and safety of therapeutic strategies; such evidence can be used by regulatory bodies and payers, and will enable differences in practice patterns to be assessed and addressed.
Acknowledgements The authors thank the following members of the wider working group, who contributed to two drafts and the approval version, for their support and consultation on the document:  Professor Maria Pia Amato  ( Department of Neurology, University of Florence, Florence, Italy ),  Ms Amy Bowen  ( Multiple Sclerosis Trust, Letchworth Garden City, UK ),  Professor William Carroll  ( Centre for Neuromuscular and Neurological Disorders, Western Australian Neuroscience Research Institute, University of Western Australia, Perth, WA, Australia ),  Professor Giancarlo Comi  ( Department of Neurology and Institute of Experimental Neurology, Università Vita-Salute San Raffaele, Milan, Italy ),  Ms Kathleen Costello  ( Vice President ,  Healthcare Access ,  National Multiple Sclerosis Society, USA) ,  Ms June Halper  ( Consortium of Multiple Sclerosis Centers/International Organization of Multiple Sclerosis Nurses, Hackensack, NJ, USA ),  Professor Eva Havrdová  ( Department of Neurology, Charles University in Prague, Prague, Czech Republic ),  Professor Bengt Jönsson  ( Department of Economics, Stockholm School of Economics, Stockholm, Sweden ),  Professor Ludwig Kappos  ( Departments of Neurology and Biomedicine, University Hospital Basel, University of Basel, Basel, Switzerland ),  Professor Dawn Langdon  ( Department of Psychology, Royal Holloway, University of London, Egham, UK ),  Professor Xavier Montalban , ( Multiple Sclerosis Centre of Catalonia (Cemcat), Vall d'Hebron University Hospital, Barcelona, Spain ),  Professor Fredrik Piehl  ( Department of Clinical Neuroscience, Karolinska Institutet, Solna, Sweden ),  Mr Nick Rijke  ( Multiple Sclerosis Society, London, UK ),  Professor Maria Trojano  ( Department of Basic Medical Sciences, Neuroscience and Sense Organs, University of Bari, Bari, Italy ).
Encourage the continuing investigation, development and use of cost-effective therapeutic strategies, of This is an author's draft of an accepted article submitted and published in Multiple Sclerosis and Related Disorders DOI: http://www. sciencedirect. com/science/article/pii/S221103481630102X 63  approaches that reduce the costs of managing MS and of alternative financing models, to improve access to treatment.  Agree and implement standardized data collection techniques, protocols and data sets, nationally and internationally, to track clinical and subclinical events in routine practice. Incorporate these into national and international MS registries and databases to generate real-world evidence of the long-term effectiveness and safety of therapeutic strategies; such evidence can be used by regulatory bodies and payers, and will enable differences in practice patterns to be assessed and addressed.
Agree and implement standardized data collection techniques, protocols and data sets, nationally and internationally, to track clinical and subclinical events in routine practice. Incorporate these into a clinical management tool to facilitate individualized practice. This is an author's draft of an accepted article submitted and published in Multiple Sclerosis and Related Disorders DOI: http://www. sciencedirect. com/science/article/pii/S221103481630102X Any other stakeholders 3. Consult National and international bodies Healthcare providers Curators of registries and databases  Maintain treatment with a disease-modifying therapy for as long Healthcare providers as a person with MS would be at risk of inflammatory disease activity Reimbursement if they were not receiving treatment; in the case of a suboptimal agencies response, make a prompt decision about whether or not to switch therapy.
Health technology assessors Reimbursement agencies  Agree and implement standardized data collection techniques, National and protocols and data sets, nationally and internationally, to track international bodies clinical and subclinical events in routine practice. Incorporate these into national and international MS registries and databases to generate real-world evidence of the long-term effectiveness and safety of therapeutic strategies; such evidence can be used by Healthcare providers Curators of registries and databases regulatory bodies and payers, and will enable differences in practice patterns to be assessed and addressed.  Ensure that access to multiple sclerosis registries and National and databases is available for those carrying out health technology international bodies assessments and economic evaluations.
Healthcare providers Curators of registries and databases National bodies may include government departments or private organizations, depending on the country in question. http://www. sciencedirect. com/science/article/pii/S221103481630102X 69 Figure A. 1. We recommend a therapeutic strategy that aims to preserve central nervous system tissue and maximize lifelong neurological reserve (an important component of brain health) by reducing disease activity. Reproduced with permission from Oxford PharmaGenesis Ltd. © 2015 Oxford PharmaGenesis Ltd.
Average Cu(I) affinities were measured mainly using BCS and an approach described previously  22, 54. For these measurements mixtures of Csp3 (~2. 5 μ M, 2. 09 μ M on one occasion for BsCsp3) and BCS (100-121 μ M) plus increasing concentrations of Cu(I) were incubated anaerobically for up to 124 h for MtCsp3 and 138 h for BsCsp3, with reported affinities from data measured after 42-43 h and 90-96 h respectively (no significant change observed at the longer incubation times). The ability of M. trichosporium OB3b mbtin to remove Cu(I) from MtCsp3, and Cu(I) removal from MtCsp3 and BsCsp3 by BCS, were both monitored by UV-Vis spectrophotometry  22. Cu(I) removal from Cu(I)-BsCsp3 by apo-BsCopZ was followed by analyzing an anaerobic mixture of the proteins using gel-filtration chromatography. Many of the above experiments required Csp3 samples to be incubated over many days and the stability of proteins over the same time period was tested by far-UV CD spectroscopy.
In vivo studies using the copA deletion strain of Escherichia coli. The published 53 copper-dependent phenotype for a Δ copA E. coli was confirmed as described in the Supplementary Methods. BsCsp3 was sub-cloned from pET29a into the XbaI and HindIII sites of pBAD33 giving pBAD33_BsCsp3. The growth of Δ copA transformed with pBAD33_BsCsp3 was investigated at a range of copper concentrations (details in the Supplementary Methods). Copper levels in cells were measured by AAS as described in the Supplementary Methods. Crystallization, data collection, structure solution and refinement. Diffraction-quality crystals were obtained as described in the Supplementary Methods. All crystallographic data were collected at Diamond Light Source Ltd, UK (beamline I02) and structures were solved by molecular replacement using Molrep implemented via the CCP4 suite  62.
Models underwent building cycles in Coot  63  and refinement in REFMAC5  64. Five percent of observations were used to monitor refinement. All models were validated using Molprobity  65  and data collection statistics and refinement details are reported in Supplementary Table  S1. Atomic coordinates have been deposited in the Protein Data Bank under accession numbers 5ARM, 5ARN and 5FIG for apo-MtCsp3, Cu(I)-MtCsp3 and apo-BsCsp3 respectively.
Acknowledgements We thank staff of the DLS synchrotron radiation source for help with diffraction data collection. This work was supported by  Biotechnology and Biological Sciences Research Council  (grant  BB/K008439/1  to C. D. and K. J. W. ), by  Newcastle University  who part-funded a  PhD studentship  (S. P. ) and by a  John William Luccock  and  Ernest Jeffcock studentship  (G. L. ). K. J. W. is supported by a  Sir Henry Dale Fellowship  funded by the  Wellcome Trust  and the  Royal Society  ( 098375/Z/12/Z ).
We hereby provide a revised chronostratigraphy for the archaeological sequence at the site. We combine these results with geological and sedimentological multi-proxy investigations to gain insights into site formation processes and the palaeoenvironmental record of the region. The older sedimentological units at Rhafas were deposited between 135 ka and 57 ka (MIS 6 -MIS 3) and are associated with the MSA technocomplex. Tanged pieces start to occur in the archaeological layers around 109 ka, which is consistent with previously published chronological data from the Maghreb. A well indurated duricrust indicates favourable climatic conditions for the pedogenic cementation by carbonates of sediment layers at the site after 57 ka. Overlying deposits attributed to the LSA technocomplex yield ages of ~21 ka and ~15 ka, corresponding to the last glacial period, and fall well within the previously established occupation phase in the Maghreb.
Therefore, we regard the age estimate for Layer 6d published by Mercier et al. [26]  as an underestimate, and argue that, without further investigations, the lower cave section at Rhafas remains undateable. [26]. Deposition of the sediments in the cave mouth section took place between 135 ka and 7. 8 ka with a major unconformity between the MSA and the overlying Neolithic (Fig  8A ). Although our OSL ages for the MSA Layers 3a and 3b are both slightly older than the corresponding TL age estimates by Mercier et al. [26] , both datasets are consistent with each other within the given error ranges as well as with the expected age of the archaeological finds based on chronologies from other sites. OSL and 14 C age determinations for the Neolithic Layer 1 yielded results of 7. 8±0. 6 ka and 6. 0±0.
Layers from the LSA, while present in the terrace area, are either not present or have been removed from the cave mouth section. Our revised chronostratigraphy from Rhafas contributes towards a rigorous investigation of evidence for human activity across the Maghreb during the Middle and Late Pleistocene. Here we compare our results with published chronological data from 25 MSA and LSA sites across western Morocco, northern Morocco, Algeria, Tunisia and western Libya (Figs 9 and 10; for site locations see Fig  1 )  [2, 3, 6, 10, 13-17, 26, 28, 31, 33, 34, 83-99]. In this analysis we consider only archaeological layers which can be clearly associated to a defined stone tool technology and have been reliably dated by absolute dating ( 14 C, TL, single aliquot OSL (SA-OSL), single grain OSL (SG-OSL), electron spin resonance (ESR) or U-series (Th/U)).
Our data corroborate previously published data and are used to catalyse a synthesis for stone tool assemblage chronologies across the Maghreb. The first phase of occupation at Rhafas associated with the MSA started at least in late MIS 6 (~134 ka) or even earlier (since MSA is also found in the as yet undateable lower cave section). Its duration was at least 60,000 years and persisted into MIS 5 (Fig  9 ). Apart from Rhafas, evidence for occupation in the Maghreb in MIS 6 or earlier is limited to the sites of Jebel Irhoud  [83] , Abrigo de Benzù  [31, 33] , Ifri N'Ammar  [10] , El Akarit  [92]  and Ain Zargha in the Jebel Gharbi  [95]. The oldest age is 254±17 ka, recorded at Benzú  [31, 33]. The onset of the MIS 5 interglacial resulted in increasingly humid climatic conditions associated with an expansion of grassland habitats in northern Africa  [68, [100] [101] [102].
It is important to note that the 14 C dates of Betrouni  [89]  from Sidi Sa should be treated with caution. Likewise, the older TL ages from El Akarit may not be reliable due to problems with dose rate determination within the sediments  [92]. The earliest reliably occurrence of tanged pieces is found at Ifri N'Ammar, and dated by TL to a weighted average of 145 ±9 ka  [10]. Apart from Ifri N'Ammar, tanged pieces do not regularly occur within Moroccan archaeological assemblages until the onset of MIS 5e ~130 ka  [2, 3, 6, [13] [14] [15] [16] [17] 26]. Tanged pieces occur even later in Algeria and western Libya: 43±1 ka at Sidi Sa  [89] , 64±21 ka at Ain Zargha  [93] , ~47 ka at Jebel Gharbi  [93, 94]  and 61±10 ka at Uan Tabu  [98]. This may be, however, an artefact of the limited chronological dataset for sites in Algeria, Tunisia and western Libya.
At Rhafas, the LSA Layers S2 and S3 date to 15±1 ka and 21±2 ka, respectively, and are consistent with the overall LSA dataset for the Maghreb. Here we follow Linstädter et al. [104]  in dividing the LSA of the Maghreb into an early LSA (or EUP), the Iberomaurusian (IBM) and the Epipalaeolithic, as indicated in purple and orange and green in Fig 10B. This recent work at Rhafas has highlighted the exceptional nature and preservation of the LSA marked by one of the earliest appearances of the microlithic bladelet industries in North Africa. The earliest phase of the LSA (Layer S3) is characterised by microliths, bladelets and backed tool industries that occur in Algeria and Morocco around 20 ka  [2, 91, 105]  and are defined as Iberomaurusian. Elsewhere in Cyrenaica similar technology at Hua Fteah was dated to ~17 ka cal BP  [106].