The frequency and severity of extreme events is expected to increase under climate change. There is a need to understand the economic consequences of human exposure to these extreme events, to underpin decisions on risk reduction. We undertook a scoping review of economic evaluations of the adverse health effects from exposure to weather-related extreme events. We searched PubMed, Embase and Web of Science databases with no restrictions to the type of evaluations. Twenty studies were included, most of which were recently published. Most studies have been undertaken in the U.S. (nine studies) or Asia (seven studies), whereas we found no studies in Africa, Central and Latin America nor the Middle East. Extreme temperatures accounted for more than a third of the pool of studies (seven studies), closely followed by flooding (six studies). No economic study was found on drought. Whilst studies were heterogeneous in terms of objectives and methodology, they clearly indicate that extreme events will become a pressing public health issue with strong welfare and distributional implications. The current body of evidence, however, provides little information to support decisions on the allocation of scarce resources between risk reduction options. In particular, the review highlights a significant lack of research attention to the potential cost-effectiveness of interventions that exploit the capacity of natural ecosystems to reduce our exposure to, or ameliorate the consequences of, extreme events. An increase in extreme events, including their frequency, intensity and modifications to their spatial extent and timing, constitutes one of the many expected consequences of climate change . ExtremeThe economic consequences of weather-related extreme events are substantial, with estimates of annual costs ranging from $94 billion to over $130 billion globally . In addiInterestingly, however, as recently noted by the Intergovernmental Panel on Climate Change (IPCC) , studiesTo our knowledge, beyond the economic evidence related to climate change in general, which has overwhelmingly focused on heat risk, there has been no review of studies that evaluate the economic costs of the adverse health effects associated with human exposure to extreme events. In addition, it is of particular interest to evaluate the latest state of the economic evidence base on risk reduction measures targeted at reducing population exposure to extreme events. We therefore conducted a scoping review of this important area of research. Scoping reviews are particularly suitable for conveying the extent and breadth of a given field of research that spans across methods and disciplines by using broad search terms and not applying quality filters ,15,16. SWe searched the PubMed, Embase and Web of Science databases in December 2015, without date limitations, for papers in English that provide an economic evaluation of the health costs resulting from human exposure to weather-related extreme events. Search keywords were determined in agreement with all three authors after an initial broad search of the literature. They included a broad range of terms relevant to the varied nature of: (i) weather-related extreme events ; and (ii) the health effects associated with them . Since the focus of the review was specifically on economic studies, these two search fields were combined (AND) with the keyword “cost” in the title or abstract. Whilst other economic-relevant keywords, such as “economic”, or “burden”, or “losses”, were initially added to the search, they were dropped as they were not found to improve the accuracy of the search that was specifically looking for cost estimates, as opposed to a qualitative assessment of the magnitude of the economic burden of extreme events.Articles had to meet three inclusion criteria. First, they had to pertain to weather-related extreme events. This means that papers that solely produced projections of health burden and associated economic impacts under various scenarios of a warmer climate were excluded. Whilst air pollution is essentially the by-product of human activity, pollution peaks often result from the conjunction of high levels of pollutant emissions and meteorological conditions ; consequently, it was decided to include pollution peaks as weather-related extreme-events. Second, articles had to include health effects, i.e., not focus solely on non-health related impacts, such as damage to assets. Third, whilst no restriction was applied to the type of economic evaluation, articles had to provide economic information. To avoid over-restricting the pool of relevant studies, monetized health impacts did not represent an inclusion criterion. However, in order to be included, studies had to include cost estimates alongside health impacts, be it costs of adaptive measures, monetized damages to assets or productivity losses for instance.n = 869) or their content was irrelevant to weather-related extreme events (n = 1338). Irrelevant articles pertained to five main categories: diseases not related to extreme events; medical therapies; burns; occupational heat exposure and ambient air pollution, since only peaks in exposure or alternatively, on pollution levels during heat waves were deemed relevant to the research question.The document selection process, underpinned by the three above-mentioned inclusion criteria, is summarized in n = 4), further discussions were held to reach consensus on inclusion or exclusion.This led to the identification of a pool of 108 articles selected for full review, all of which could be retrieved. From this pool of articles, 98 articles were excluded after full review by Laetitia Schmitt and cross-validation with the other two authors (Piran White and Hilary Graham). More specifically, articles suggested for exclusion by Laetitia Schmitt were classified according to four main categories of reasons for exclusion from each of which Piran White and Hilary Graham independently took random samples of a minimum of five articles, in order to check for the validity of the exclusion decision. This cross-validation process was also performed for articles suggested for inclusion. For articles for which there was inconsistency between the three authors . A second category comprised general reviews, as well as studies of the burden of climate change that solely provided an evaluation of the effects under projections of changes in mean global temperatures, as opposed to effects associated with specific extreme events  was reviewed with respect to five key features: (i) general descriptive information, e.g., publication date, environmental hazard and geographical region of focus; (ii) type of research output, e.g., burden evaluation, economic appraisal, descriptive analysis; (iii) method used to measure and to monetize health effects; (iv) consideration of distributional effects; and (v) consideration of ecosystem services to help alleviate risk and damages. Data extraction was conducted by Laetitia Schmitt and checked by Piran White and Hilary Graham. The complete set of information extracted from each study can be found in Despite the absence of date limitations in the search, the earliest relevant study was published in 1999, and two-thirds (13 out of 20) of the articles were published over the last five years (2011–2015). As An analysis of the distribution of the pool of identified studies according to their primary environmental hazard and geographical region of focus  shows thExtreme temperatures (heat waves mainly) accounted for more than a third of the pool of studies (seven studies out of 20), closely followed by flooding (six studies out of 20). No economic study was found on drought. Whilst extreme temperatures have been considered in all but one region covered by the pool of identified articles , flooding has been the main focus of studies in Asian countries and Turkey. All studies on hurricanes or tropical storms are from the U.S. whereas the two studies on pollution peaks are based on case studies in Asia .Studies were heterogeneous in terms of objectives and methodology and were classified into six categories—labelled A to E—as represented in n = 10) were classified as burden evaluation studies (Group A). They exhibited great variation in methods and could be further subdivided into four sub-groups  from studies that relied on an empirical estimation of the functional relationship between exposure and effect using time series data specific to their case studies is expected to be higher than estimates based on secondary epidemiological evidence , since extreme events are very context specific and existing epidemiological data may not be easily transferable to different contexts and populations.The significance of descriptive studies results (Group B), which only exploited correlation between selected variables of interest, will greatly depend on the temporal and spatial scale of the data and on the accuracy of the records . The three descriptive studies of Group B used data for extensive time-periods (≥25 years), in order to evaluate time trends in impacts at the country  or regional level (eastern Black Sea basin).The main limitation of WTP studies based on stated preference methods (Group C) is that they rely on hypothetical scenarios that may lead to several biases. Nevertheless, the presently included WTP studies implemented innovative approaches in an effort to address the validity issues deemed most relevant to their specific case study. Matsushima et al.  valued WPopulation-based surveys results (Group D) may suffer from recall and/or strategic bias, where interviewees may exaggerate the severity of their losses if they believe this might help them to obtain further assistance.The only economic appraisal study  identifFinally, the statistical study constituting Group F  providesThe health impacts of extreme events can be categorised into direct effects, including injuries, deaths and mental health difficulties and indirect effects that result from the primary damage . This inMost studies focused on direct impacts. The four main types of health metrics used were: (i) deaths; (ii) hospital admissions and outpatients visits; (iii) cases of acute morbidity or injuries; and (iv) depressive disorders or reduction in well-being. Death was used to measure the health burden associated with all four categories of extreme events represented by the selected studies, i.e., hurricanes, flooding, heat waves and air pollution peaks. By contrast, mental health problems were solely considered with regards to flooding  and,Only one study  specificThe total welfare effect associated with adverse health end-points typically encompasses three elements: (i) healthcare resource use; (ii) productivity loss; and (iii) dis-utility from suffering or life-shortening, where the latter component commonly drives the welfare loss associated with premature death in older people . The monOut of the 10 studies that used death to quantify health impacts, only four applied a monetary value to this outcome by multiplying it with a value of statistical life. This is not surprising given that monetizing death is less useful for descriptive studies investigating trends in effects or for studies reporting results from population-based surveys (which represent five studies in our review).With the exception of the studies that specifically aimed to estimate the WTP for morbidity risk reduction ,34, the Nine studies, ,34,36,39There is a substantial literature on the protective benefits of natural ecosystems, such as coastal wetlands, riparian forests and reefs, against the devastating effects of flooding and hurricanes ,43,44. IAll studies indicate that the economic cost associated with the adverse impacts of extreme events on human health is substantial. Whilst it is not the aim of this review to report all quantitative estimates, key economic findings reported by each study can be found in The comparative study by Knowlton et al.  of the hMore importantly, the two studies that included burden projections under various climate scenarios ,24 show Whilst extreme events are typically brief, their consequences for public health may last over long time horizons. For instance, Fonseca et al.  estimateAlthough the indirect long-term consequences of extreme events are potentially large and, in some cases, expected to substantially contribute to the total economic impact of these events, they appear to be rarely examined (two studies out of the pool of relevant studies). The reason is that, since these impacts are temporally separated from event onset, it is much more resource-intensive to capture them, requiring for instance follow-up surveys or modelling expertise to extrapolate health consequences later in life.The analyses of Yüksek et al.  and KunkEconomic factors were also found to play a major role in shaping people’s attitudes towards the risk of extreme events. For instance, Yüksek et al.  suggest A number of population subgroups, such as older people, single mothers, patients with a chronic condition and socio-economically disadvantaged communities, was found to bear a disproportionate health burden associated with extreme events. Whilst the review does not represent the overall body of evidence on vulnerability factors, it is worth noting that its findings are in line with the literature on the distributional effects of extreme events, heat-stress in particular ,48.All four studies that investigated the interactional effect of age and extreme temperatures found an increased vulnerability to heat-stress associated with age ,22,23,24Low income was also found to be a factor associated with vulnerability. Merrill et al.  reportedPeople on low income are expected not only to be more vulnerable to direct short-term effects but also to suffer a disproportionate burden of indirect consequences of events in the long run. In the U.S., Zahran et al.  showed tIn developing countries, poorer households and households with livelihoods dependent on the exploitation of natural resources are expected to be more vulnerable to extreme events, such as floods, as the associated damage makes up a significantly larger portion of their annual income . With reIt is worth restating that the review exclusively focused on economic evaluations of adverse health effects resulting from human exposure to extreme events. It therefore did not aim to review the overall evidence on the functional relationships between exposure to the various types of extreme events and health effects. Similarly, owing to its focus on extreme events, the review did not encompass the growing number of studies that provide projections of the health and economic burden associated with a future global rise in temperatures. It is nevertheless of interest to note that this excluded literature, namely exposure-response functions or health burden projections under climate change scenarios, has so far overwhelmingly focused on heat stress as a risk factor .Whilst the databases searched are the ones widely used in the health and environment fields, by holding information on published peer-reviewed research, they are likely to be biased toward studies in high-income countries, thus leading to an under-representation of the body of “grey” research in low-income countries. In contrast, we do not consider that the exclusion of non-English language papers will have introduced a publication bias into our review. While we did not collect information on the number of non-English papers, a recent systematic review of extreme water-related weather events and waterborne disease that searched standard databases and included English and non-English language papers found that only 5% of the papers were not in English, and this small group was in other European languages .Collectively, the studies in our review, which cover a diverse set of case studies, represent a valuable body of evidence on the size of the economic burden associated with the adverse health effects caused by exposure to weather-related extreme events. Alongside the literature on the health effects of climate change, the identified studies also provide policy-makers with an indication of how much this burden may grow by the end of the century, especially with regards to extreme temperatures.In line with the wider literature on natural disasters , our revTwo studies identified in this review ,27 have Whilst most of the research on the health and associated economic effects of extreme events has focused on physiological impacts , the recent attempts at valuing well-being and mental health effects will help provide a more comprehensive picture of the range of economic impacts. Efforts to estimate individuals’ welfare loss from mental health effects associated with exposure to climatic extremes should be particularly encouraged in light of growing evidence that these effects may be substantial  and the Finally, the studies contribute to the larger body of evidence on the factors driving the distribution of adverse impacts and to the identification of vulnerable population subgroups stratified by demographics  and health condition. These findings are key to the design and implementation of adaptation measures and, more generally, to inform the development of “healthy public policy”, which calls for an explicit consideration of health and equity matters in all policy areas .The recent increasing research focus on the economic implications of the health impacts from extreme events see  coincideIn particular, despite wide search terms and a long review period (undated to December 2015), we found no relevant study in Africa, Latin and Central America and the Middle East and only one study in Europe. This is an important gap, given that some of these areas are likely to experience severe impacts from climate change-related extreme events ,54,55 anAlthough decision-makers require evidence on the economic consequences of the public health burden associated with extreme events, the greatest evidence gap is in economic evaluations of possible interventions to reduce this burden, in order to allocate constrained resources towards the most cost-effective ones. One striking finding of this review is that despite the WHO’s 2009 call for further research on interventions to control climate-sensitive health risks and the fact that the large majority of the pool of included studies were published in the last five years, only one out of the 20 economic studies identified was an economic appraisal of a risk reduction measure. This economic evaluation pertained to a heat warning system  and was This finding is corroborated by results from a recent systematic review by Bouzid et al. , which hOur review also indicates that very little research attention has been given to the public health dimensions of natural resource management and, more specifically, to the exploitation of the capacity of natural ecosystems to reduce human exposure to extreme events. This is a highly significant gap in the evidence base, in light of evidence that poor land management has been identified as a key factor exacerbating our vulnerability to extreme events see . There iFinally, the building of a body of economic evidence to support resource allocation between competing strategies to adapt against a given type of extreme event would require a common methodological framework with regards to the range and duration of health impacts included and the approach to monetization. The choice of the range and duration of impacts are related, whereby indirect impacts typically occur in the long run. The identification of the appropriate analysis time horizon should therefore assess whether indirect effects, such as treatment disruption following damages to infrastructure following a hurricane or delay in care provision due to peaks in healthcare demand during a heat-wave, are likely to be influential to the analysis. Finally, the evaluation of competitive interventions should ideally be undertaken from the same perspective, e.g., healthcare system or society, as the chosen perspective of analysis will drive the approach to monetizing health effects see .Our scoping review has shown that, although the last five years have seen increasing research interest in the economic consequences of the health effects associated with human exposure to extreme events, the evidence base remains thin with limited geographical coverage. We found no studies in Africa, Latin and Central America and the Middle East, a critical gap given the projected distribution of climate-related extreme events for the future.The economic studies identified were heterogeneous in terms of objectives and methodology and provided a mix of descriptive analyses, WTP estimation for health risk reduction, burden estimation and economic appraisal. However, when considered altogether, they clearly indicate that extreme events will increasingly become a pressing public health issue with strong welfare and distributional implications. Health impacts and associated consequences on healthcare budgets, productivity and individuals’ well-being may be incurred long after event occurrence and are expected to exacerbate health inequalities between income subgroups.Whilst the evidence base identified by our review underlines the importance of addressing the health impacts of extreme events, it provides policy-makers with little economic information on which to base decisions about the allocation of scarce resources between potential risk reduction options. In particular, our review highlighted a significant lack of research attention to the potential cost-effectiveness of interventions that exploits the capacity of natural ecosystems to reduce our exposure to extreme events, despite evidence that poor land management contributes to exacerbating our vulnerability to them.


Projectile technology is considered to appear early in the southern African Middle Stone Age (MSA) and the rich and high resolution MSA sequence of Sibudu Cave in KwaZulu-Natal has provided many new insights about the use and hafting of various projectile forms. We present the results of a functional and technological analysis on a series of unpublished serrated bifacial points recently recovered from the basal deposits of Sibudu Cave. These serrated tools, which only find equivalents in the neighbouring site of Umhlatuzana, precede the Still Bay techno-complex and are older than 77 ka BP. Independent residue and use-wear analyses were performed in a phased procedure involving two separate analysts, which allowed the engagement between two separate lines of functional evidence. Thanks to the excellent preservation at Sibudu Cave, a wide range of animal, plant and mineral residues were observed in direct relation with diagnostic wear patterns. The combination of technological, wear and residue evidence allowed us to confirm that the serration was manufactured with bone compressors and that the serrated points were mounted with a composite adhesive as the tips of projectiles used in hunting activities. The suite of technological and functional data pushes back the evidence for the use of pressure flaking during the MSA and highlights the diversity of the technical innovations adopted by southern African MSA populations. We suggest the serrated points from the stratigraphic units Adam to Darya of Sibudu illustrate one important technological adaptation of the southern African MSA and provide another example of the variability of MSA bifacial technologies. The South African Middle Stone Age (MSA) surprises by the multiplicity of the archaeological discoveries, which may be attributed in part to the research intensity in this part of the world and partly to the unique nature of the landscape and human behaviors. Today, the South African MSA has become an ideal canvas for the development and elaboration of models helping us to understand the first societies of anatomically modern humans (AMH), before their dispersal on the Eurasian continent. Important sites such as those of Klasies River main site (KRM), Blombos Cave (BBC), Diepkloof Rock Shelter (DRS), Pinnacle Point (PP) and also Sibudu Cave have been instrumental to scientific research and model building. The purpose of this article is to present new evidence as testament to the originality of the behavioral traits that characterize the South African MSA. Our study focuses on the newly excavated MIS5 levels of the site of Sibudu Cave.Technical innovations are important testimonials of the evolution of human societies since they have the potential to reflect new adaptations of societies to their environment, new social and economic organizations, as well as differences in cognitive architectures ,2. TechnThe early appearance of thermal treatment for improving stone knapping qualities ,4, the uQuestions about the timing and the type of projectile points in the history of hunter-gatherer societies comes from fundamental research on the history of techniques and are the subject of a rich literature and debate. Elements under discussion touch upon aspects of the recognition of functional stigmata  but also of the implications of certain interpretations . In the South African Stone Age, the presence of projectile points has been proposed for the site of Kathu Pan dated to 500 ka BP , but serIn this paper, we focus on an unpublished collection of bifacial serrated points that was discovered in the deep deposits of the site of Sibudu; these ancient occupations were individualized under the name of the “serrates layers”. These serrated pieces, also mentioned for the neighboring site of Umhlatuzana ,16, deriSibudu Cave, is situated approximately 40 km north of Durban and 15 km inland of the Indian Ocean. It is a rock shelter perched on a steep west-south-west facing cliff 20 m above the uThongathi River in the northern part of KwaZulu-Natal Province (KZN), South Africa . During Unlike the upper part of the deposits that are predominantly composed of anthropogenic deposits ,22, the The sequence includes occupations that are characteristic for the final MSA, late MSA, post HP, HP and SB. The lowermost layers excavated by Wadley (Light Brownish Grey (LBG) and Brown Sand (BS), before a team directed by Conard took the head of the excavation, were informally named ‘pre-SB’ . The pre-SB excavated by Wadley, including LBG and the upper part of BS (BS to BS10), describe lithic assemblages with flakes as well as blades and few formal tools, excluding bifacial pieces with the exception of one specimen from LBG; though this probably derived from the directly overlying SB layers . The you2 (ca. 1 m3 of sediment) excavated in five field seasons from 2012–2016. Due to the high find density of lithic single finds . The serrated pieces come from the layers Bart, Bea, Casper, Chantal and Darya. We identified a total of 25 serrated pieces   and bifacially  retouched blanks that were laterally or bilaterally serrated (n = 14). While we recognize two techno-typological groups, we cannot discern clear differences between them in terms of their morphology or dimension. In general, we suggest that these two reduction sequences reflect different ways to obtain a similar result, namely a triangular elongated tool with serrated edges. However, we again observe a difference between the quartz pieces and those made from other rock types, as the quartz pieces always correspond to the category of bifacially shaped blanks that have been bifacially serrated. We will further elaborate on how we interpret differences between the raw materials that were used by inhabitants of Sibudu, in the discussion.To interpret size and shape differences, we first have to acknowledge the technological variability within this population or, in other words, their chaînes opératoires, we integrate some preliminary observations based on the bifacial pieces (not serrated) derived from the same layers as the serrated pieces. We will refer to these non-serrated pieces as the ‘formal bifacial pieces’. Of the total number of 168 bifacials, 143 are formal bifacial pieces, and the rest are serrated. This means that approximately one out of every six bifacial pieces was serrated.For a better understanding of the chaîne opératoire as deduced from the full assemblage of bifacial pieces begins with the knapping of elongated products. These blanks indicate that there would not have been a great degree of pre-determination and from the presence of cortex often seem to originate from an initial phase of the core reduction. Currently, there appears to be no specific core reduction sequence that was oriented toward the production of blanks to be selected for bifacial shaping. Once the toolmakers selected the appropriate piece, they shaped it by direct percussion until they achieved the desired dimension and shape in terms of bilateral and bifacial symmetries. The set-up of the desired forms was therefore related to the different parameters of the percussive technique, i.e. the force that was applied, the motion of the percussion  and the location of the impact point (more or less at the interior of the edge). It is only after this shaping procedure that a series of notches was set up, intended to serrate the edges.The Interestingly, no firm signs of reworking were recognised on the serrated pieces, suggesting that the serration was not only the last stage of the manufacturing process, but also its final stage. It suggests to us the existence of a techno-economical distinction between the serrated bifacial pieces that represent finished tools (in terms of morphometric characteristics) and the formal bifacial pieces that seem to have been shaped at different times throughout their life cycles. We can draw two primary conclusions from this observation. First, the serrated pieces under study can all be regarded as finished forms, with the exception of the pieces that fractured during the manufacturing process. Second, the variability of raw materials, dimensions and shapes is not related to differences in their stages of discard.We note a certain amount of variation between the serrated points according to the notches. First of all, we have to acknowledge that the serration is not equally explicit on all the pieces. Some tools are regularly serrated all along their edges while others show more discontinuous serrations. Some tools have deep notches while on others they are very shallow. Also, some tools are bifacially notched while others are only unifacially serrated. The serration never occurs at the base of the points—notches are always visible on the medial part and, to a lesser extent, on the distal part. We consider that this variability is related to the function of the pieces or to the tool that was used to serrate the blank. To help determine the causes of variability we took measurements of all notches , using Photoshop software. The notches have a mean width of 3.2 mm, with a standard deviation of 1.7 mm, and a mean depth of 0.5 mm, with a standard deviation of 0.3 mm.Apart from the raw material, functional factors may explain the variation we observe among the serrated pieces. For the functional analysis, 18 bifacially serrated points or point fragments were considered, as the rest of seven pieces appear not to have been completed, and thus, were never used. The pieces come from the layers Bart, Bea, Casper and Chantal, and also include one serrated piece from the lowermost layer Darya. From the total sample of 18 bifacial serrated points and point fragments, one serrated point with a broken tip (B5-863) had to be excluded due to significant iron deposits and cracking, which prevented a reliable functional analysis. An independent use-wear and residue analysis were performed on the remaining 17 artefacts . DiffereThe serrated pieces from Sibudu represent one peculiar innovation that has presently received little attention. While serration has long been associated with the pressure technique (Crabtree 1973), the question of the technique used to notch the edges of the bifacial blanks still needs to be firmly demonstrated. Similarly, the functional reason for serrated edges still remains to be clarified. It was with two questions in mind—1) how was the serration applied?, 2) what was the serration for?–that we established our methodology.Tools were first screened under a binocular stereoscopic microscope (magnifications up to x56). Potential evidence of use and hafting was documented and a working hypothesis was proposed. Based on this broad examination, relevant tools were selected for detailed functional analysis including residues and use-wear . While aMost tools prior to screening were unwashed and unhandled. However, all had been handled for photography prior to the detailed functional analysis. Such handling resulted in contamination residues, consisting of skin flakes from dust and handling, fibres including easily recognised synthetic fibres, plasticine that was used for mounting some specimens while photographing them, and possibly some of the starch granules . To avoiFifteen tools, including broken fragments, with diagnostic production and/or use-related attributes were selected for residue analysis. The analysis was based primarily on morphological identification of microscopic residues using stereo binocular, metallurgical, transmitted and occasionally scanning electron microscopy.The initial stages of the analysis followed standard micro-residue analytical procedures e.g., ,38) usin usin38])In a subsequent stage, following procedures adopted by Loy  and otheTo further assess residue presence and abundance, tools were placed into an ultra-sonic bath (USB) with distilled water to remove samples of remaining residues from tool surfaces. To help remove contaminants such as fibres and skin cells derived from handling and exposure to air-borne dust, tools were lightly washed in distilled water prior to USB. Treatment was five minutes per bath. Distal and proximal portions of unbroken tools were treated separately. Likewise, for broken pieces, distal or proximal and medial sections of tools were treated separately. For whole tools medial sections were sampled by immersing the already treated proximal ends together with un-treated medial sections into water. Residues removed in this way were analysed in accordance with the pipette samples. In instances where very large amounts of residue were obtained via the USB, sub-samples were scanned until the number of new types encountered in samples plateaued. It should be noted that four tools with sufficient residues for gas chromatography-mass spectrometry (GC-MS and/or GC-GC) analysis and the proximal to medial portion of another tool were not given the USB treatment. The inclusion of the USB procedure has the advantage that samples of all relevant residues were extracted and no further precautions were necessary during subsequent handling and analysis.Selected residues on five tools (four selected for GC-MS) were examined and characterised with the environmental SEM facility (FEI XL30 ESEM-FEG) available at the University of Liège. Micrographs were obtained for respective residues and elemental energy dispersive X-ray (EDX) analysis was undertaken. No coatings were applied during this procedure.3 of each sample was placed into a 6 ml vial with distilled water and disaggregated by vigorous shaking for 2 minutes, then USB treatment for five minutes. Sub-samples of the disaggregated samples were transferred to microscope slides and analysed in accordance with the procedures used for the pipette and USB samples of tool residues.To facilitate our interpretations of production/use-related residues vs environmental/post-depositional residues, analysis of 7 sub-samples of sedimentary layers associated with the stone tools was undertaken . To ensuCommelinideae (grass/sedge) plant material and some woody angiosperm plants including Dilleniidae species   . Diagnosntenance , and ultntenance ,22,42.Procavia capensis); currently a common inhabitant of the rock shelter and highly likely to have lived there during the MSA. This small-sized mammal browses upon a broad spectrum of plants, including sedges and grasses, as well as twigs, shoots, leaves and flowers from shrubs and small trees, lichens and liverworts )On 14 points or point fragments, impact-related damage was observed in association with animal residues and wear features that confirm the points were used as elements in hunting weapons. The distribution of the evidence confirms them having been mounted as tips on shafts. Use-related residues occur in the distal sections of the stone tools and mainly consist of proteinaceous and related residues including tissue fragments, blood, fat and bone, which indicate usage on animal material. The encrustation of several residues within impact-related scarring confirms the tools were used as hunting weapons.Seven complete projectile points were identified, four of which were identified with a high level of confidence  and three with moderate confidence . In addiThe remaining points comprise one distal fragment, one basal fragment and one complete point. These pieces seem to have remained unused: they were mostly preforms fractured during production. It cannot be entirely excluded that some of these fragments fractured in use, but there is insufficient evidence from use-wear traces to support this with any degree of confidence.The projectile evidence consists of a combination of different impact-related fractures and removals on the tips and lateral edges of the points –17. ThisA pronounced difference was observed between the damage patterns on the points made from quartz in comparison to those made from dolerite or hornfels. Damage on the former was significantly more limited and primarily consisted of small unifacial scars and crushing, while significant damage was observed on the dolerite and hornfels points, including partial explosions of the tip. This corresponds to what was also observed experimentally and it is linked to the difference in hardness between the raw materials.The occurrence of transversal fractures is another relevant element for points that may have served as projectiles. In the case of the Sibudu serrated points, this element needs to be integrated with the raw materials used, as these differ in their susceptibility to damage and fracturing. Only 3 of the points made from dolerite (n = 7) had transversal fractures, one of which was only partial , while only one of the quartz points (n = 7) remained complete. Reasons for such discrepancy is probably due to the overall point size differences in the two groups, as well as differences in raw material hardness and the crystalline structure affecting resistance to impact shock.Also, it is documented experimentally that hafting has an influence on the occurrence of transversal fractures, whereupon the least resistant element fractures upon impact . Stone tUnder high magnification, linear features as well as polishes and rounding are visible. In particular the linear features, including MLIT’s  are Equus species of South Africa, or one of the Bovidae species which includes impala. However, this evidence should be treated with caution as one hair fragment with poorly visible hair scales is not sufficient for a positive identification. Further chemical analyses may provide a more definitive answer.Convincing evidence of projectile use also comes from an abundance and broad array of well-preserved animal residues prevalent on all the examined unbroken pieces, as well as three distal fragments ; Fig 19.Another interesting question regarding possible use-related residues comes from the abundance of very small to small sub-round and polygonal starch granules recovered from the tip of the small quartz distal fragment 1075.1. The mean minimum and maximum diameters of granules were 4.98 ± 1.01 and 5.57 ± 1.08 respectively (N = 50) . There aEvidence of hafting was observed in the form of wear traces and residues in the proximal parts of several pieces. Hafting wear evidence primarily consists of scarring, although some limited polish, rounding or linear features occasionally occur Figs  and 20. Podocarpus falcatus wood (Podocarpus is based on the co-occurrence of micro-fossils: starch that occurs in Podocarpus (often a range of morphotypes occurs), tissue fragments with the same cellular arrangement as Podocarpus, fibres and phytoliths. With the possible exception of tissue fragments with isometric crystals, which are strongly diagnostic, none of these micro-fossils in themselves are specific to the genus. However, when they occur all together on one tool, or frequently, across an assemblage of tools, they can be relevant and strongly diagnostic, as is the case here. This interpretation based on morphological analysis is supported by previous studies using chemical analysis of residues on MSA stone tools from two other South African sites, DRS  and Bor. 56 ka; ). At thorpus sp. .Some of the resinous residues occur with fat, micro-charcoal, long strands of plant tissue and red ochre/hematite, collagenous tissue sheets and sinew ; Fig 24.It appears that sinew, dermis and plant tissue were part of the fixation agent or that bindings may have been used in combination with the resin. In some cases large sheets of sinew were clearly compressed along and around edges. However, the extensive spread of animal residues upon impact could account for this and the attribution of animal residue to the potential use of bindings is difficult to ascertain (cf. ). The reUrena lobata L. and Pavonia spp. are likely candidates. Although the Pavonia genus is endemic to the African continent, Urena is thought to be derived from Asia, but this is not known for certain [Pavonia schimperiana Hochst. ex A. Rich., are known to have been used for arrow shafts [Of special interest with regard to possible shaft or binding residues is the small serrated quartz piece 1170 . Numerou certain . Neverth certain . Importaw shafts . TherefoPavonia and Urena spp.The size of the points, in particular their width and thickness, is interesting, and has special implications with regard to hafting. Maximum widths vary between 13 mm and 39 mm for all complete points. Only one quartz point is complete (width 13 mm), but based on at least one projectile base fragment in quartz, a width up to 17 mm is possible. For dolerite, widths vary between 14–39 mm for complete points; for hornfels, maximum widths vary between 23–28 mm, for the quartzite point the maximum width is 18 mm. These maximum widths are relevant in view of the maximal width of the shaft on which these points can potentially be mounted given that their morphology and wear pattern dictates that they would have been mounted in a terminal axial position on the shaft. A shaft end width cannot be wider than the point width as it would stop the projectile from intruding into the animal. To have an even more accurate estimate, the width at the base is also relevant. For quartz, the basal width varies between 9–12 mm, for dolerite between 15–24 mm, for hornfels between 18–22mm. This suggests that either two shaft types and potentially different shaft widths may have been used for the quartz points versus the other points, or one shaft width of about 12 mm was used for all points. The point thickness is also interesting in this regard. While the length and width of the points may vary, their thickness is relatively constant and averages around 8 mm (min. 6 –max. 10 mm) for complete points, independent of raw material. Hence, there seems to have been a conscious attempt to reduce point thickness, suggesting that only one shaft diameter was used. The point thickness is indeed important with respect to hafting, for the shaft diameter and the haft type (juxtaposed or split). Both size parameters indicate that shafts of maximum 12 mm in diameter were probably used. This fits remarkably well with the stem size of the Malvaceae shrubs, Pressure flaking has long been purported to originate as recently as ca 25–20,000 years BP in the Solutrean context –78. HoweAt Sibudu, pressure flaking was previously indicated for the HP layers of Sibudu Cave based on the recovery of bone compressors  and of qMore recently, Högberg and Lombard  have fouIn this context, our study of the serrated pieces of Sibudu provides more evidence for the timing and functional range of the use of pressure in the southern African MSA. Our study is based on multiple lines of evidence . It shows that the serrated bifacial points of Sibudu Cave have been manufactured by pressure with bone compressors. This is not only indicated by the presence of fragments of bone compressors found in association with the points, but also by a very strong body of evidence from technological as well as microscopic wear and residue analyses that bear witness to the contact with bone on the edges of tools within the concavities of retouch negatives. Hence we can conclude that the pressure technique was used to serrate edges of bifacial and unifacial points and that it is older than 77 ka in South Africa.At Sibudu, we have not clearly recognized other evidence supportive of a broader use of pressure. However, we acknowledge that the use of pressure might have been employed variously at the last stage of the shaping, for example, to prepare platforms, to shape the points and, of course, to serrate the edge. In other words, we see no contra-indications of a broader use of bone compressors while shaping a bifacial piece. The use of pressure has technical advantages. It markedly diminishes the risk of failure by having more accurate contact points (priority is given to precision and not to force) and thereby it reduces the risk of breakage. Indeed, though pressure in the hand does not avoid the risk of breakage, the use of such a technique diminishes the vibration waves that expand through the blank, which are often regarded as the main cause of breakage during shaping. We acknowledge that the knappers of Sibudu, though their first intention might have been to serrate edges, might have benefited from the other advantages offered by this technique. Further analysis will provide more information in this regard. One advantage associated with pressure lies in its potential to shape new designs and create these with more consistency.chaînes opératoires: bifacially shaped blanks that have been bifacially serrated and bifacially  retouched blanks that were serrated. The pieces made from quartz only correspond to the former described chaîne opératoire. Moreover, fewer accidents during the serration procedure seemed to have occurred on quartz, as all pieces are finished and show traces of use apart from one specimen. In addition, the raw materials also have considerable size variation. The quartz points are generally smaller than the other rock types relative to the size of the original chosen blanks, but potentially there is also variation in relation to use and hafting.Though the tool production clearly aimed at triangular elongated pieces with serrated edges, we observed an internal variability in the population of serrated pieces from Sibudu. The toolmakers did not use specific original blanks to further shape them into the desired tools. The selection of raw material however, had a great influence on the end-product. For all rock types except quartz, we identified two Our evidence shows that the serrated points have been used as hafted elements in hunting weapons. An association of impact-related wear features and animal residues were observed on the used portions of the points, while hafting-related wear traces and residues were identified on the non-active tool portions. These observations push back the age of hafted projectiles, identified based on functional evidence, for South Africa. Previously, hafted projectiles were identified based on wear and residues for the HP and post-HP MSA of Sibudu Cave ,56,69, wHence, there is growing evidence for hafted projectiles in South Africa of similar ages to other areas, such as Northern Africa ,84 and tEvidence for hafting of the serrated points is equally strong, especially for the use of a compound adhesive for mounting the points to their shafts. The adhesive seems to be similar to that identified by Wadley and colleagues  for the Urena and Pavonia) definitely fit with these criteria and their use as projectile shafts has been documented ethnographically [Macaranga spp.) occur in medial and proximal residues of another slightly larger quartz piece 632, they also occur in distal residues and in the associated sediment samples and may therefore be derived from the sedimentary context rather than a wooden shaft. Given that one of the smallest and one of the largest and widest tools in the assemblage have residues suggestive of being hafted to the short stems of a Malvaceae shrub, it is conceivable that all the pieces in the assemblage were similarly hafted and used in the same manner.It has been inferred based on the location and orientation of the functional evidence that the serrated points would have been mounted as tips on the extremity of a shaft. This is further supported by their symmetrical morphology and shape. An end-on position implies that their size provides conclusive information about shaft widths that were used. Based on the measured widths and thicknesses of the serrated points, it is inferred that a shaft type with a maximum diameter of 12 mm was probably used. The predominantly narrow stems of the shrubby Malvaceae species  spear/arrow shafts that were delivered with a flexible spear-thrower, involving a simple cord twisted around the shaft and used to project the weapon similar to how a sturdy spear-thrower in wood or hard animal material would be used but at lower velocities. None have been documented for Africa, but this is of course also due to the poor chance of cord being preserved. However, based on available data for spears  and praThe question remains whether the size difference between the quartz points and the points made from other raw materials reflects different weapon types. Ethnographically, it has been documented that different projecting modes may co-exist, for example, a thrusting weapon and a projected weapon . GeneraThe new assemblages unearthed at Sibudu fuel the discussion on the temporal and spatial distribution of the bifacial phenomenon during the southern African MSA ,82,102. While the affiliation of the serrates layers within the SB techno-complex may be disputed, it is worth noting that the layers of Sibudu that include the serrated pieces differ in many ways from the overlying SB, though the toolmakers used the same spectrum of raw materials with a clear preference toward dolerite. The main differences between the two relate first to their reduction sequences as the SB is largely dominated by bifacial reduction sequences, with bifacial shaping flakes that compose 91.8% of the lithic assemblage and only a very low proportion of cores . This isThe set of serrated bifacial pieces discovered at Sibudu increase the range of morphological variability within the MSA bifacial pieces. Presently, similar specimens have only been documented in the sequence of Umhlatuzana, but also, a few specimens appear to occur in the so-called ‘Rhodesian Still Bay’ –109. At Morphologically, the serrated points of Sibudu Cave are less elongated than those of Umhlatuzana and the serration on the Sibudu points appears to be overall less indented . HowOur results concur with other authors ,82,102 tpointes aveyronnaises’ from the Chalcolithic context of the Grands Causses Region [Serrated bifacial points occur much later in other areas. Different types of serrated points are known from the Paleoindian period of California and the Southwest of the USA ,115. Anos Region . One ints Region ,118,119.Based on the present literature, the role of the serration on the points has different interpretations. Many authors have suggested that the serration was not necessarily orientated towards function and that such pieces represent a specific design related to specific contexts such as burials or ceremonies , or usedThere is a substantial variation within the set of published serrated points, in terms of morphologies and dimensions (of the blanks and of the notches) as well as potentially, of purposes. The serrated pieces from KZN, both from Sibudu Cave and Umhlatuzana, offer such examples of inter- and intra-variability. Unlike published and later specimens , the seThe analysis of the Sibudu points does not allow a definite conclusion on the functional significance of the serration, but some hypotheses can be proposed. The serration increases the contact area of the point with the animal target upon insertion, which may increase the haemorrhage and bleeding of the animal. While bifacial retouch reinforces the edges and makes them more resistant to damage during projectile impact, it also reduces the cutting capacity of the edges. The serration is perhaps a way to compensate for this loss by again increasing the damaging effect of the edges upon impact, which may lead to an increase in penetration . It may Based on a detailed study of the technological characteristics of the points, the shaping flakes, the wear and residue evidence and the recovery of bone compressors, we show that the bifacial serrated points from the lowermost deposits (Adam to Darya) of Sibudu Cave were notched by pressure flaking. This pushes back the date of the oldest evidence of pressure flaking that was until now associated with the SB context of Blombos Cave dated to ca. 75 ka and with the points from Umhlatuzana said to be older than 70 ka. In addition, the data from Sibudu Cave confirm that the pressure technique may be applied for different production stages, either shaping as demonstrated at Blombos Cave or serrating as it has been proposed at Umhlatuzana.This technology and the set of serrated tools find no equivalent in the present record with the exception of the site of Umhlatuzana. Unlike Sibudu, the pieces from Umhlatuzana are argued to be associated with the SB techno-complex . By contThe excavation of the layers containing serrated points of Sibudu Cave helps to complete our picture of the succession of technological phases that occurred in KwaZulu-Natal and South Africa. Similar to the Pietersburg Industry, our data show that bifacial technology is not restricted to the SB: it actually appears earlier in time and has punctuated manifestations. The implications of these new assemblages of Sibudu Cave within the context of the chrono-cultural framework of the southern African MSA suggest that the bifacial manifestations were diverse and autonomous in South Africa. The data from Sibudu indicate that the bifacial phenomenon represents several temporal and/or regional phases.The serrated pieces from Sibudu Cave introduce new insights in the significance of MSA bifacial technologies. In the SB of DRS for example, the bifacial pieces have been interpreted as cores and mobile tools that were (re-)sharpened from time to time up until their discard , within the framework of populations with a fair degree of mobility. The SB assemblage of Blombos Cave indicates that the on-site manufactured bifacial pieces were used as spear tips for hunting , while iIn addition, the wear and residue evidence shows that these bifacial points were hafted with a compound adhesive as tips on projectile shafts and that they were used to hunt animals. This evidence pushes back the date of projectile points identified based on wear and residue analysis for South Africa to a date older than 77 ka BP. While the functional evidence allowed the identification of the serrated points as projectiles, their exact projecting mode is more difficult to interpret. Nevertheless, there are distinct arguments in favour of bow-and-arrow technology or, alternatively, perhaps flexible spear-throwers (cords).The serration itself is a functional innovation that is presently unique in the MSA. Such functional implements have been documented in much more recent contexts, for instance, during the Holocene in Western Europe, the Paleoindian period of North America and the last millennium in Australia. While denticulates and notches are common modifications on tools, the serration itself seems to be restricted to few contexts and can be regarded as a strong techno-cultural marker.


Background: Despite the guidelines for Economic and Public Health Assessment Committee (CEESP) submission having been available for nearly six years, the dossiers submitted continue to deviate from them, potentially impacting product prices.Objective: to review the reports published by CEESP, analyse deviations from the guidelines, and discuss their implications for the pricing and reimbursement process.Study design: CEESP reports published until January 2017 were reviewed, and deviations from the guidelines were extracted. The frequency of deviations was described by type of methodological concern .Results: In 19 reports, we identified 243 methodological concerns, most often concerning modelling, measurement and valuation of health states and results presentation and sensitivity analyses; nearly 63% were minor, 33% were important and 4.5% were major. All reports included minor methodological concerns, and 17 (89%) included at least one important and/or major methodological concern. Global major methodological concerns completely invalidated the analysis in seven dossiers (37%).Conclusion: The CEESP submission dossiers fail to adhere to the guidelines, potentially invalidating the health economics analysis and resulting in pricing negotiations. As these negotiations tend to be unfavourable for the manufacturer, the industry should strive to improve the quality of the analyses submitted to CEESP. In France, health technology assessment (HTA) for medicines traditionally was clinically driven and was performed solely by the Transparency Committee  – a scientific committee of the French National Authority for Health . However, in 2008, the social security funding law (LFSS) tasked HAS with assessing healthcare interventions and providing recommendations on the most cost-effective medical care and prescription strategies. A dedicaCEESP was initially created as an internal HAS working group with no legal entity, and was introduced in the Social Security Code as a specialised committee following the LFSS for 2012. The decrde facto voting members of the Pricing Committee,[The objective of the CEESP assessment has been clearly defined as providing a tool to inform payers when setting prices for pharmaceuticals and devices. Althoughommittee, their imThe HAS guideline for manufacturers submitting dossiers to CEESP recommends using cost-effectiveness analysis, where quality-adjusted life year (QALY) is listed as one of the options for measuring effectiveness. OvertimeAlthough the technical guidelines for economic evaluation were developed in 2011, along with other guidance for submission, in practice, manufacturers’ submission dossiers continue to deviate from the guidelines, in some cases containing deviations that are considered to have a major impact on the credibility of the results. The aim of this study was to review the assessment reports for pharmaceuticals published by CEESP, and to identify the type of deviations pointed out therein.The official HAS website was screened to identify CEESP pharmaceutical assessment reports published up to January 2017. An Excel table was used to extract (for each report): the name of the product, the international non-proprietary name (INN), date of report publication, overall conclusion on CEESP methodological concerns , and IAB score. All CEESP reports were reviewed, and key deviations from the guidelines were identified and classified into two levels, presented in objective of the study;consistency of the economic evaluation with HAS methodological guidelines, including cost-effectiveness analysis and optional budget impact analysis;CEESP conclusion;appendix presenting all the details about: submission objective, the product and its indication, regulatory history;appendix presenting in detail the CEESP critical analysis of the health economics study, and the results of the health economics study itself (ICER at the requested price and at other prices), taking into account uncertainty and SA.Nineteen CEESP assessment reports for pharmaceuticals were identified on the HAS official website . All of Fourteen of the submissions were for initial registration on the list of reimbursable medicines; two were for registration renewal and three for the extension of indication. All of the reports are summarised in Supplementary Table 1.Overall 243 CEESP methodological concerns about methodological deviations from the HAS guidelines were identified . Almost In the 19 CEESP reports analysed, we identified 75 deviations from the guidance on measurement and valuation of health states and costs, 79 modelling-related deviations, and 61 deviations linked to results presentation and SA. Costs and health states represented, respectively, 56% and 44% of deviations related to measurement and valuation. Deviations related to costs were captured in the following groups: measurement and calculation (52%), cost type (12%) and valuation of costs (36%). Amongst health state-related deviations, 82% were assigned to measurement (methods and data) and 18% to valuation of health states.Deviations related to modelling concerned transition estimates (43%), model structure (39%), the modelled population (13%) and programming errors (5%). Deviations concerning transition estimates related to estimation methods (38%), efficacy data sources (29%), data extrapolation (18%) and reporting issues (15%).Deviations from the guidelines on results presentation and SA concerned SA (59%), presentation of the cost-effectiveness results (20%), and internal/external validity and study limitations (21%). Deviations from guidance on SA were divided between probabilistic/deterministic analyses (86%) and scenario analyses (14%). Distinguishing between probabilistic and deterministic analyses was difficult, as CEESP frequently reports a single deviation for both of them.Finally, 26 deviations were linked to structural choices, mainly to comparators that were inconsistent with clinical practice. Only two products deviations regarded as important were related to study objectives (both medications are indicated for the treatment of adults infected with hepatitis C).Our attention was first drawn towards the major methodological concerns, due to their substantial impact on the manufacturer, whose product is excluded from automatic price setting by external reference pricing and becomes subject to complex, long and usually inflexible pricing negotiations, as for products with marginal or no additional benefit.Results presentation issues, like missing efficiency frontier or wrong calculation for ICER (e.g. ICER pooled between heterogeneous populations), and inappropriately conducted SA  appear as the primary cause for major methodological concerns (six of 11). This is surprising, as it should be quite straightforward to address such comments either in the initial dossier, or following the CEESP review. The two weeks granted to address the CEESP comments should be sufficient to appropriately present the results, or provide a full SA package. Although it is possible that this required a major programming change not addressable in two weeks, it is likely that either the manufacturer misunderstood the requirements or deliberately decided not to address them. In any case the manufacturer has the possibility to ask for a clock stop during the technical exchange.The modelling-related major methodological concerns, linked to estimation of transition probabilities, modelled population or inappropriate structure, represented three cases out of 11. If improperly handled in the initial submission, these types of methodological concerns may be difficult to deal with within the two-week window given to address the CEESP comments. The risk of such issues should be considered in the initial submission.Finally, structural choices  and health state valuation were reported once each as cause of major methodological concerns.In our study sample, seven dossiers (37%) received a global major methodological concern, which is consistent with data based on 30 opinions previously published by HAS. Ten out Important methodological concern may also have serious implications for the manufacturer, as an accumulation of important methodological concerns may lead to a global major methodological concern. Most frequently, important methodological concerns were related to modelling (27 out of 80), followed by results presentation and SA with 23 cases. Obviously, manufacturers should focus their efforts on defining a model structure that is able to capture all relevant outcomes and discriminate in a fair way between treatment strategies.While comparative strategies are well identified and extensively reported in the CT dossier, they are often insufficiently documented for the CEESP dossier, and the choice of comparator(s) for the modelling exercise remains controversial. Although some comparators may not be identified because of their very low use in France, it is likely that some are not considered on purpose, to avoid evidencing some undesirable features. The consultation with CEESP, which happens to be quite open for this process, is the right forum to address those questions. From the authors’ experience, both parties – manufacturers and CEESP – carry the responsibility for an often too superficial discussion in these consultations. Moreover, these consultations usually take place quite late in the process, leaving little room for major adjustments. In any case, it remains the manufacturer’s responsibility to identify all comparators, and to justify why some are excluded from the base case analysis. Some examples of justification include: no price, very low market share, and no clinical data available. CEESP will not state at the early meeting whether a competitor should be included or not. It may advise whether the justification is acceptable, but will not give a definite answer.The most recent CEESP opinion, accessible on the HAS website in January 2017, is dated September 2015. Thus, less than half of the pharmaceutical opinions that CEESP has finalised and communicated to the Pricing Committee are publicly available. In fact, HAS only publishes CEESP opinions after the price negotiations are concluded. This situation is unique to France and rather unfortunate, as it prevents the stakeholders from learning from the experience and identifying CEESP expectations. It clearly suggests that the pricing process is not transparent, as third parties are unaware of the grounds on which the pricing discussions are based. On the contrary, the CT report – which is the main driver for pricing and reimbursement decisions – is made publicly available when final. In a transparent democracy, there is no reason to keep confidential a HTA assessment performed by a public agency that is expected to protect public health. This situation appears unfounded and unacceptable.In its assessment report, CEESP provides multiple inputs to the Pricing Committee when the ICER estimate is considered free of major methodological concerns. Increasingly, CEESP does not limit itself to reporting deviations from the guidelines identified in the methodology, as was the case in the initial assessment reports. More and more, CEESP tends to put its assessment in perspective, to help payers interpret and better use its opinion. This trend is partly visible in the review of the published reports, but it is mainly obvious through the authors’ experience, when reviewing the most recent reports that are not yet publicly available. The broader perspective provided by CEESP includes a strategic interpretation, mainly of the level of uncertainty, the comparator, the feasibility of addressing the uncertainty for the manufacturer, the nature of future evidence that should be collected to address the uncertainty, the ICER estimate under alternative assumptions, and the robustness of clinical evidence. If there are no major methodological concerns, the CEPS will guarantee the average EU price, but will negotiate a rebate to make the net price cost-effective. Thus, the listed price will no longer reflect the cost for the national health insurance. This process resembles the English one, where manufacturers of products that represent substantial innovative features have the opportunity to negotiate a Patient Access Scheme  , with a potential for curing a substantial proportion of patients, raised difficulties when modelling the survival curve while the data are still relatively immature. Evidence has accumulated to support that standard modelling of survival, in terms of drug effect extrapolation beyond RCT duration, does not apply to IOs. Based on the authors’ experience, CEESP remains resistant to any new modelling methods that would account for a proportion of cured patients, while NICE has acknowledged the limitations of the current methodologies. This attitude of CEESP is driven by its preference to adopt a conservative approach and avoid taking any risk with data extrapolation, which may dramatically impact the ICER. This is likely to become a more critical issue in the near future, as multiple new indications for IOs are in development, including in earlier treatment lines, and in combination with other treatments. Because of the high anticipated benefit of those therapies, they are expected to reach the market with a single phase IIB study. This means even more uncertainty for CEESP, as survival modelling will be absolutely necessary to appreciate the value of those products and the method used will dramatically impact the value assessment. Thus, survival extrapolation beyond clinical trial results will become one of the most critical and controversial sources of uncertainty for dossiers submitted to CEESP in the future.CEESP increasingly pinpoints the need for future evidence to strengthen the ICER estimate. This evidence may be related to a better understanding of current clinical practice, associated cost and outcomes. It is often focused on how the product will be used after launch, in which population, and what will be the associated outcome.This information is an obvious call for coverage with evidence development, framing the nature of the studies to be requested by the Pricing Committee for the future reassessment of the drug. It may also trigger an earlier reassessment to address some of the uncertainties before the usual five-year reassessment period. CEESP considers that if an uncertainty may be addressed through a post-launch commitment within less than three years, it is acceptable to go for coverage with evidence development. If it woCEESP will, under some circumstances, run the model using different assumptions or different inputs than the manufacturer and provide this information to the CEPS. This information may be very useful for the Pricing Committee, as it may enhance the robustness of the ICER estimate and reduce the uncertainty.CEESP may sometimes evaluate the quality of the clinical evidence, allowing the Pricing Committee to integrate those limitations in the price negotiation with the manufacturer. Low quality of clinical evidence is attributable to the development plan and clinical trial design, which is a responsibility of the manufacturer. Therefore, the more lenient approach expected when an aspect of uncertainty is impossible to address may not apply, and the Pricing Committee may adopt a stricter attitude in the negotiation.While the review of clinical evidence is performed by CT at HAS, it appears from recent research that the concerns of CEESP regarding clinical trial robustness are generally consistent with the CT ones. However, the CT evaluation is more comprehensive and may be, in the future, a useful source of information for CEESP.While jurisdiction transferability is rarely addressed by CEESP, and more often by CT, generalisability is consistently discussed. Unfortunately, it is not addressed in a systematic way, but rather considered through value judgement and questioning the generalisability of outcomes, with no clear assessment of how poor or no generalisability impacts the interpretation of clinical trials results. In most cases, CEESP reports substantial doubts on the generalisability of the modelling outcome, but, occasionally, they may instead state that the generalisability is high. The top-line level of assessment makes it very difficult to integrate such non-quantitative judgement into the pricing negotiations. This is clearly an area for improvement in the future.External validity remains an important question and needs to be well addressed by the applicant, as it may jeopardise the pricing outcome. If the external validity is not well addressed in the manufacturer’s application, it will lead to an overall poor CEESP assessment and raise questions regarding uncertainty. Thus, the applicant should make substantial efforts to address external validity issues in the health economics analysis, for example through confronting the model with epidemiological evidence, burden of illness studies, and other models.Internal validation is an important point for the CEESP assessment. Whatever the quality control performed, any model – especially when complex – may never be completely free of errors. Of the 19 models analysed, four programming errors in three different models were reported by CEESP. Out of the four, three led to important methodological concerns. If the applicant has documented an extensive internal validation, then the discovery of programming errors would be less detrimental to the outcome of the assessment.In the reassessment of a product, which is expected every five years in France, providing national real-world evidence to feed the model is highly appreciated by CEESP. In contrast, not providing such information raises questions regarding the good will and commitment of the manufacturer, and may lead to a more stringent assessment. This real-world evidence may be based on database analysis, registries, ad-hoc cohort studies or chart abstraction. Any efforts to use national data to evaluate the efficiency of a product in the French context is seen as positive by CEESP.CEESP is expected to state the conditions for efficiency of a new product, which are considered important for price negotiation by the Pricing Committee. However, this concept is unclear, and no definition is yet available. In the framework agreement (accord cadre) between the Pricing Committee and the French National Research Based Pharmaceutical Union (LEEM), the condInitially, the CEESP opinion was supposed to provide an assessment of the deviations from the HAS guidelines within the methodology of the submitted dossier. This is now the first step of the CEESP conclusion. The second step considers the conditions for efficiency, reflecting a growing role of CEESP in advising the Pricing Committee, but will be documented only if no global major methodological concern has been expressed. During this second step of assessment, CEESP will assess the conditions for efficiency and interpret the efficiency frontier. The efficiency frontier is, however, not an appropriate way to overcome the lack of ICER threshold that allows drawing conclusions on efficiency.,21The French health economics assessment remains inefficient in some aspects. There is a duplication of work between CEESP and CT, as CEESP does not benefit from CT input. This duplication of work within the same public organisation is unlikely to persist, as there is a high requirement for improving the efficiency of governmental administration.It is considered that about 50% of CEESP opinions will not be used, as – ultimately – after the CEESP assessment, CT may not grant the IAB score of I–III that makes the product eligible for health economics assessment.However, it is possible that the Pricing Committee might make use of these assessments during price negotiation.de facto implicitly exists, renders CEESP conclusions complex to formulate and often unclear. CEESP will accommodate the issue in its wording and perform multiple interpretations of the results for different potential thresholds. Moving towards an explicit threshold is now imperative for producing clear and easily interpretable opinions.The lack of clarity about a threshold that Overall, the importance of health economics for the pricing of innovative pharmaceuticals has grown within the French environment. CEESP has gained high credibility through professional and expert management of its duties defined by law. The quality of the CEESP assessment reports is recognised and the intellectual acuity of the assessors is obvious when reviewing them. Over time, the level of CEESP expectations has been increasing, and applications should not be expected to differ in terms of strength and quality from those submitted to NICE. The influence of the CEESP assessment on the Pricing Committee decisions is growing fast. For the manufacturers, the consequences of global major methodological concerns are severe, warranting continuous efforts to match the CEESP expectations. At more than a third, the proportion of dossiers submitted to CEESP that warrant a global major methodological concern is currently too high and could be expected to decrease over time, thanks to the growing experience of the applicants, the development of study reporting templates, and further specification of the HAS health economics guidelines. The most frequent major methodological concerns, related to results presentation and SA, should be better addressed by applicants in the future. The applicants’ efforts to file an appropriate dossier will substantially increase to match the efforts made when preparing NICE dossiers in the UK. The French pharmaceutical market is by far larger than the UK one, and has Click here for additional data file.


Raising interest in the interaction between humans and climate drivers to understand the past and current development of floods in urbanised landscapes is of great importance. This study presents a regional screening of land-use, rainfall regime and flood dynamics in north-eastern Italy, covering the timeframe 1900–2010. This analysis suggests that, statistically, both climate and land-use have been contributing to a significant increase of the contribution of short duration floods to the increase in the number of flooded locations. The analysis also suggests that interaction arises, determining land-use dynamics to couple with climatic changes influencing the flood aggressiveness simultaneously. Given that it is not possible to control the climatic trend, an effective disaster management clearly needs an integrated approach to land planning and supervision. This research shows that land management and planning should include the investigation of the location of the past and future social and economic drivers for development, as well as past and current climatic trends. The year 2015 was a remarkable year in global policy with the publication of three milestone UN agreements regarding the Disaster Risk Reduction, Sustainable Development Goals and Climate Change237101112131410111517Ch) (see Chapter Methods: Observatory data). An index of rainfall concentrationa) describes the input given by short but intense rainfall to the total rainfall amount, to investigate the climate dimension. Finally, flood dynamics are studied using an index of flood concentration (Fla) indicating the contribution of short duration floods respect to the increase in the percentage of the flooded locations .While the global process of urbanisation continues, world’s climate changes result in more frequent and more intense floodingThe analysis focuses on the Veneto region  , a paradCitta diffusaLike many other highly developed nations, highly governed landscapes such as the reclaimed areas of Veneto, are landscapes that have been subject to even greater degrees of human manipulation than normal cultural landscapes26p-value 0.0275). The imperviousness in the 70s  increased more than 30% per year, resulting in Veneto being the second Italian region for GDP283/ha. Covering land with impermeable layers reduces the amount of rain that can be absorbed by the soil. The average changes in imperviousness between 1970 and 1990 (~6%) and between 1990 and 2009 (~2%) can roughly imply in a loss of ~30 M m3 and ~10 M m3 of water storage over the whole region. In cities with a high proportion of sealed surfaces this loss of storage, especially during heavy rains, can quickly overwhelm drains, causing sewage systems to overflowThe analysed urban sprawl and the development of urban land also transformed the properties of soil, reducing its capacity to perform its essential functions. A fully functioning soil for the analysed landscapeThe climatic trends  are in lp-value 0.086) trend of increase of the concentration of the rainfall. The average Climatic aggressiveness (Cla) moves from 0.59 (in 1910–1930) to a value of 0.64. The high value of the last timeframe might be in line with the changes in the decadal climate of the years 1991–2000 and 2001–2010a seems to increase constantly during the five timeframes, the timeframe 1970–1990 shows a sensible decrease in the index compared the previous time spans, especially in the central part of the region. Climatically, the region registered a statistically negative trend in the yearly amount of rainfall, more marked in the winter season, with a drastic variation of the winter events in the 80s38Overall, there is a general statistically significant  of the region appears to be the one distinctly different from the rest of the area regarding precipitation concentration, with the higher values of ClThe overall trend between the percentage of flooding days in each year and the number of flooded locations for the whole 1900–2010 timeframe shows the presence of drastic changes in the curve steepness  are related to major flood events that affected the region in 1928 . In the timeframe 1950–1970, the high slope of the trend is mostly due to the two major events (1951 and 1966). Differently, in the recent decade (1990–2010), the trend seems to be related to a larger number of flood events with a relatively shorter duration (fewer days of floods), which hit a greater number of locations, in addition to the two major floods (1992 and 1998). Thus, suggesting a larger coupling of the land-use and climatic influence for the more recent timeframe.It is interesting to notice that 1) the analysis of the days of floods VS flooded locations allows to identify clearly major events; 2) between these major events, the trends between days of flood and the percentage of the flooded locations appear to be constant. Analysing the graph considering the timeframes proposed for the research , it is possible to define statistically significant relationships .The 1910 to 2010 trend is non-significant, both including and excluding the major flood events. The data in the 1910–1930 timeframe are, however, hindered due to the nature of the considered database, that covers only non-systematically the periods 1900 to 1916In both 1970–1990 and 1990–2010, the areas having the larger changes in imperviousness  do not nch and Cla have a significant effect on Fla.In both timeframes, there is a significant relationship between the flood concentration and the rainfall concentration . Individm changes in 5 in 101115The statistical significance and the changes in order of magnitude  while varying the other. The average effect is shown as a circle, while the horizontal bars are showing the confidence interval for the estimated effect.To better exemplify and analyse the interaction among changes in imperviousness and climatic concentration, a at the increase in rainfall concentration . However, for Medium-Low values of Cla, changes in imperviousness does not seem to have a great impact on the flood concentration, but still, they imply a slightly positive variation in Fla, at least in the 1970–1990 timeframe. It is interesting to notice, however, that for the least aggressive climate  effect on the flood concentration  and changes in imperviousness (Impup) upstream it is possible to partially draw the same conclusions as described for the local Cla and Impch .For the rainfall concentration  has an opposite effect on the local flood concentration. However, when the local imperviousness changes are high (Impch = High), the changes in climate upstream lose their effect on Fla  the location of values and key components of the economy provided and provides the primary reason for developments being placed there, but at the same time created and creates risks for the society in terms of flood-exposed goods and thus loss potential (high flood aggressiveness); (ii) in areas where the economy shifts are less evident , the changes in rainfall intensity upstream might assume a greater importance, transferring their consequences downstream, depending on the local rainfall intensity.From the analysis, it can be seen that while climate highly impact the flood trends, but with constant influences, many drivers connected to land use are also prominent, and they change during the years. The economic development and consequent increase in urban areas historically effected the largest extent in the region (in 1970–1990). For the same timeframe, the climatic trend in the area was highly aggressive towards the coastal areas, and population and hence consumption, but also higher exposure, was biased towards the same area. These two changes coupled locally, resulting in the highest flood concentration. Differently, in 1990–2010, the rainfall status showed similar behaviours, but urbanisation increase mostly in a relatively larger area of the lower Pre-Alps in addition to the floodplain, thus interactions between land use and climate might have been transferred downstream, increasing the flood concentration in an area where such issue was already evident in the past. This type of interactions can also be foreseen for the future, although as of now they remain relatively unexplored.This research emphasises the need for an integrated analysis system that can represent the effects of climate, and the interface with socio-economic effects as both drivers and receptors of flood risk . Given that the climatic trend cannot be controlled, an effective land management clearly needs an integrated approach for catchment planning and supervision. It should cover the analysis of the location of the past and future drivers for development as well as the past and future drivers of climatic inputs.All Saints flood (2010), that caused the largest up to date economic and social impact in the region. This timeframe has been divided four intervals  considering that 20 years could be long enough for meaningful assessments of climate changeThe analysis focuses on the years 1910 to 2010, excluding 2010. This, to investigate dynamics antecedent to the year of the To investigate the changes in floods, a complete database of floods and landslide events is availableFor the change in land use, the analysis focused on the variations in the built-up areas (or changes in imperviousness). This because changes in artificial coverage have a dual effect on floods: i) a direct hydrologic effect increasing runoff, and ii) an increase in the exposed number of goods. Furthermore, changes in the built-up areas can imply a modification to the drainage system, with changes to the drainage network and conversion to urban drainage system15Ufficio Idrografico del Magistrato alle Acque di Venezia). Specifically, the products used in this study are rain gauge quantitative precipitation estimates in daily accumulation. The ARPAV dataset comprises rainfall values from 1994 to current days. The Hydrographic Office network, instead, covers the XX century, up to 1994, when the management of the rain-gauge network was delegated to the regional environmental protection agencies.For the rainfall dataset, data related to the number of days of rain, and the related cumulated rainfall, were acquired from the automatic weather station network of the Regional Agency for Environmental Protection and Prevention of Veneto (ARPAV), and from the historical values recorded by the network of the Hydrographic Office of the Venice Water (a) ranges from 0 to 1, and higher values imply that less days of rain contribute to a notable increase in the accumulated rainfall. The idea of concentration was extended to floods, considering the number of days of flood and the number of flooded sites within the same municipality. Higher values of the flood concentration index (Fla) imply that less days of flood contribute to a notable increase in the percentage of the flooded locations.The index of rainfall concentrationi), is listed. From these values, the cumulative frequencies are obtained (∑ni) by adding the absolute frequencies of all the classes up to the one under consideration, the last one included. ni is multiplied, class by class, with the class midpoint, obtaining the total of each class (Pi). The cumulative frequencies of Pi (∑Pi) are computed. Finally, ∑Pi and ∑ni are presented in percentages respect to their total. These results give the graphic representation shown in For the computation of the indices, the considered variable  is divided into classes, and it is presented in ascending order. For each class, a midpoint is evaluated, as a sufficiently precise characterizationIn both cases, the resulting polygonal line is markedly exponential and can be represented by an exponential curve of the typea and b can be computed by means of the least-squares methodwhere S enclosed by the bisector and the polygonal line provides a measure of concentration because the greater the area, the greater the concentration.The bisector of the graphs in a and b  or municipality centroid (for Fla) using two different techniques. For the Cla, the ordinary kriging interpolator was chosen to make this study comparable to a previously published research showing values of the Cla for the regiona, a simple inverse distance weighting technique was applied: this considering the localised nature of a flood .Distributed maps were then obtained by interpolating the local values for each rainfall station (for Clup) and rainfall concentration (Clup) were accumulated downstream, based on the local topography and flow directionsch and ‘upstream changes in imperviousness’ or ‘upstream land use changes’ when speaking about Impup. Similarly, ‘local climatic concentration’ or ‘local climatic aggressiveness’ will be used for Cla in opposition to ‘upstream climatic concentration’ or ‘upstream climatic aggressiveness’ for Clup.To evaluate the effect due to land-use changes and climatic concentration downstream, imperviousness  or Imp (Impj) to all locations found having flood concentration in the range of Flj − 0.01 – Flj + 0.01. For discussion purposes, the binned values for each parameter have been classified in four classes named High, Medium-High, Medium-Low and Low according to a Natural Breaks Classification, seeking to minimise each class’s average deviation from the class mean, while maximising each class’s deviation from the means of the other groups. The significance of each model was given through an analysis of variance (ANOVA). All the assumptions for the regression models were checked and, in the case of non-linearity between explanatory and response variables, the datasets were opportunely transformed. As for the other trends, the significance threshold level for the ANOVA was set to p < 0.10.The relationship between landuse, climate, and flood aggressiveness relies on the time frames 1970–1990 and 1990–2010, for which there was the availability of all three parameters. The flood concentration was set to be the dependent variable, while imperviousness changes and rainfall concentration were configured to be the explanatory variables. Multiple linear regression models were used to test the ability of each explanatory variable, taken as a single predictor or implying an interaction (the situation in which the simultaneous influence of two variables on a third is not additive) among them, to predict the response variable. To reduce the high variability, the raw flood concentration values were aggregated (binned) into 0.01 intervals, and a mean value for each bin was evaluated. Significant samples for the analysis were therefore obtained by assigning an average value of FlHow to cite this article: Sofia, G. et al. Flood dynamics in urbanised landscapes: 100 years of climate and humans’ interaction. Sci. Rep.7, 40527; doi: 10.1038/srep40527 (2017).Publisher's note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.