Clémentine Ols
email: clementine.ols88@gmail.com

Valérie Trouet

Martin P Girardin

Annika Hofgaard

Yves Bergeron

Igor Drobyshev

Post-1980 shifts in the sensitivity of boreal tree growth to North Atlantic Ocean dynamics and seasonal climate Tree growth responses to North Atlantic Ocean dynamics

Keywords: Climate change, Dendrochronology, Climate-growth interactions, Response functions, Teleconnections, Arctic amplification

 A significant boreal tree growth response to oceanic and atmospheric indices emerged during the 1980s.  This was particularly observed in western and central boreal Quebec and in central and northern boreal Sweden.  The post-1980 sensitivity to large-scale indices synchronized with changes in tree growth responses to local climate.

 Future large-scale dynamics may impact forest growth and carbon sequestration to a greater extent than previously thought.

Introduction

Terrestrial biomes on both sides of the North Atlantic Ocean are strongly influenced by Arctic and Atlantic oceanic and atmospheric dynamics [START_REF] D'arrigo | NAO and sea surface temperature signatures in tree-ring records from the North Atlantic sector[END_REF][START_REF] Ottersen | Ecological effects of the North Atlantic Oscillation[END_REF][START_REF] Gerardin | Une classification climatique du Québec à partir de modèles de distribution spatiale de données climatiques mensuelles : vers une définition des bioclimats du Québec. Direction du patrimoine écologique et du développement durable[END_REF]. Some mid-20 th century changes in the dynamics of the North Atlantic Ocean have been considered as early signs of tipping points in the Earth climate system [START_REF] Lenton | Tipping elements in the Earth's climate system[END_REF][START_REF] Lenton | Early warning of climate tipping points[END_REF]. The Atlantic Meridional Overturning Circulation (AMOC) exhibited an exceptional slow-down in the 1970s [START_REF] Rahmstorf | Exceptional twentieth-century slowdown in Atlantic Ocean overturning circulation[END_REF]. The cause of this slow-down is still under debate, but possible explanations include the weakening of the vertical structure of surface waters through the discharge of low-salinity fresh water into the North Atlantic Ocean, due to the disintegration of the Greenland ice sheet and the melting of Canadian Arctic glaciers. A further weakening of the AMOC may possibly lead to a wide-spread cooling and decrease in precipitation in the North Atlantic region [START_REF] Sgubin | Abrupt cooling over the North Atlantic in modern climate models[END_REF], subsequently lowering the productivity of land vegetation both over northeastern North America and northern Europe [START_REF] Zickfeld | Carbon-cycle feedbacks of changes in the Atlantic meridional overturning circulation under future atmospheric CO2[END_REF][START_REF] Jackson | Global and European climate impacts of a slowdown of the AMOC in a high resolution GCM[END_REF]. Despite increasing research efforts in monitoring climate-change impacts on ecosystems, effects of late 20 th century changes in North Atlantic Ocean dynamics on mid-to high-latitude terrestrial ecosystems remain poorly understood.

The dynamics of North Atlantic oceanic and atmospheric circulation, as measured through the AMOC, North Atlantic Oscillation (NAO) and Arctic Oscillation (AO) indices, strongly influence climate variability in northeastern North America (NA) and northern Europe (NE) [START_REF] Hurrell | Decadal trends in the north atlantic oscillation: regional temperatures and precipitation[END_REF][START_REF] Baldwin | Propagation of the Arctic Oscillation from the stratosphere to the troposphere[END_REF][START_REF] Wettstein | The influence of the North Atlantic-Arctic Oscillation on mean, variance, and extremes of temperature in the Northeastern United States and Canada[END_REF]. NAO and AO indices integrate differences in sea-level pressure between the Iceland Low and the Azores High [START_REF] Walker | Correlation in seasonal variation of weather. IX. A further study of world weather[END_REF], with high indices representative of increased west-east air circulation over the North Atlantic. Variability in AMOC, NAO and AO indices affects climate dynamics, both in terms of temperatures and precipitation regimes. Periods of high winter NAO and AO indices are associated with below-average temperatures and more sea ice in NA and a warmer-and wetter-than-average climate in NE. Periods of low winter NAO and AO indices are, in turn, associated with above-average temperatures and less sea ice in NA and a colder-and dryer-than-average climate in NE [START_REF] Wallace | Teleconnections in the geopotential height field during the Northern Hemisphere Winter[END_REF][START_REF] Hellström | The influence of the North Atlantic Oscillation on the regional temperature variability in Sweden: spatial and temporal variations[END_REF]. Low AMOC indices induce a wide-spread cooling and decrease of precipitation across the high latitudes of the North Atlantic region [START_REF] Jackson | Global and European climate impacts of a slowdown of the AMOC in a high resolution GCM[END_REF].

Boreal forests cover most of mid-and high-latitude terrestrial regions of NA and NE and play an important role in terrestrial carbon sequestration and land-atmosphere energy exchange [START_REF] Betts | Offset of the potential carbon sink from boreal forestation by decreases in surface albedo[END_REF][START_REF] Bala | Combined climate and carbon-cycle effects of large-scale deforestation[END_REF][START_REF] De Wit | Climate warming feedback from mountain birch forest expansion: Reduced albedo dominates carbon uptake[END_REF]. Boreal forests are sensitive to climate change [START_REF] Gauthier | Boreal forest health and global change[END_REF]. Despite general warming and lengthening of the growing season at mid-and high-latitudes [START_REF] Karlsen | Growing-season trends in Fennoscandia 1982-2006, determined from satellite and phenology data[END_REF]IPCC, 2014), tree growth in many boreal regions lost its positive response to rising temperatures during the late-20 th century [START_REF] Briffa | Reduced sensitivity of recent tree-growth to temperature at high northern latitudes[END_REF]). An increasing dependence on soil moisture in the face of the rapid rise in summer temperatures may counterbalance potential positive effects on boreal forest growth of increased atmospheric CO2 concentrations [START_REF] Girardin | No growth stimulation of Canada's boreal forest under half-century of combined warming and CO2 fertilization[END_REF]. During the late 20 th century, large-scale growth declines [START_REF] Gerardin | Une classification climatique du Québec à partir de modèles de distribution spatiale de données climatiques mensuelles : vers une définition des bioclimats du Québec. Direction du patrimoine écologique et du développement durable[END_REF] and more frequent low growth anomalies [START_REF] Ols | Previous growing season climate controls the occurrence of black spruce growth anomalies in boreal forests of Eastern Canada[END_REF]-in comparison with the early 20 th century-have been reported for pristine boreal spruce forests of NA. In coastal NE, climatic changes over the 20 th century have triggered shifts from negative significant to non-significant spruce responses to winter precipitation [START_REF] Solberg | Shifts in radial growth responses of coastal Picea abies induced by climatic change during the 20th century, central Norway[END_REF]. Annual variability in boreal forest tree growth patterns have shown sensitivity to sea ice conditions [START_REF] Gerardin | Une classification climatique du Québec à partir de modèles de distribution spatiale de données climatiques mensuelles : vers une définition des bioclimats du Québec. Direction du patrimoine écologique et du développement durable[END_REF][START_REF] Drobyshev | Atlantic SSTs control regime shifts in forest fire activity of Northern Scandinavia[END_REF] and variability in SSTs [START_REF] Lindholm | Growth indices of North European Scots pine record the seasonal North Atlantic Oscillation[END_REF]. All changes in boreal tree growth patterns and climate-growth interactions listed above may be driven by the dynamics of the North Atlantic Ocean. Understanding current and projected future impacts of North Atlantic Ocean dynamics on boreal forest ecosystems and their carbon sequestration capacity calls for a deeper spatiotemporal analysis of tree growth sensitivity to large-scale oceanic and atmospheric dynamics.

The present study investigates tree growth responses to changes in North Atlantic

Ocean dynamics of two widely distributed tree species in the boreal forests of northeastern North America (black spruce) and northern Europe (Norway spruce). We investigated treegrowth sensitivity to seasonal large-scale indices (AMOC, NAO; AO) and seasonal climate (temperature and precipitation) over the second half of the 20 th century. We hypothesize that shifts in tree growth sensitivity to large-scale indices and local climate are linked to major changes in North Atlantic Ocean dynamics. This study aims to answer two questions: (i) has boreal tree growth shown sensitivity to North-Atlantic Ocean dynamics? and (ii) does tree growth sensitivity to such dynamics vary through space and time, both within and across NA and NE? 2 Material and methods

Study areas

We studied two boreal forest dominated areas under the influence of large-scale atmospheric circulation patterns originating in the North Atlantic: the northern boreal biome of the Canadian province of Quebec (50°N-52°N, 58°W-82°W) in NA and the boreal biome of Sweden (59°N-68°N, 12°E-24°E) in NE (Fig. 1a). The selection of the study areas was based on the availability of accurate annually-resolved tree growth measurements acquired from forest inventories.

In northern boreal Quebec, mean annual temperature increases from north to south (-5 to 0.8 °C) and total annual precipitation increases from west to east (550 to 1300 mm), mainly due to winter moisture advection from the North Atlantic Ocean [START_REF] Gerardin | Une classification climatique du Québec à partir de modèles de distribution spatiale de données climatiques mensuelles : vers une définition des bioclimats du Québec. Direction du patrimoine écologique et du développement durable[END_REF]. In boreal Sweden, annual mean temperature increases from north to south (-2 to 6 °C) and annual total precipitation decreases from west to east (900 to 500 mm), mostly because of winter moisture advection from the North Atlantic Ocean that condenses and precipitates over the Scandinavian mountains in the west (Sveriges meteorologiska och hydrologiska institut (SMHI), 2016).

The topography in northern boreal Quebec reveals a gradient from low plains in the west (200-350 m above sea level [a.s.l.]) to hills in the east (400-800 m a.s.l.). In boreal Sweden, the topography varies from high mountains (1500-2000 m a.s.l.) in the west to low lands (50-200 m a.s.l.) in the east along the Baltic Sea. However, mountainous coniferous forests are only found up to ca. 400 m a.s.l. in the north (68°N) and ca. 800 m a.s.l. in the south (61°N).

Tree growth data

We studied tree growth patterns of the most common and widely distributed spruce species in each study area: black spruce (Picea mariana (Mill.) Britton) in Quebec and Norway spruce (P. abies (L.) H. Karst) in Sweden. A total of 6,876 and 14,438 tree-ring width series were retrieved from the Quebec (Ministère des Ressources naturelles du Québec, 2014) and Swedish forest inventory database (Riksskogstaxeringen, 2016), respectively. We adapted data selection procedures to each database to provide as high local coherence in growth patterns as possible.

For Quebec, core series were collected from dominant trees on permanent plots (three trees per plot, four cores per tree) between 2007 and 2014. Permanent plots were situated in unmanaged old-growth black spruce forests north of the northern limit for timber exploitation.

Core series were aggregated into individual tree series using a robust bi-weighted mean (robust average unaffected by outliers, [START_REF] Affymetrix | Statistical Algorithms Description Document[END_REF]. To enhance growth coherence at the local level, we further selected tree series presenting strong correlation (r > 0.4) with their respective local landscape unit master chronology. This master chronology corresponds to the average of all other tree series within the same landscape unit (landscape units are 6341 km 2 on average and delimit a territory characterized by specific bioclimatic and physiographic factors [START_REF] Robitaille | Paysages régionaux du Québec méridional[END_REF]). This resulted in the selection of 790 tree series that were averaged at the plot level using a robust bi-weighted mean. The obtained 444 plot chronologies had a common period of 1885-2006 (Table 1). Plot chronologies were detrended using a log transformation and a 32-year spline de-trending, and pre-whitened using autocorrelation removal [START_REF] Cook | The smoothing spline: an approach to standardizing forest interior tree-ring width series for dendroclimatic studies Tree-Ring[END_REF]. Detrending aims at removing the lowfrequency age-linked variability in tree-ring series (decreasing tree-ring width with increasing age) while keeping most of the high-frequency variability (mainly linked to climate). Prewhitening removes all but the high frequency variation in the series by fitting an autoregressive model to the detrended series. The order of the auto-regressive model was selected by Akaike Information Criterion [START_REF] Akaike | A new look at the statistical model identification[END_REF].

For Sweden, core series were collected within the boreal zone of the country (59°N-68°N) on temporary plots between 1983 and 2010. Temporary plots were situated in productive forests, i.e. those with an annual timber production of at least 1m 3 /ha. These forests encompass protected, semi-natural and managed forests. In each plot, one to three trees were sampled, with two cores per tree. Swedish inventory procedures do not include any visual and statistical cross-dating of core series at the plot level. To filter out misdated series, we aggregated core series into 4067 plot chronologies using a robust bi-weighted mean, and compared them to Norway spruce reference chronologies from the International Tree-Ring Data Base (International Tree Ring Data Bank (ITRDB), 2016). In total, seven ITRDB reference chronologies were selected (Fig. 1b), all representative of tree growth at mesic sites in boreal Sweden. Plot and reference chronologies were detrended and pre-whitened using the same standard procedures used for the Quebec data. Each plot chronology was then compared with its geographically nearest reference chronology -determined based on Euclidean distance -using Student's t-test analysis [START_REF] Student | The probable error of the mean[END_REF]. Plot chronologies with a t-test value lower than 2.5 with their respective nearest reference chronology were removed from further analyses (the t-test value threshold was set up according to the mean length of plot chronologies (Table 1)). A total of 1256 plot chronologies (with a common period of passed this quality test (Table 1).

Spatial aggregation of plot chronologies into regional chronologies in each study area

Quality checked chronologies at the plot level were aggregated into 1° x 1° latitude-longitude grid cell chronologies within each study area (Fig. 1b). Grid cell chronologies were calculated as the robust bi-weighted mean of all plot chronologies within each grid cell. 1812-2008 1929-2008 containing less than three plot chronologies were removed from further analyses. This resulted in a total of 36 and 56 grid cell chronologies in Quebec and Sweden, respectively (Fig. 1b, Table 1). Grid cells contained on average 12 and 23 plot chronologies in Quebec and Sweden, respectively (Table 1).

To investigate the influence of spatial scale in climate-growth sensitivity analyses, we performed an ordination of grid cell chronologies within each study area over their common period (Fig. 1c). The common period between grid cell chronologies was 1885-2006 and 1936-1995 in Quebec and Sweden, respectively. Ordination analyses were performed in R using Euclidean dissimilarities matrices (dist function) and Ward agglomeration (hclust function) methods. Three main clusters were identified in each study area (Fig. 1c). Spatial extents of all clusters were consistent with well-defined bioclimatic regions, providing support to data selection procedures. In Quebec, clusters identified in the West (Q_W) and the East (Q_E) corresponded well to the drier and wetter northern boreal region, respectively (Fig. 1b &c). In Sweden, the cluster identified in the South (S_S) corresponded to a combination of the nemo-boreal and southern boreal zones [START_REF] Moen | National Atlas of Norway. Vegetation[END_REF]. The Swedish central (S_C) and northern (S_N) clusters corresponded to the mid-boreal and northern boreal zones, respectively (Fig. 1b &c) [START_REF] Moen | National Atlas of Norway. Vegetation[END_REF]. Regional chronologies were built as the average of all grid cell chronologies within a cluster. In Sweden, inter-cluster correlations were all significant and ranged from 0.77 (S_S vs S_N) to 0.94 (S_C vs S_N). In Quebec, inter-cluster correlations were all significant and ranged from 0.44 (Q_W vs Q_E) to 0.52 (Q_C vs Q_E) (see Appendix S1-S3 in Supporting Information). Henceforward, the terms 'local level' and 'regional level' refer to analyses focusing on the grid cell chronologies and the six regional chronologies, respectively. ⋇ (swed011, swed012, swed013, swed014, swed015, swed017 and swed312). The grey shading indicates the boreal zone delimitation according to [START_REF] Brant | An introduction to Canada's boreal zone: ecosystem processes,health, sustainability, and environmental issues[END_REF].

Climate data

For each grid cell, we extracted local seasonal mean temperature and total precipitation data from the CRU TS 3.24 1° x 1° [START_REF] Harris | Updated high-resolution grids of monthly climatic observations ---the CRU TS3.10 dataset[END_REF], with seasons spanning from the previous (pJJA) through the current summer (JJA). Climate data were further aggregated at the regional level as the robust bi-weighted mean of climate data of all grid cells contained in each regional cluster (Fig. 1b &c). Seasonal AMOC indices (1961( -2005( , first AMOC measurements in 1961) ) were extracted from the European Center for Medium-Range Weather Forecast (Ocean Reanalysis System ORA-S3). Seasonal AO andNAO indices (1950-2008) were extracted from the Climate Prediction Center database (NOAA, 2016). Seasonal AMOC, NAO, and AO indices included previous summer, winter (DJF), and current summer. All seasonal climate data were downloaded using the KNMI Climate Explorer [START_REF] Trouet | KNMI Climate Explorer: A web-based research tool for high-resolution paleoclimatology[END_REF]) and were detrended using linear regression and thereafter pre-whitened (autocorrelation of order 1 removed from time series).

Links between seasonal climate and growth patterns

Analyses were run over the 1950-2008 period (the longest common period between tree growth and climate data), except with AMOC indices which were only available for 1961-2005. Tree growth patterns were correlated with seasonal climate variables (previous-tocurrent summer temperature averages and precipitation sums) and seasonal indices (previous summer, winter, and current summer AMOC, NAO, and AO) at the regional and local levels.

To minimize type I errors, each correlation analysis was tested for 95% confidence intervals using 1000 bootstrap samples. In addition, moving correlation analyses (21-yr windows moved one year at a time) were performed at the regional level using the same procedures as above. All calculations were performed using the R package treeclim [START_REF] Zang | treeclim: an R package for the numerical calibration of proxyclimate relationships[END_REF].

For more details regarding bootstrapping procedures please see the description of the "dcc" function of this package.

Results

Tree growth responses to seasonal climate

Some significant climate-growth associations were observed at the regional level (Fig. 2).

Significant associations at the local level displayed strong spatial patterns and revealed heterogeneous within-region growth responses (Figs. 3 and4). Moving correlations revealed numerous shifts in the significance of climate-growth associations around 1980 (Fig. 5).

Quebec

No significant climate-growth associations were observed at the regional level in western boreal Quebec over the entire study period (Fig. 2). Some significant positive responses to previous winter and current spring temperatures were observed at the local level, but these concerned a minority of cells (Fig. 3). Moving correlations revealed that Q_W significantly correlated with previous summer precipitation (negatively) before the 1970s, with previous winter temperatures (positively) from the 1970s and with current spring temperatures (positively) from 1980 (Fig. 5).

Tree growth in central boreal Quebec significantly and positively correlated with current summer temperatures at the regional and local levels (Figs. 2 and3). Numerous negative correlations between tree growth and spring precipitation were observed at the local level (Fig. 3). Moving correlations revealed an emerging correlation between Q_C and previous winter temperatures in the early 1970s (significant during most intervals up to most recent years) (Fig. 5).

No significant climate-growth associations were observed in eastern boreal Quebec at the regional level (Fig. 2). At the local level, some positive significant correlations with current summer temperatures were observed (Fig. 3). Moving correlations revealed that Q_E correlated significantly and positively with current summer temperatures up to the early 1970s (Fig. 5). Significant correlations (P < 0.05) are marked with a star. Analyses were computed between grid cell chronologies and local seasonal climate data extracted for each grid cell from the CRU TS 3.24 1° x 1° [START_REF] Harris | Updated high-resolution grids of monthly climatic observations ---the CRU TS3.10 dataset[END_REF]. Seasons included previous summer (pJJA), previous autumn (SON), winter (DJF); current spring (MAM) and current summer (JJA). To visualize separation between regional clusters (Q_W, Q_C, and Q_E, cf. Fig. 1) correlation values at Q_C grid cells are plotted with circles.

Significant correlations (P < 0.05) are marked with a black dot.

Sweden

Tree growth in southern boreal Sweden correlated significantly and negatively with previous summer and winter temperatures at the regional and local levels, the correlation with winter temperatures concerning however only a minority of cells (Figs. 2 and4). Moving correlations indicated that the negative association with previous summer temperatures remained significant up to the early 1990s and that the negative association with winter temperatures emerged after 1980 (Fig. 5).

In central boreal Sweden, tree growth significantly and negatively correlated with previous summer temperatures both at the regional and local levels (Figs. 2 and4). Some additional significant correlations with winter temperatures (negative) and with current summer temperatures (positive) were observed at the local level (Fig. 4). Moving correlation analyses revealed a significant positive correlation between S_C and current summer temperatures that dropped and became non-significant at the end of the study period (Fig. 5). In addition, the correlation between S_C and previous summer precipitation shifted from significantly negative to significantly positive during the 1980s (Fig. 5). S_C became significantly and negatively correlated with previous summer temperatures after the 1980s and stopped being significantly and negatively correlated with previous autumn precipitation and with winter temperatures at the end of the 1970s (Fig. 5).

Tree growth in northern boreal Sweden correlated significantly with previous summer (negatively) and current summer temperatures (positively) both at the regional and local levels (Figs. 2 and4). At the local level, tree growth in some cells significantly and negatively correlated with winter temperatures (Fig. 4). Significant and negative responses to current summer precipitation were observed at northernmost cells (Fig. 4). Moving correlations revealed that the positive association with current summer temperatures was only significant at the beginning and at the end of the study period (Fig. 5). After the 1980s, significant positive associations with previous autumn temperatures emerged (Fig. 5) and the significant negative association with winter temperatures disappeared. Analyses were computed between grid cell chronologies and local seasonal climate data extracted for each grid cell from the CRU TS 3.24 1° x 1° [START_REF] Harris | Updated high-resolution grids of monthly climatic observations ---the CRU TS3.10 dataset[END_REF]. Seasons included previous summer (pJJA), previous autumn (SON), winter (DJF); current spring (MAM) and current summer (JJA). To visualize the separation between regional clusters (S_S, S_C, and S_N, cf. Fig. 1) correlation values at S_C grid cells are plotted with circles.

Significant correlations (P < 0.05) are marked with a black dot. extracted for each grid cell from the CRU TS 3.24 1° x 1° [START_REF] Harris | Updated high-resolution grids of monthly climatic observations ---the CRU TS3.10 dataset[END_REF] and then aggregated at the regional level by robust bi-weighted mean. Seasons included previous summer (pJJA), previous autumn (SON), winter (DJF); current spring (MAM) and current summer (JJA). Moving correlations were calculated using 21-yr windows moved one year at a time and are plotted using the central year of each window. Windows of significant correlations (P < 0.05) are marked with a dot.

Links between tree growth patterns and large-scale indices

Some significant associations were found between tree growth and large-scale indices (Figs.

6, 7, and 8). Moving correlation analyses revealed some shifts from pre-1980 insignificant to post-1980 significant correlations (Fig. 9). The seasonal indices involved in these shifts varied across regional chronologies.

Quebec

Tree growth in western boreal Quebec was significantly and negatively associated with the winter AMOC and the winter AO indices at the regional level (Fig. 6). At the local level, these associations concerned, however, a minority of cells (Fig. 7). Moving correlations revealed that the regional negative association with winter AMOC was only significant in the most recent part of the study period (Fig. 9). Significant negative correlations between Q_W and current summer NAO and AO indices were observed from the 1980s up to the most recent years, at which point they show a steep increase and become non-significant (Fig. 9).

In central boreal Quebec, no significant associations between tree growth and seasonal indices were identified at the regional or local level (Figs. 6 and7). Moving correlations indicated significant negative correlations with previous summer NAO and AO indices of during the 1970s, with winter NAO and AO indices during the 1980s and with current summer NAO and AO indices from the 1980s up to the most recent years (Fig. 9).

No significant association was identified between large-scale indices and tree growth in eastern boreal Quebec (Figs. 6,7,and 9). are marked with a black dot.

Sweden

No significant association between tree growth in southern boreal Sweden and seasonal largescale indices was identified at the regional or local level (Figs. 6 and8). Moving correlations revealed, however, significant negative associations between S_S and the winter AMOC index before the 1980s (Fig. 9).

In central boreal Sweden, tree growth significantly and positively correlated with the current summer NAO index at the regional level (Fig. 6). At the local level, this correlation concerned, however, a minority of cells (Fig. 8). Moving correlations revealed that the significant positive association with the current summer NAO index emerged in the early 1980s (Fig. 9) and that S_C significantly correlated with the current summer AMOC index during the 1980s (Fig. 9).

In northern boreal Sweden, tree growth significantly correlated with the current summer NAO index (positively) and with the winter AO index (negatively) at the regional level (Fig. 6). At the local level, the positive association with summer NAO concerned a large majority of cells and the negative association with the winter AO index concerned only very few cells (Fig. 8).

Moving correlation analyses indicated that the positive association between S_N and the current summer NAO index was only significant after the 1980s and that S_N significantly correlated with current summer AMOC during most of the 1980s (Fig. 9). Significant correlations (P < 0.05) are marked with a black dot.

Spatial aggregation of tree growth data

The high correlation between the regional chronologies in NE (Appendix S1), especially between the central and northern chronologies, could have supported the construction of one single boreal Sweden-wide regional chronology. Climate-growth analyses at the regional and local level revealed, nevertheless, clear differences across space in tree growth sensitivity to climate (Fig. 4) and to large-scale indices (Fig. 8), with a higher sensitivity in northernmost forests. The aggregation of tree growth data across space, even if based on objective similarity statistics (Appendix S1), may, therefore, mask important local differences in climate-growth interactions [START_REF] Macias | Growth variability of Scots pine (Pinus sylvestris) along a west-east gradient across northern Fennoscandia: A dendroclimatic approach[END_REF]. Our results demonstrate that spatial aggregation should not be performed without accounting for bioclimatic domains especially when studying climategrowth interactions. In practice, one should at least check that a spatial similarity in tree growth patterns is associated with spatial similarity in seasonal climate. The use of both the regional and local scales regarding climate-growth interactions, as in the present study, is, therefore, recommended to exhaustively and more precisely capture cross-scale diverging and emerging tree growth patterns and sensitivity to climate.

Post-1980 shifts towards significant influence of large-scale indices on boreal tree growth

The emergence of a post-1980 significant positive tree growth response to the current summer NAO index in central and northern boreal Sweden (Fig. 9) appears to be linked to spatial variability in the NAO influence on seasonal climate (Fig. 10). Summer NAO has had little to no influence on summer climate variability over the entire period 1950-2008 in boreal Quebec or Sweden (Appendix S4). However, the partitioning of the period into two sub-periods of similar length (1950-1980 and 1981-2008) revealed a northeastward migration of the significant-correspondence field between the summer NAO index and local climate, particularly in NE (Fig. 10). Over the 1981-2008 period, the summer NAO index was significantly and positively associated with temperature and negatively with precipitation in boreal Sweden (Fig. 10). Higher growing-season temperatures, induced by a higher summer NAO, might have promoted the growth of temperature-limited Swedish boreal forest ecosystems, explaining recent positive response of tree growth to this large-scale index in the central and northern regions (Fig. 9). The northeastward migration of the NAO-climate spatial field may be an early sign of a northward migration of the North Atlantic Gulf stream [START_REF] Taylor | The North Atlantic Oscillation and the latitude of the Gulf Stream[END_REF] or a spatial reorganization of the Icelandic-low and Azores-high pressure NAO's nodes [START_REF] Portis | Seasonality of the North Atlantic Oscillation[END_REF][START_REF] Wassenburg | Reorganization of the North Atlantic Oscillation during early Holocene deglaciation[END_REF]. The August Northern Hemisphere Jet over NE reached its northernmost position in 1976 but thereafter moved southward, despite increasing variability in its position [START_REF] Trouet | Recent enhanced high-summer North Atlantic Jet variability emerges from three-century context[END_REF]. This southward migration of the jet may weaken the strength of the observed post-1980 positive association between boreal tree growth and the summer NAO index in NE in the coming decades. period were extracted from NOAA's climate prediction center. Summer mean temperature and total precipitation are those of CRU TS 3.24 1° x 1° [START_REF] Harris | Updated high-resolution grids of monthly climatic observations ---the CRU TS3.10 dataset[END_REF]. All correlations were computed in the KNMI Climate Explorer (https://climexp.knmi.nl [START_REF] Trouet | KNMI Climate Explorer: A web-based research tool for high-resolution paleoclimatology[END_REF]). Indices and climate variables were normalized (linear regression) prior to analyses. Only correlations significant at P < 0.05 are plotted.

The post-1980 significant negative associations between tree growth and summer NAO and AO indices in boreal Quebec are more challenging to interpret. There was no evident significant tree growth response to summer temperature in these regions when analyzed over the full 1950-2008 period (Fig. 4). Yet, some significant positive associations between tree growth and temperatures were observed with winter temperatures from the 1970s (in central Quebec) and with spring temperatures from the 1980s (in western Quebec only) (Fig. 5). These associations indicate that tree growth in boreal Quebec has been limited by winter and spring climate since the 1970s and 1980s, respectively. Below-average summer temperatures induced by high summer NAO and AO may exacerbate the sensitivity of tree growth to low temperatures. Noting that no significant post-1980 association was observed between temperature and summer NAO and AO indices in Quebec (Fig. 10), the emerging negative tree growth response to summer NAO and AO indices may indicate a complex interplay between large-scale indices and air mass dynamics and lagged effects over several seasons [START_REF] Boucher | Decadal variations in eastern Canada's taiga wood biomass production forced by ocean-atmosphere interactions[END_REF].

In western Quebec, tree growth was negatively influenced by the winter AMOC index at the regional level (Fig. 6). This relationship appears to be linked to a significant positive association between tree growth and spring temperature (Figs. particularly through their control upon fire activities (Macias Fauria & Johnson 2006[START_REF] Goff | Historical fire regime shifts related to climate teleconnections in the Waswanipi area, central Quebec, Canada[END_REF]. These indices have not been investigated in the present study but might present some additional interesting features.

Contrasting climate-growth associations among boreal regions

Post-1980 shifts in tree growth sensitivity to seasonal climate differed among boreal regions.

In NA, we observed the emergence of significantly positive growth responses to winter and spring temperatures. In NE, observed post-1980 shifts mainly concerned the significance of negative growth responses to previous summer and winter temperatures. Warmer temperatures at boreal latitudes have been reported to trigger contrasting growth responses to climate [START_REF] Wilmking | Recent climate warming forces contrasting growth responses of white spruce at treeline in Alaska through temperature thresholds[END_REF] and to enhance the control of site factors upon growth [START_REF] Nicklen | Local site conditions drive climate-growth responses of Picea mariana and Picea glauca in interior Alaska[END_REF]. This is particularly true with site factors influencing soil water retention, such as soil type, micro-topography, and vegetation cover [START_REF] Düthorn | Influence of micro-site conditions on tree-ring climate signals and trends in central and northern Sweden[END_REF].

Despite a generalized warming at high latitudes [START_REF] Serreze | The emergence of surface-based Arctic amplification[END_REF], no increased sensitivity of boreal tree growth to precipitation was identified in the present study, except in central Sweden where tree growth became positively and significantly correlated to previous summer precipitation (Fig. 5). This result underlines that temperature remains the major-growth limiting factor in our study regions.

The observed differences in tree growth response to winter temperature highlight diverging non-growing season temperature constraints on boreal forest growth. While warmer winters appear to promote boreal tree growth in NA, they appear to constrain tree growth in boreal NE. Such opposite responses to winter climate from two boreal tree species of the same genus might be linked to different winter conditions between Quebec and Sweden. In NA, winters conditions are more continental and harsher than in NE (Appendix S5). Warmer winters may therefore stimulate an earlier start of the growing season and increase growth potential [START_REF] Rossi | Lengthening of the duration of xylogenesis engenders disproportionate increases in xylem production[END_REF]. However, warmer winters, combined with shallower snow-pack, have been shown to induce a delay in the spring tree growth onset, through lower thermal inertia and a slower transition from winter to spring [START_REF] Contosta | A longer vernal window: the role of winter coldness and snowpack in driving spring transitions and lags[END_REF]. This phenomenon might explain the negative association between tree growth and winter temperatures observed in NE.

The post-1970s growth-promoting effects of winter and spring temperature in NA (Fig. 5) suggest, as ealier reported by [START_REF] Charney | Observed forest sensitivity to climate implies large changes in 21st century North American forest growth[END_REF] and [START_REF] Girardin | No growth stimulation of Canada's boreal forest under half-century of combined warming and CO2 fertilization[END_REF], that, under sufficient soil water availability and limited heat stress conditions, tree growth at midto high-latitudes can increase in the future. However, warmer winters may also negatively affect growth by triggering an earlier bud break and increasing risks of frost damages to developing buds [START_REF] Cannell | Climatic warming, spring budburst, and frost damage on trees[END_REF] or by postponing the start of the growing season (see above, [START_REF] Contosta | A longer vernal window: the role of winter coldness and snowpack in driving spring transitions and lags[END_REF]. This might provide an argument against a sustained growth-promoting effect of higher seasonal temperatures [START_REF] Gerardin | Une classification climatique du Québec à partir de modèles de distribution spatiale de données climatiques mensuelles : vers une définition des bioclimats du Québec. Direction du patrimoine écologique et du développement durable[END_REF].

Gradients in the sensitivity of tree growth to North Atlantic Ocean dynamics across boreal Quebec and Sweden

Trees in western and central boreal Quebec, despite being furthest away from the North Atlantic Ocean in comparison to trees in eastern boreal Quebec, were the most sensitive to oceanic and atmospheric dynamics, and particularly to current summer NAO and AO indices after the 1970s. In these two boreal regions, tree growth responses to large-scale indices were stronger and more spatially homogeneous than tree growth responses to regional climate. This suggests that growth dynamics in western and central boreal Quebec, despite being mainly temperature-limited, can be strongly governed by large-scale oceanic and atmospheric dynamics [START_REF] Boucher | Decadal variations in eastern Canada's taiga wood biomass production forced by ocean-atmosphere interactions[END_REF]. The tree growth sensitivity to the winter AMOC index observed at regional level in western boreal Quebec might directly emerge from the correspondence between AMOC and winter snow fall. Western boreal Quebec is the driest and most fire-prone of the Quebec regions studied here. Soil water availability in this region strongly depends on winter precipitation. High winter AMOC indices are associated with the dominance of Arctic air masses over NA and leads to decreased snowfall (Appendix S4).

Large-scale indices, through their correlation with regional fire activity, can also possibly override the direct effects of climate on boreal forest dynamics [START_REF] Drobyshev | Environmental controls of the northern distribution limit of yellow birch in eastern Canada[END_REF][START_REF] Zhang | Stand history is more important than climate in controlling red maple (Acer rubrum L.) growth at its northern distribution limit in western Quebec, Canada[END_REF]. Fire activity in NA strongly correlates with variability in atmospheric circulation, with summer high-pressure anomalies promoting the drying of forest fuels and increasing fire hazard [START_REF] Skinner | The Association Between Circulation Anomaliesin the Mid-Troposphere and Area Burnedby Wildland Fire in Canada[END_REF], Macias Fauria & Johnson 2006) and low-pressure anomalies bringing precipitation and decreasing fire activity.

In Sweden, the northernmost forests were the most sensitive to North Atlantic Ocean dynamics, particularly to the summer NAO (Fig. 8). These high-latitude forests, considered to be 'Europe's last wilderness' [START_REF] Kuuluvainen | North Fennoscandian mountain forests: History, composition, disturbance dynamics and the unpredictable future[END_REF], are experiencing the fastest climate changes [START_REF] Hansen | Global surface temperature change[END_REF]. Numerous studies have highlighted a correspondence between tree growth and NAO (both winter and summer) across Sweden [START_REF] D'arrigo | NAO and sea surface temperature signatures in tree-ring records from the North Atlantic sector[END_REF][START_REF] Cullen | Multiproxy reconstructions of the North Atlantic Oscillation[END_REF][START_REF] Linderholm | Dendroclimatology in Fennoscandiafrom past accomplishments to future potential[END_REF], with possible shifts in the sign of this correspondence along north-south [START_REF] Lindholm | Growth indices of North European Scots pine record the seasonal North Atlantic Oscillation[END_REF] and west-east gradients [START_REF] Linderholm | Tree-ring records from central Fennoscandia: the relationship between tree growth and climate along a west-east transect[END_REF].

Our results identified a post-1980 positive correspondence between tree growth and summer NAO, spatially restricted to the northernmost regions (Figs. 8 and9). This emerging correspondence appears linked to the combination of a growth-promoting effect of higher temperature at these latitudes (Fig. 5) and a northeastward migration of the spatial correspondence between NAO and local climate (Fig. 10). Boreal forests of Quebec (western and central) and Sweden (central and northern) emerged as regions sensitive to large-scale climate dynamics. We, therefore, consider them as suitable for a long-term survey of impacts of ocean-atmosphere dynamics on boreal forest ecosystems.

Fig. 1

 1 Fig. 1 a: Location of the two study areas (black frame); b & c: Clusters identified in each study area by ordination of 1° x 1° latitude-longitude grid cell chronologies. Ordination analyses were performed over the common period between grid cell chronologies in each study area using Euclidean dissimilarities matrices and Ward agglomeration methods. The common period was 1885-2006 for Quebec and 1936-1995 for Sweden. Ordinations included 36 and 56 grid cell chronologies in Quebec and Sweden, respectively. A western (Q_W), central (Q_C) and eastern (Q_E) cluster were identified in Quebec and a southern (S_S), central (S_C) and northern (S_N) cluster were identified in Sweden. Reference chronologies

Fig. 2 .

 2 Fig. 2. Tree growth responses to seasonal temperature averages (a) and precipitation sums (b) at the regional level over the 1950-2008 period, as revealed by correlation analyses. Analyseswere computed between the six regional chronologies (Q_W, Q_C, and Q_E in NA; and S_S, S_C and S_N in NE) and seasonal climate data. Climate data were first extracted from the CRU TS 3.24 1° x 1°[START_REF] Harris | Updated high-resolution grids of monthly climatic observations ---the CRU TS3.10 dataset[END_REF] for each grid cell and then aggregated at the regional level by a robust bi-weighted mean. Seasons included previous summer (pJJA), previous autumn (SON), winter (DJF); current spring (MAM) and current summer (JJA).

Fig. 3 .

 3 Fig. 3. Tree growth responses to seasonal temperature averages (a) and precipitation sums (b) at the local level over the 1950-2008 period in Quebec, as revealed by correlation analyses.

Fig. 4 .

 4 Fig. 4. Tree growth responses to seasonal temperature averages (a) and precipitation sums (b) at the local level over the 1950-2008 period in Sweden, as revealed by correlation analyses.

Fig. 5 .

 5 Fig. 5. Moving correlations between regional seasonal temperature averages (red lines) and precipitation sums (blue lines), and the six regional chronologies (Q_W, Q_C, and Q_E in NA; and S_S, S_C and S_N in NE) over the 1950-2008 period. Climate data were first

Fig. 6 .

 6 Fig. 6. Correlation between seasonal AMOC (a), NAO (b), and AO (c) indices and the six regional chronologies (Q_W, Q_C, and Q_E in NA; and S_S, S_C and S_N in NE). Seasonal indices include previous summer (pJJA), winter (DJF), and current summer (JJA), and were calculated as mean of monthly indices. Correlations were calculated over the 1961-2005 period for AMOC, and over the 1950-2008 period for NAO and AO. Significant correlations (P < 0.05) are marked with a star.

Fig. 7 .

 7 Fig. 7. Correlation between seasonal AMOC (a), NAO (b), and AO (c) indices, and growth patterns at the local level in Quebec. Seasonal indices include previous summer (left-hand panels), winter (middle panels), and current summer (right-hand panels), and were calculated as mean of monthly indices. Correlations were calculated over the 1961-2005 period for AMOC, and over the 1950-2008 period for NAO and AO. To visualize the separation between regional clusters, correlation values at Q_C grid cells are plotted with circles. Significant correlations (P < 0.05)

Fig. 8 .

 8 Fig. 8. Correlation between seasonal AMOC (a), NAO (b), and AO (c) indices, and growth patterns at the local level in Sweden. Seasonal indices were calculated as mean of monthly indices and include previous summer (left-hand panels), winter (middle panels), and current summer (right-hand panels). Correlations were calculated over the 1961-2005 period for AMOC, and over the 1950-2008 period for NAO and AO. To visualize the separation between regional clusters, correlation values at S_C grid cells are plotted with circles.

Fig. 9 .

 9 Fig. 9. Moving correlations between previous summer (pJJA; left-hand panels), winter (DJF; middle panels) and current summer (JJA; right-hand panels) large-scale indices, and the six regional chronologies (Q_W, Q_C, and Q_E in NA; and S_S, S_C and S_N in NE). Largescale indices include AMOC (black), NAO (red), and AO (blue). Moving correlations were calculated using 21-yr windows moved one year at a time and are plotted using the central year of each window. Correlations were calculated over the 1961-2005 period for AMOC, and over the 1950-2008 period for NAO and AO. Windows of significant correlations (P < 0.05) are marked with a dot.

Fig. 10 .

 10 Fig. 10. Correspondence between summer NAO (a) and AO (b) indices and local summer climate (mean temperature and total precipitation) between 1950 and 1980 (left-hand panels) and between 1981 and 2008 (right-hand panels). NAO and AO indices over the 1950-2008

  5 and 9). Positive winter AMOC indices are generally associated with cold temperatures in Quebec, and particularly so in the West (Appendix S4). Positive winter AMOC indices are associated with the dominance of dry winter air masses of Arctic origin over Quebec, and may thereby delay the start of the growing season and reduce tree-growth potential. Forest dynamics in NA have been reported to correlate with Pacific Ocean indices such as the Pacific Decadal Oscillation (PDO) or the El-Nino Southern Oscillation (ENSO),

Table 1 .

 1 Characteristics of tree-ring width chronologies*. 198 *Data for Q_W, Q_C and Q_E chronologies respectively. **Data for S_S, S_C and S_N chronologies respectively.

Acknowledgements

This study was financed by the Natural Sciences and Engineering Research Council of Canada (NSERC) through the project 'Natural disturbances, forest resilience and forest management: the study case of the northern limit for timber allocation in Quebec in a climate change context' (STPGP 41344-11). We acknowledged financial support from the Nordic Forest Research Cooperation Committee (SNS) through the network project entitled 'Understanding the impacts of future climate change on boreal forests of northern Europe and eastern Canada', from the EU Belmont Forum (project PREREAL), NINA's strategic institute program portfolio funded by the Research Council of Norway (grant no. 160022/F40), the Forest Complexity Modelling (FCM), an NSERC funded program in Canada and a US National Science Foundation CAREER grant (AGS-1349942). We are thankful to the Ministry of Forests, Wildlife and Parks (MFFP) in Quebec and to the Swedish National Forest Inventory (Bertil Westerlund, Riksskogstaxeringen, SLU) in Sweden for providing treegrowth data. ID thanks the Swedish Institute for support of this study done within the framework of CLIMECO project.

Appendix A -Supplementary data

Supplementary data to this article can be found online at https://doi. org/10.1902/j.gloplacha.2018.03.006


Keywords: Reimbursement, regenerative medicine, valuation, publications, trade organisations, orphan drugs, risk-sharing agreements

Aims

This paper aims to map the trends and analyse key institutional dynamics that are constituting the policies for reimbursement of Regenerative Medicine (RM), especially in the UK. Materials & Methods Two quantitative publications studies using Google Scholar and a qualitative study based on a larger study of 43 semi-structured interviews.

Results

Reimbursement has been a growing topic of publications specific to RM and independent from orphan drugs. Risk-sharing schemes receive attention amongst others for dealing with RM reimbursement. Trade organisations have been especially involved on RM reimbursement issues and have proposed solutions.

Conclusion

The policy and institutional landscape of reimbursement studies in RM is a highly variegated and conflictual one and in its infancy.

of the publications landscape, one overarching and one more specific, combined with one in-depth study of the most contested aspects of the RM reimbursement debate. Thus the publication studies describe the emerging forms and sites of RM reimbursement analysis, while the in-depth (interview-based) study presents the most crucial content of the conflictual debates in the field.

II-Methodology and Results

In this section, we present the methods/results of each of the three complementary studies. We undertook two quantitative studies of publications using Google Scholar and a qualitative study based on interviews.

The time periods the publication searches covered are 2015 and/or 2016. Practically, these were the most recent periods available at the time of our study. Scientifically, the question of RM reimbursement emerged as a prominent issue from 2015. Hence, our systematic searches do not cover earlier publications, although a few relevant publications previous to 2015 are referred to in our discussion.

Google Scholar (GS) was chosen as most relevant for the purposes of this research, following review of options [START_REF] Harzing | Google Scholar as a new source for citation analysis?[END_REF][START_REF] Winter | The expansion of Google Scholar versus Web of Science: a longitudinal study[END_REF][START_REF]Google Scholar compared to Web of Science: A Literature Review[END_REF]14]. GS is interdisciplinary and met our supposition that publications on RM reimbursement will be found in various fields of research, and probably more in Social and Human Sciences (SHS) or economics. GS also is not confined to peer-reviewed articles, and it is free to use and thus accessible beyond academia. We supposed transparency and thus wider accessibility are key aspects of RM's reimbursement politics. However, GS also has many limitations, notably it is not as comprehensive or precise as other search interfaces. Therefore, our set of selected articles includes both very detailed publications on RM reimbursement as well as others where it is referred to without being the main focus. Therefore, our results are broadly indicative rather than definitive. We present the results of the three studies below.

1) Reimbursement topics in the publications landscape of RM

For the first study, GS has been used for systematic searches to identify trends in RM publications (referring here to every publication whatever the format is: journals, book, Doctoral dissertation…) during 6 months from January 2016 to July 2016. The full search strategy is available from supplementary file 1. In summary, the following keywords were used: "regenerative medicine" OR "advanced therapy" OR "gene therapy" OR "cell therapy" OR "tissue engineered product" OR "innovative therapies" (that we call "regenerative medicine based products": RMPs), combined with and without the word "UK", and with combinations including or excluding "reimbursement", "risk-sharing", and "orphan drugs". The names of different countries were also included: UK, France, Germany, Japan, South Korea, USA (United States). Various adjustments such as averaging of results over 6 monthly periods were made to allow for GS's performance (Supplementary file 1). New systematic researches were added in February 2016 or in March 2016. (Where averages have been calculated over 6 months or over 5 months instead of 7 months, they are respectively marked with a single (6 months average marked*) or a double (5 months average marked**) star, in the tables presented). The results are integrated in an Excel table (Supplementary file 2). This analysis addressed questions including: Is the question of reimbursement prominent among RM publications generally? Is reimbursement discussed to similar extents in the countries that are the most active in the RM field? Is RM reimbursement specifically considered compared to other expensive medicinal products, especially orphan drugs? Is risk-sharing the most discussed managed entry reimbursement option? The results of our analysis are below.

First, reimbursement of RMPs has been a growing topic of publications between 2015 and 2016, even excluding orphan drugs. Publications on reimbursement/risk-sharing were more numerous in the first six months of 2016 than in the whole year 2015. However, reimbursement/risk-sharing is not a very prominent primary topic, judged by use of these terms explicitly in publications' titles. This is even more true for the UK, as there was no publication including these terms in UK-origin titles.

However, when including orphan drugs the picture changes. Risk-sharing is associated with orphan drugs in more publications (there were generally more than twice as many publications when orphan drugs was included associated with risk sharing. This difference was smaller when orphan drugs was associated with reimbursement as a general term. (Table 1) 1 and supplementary file 2) although there were fewer publications on RM risksharing than on RM reimbursement generally. Thus, the orphan drug focus is greater than that on RMPs, though the latter is attracting an independent set of publications, both on reimbursement generally and risk-sharing in particular.

Finally, regarding the 2015 publications related to reimbursement of RMPs, the UK had the fifth most references (183 results) behind the USA (416 results), Japan (239 results) and Germany (237), close to France (188 results) and before South Korea (56). However, it should be noted that, given GS limitations, these countries could be mentioned in the publications data or as countries of affiliation of the authors (Table 2). Thus, UK RM reimbursement is a recent and growing topic of publications, and it appears less developed than in the USA, Japan, Germany, and France, both related to and independent from orphan drugs, and not only linked to risk-sharing agreements as a main policy option.

2) Profiling political characteristics of the RM reimbursement publications landscape

The second study is based on a deeper quantitative analysis of targeted publications identified from the first study. Out of 182 publications found in February 2015, 5 appear twice and 127 have been excluded following inspection as being out of our scope. Thus, our working material is based on 50 publications in 2015. These 50 publications have been classified in different Excel tables to distinguish the various research fields they come from for each type of publications: Journals, books chapters, books, thesis and other types of publications see Supplementary file 3).

This analysis addressed questions including: In which types (journals, book chapters, books, thesis or other kinds of publications) of publications is reimbursement of RM considered? (We hypothesise that books and theses are less accessible than journals for most stakeholders in the field). In which field of research (clinical, SHS, economics, public health, business, other) is reimbursement of RM considered? In which clinical areas is reimbursement of RM considered? Are there dominant journals? Is reimbursement of RM considered by few publishers or many? What is the UK position and authorship in these publications?

Our analysis shows that publications related to RM reimbursement are mainly found in journals (74%; N= 37/50), especially in public health (100%; N= 4/4), clinical (95.7%; N=22/23) and economics (75%; N= 3/4), showing the predominance of the journal format in these disciplines. Nevertheless, a sizeable proportion appears in other formats and so may be less accessible. In addition, the sharing of publications between journals, books' chapters, books, doctoral dissertations, and other types of publications is much more balanced in SHS and business fields. The clinical and economic areas have a similar sharing of publications types regarding RM reimbursement: mainly journals (95.7 % for the clinical area and 75% for the economics area) and few in book chapters (4.3 % (N= 1/23) for the clinical area and 25% (N= 1/4) for the economics area). In the public health area 100% (N= 4/4) publications on RM reimbursement are in journals. On the other hand, the business discipline is an exception, with no publication in journals and more equally represented (together with the SHS area) across other formats of publications (Table 3), suggesting that this discipline may be a less visible area of the landscape Reimbursement of RM is also considered by a wide range of different journals. Indeed, 83.7% (N= 31/37) appeared in separate journals across all fields, suggesting a very diffuse and emerging picture. Nevertheless, the public health and economics fields appeared as significant exceptions with 3/4 of public health articles published in the "Journal of Market Access and Policy", 2/3 of economics journals' publications published in the "Value in Health" journal (Table 7). Thus, it appears RM reimbursement publications are mainly in clinical journals although reimbursement might be considered primarily an SHS or Economics topic. This may be linked to the overall numeric domination of clinical publications compared to SHS or economics publications, or to the interest of medical practitioners and researchers in scenarios for clinical translation. While the question of RM reimbursement was often considered generally, where specific disease areas are targeted, it corresponded to those in which RM is closer to or already in the clinic: Skin and respiratory disease, haematological and orthopaedic and neurologic and ophthalmologic diseases. Finally, two journals (Journal of Market Access and Policy and Value in Health) and two publishers (Elsevier and Universities as a group) seem to be the most active on the topic of RM reimbursement.

3) Trade associations' positions on RM reimbursement issues

We now turn from the forms and disciplines with which reimbursement is being studied and debated to the actual content of the key debates and proposals. Thus, the third analysis is part of a study based on 43 semi-structured interviews of stakeholders from key institutions in the field of RM in the UK, conducted in 2015 and 2016: national bodies (5), service providers (3), consultancy companies/law academics (4), regulatory agencies/Institute (4), Innovation networks (organisations that promote relevant innovation) (4), trade organisations (4), funders (2), health professional organisations (4), research charities [START_REF] Helgesson | Values and Valuations in Market Practice[END_REF], other institutions (4). (Details of the organisations are available in Supplementary file 4). Interviews lasted around 1hour, generally at the offices of the interviewees and covered both general questions on the interviewees' current perceptions of the RM field and of its prospects and specific questions modified according to each interviewee/institution.. Informed consent was obtained and interview transcripts were anonymised, and coded and analysed using Nvivo qualitative analysis software. The analysis of the whole set of interviews is the subject of another paper.

In this manuscript we target trade associations, as they were the category of stakeholders most involved and most critical of existing protocols on RM reimbursement. We supplemented the interviews with in-depth Internet searches, especially on the websites of the trade associations. We highlight key results and comments from four interviews in three associations. Although a small number, representatives of the associations held key senior positions and, of course, represent the views of many member firms and other organisations. To preserve anonymity we identify the trade organisations/interviewees by a number.

All the trade associations considered reimbursement to be a current issue:

"So I think we have the academic excellence, some significant infrastructure, a growing community on the positive side. What we don't have is a route to reimbursement." (Trade organisation 2)

One trade association highlights the uncertainty of reimbursement decisions: unclear remits of relevant institutions in the context of multiple reimbursement pathways:

"At the moment, we have some theoretical routes and we have a number of European companies that have gone bust trying to solve this problem." (Trade organisation 2)

Trade associations specifically highlight the contradictions or lack of collaboration between the National Institute for Health and Care Excellence (NICE) and National Health Service (NHS) England. Specific issues identified included: different criteria used by NICE and NHS England such as the gap between marketing authorisation and reimbursement decision; a perceived need for NICE and NHS England integration in an 'holistic system'; tension between NICE and NHS England, although recognition that NICE Office for Market Access has been established to provide clarifications regarding procedures; alleged problems with NICE methodologies; NHS England's specialised commissioning (i.e. many innovations competing for access to the specialised commissioning budget, NHSE not being seen as good at commercial access models); difficulties relating to the cost and choices to be made, long-term and uncertainty of evidence; routes to adoption in the clinic; the differences between devolved nations; difficulty of reaching a common product assessment at the European level; and the impact of (NICE) reimbursement decisions:

"For things that go to NICE, whatever they are, that absolutely affects their fortune in the market and through the rest of their lifecycle. So the signal that NICE sends absolutely affects the commercial success of medicines and that will be true of regenerative medicines." (Trade Organisation 4)

Moreover, three out of four trade organisations expressed views on reimbursement methodologies for RM. One trade association considered NHSE methodologies had already changed but that NICE methodologies should be revised for RMPs. Indeed, three trade organisations explicitly said there is a need for change in reimbursement methodologies.

Regarding the possible establishment of a specific government supported fund for RM, one trade organisation was clearly in favour of it, while 2 others were not opposed to it. A fund for innovative medicines was seen as more acceptable than a disease-type fund such as the Cancer Drugs Fund [START_REF] Littlejohns | Challenges for the new Cancer Drugs Fund[END_REF], but it should be a 'transition' fund. They highlighted that the advantages of a specific fund for RM would be especially to provide flexibility. Moreover, as a budget is necessary to make a system change, the fund would be a powerful and potent mechanism for market access although it raised issues: "There's no doubt that if you want to get something done and you want to make a system change, you create a ring-fenced budget. (…) So in terms of market access it's (a specific fund is) a very powerful and potent mechanism, but it goes against the grain of travel of the system, which is not to have centralised budgets for things, but to have devolved responsibility and decision-making spread out across the system." (Trade organisation 4)

Finally, trade associations have made proposals for the reimbursement of RM based products. First, collaborations should be enhanced between marketing authorisation and reimbursement steps, that is, between regulatory agencies and reimbursement bodies. Indeed, "A partnership approach (between developers and gatekeepers) has the potential to reduce the time and cost of development, while improving clinical relevance of studies and their assessment of cost-effectiveness. Improving public health through appropriate uptake of medicines at lower cost and improved cost-effectiveness, without any reduction in development standards or scrutiny, is an important incentive to develop new methodology. Real time database utilisation, new analytical methods and adaptive approaches can underpin this." [START_REF]Reengineering Medicine Development: A stakeholder discussion document for cost-effective development of affordable innovative medicine[END_REF] Second, one trade association emphasised that changes should occur at NHS England: a perceived need for direct producer engagement with NHS England, a key aspect being 'good horizon scanning' at NHS England, whilst approving the new clinically focused routes for reimbursement (i.e. Clinical Reference Groups). Third, one trade organisation highlighted a need for general systemic changes to achieve a healthcare service with a good way of both monitoring and assessing patient performance over time, and the need for industry to have a coherent business strategy. Fourth, two trade organisations underlined that a broader or specific view should be taken for RMPs such as a need for different thinking around the benefits models, especially where there is a curative effect. Fifth, one trade organisation has envisaged 'adaptive pathways' [17] as a solution for RM based products as they could take into account their specific issues, while another referred to risk-sharing or annual/stages payment models:

"The key thing is there has to be recognition that the risk has to be shared between the company and the system. So it's no good if the system says, 'Okay, you'll have to supply the medicine for free through this period and we'll look at it again in two years.' There needs to be more flexibility to say, 'Okay, so maybe the medicine will be provided at a different in-market commercial price for this period,' but then, if the data supports it, the price should go up. (...) and it's only if we accept that that we're properly accepting that value should be linked to price."(Trade organisation 4)

However, one trade organisation highlighted, as above, that these reimbursement models need connectivity between regulatory and HTA bodies, and between NICE and NHS England, early discussions with HTA bodies and a structured framework for data collection. Finally, one trade organisation welcomed the Japanese model for faster access to market and conditional reimbursement [START_REF] Sipp | Conditional approval: Japan lowers the bar for regenerative medicine products[END_REF] although it recognised it needs to be tested.

Thus, beyond recognising reimbursement issues for RMPs, trade organisations generally have views on what are these issues and how they could be solved. Indeed, BIA and ABPI recognise these issues on their websites or positions papers, especially from 2015 [START_REF]Delivering value to the UK-The contribution of the pharmaceutical industry to the patients, the NHS and the economy[END_REF][START_REF]Manifesto: our agenda for change[END_REF][START_REF] Abpi | Adapting the innovation landscape, UK Biopharma R&D sourcebook[END_REF][START_REF] Bia | Update, Influencing and shaping our sector[END_REF][START_REF] Bia | Update, Influencing and shaping our sector[END_REF][START_REF]Briefing Paper: Advanced Therapy Medicinal Products and Regenerative Medicine[END_REF], in collaboration together [START_REF] Abpi | Early Access Medicines Scheme[END_REF] and with other trade associations as well [START_REF] Casmi | Adaptive Licensing[END_REF][START_REF] Bivda | From vision to action: Delivery of the Strategy for UK Life Sciences[END_REF][START_REF] Bia | One nucleus, Mediwales. UK Life sciences manifesto[END_REF], following some earlier statements [START_REF]BIA policy and parliamentary impact in Quarters Two and Three[END_REF][START_REF] Mestre-Ferrandiz | The many faces of Innovation, A report for ABPI by the Office of Health Economics[END_REF]. ABPI was represented on this topic at the 2015 conference of the International Society For Pharmacoeconomics and Outcomes Research (ISPOR) [31].

The general views of the trade organisations could be summarised by this statement:

"Ultimately a major consideration is whether payors -especially the NHS in the UK -can afford to use the medicine. Biological medicines, especially advanced therapies like cell and gene therapies, have particularly high development and manufacture costs. But they may also provide healthcare benefits that ultimately save the NHS money down the line. There is a need for policymakers to consider short, versus long-term, trade-offs and to propose models for realistic reimbursement plans." [START_REF] Bia | One nucleus, Mediwales. UK Life sciences manifesto[END_REF]

4) Discussion

In this section, we summarise and discuss the main results of the three studies:

The valuation of regenerative medicine involves a politics of stakeholder institutions and emerging policy discourse evident in the interview positions and publication profiles that we have presented. It could be considered that 2015 constituted a turning-point in that reimbursement and adoption in the NHS became a key issue in new national reports [START_REF]General proposals to solve the RM reimbursement challenges 33 NICE. Exploring the assessment and appraisal of regenerative medicines and cell therapy products[END_REF]33]. Moreover, the reimbursement of the first authorized Advanced Therapy Medicinal Product (ATMP), Chondrocelect in 2009, was turned down for reimbursement both in France and in the UK. In 2016, its marketing authorization holder, Tigenix NV, decided to withdraw its marketing authorization, as did Dendreon/Valeant for Provenge in 2015, for commercial reasons. Thus, the commercial viability of ATMP and RM products, as linked to the decisions of reimbursement by national bodies, became a key challenge. Indeed, "the reimbursement point is the keystone from which an allowable COGs [Cost of Goods] is determined by subtracting business costs." [START_REF] Mount | Cell-based therapy technology classifications and translational challenges[END_REF] These developments show the volatile environment in which valuation and reimbursement of RMPs is being debated. We have shown that it has been a growing Our publications analysis and interviews suggest that the UK's position in the emerging RM reimbursement landscape is similar.

Clearly, trade organisations have been very involved in RMPs reimbursement debates, as one would expect. Indeed, the industry is the most critical of RM valuation issues. Industry generally will not develop medicines lacking likely wide reimbursement and thus uncertain return on investment. Trade organisations consider more flexibility is needed, notably regarding NICE methodologies for assessment. In the context of limited budgets for healthcare, we showed in our interview and internet study that several key trade organisations argue that new flexible routes for reimbursement are needed to ensure patient access to the latest medical advances, including RMPs.

Beyond acceptance for risk-sharing schemes, while highlighting their limits, trade organisations emphasised the need for more collaboration between key stakeholders as a main solution to reimbursement issues. Some measures have been taken toward this objective, such as promotion of early contact with regulators and HTA bodies notably through the NICE Office for Market Access. The latter's objectives include defining acceptable evidences in a context of uncertainty with a curative treatment, and supporting navigation between the different gatekeepers. This is seen as particularly necessary given the challenge of an "increase in demand for 'real world' evidence by HTA, payers and regulators", i.e. their "growing interest in relative effectiveness" [START_REF] Abpi | Securing a future for innovative medicines: A discussion paper[END_REF].

5) Conclusion

We conclude that the policy and institutional landscape of reimbursement studies in RM is a highly variegated one and in its infancy. The two publications studies gave details on the amount of activities going on, the potential gap in the field, and signs of both general and niche trends. The volume of publications is growing, as researchers and analysts in a wide variety of disciplines and types of organisation start to grapple with reimbursement challenges. The interviews study highlights trade associations as closely engaged with debating at a high level the possible reimbursement scenarios for RM, and pointing to ways in which current technology assessment and healthcare infrastructures could be improved to favour RM enterprise. The analysis that we have provided is particularly relevant to the stakeholders involved in policy making in RM, and industry and academia. It offers a picture of the emerging landscape of RM reimbursement actors and issues that can inform the various stakeholders' participation in its future analysis, potential, and development.

Summary Points

• Reimbursement of RM based products has been a growing topic of publications between 2015 and 2016, independently from orphan drugs. • Risk-sharing schemes are only one strategy for dealing with RM reimbursement, albeit a widely debated one. • Reimbursement and risk-sharing are distinct issues for RM, although there is an overlap with the same issues for orphan drugs. • The UK's position in the RM reimbursement publication landscape is in keeping with several reports on the global dynamics of RM.

• Trade organisations have been very involved on RM based products reimbursement issues. • Trade organisations have detailed views on reimbursement issues for RM especially the high cost versus the uncertainty regarding long-term evidence. • Trade organisations have various proposals to solve RM reimbursement issues, emphasising a need for more collaboration between several key national-level actors.

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Table

Table 2 : 2015 publications related to reimbursement of RMPs per country

 2

		UK	France Germany Japan	South Korea United States
	Reimbursement	183 188*	237*	239*	56*	416*
	Anywhere Year
	2015

Table 3 :

 3 Different types of publication formats by discipline of our first suppositions has been verified in that publications related to RM reimbursement are found in a range of different fields of research. However, the dominant field is not SHS (28.0%; N= 14/50) nor economics (8.0%; N= 4/50) but is clinical (46.0%; N= 23/50); public health being more or less equivalent to economics (8.0%; N= 4/50) and business (10.0%; N= 5/50). Thus, the questions of RM reimbursement are being formulated mainly in clinical and SHS disciplinary publications (

	Clinical SHS	Economics Public	Business Total
		Health

Table 4 ) . Table 4 : Range of different publications subject areas/types

 4.4

	Clinical	SHS	Economics Public	Business	Total
				Health
	23	14	4	4	5	N= 50
	46,0%	28,0%	8,0%	8,0%	10,0%	N=
						100%

Of the clinical articles, most were in generalist medical journals (45.5%; N= 10/22). When specific disease areas were the focus, skin and respiratory diseases had received most attention (13.6% each; N= 3/22), followed by haematological and orthopaedic (9.1% each; N= 2/22), and finally neurologic and ophthalmologic diseases (4.5% each; N= 1/22). It is notable that publications had not targeted important clinical fields such as cardiovascular, gastroenterological and cancers other than blood diseases (Table

5

).

Table 5 : Disease areas in clinical publications

 5

	(Among the book chapters, the Gaucher disease has been considered both as an
	haematologic disease (Type 2) and as a neurologic disease (Types 2 and 3).)
		Number of	Number	of	Total
		articles	books' chapters	N=23
		N= 22	N= 1
	General	10	0		10
		45,5%	0%		43,5%
	Haematological	2	1		3

Furthermore, while "United Kingdom" was one of our selection criteria, first authors are from the UK in 40% (N= 20/50) of all the publications. The clinical and SHS areas are the main fields with UK first author's affiliation when we consider all types of publications (clinical area (20%; N= 10/50) and SHS area (12%; N= 6/50)), or journals only (clinical (66.7%; N= 10/15) and SHS (20%; N= 3/15) journals)) (Table

6

).

Table 6 : UK first author affiliation

 6

			Clinical SHS	Economics Public	Business Total
						Health
	UK first in	10/15	3/15	1/15	1/15	0/15	15/50
	journals		66,7%	20%	6,7%	6,7%	0%	30%
	UK first in	0/2	1/2	0/2	N/A	1/2	2/50
	book chapters	0%	50%	0%		50%	4%
	UK first in	N/A	0/1	N/A	N/A	1/1	1/50
	books			0%			100%	2%
	UK first in	N/A	2/2	N/A	N/A	0	2/50
	thesis			100%			0%	4%
	UK first in	N/A	N/A	N/A	N/A	0/0	0/50
	other						0%	0%
	publication
	UK first author	10/50	6/50	1/50	1/50	2/50	20/50
	in	all	20%	12%	2%	2%	4%	40%
	publications
	(N=50)

Table 7 : Publications in range of different journals

 7 of publishers was also evident. Four publishers shared 52% (N=26/50) of RM reimbursement publications, and Elsevier and universities covered the widest range of different fields (4): clinical, SHS, economics and public health for Elsevier, and clinical, SHS, economics and business for universities, suggesting a mix of commercial and non-profit commitment to the field. Most other publishers were specific to one or two fields.

		Clinical SHS	Economics Public	Business Total
					Health
	Publications	19/22	8/8	2/3	2/4	0/0	31/37
	in different	86,3%	100%	66,7%	50,0%	0%	83,7%
	journals
	A wide spread

topic of focused publications between 2015 and 2016, the vast majority of which appear in very disparate avenues or 'spaces' geared to various disciplinary audiences and interested parties. Nevertheless, clinical and especially generalist medical journals were shown to be dominating, and at least two specialist journals have appeared recently, which are likely to see more RMP reimbursement contributions.

Many of the reimbursement challenges are not specific to RMPs, because other fields such as orphan drugs can also have high up-front costs [START_REF] Gardner | Are there specific translational challenges in regenerative medicine? Lessons from other fields[END_REF][START_REF] Nice | Exploring the assessment and appraisal of regenerative medicines and cell therapy products[END_REF]. However, we maintain that some kinds of RMPs raise specific challenges, such as gene therapies when they are curative [START_REF] Carr | Gene therapies: the challenge of super-high-cost treatments and how to pay for them[END_REF]. We have shown that risk-sharing specifically is far less discussed than reimbursement generally. This result accords with risk-sharing schemes being just one strategy for dealing with RM reimbursement, albeit a widely debated one. Indeed, these schemes can be considered as one way of addressing the uncertainties regarding the alternative approaches to the valuation of RM between different actors, especially the NHS and the producer/manufacturer.

Reimbursement and risk-sharing are distinct issues for RM, although there is an overlap with the same issues for orphan drugs. RMPs can be medicinal products, especially ATMPs. For instance, Holoclar, the first stem cell-based medicinal product approved for use in the EU, is both an ATMP and an orphan medicinal product, and as such benefits from the incentives of both regulatory frameworks [START_REF] Gerke | EU Marketing Authorisation of Orphan Medicinal Products and Its Impact on Related Research[END_REF]. More globally, among the eight ATMPs authorised on the EU market to date, four are orphan drugs. As those cases show, orphan drugs and RM based products often share the two main features of high cost and uncertainties around evidence and value [START_REF] Bubela | Bringing regenerative medicines to the clinic: the future for regulation and reimbursement[END_REF]40]. However, these same uncertainties are also seen in the weak long-term evidence for RMPs that are not orphan drugs. Even though there was an increase in using risk-sharing schemes in Europe generally [START_REF] Adamski | Risk sharing arrangements for pharmaceuticals: Potential considerations and recommendations for European payers[END_REF] and they have been considered suitable for orphan drugs [START_REF] Campillo-Artero | Risk sharing agreements: with orphan drugs?[END_REF], there should be further exploration of whether such schemes might be more applicable to orphan drugs than RM products, as our findings imply. Such considerations are important to the political design of the markets and health system adoption of different subsectors of RM and related enterprise.

We showed in the first study the UK's position in the RM reimbursement publication landscape. Those results are in keeping with several reports in the field of RM evidencing different countries' positions addressing RM challenges broadly: "The UK needs to be ambitious and act quickly to get ahead. The USA, Canada and Japan are particularly active in this space and, although the UK is preeminent in Europe; Germany, Italy, France and Spain, in particular are rapidly reviewing how they can also capture these investments." [START_REF]Advanced Therapies Manufacturing Task Force Action Plan. Retaining and attracting advanced therapies manufacture in the UK[END_REF] Regarding the distribution of RM tissue engineering firms and research institutes:

"When we look at the geographic distribution of tissue engineering firms and research institutes, the U.S. with 52% leads the market followed by Germany (21%), Japan (16%), the UK (7%), and Sweden (4%)." [START_REF]Stem Cell Regenerative Medicine Market : Global Demand Analysis & Opportunity Outlook 2021[END_REF] This pattern has been established for some time across the biopharmaceutical sector said to reflect 'longstanding problems: limited venture capital finance, a fragmented patent system, and relatively weak relations between academia and industry.' [START_REF] Hogarth | Regenerative medicine in Europe: global competition and innovation governance[END_REF].