The aim of this study was to compare lower dental arch changes using two types of space regainers, including a removable appliance with a distalizing screw and a fixed double-banded appliance. n = 19). Pre- and posttreatment dental casts and lateral cephalograms of patients were evaluated to compare the effects of the two space-regaining devices on the mandibular dental arch. The data were analyzed using paired and independent t-tests.  In this case-control study, the study sample was comprised of thirty-eight children with mixed dentitions, all of whom had unilateral space deficiency due to premature loss of the second deciduous molar in the mandibular arch. Patients were treated with either a removable appliance with a distalizing screw or a fixed double-banded space regainer (DBSR) (P < 0.001). The mean amount of IMPA changes was significantly greater in the distalizing screw group than in the DBSR group (P < 0.05). But, there were no statistically significant differences between the mean changes of available space, molar angle, and the first molar distance to the mandibular plane and symphysis in the distalizing screw and the DBSR group (P < 0.05). The DBSR group's treatment time was significantly shorter (P < 0.001).  Available space, molar angle, IMPA, and the first molar distance to the mandibular plane and symphysis increased significantly in both groups ( The removable device with a distalizing screw and the DBSR were both able to regain mild-to-moderate unilateral space loss, achieving an increase in molar angle, IMPA, and molar extrusion. However, treatment time with the DBSR was shorter and with less incisor tipping as a side effect. The proper management of space loss due to the premature loss of primary teeth is an important aspect of preventive and interceptive orthodontics. Dental caries is the most common cause of early loss of primary teeth. Other causes include trauma, ectopic eruption, congenital disorders, and early root resorption of primary teeth. Studies indicate that when a primary second rather than a primary first molar is lost, or if tooth loss happens at an earlier age, or in crowded dentitions, greater space loss is expected , 2.The premature loss of primary teeth, particularly primary molars, allows mesial movement of the first permanent molar and distal drifting of the primary canine, which can disturb the integrity of the arch and may cause impaction or ectopic eruption of the second premolar , 4. It hWhen space loss occurs, space regainers are required on a routine basis. Space regainers are the appliances that move the tooth mesially or distally to recover the lost space. These appliances help the permanent teeth erupt properly in their right place , 9. If pDifferent removable and fixed appliances are used for space regaining. Fixed space regainers are sliding loop regainer, open coiled space regainer, Gerber space regainer, double-banded space regainer, pendulum appliance, distal jet appliance, and lip bumper , 12. RemRemovable devices may be used in the mandibular arch for moderate quantities of space recovery just as they are used in the maxillary arch, but they are generally less satisfying because, compared to the removable plate in the maxillary arch, they are more fragile and vulnerable to breakage. Lower removable plates do not have palatal anchorage support and may not fit as well , and it Therefore, numerous intra-arch devices have been implemented that have reduced dependency on patient cooperation. One of these devices is the double-banded space regainer, which is composed of two bands and a nickel titanium (NiTi) spring, which can recover space due to the superelasticity of the NiTi wire. For the first time in 2012, Chalakkal et al.  reportedThe removable plate with a distalizing screw has been shown by da Costa et al.  to recovThe protocol for this study was approved by the Shiraz University of medical science ethics committee with number IR.SUMS.DENTAL.REC.1398.111.The children were 7 to 11 years of age, all of whom had mixed dentitions.All of the children had 3–5 mm reduced mandibular perimeter due to premature loss of second primary molar.In all subjects, the mandibular permanent incisors and first molars had erupted, and primary or permanent canine had erupted on the space loss side.The space loss was unilateral in all cases.Patients had normal skeletal growth patterns.Second permanent molar was in a position apical to the first molar's cementoenamel junction (CEJ).No history of orthodontic treatment before.Good oral hygiene and cooperation.The mesial angulation of none of the first permanent molars differed by more than 10 degrees from normal.The study sample was comprised of two groups of 19 children between the ages of 7 and 11. One group was treated with a removable appliance with a distalizing screw and the other with a fixed double-banded space regainer for molar distalization. The subjects were selected retrospectively, and the treatments were provided by one clinician. All subjects met the following criteria:The above inclusion criteria were confirmed according to the information in the patients' records and the pretreatment documents, including intraoral photographs, orthopantomograms, lateral cephalograms, dental models, and the results of space analysis. However, the measurements for space analysis were done again on pretreatment dental models, and the results of space analysis in patients' records were confirmed.Sample size calculation was based on the study of da Costa et al. . With anThe device was fabricated on the working cast and featured a Hawley's loop , three or four retention clasps, one distalizing screw on the side of space loss, and an acrylic lingual baseplate . InformaThe design of this appliance was similar to that described by Chalakkal et al. , with thT1) and at the end of active space-regaining treatment (T2), and stone models were made using type IV dental gypsum . To determine the required space for the eruption of permanent canine, first and second premolar, the modified Tanaka-Johnston equation was used [Alginate impressions  were taken before placement of space regainers  at 80–85 kV with a source-midsagittal plane distance of 1.5 m and a film-midsagittal plane distance of 15 cm so that the radiographic magnification factor was similar in all cephalograms.T1) and posttreatment (T2) cephalograms were used for cephalometric measurements. The lateral cephalograms were traced on acetate paper sheets using a lead pencil. The lower incisor angulation was measured as the angle formed by the long axis of the incisor to the mandibular plane (IMPA). The difference between the IMPA measurements on pre- and posttreatment cephalograms indicated the proclination of the lower permanent incisors that worked as part of the anchorage for the space-regaining device (Pre- (g device . To deteg device  20]. Mo. MoT1) ag device  [20]. Thg device . Molar vThe duration of treatment was determined in months for each patient. This was the period of time between the first activation of each device and when the required space for the eruption of the second premolar was regained, and the treatment was completed.t-test was used to compare pre- to posttreatment variables, and independent t-test was used to assess whether differences in means between the groups achieved statistical significance. The level of significance was set at 0.05.The data were analyzed using SPSS version 26. The mean and standard deviation (SD) were calculated for each variable used in analyzing the casts and lateral cephalograms. The distributions of all variables were normally based on the Shapiro-Wilk test. Paired In order to determine the error of the method, two weeks after the first measurements, records of 10 randomly selected subjects were remeasured by the same examiner. The intraexaminer error was assessed using the intraclass correlation coefficient (ICC). The ICC was in the range of 0.92–0.98. Hence, the measurements enjoyed sufficient reliability.T1 (pretreatment) between the two groups (P > 0.05).The study sample consisted of 19 subjects (11 girls and 8 boys) with a mean age of 10.0 (SD 1.38) in the distalizing screw and 19 subjects (10 girls and 9 boys) with a mean age of 9.9 (SD 0.84) years in the DBSR group. The two groups were homogeneous because no significant difference was found for the variables measured at P < 0.001). There was no significant difference in the amount of space regained between the distalizing screw (3.53 mm) and the DBSR (3.51 mm) groups (P=0.974).Dental cast measurements showed that the available space increased significantly in both groups (P < 0.001) which means that both devices tipped the first molar distally. The DBSR group had a greater mean change in molar angle (3.1°) than the distalizing screw group (2.2°). However, the difference between groups was not statistically significant (P=0.078).Cephalometric measurements showed that molar angle increased significantly in both groups (P < 0.001). The mean amount of IMPA change was significantly greater in the distalizing screw (3.3°) group than in the DBSR (2.1°) group (P < 0.05).Results showed that the incisor mandibular plane angle, or IMPA, increased in both groups by the space-regaining treatment (P < 0.001). There was no statistically significant difference in the mean distance changes between the distalizing screw and the DBSR group (P=0.5).The amount of molar distance from the posterior margin of the symphysis increased significantly in both groups (P < 0.001). The average increase was 2.0 mm in the distalizing screw and 2.3 mm in the DBSR group, with no significant difference between the groups (P=0.317).There was a significant increase in the distance between the mesiobuccal cusp tip of the first molar and the mandibular plane in both the distalizing screw and DBSR groups .The average molar distalization time for the distalizing screw group was 11.6 ± 1.96 months, whereas in the DBSR group, the corresponding time was 8.1 ± 2.21 months. Thus, the treatment time for the distal molar movement was significantly shorter for the DBSR than for the distalizing screw group  with the conventionally used removable plate. The DBSR uses Ni-Ti coil springs for molar distalization, which can generate continuous light forces over a wide range of activation . In addiIn the present study, to determine the required space, the modified Tanaka-Johnston equation was used, which has been shown to accurately estimate the size of unerupted canines and premolars in the Iranian population . The resThe amount of molar distance from the posterior margin of the symphysis increased significantly in both groups, and there was no statistically significant difference between the two study groups. These results mean that a noticeable amount of space recovered in both groups was due to the distal bodily movement of the first permanent molar . It should be noted that in the analysis of lateral cephalometry images, evaluating bilateral structures such as first molars can be challenging due to the presence of two shadows of these structures. In the current study, the selection of subjects with unilateral space loss made it possible to distinguish between the right and left first molars more easily. This means that the mesially located first molar in the lateral cephalogram was considered as the molar on the space loss side. Moreover, unlike the molar on the space loss side, the position of the molar on the opposite side did not change considerably between the pre- and posttreatment cephalograms. Another helpful criterion for differentiating the two molars was that the image of the left molar was usually less distorted as it was closer to the film.Intraoral molar distalization has some side effects, including tipping of incisors or premolars (or both) in different amounts depending on the choice of distalization appliance . In the While there was a significant increase in IMPA after treatment with DBSR in the current study, there are no previous data in the literature about changes in IMPA after treatment with this appliance. Looking at the present results, by using DBSR, molar distalization seems to have occurred with less proclination of the lower anteriors with respect to the distalizing screw. It can be due to the fact that in the distalizing screw, the acrylic plate is in direct contact with the lingual surfaces of incisors and transmits the force generated by the Jack screw to the teeth in a labial direction. It can also be related to the probable misfit and displacement of the acrylic plate. When using mandibular removable plates in the clinic, it is often observed that after some time, the acrylic plate may not fit well; this is perhaps because the molar does not distalize as much as the Jack screw is opened, which leads to a misfit of the plate. In this situation, the anterior part of the acrylic plate contacts the incisors closer to the incisal edge and further from the center of rotation of the tooth, causing more tipping of these teeth. Another reason that may explain this result is the fact that when lighter forces are applied, anchorage loss is expected to be less . The Ni-Molar tipping is another common finding in cases of molar distalization. In the present study, the removable plate with a distalizing screw and the double-banded space regainer both tipped the first permanent molar distally and increased the molar angle. In the study of da Costa et al. , distal Considering the vertical changes, both appliances extruded the mandibular molar and no significant difference was observed between the amounts of extrusion in the two study groups. Extrusion of the first molar was also observed in the study of Byloff et al.  with theThe basis of an efficient orthodontic treatment is a good understanding of the tooth movement rate and the amount of anchorage loss as well . In the This was a retrospective study and also had the limitation of sample size, which should be overcome by future prospective studies with larger sample sizes. Also, it is suggested to evaluate movements of the tooth mesial to the space loss region in future studies.Within the limitations of this study, it was concluded that the removable device with a distalizing screw and the DBSR are both able to regain mild-to-moderate unilateral space loss when used in patients with mixed dentition, resulting in an increase in molar angle, IMPA, and molar extrusion. But, the DBSR seemed to be more efficient since it had a shorter treatment time and a lower side effect of incisor tipping. However, the removable device can be implemented in patients with low incisor protrusion and good cooperation, with the advantage of better oral hygiene maintenance.


Standard proxies for reconstructing surface mass balance (SMB) in Antarctic ice cores are often inaccurate or coarsely resolved when applied to more complicated environments away from dome summits. Here, we propose an alternative SMB proxy based on photolytic fractionation of nitrogen isotopes in nitrate observed at 114 sites throughout East Antarctica. Applying this proxy approach to nitrate in a shallow core drilled at a moderate SMB site (Aurora Basin North), we reconstruct 700 years of SMB changes that agree well with changes estimated from ice core density and upstream surface topography. For the under-sampled transition zones between dome summits and the coast, we show that this proxy can provide past and present SMB values that reflect the immediate local environment and are derived independently from existing techniques. Snow accumulation rates in Antarctica can now be reconstructed from nitrate isotopes in snow and ice. This independent technique offers scientists a new tool for studying how Antarctic climate changed in the past and how it may change in the future. Since even small shifts in the surface mass balance (SMB) across Antarctic ice sheets can redistribute huge masses of water between the cryosphere, ocean, and atmosphere, a clear understanding of how its SMB has responded to past climate change is crucial for calibrating forecast models of the global environment and properly interpreting ice cores10. Despite this pressing importance, much of Antarctica has insufficient records of both modern and past SMB values, particularly in the transitional zone between the <1000 m elevation wet coastal periphery and the >3000 m elevation ultra-dry dome summits. Although this transitional zone comprises 50% of Antarctica’s surface area11, it hosts few long-term scientific stations and is much less targeted for intensive scientific research and deep (>100 m) ice core studies. Because this zone has a highly dynamic SMB system affected by strong wind-driven transport, rugged small scale surface features, and infrequent but high impact precipitation events, our lack of dedicated studies of the transitional zone impedes a comprehensive understanding of past and present SMB changes in Antarctica.Antarctica holds a critical role in the Earth’s hydrosphere, providing long-term storage of 27 million km12. This has left vast regions of Antarctica with no ground-verified SMB data.This lack of data is largely a result of logistical challenges with observing the intermediate SMB values in this transitional zone when using existing techniques. Determining modern SMB for new sites typically requires either installing stake transects that need multiple return visits spanning several years or coring several meters of firn to identify the increasingly buried 1992 Pinatubo volcanic horizon with geochemical analysis. However, the limited time and resources during research expeditions to remote areas usually prevents intensive modern SMB surveys with these methods, and, as a result, existing SMB records in the transition zone are largely restricted to a few frequently traveled supply traverse routesδ2H or δ18O) is used to derive snow accumulation rate through water vapor saturation10. However, this approach does not account for wind-driven transport and sublimation of surface snow at warmer and lower elevation sites15. Additionally, water isotopes reflect many environmental factors other than temperature, such as atmospheric circulation changes, transport pathways, and moisture sources, which can lead to large uncertainty and/or bias in reconstructed SMB17. Changes in ice density along the cores may be converted to SMB provided that they are well-dated, but density-based reconstructions become increasingly uncertain with depth due to thinning and deformation of ice layers18 and may be impossible in zones with heavy ice deformation. Cores are also commonly damaged during the drilling and transportation process, and this can make accurate physical measurements of mass and volume very difficult, particularly for the shallow firn segments. There is thus a strong need for alternative independent proxies that record local SMB for modern climatology studies, paleoclimate reconstructions, and ice sheet modeling while avoiding the problems inherent in existing methods.Although ice cores have been drilled from a few sites in the transitional zone, extracting SMB histories from these cores is often difficult. At interior dome sites, proxy air temperature from water isotopes  of nitrate (NO3−)  when exposed to ultraviolet light (λ = 290–350 nm). Because 14NO3− is more readily photolyzed than 15NO3−, the δ15N of NO3− (δ15NNO3) remaining in the snow will increase from its initial depositional value of ≈−20 to +20 ‰ to values as high as +400 ‰28 as the isotopically lighter photolytic NOx product is ventilated and lost to the atmosphere. Although NO3− can also be lost through HNO3 volatilization, we interpret δ15NNO3 solely through photolysis since volatilization does not strongly fractionate NO3− and should be a very minor component of NO3− loss outside of the warmest coastal zones30. Additionally, while the oxygen in NO3− also undergoes isotopic fractionation through photolysis, its interpretation is complicated by isotopic interactions with snow and water vapor31 and is not further discussed here.Here, we present one such SMB proxy based on photolysis-induced changes in the 35. Photolysis and the resulting isotopic fractionation of NO3− cease once snowfall buries NO3− beneath the photic zone, and the δ15NNO3 value of the NO3− buried in the archived zone (δ15NNO3arc) is assumed to be preserved indefinitely in glacial ice32. The final δ15NNO3arc value reflects the sum total of photolysis inducing radiation experienced by NO3− during the burial process, which, assuming stable insolation and photic zone depth, is itself determined by the rate at which the NO3− is buried and thus inversely related to SMB36. Modeling . Calculated and referenced SMB values are given here with units of kg m−2 a−1, which is equal to mm w.e. a−1.Photolysis is limited to the depth where light penetrates and initiates photochemical reactions, and so the snowpack can be divided into an uppermost photic zone  and a deeper archived zone3− in snow and firn from 92 East Antarctic shallow pits and cores that are reported here. Combined with 43 previously published δ15NNO3arc samples37, this constitutes a database of 135 total δ15NNO3arc values representing 114 distinct sites across East Antarctica  or as an output from the Modèle Atmosphérique Régional (MAR) forced by ERA-interim reanalysis data13 and adjusted for a dry-site bias (SMBadjMAR)  = 6.98 ± 0.19 SMB−1 − 0.02 ± 0.01 . Moreover, this relationship is within modeled expectations that use best estimates for photolytic and isotopic fractionation parameters  may not always have been followed due to logistical challenges and time constraints. Additionally, the resolution of MAR and other regional climate models cannot capture the impact of small surface features on local SMB, and even hyperlocal SMB variability  caused by sastrugi and drifts might be missed by nearby stakes or other ground observations of SMB. Assuming that these factors are not biased toward over- or underestimating SMB, we can expect the SMBδ15N regression to provide accurate modeled values despite these prediction intervals. The precision of the regression and its SMBδ15N modeled outputs should also improve in the future with the addition of data from new sites using best sampling protocols and improved regional climate modeling.The SMB and δ15NNO3arc observed in samples , illustrating the vast spatial impact of photolytic NO3− loss. The highest modeled values, excluding some small coastal regions with very low or negative modeled SMBs  where NO3− archiving is not expected, are found on the interior high plateau of East Antarctica between Dome C and Dome Fuji, in agreement with previous global chemical transport models33. Although millennial-scale changes in global NO3− dynamics and atmospheric oxidative capacity are not currently well constrained, the factors parameterized in Eq.  uses ≈5 nmol of NO3− for δ15NNO3 analysis and ≈100 nmol to include oxygen isotope anomaly (Δ17ONO3) analysis, the potential resolution of the SMBδ15N proxy depends upon the NO3− concentration of the snow or ice sample and upon the mass of snow or ice comprising each sample. For the samples included in our field database, NO3− concentrations ranged between 5 and 131 ng g−1, with lower values at drier sites. To collect 100 nmol of NO3− for maximum isotopic data, these concentrations require between 0.05 to 1.15 kg of snow or ice, with a median requirement of 0.15 kg. For snow pits, sampling at a 2 cm depth interval requires only 0.01–0.16 m2 surface area collected per sample, and thus the storage and transport logistics for large numbers of samples are more restrictive for snow pits than physical sampling limitations. Ice core sampling resolution is dependent upon the core diameter and percent of core available for NO3− recovery. We find that 2–3 samples per ice core meter are typically achievable even when the ice core is only partly partitioned for NO3−, and higher resolution is possible with cores that are drilled solely or primarily for NO3− isotopic analysis.Since the most advanced established technique for NO−2 a−1, the SMBδ15N proxy is best suited for sites with SMB values between 40 and 200 kg m−2 a−1. Shallow cores from very dry Dome A and Dome C have lower δ15NNO3arc values at 2–6 m below the surface than at the ~1 m base of the photic zone, possibly because photolytic NOx can be transported downward through firn air convection and re-oxidized into NO3− with low δ15NNO3 values  because NO3− is buried below the photic zone in less than a year. Despite the short photic zone residence time, more than 80% of NO3− is deposited during sunnier months outside of winter polar night39 and some photolytic loss is still likely. As a result, NO3− samples that integrate multiple years of accumulation at high SMB sites might still resolve differences in SMB , a site with moderate modern SMB (≈120 kg m−2 a−1) located midway between coastal Casey Station and the Dome C summit  and has values ranging from 49 to 208 kg m−2 a−1 , and thus any impacts from individual precipitation events or seasonal extremes are attenuated. Overall, the SMB values at this site show fairly large variability (coefficient of variation = 0.21). The mean SMBδ15N in the 20th century (126 ± 26.5 kg m−2 a−1) is 34% greater than the mean SMBδ15N before 1900 CE (94 ± 18 kg m−2 a−1) and nearly 52% greater than the driest century that spans the 1600s CE (83 ± 20 kg m−2 a−1)  Fig. .Fig. 4Reδ15NNO3arc values reflect the snow burial speed of the immediate overlying area, short-term variability in SMBδ15N is likely dominated by small spatial scale factors such as surface roughness 43 and local weather 45. However, the SMBδ15N patterns observed over decadal to centennial scales more likely represent changes to the broader regional environment as the local environmental “noise” has less impact when data is aggregated at longer timescales. Finally, it is important to note that the SMBδ15N values reflect the immediate local snow accumulation, and so some short duration events  with major region-spanning impacts may not be preserved in an individual ice core due to periods of surface erosion and/or mixing46. This feature should not, however, be viewed as a drawback of the SMBδ15N proxy. Rather, the SMBδ15N record is accurately reflecting the actual SMB experienced at the core site, which is a critical factor to accurately calculating and interpreting other environmental proxies contained in the ice core, such as biogeochemical fluxes.Since δ15N values with SMB calculated using the physical density of the ice core and its age-depth relationship (SMBdensity). Because the measurements for SMBdensity are typically performed on each individual ice core segment, it generally has a lower potential resolution than SMBδ15N which, in contrast, can have multiple values per core segment. Still, SMBdensity functions well as an established benchmark for validating newer SMB proxies like SMBδ15N. For each 1-m core segment of ABN1314-103, we calculated a SMBdensity value by dividing the segment’s mass (kg) by both its volume (m3) and the age difference between the top and bottom of the segment (a m−1). The SMBδ15N (aggregated to match the 1-m resolution) and SMBdensity share very similar mean values  and total SMB ranges , and the two SMB reconstructions have a similar pattern of variation with a moderate Pearson correlation   Fig. . The cor−147. This means that the ice in ABN1314-103 actually accumulated as snow along a continuous 11.5 km transect upstream of the current ABN drilling site, with the oldest and deepest ice originating from the most distant upstream position. Using the horizontal ice flow rate and the ABN1314-103 core’s age-depth model, we can estimate the position along the upstream transect where the snow for each depth in the core originally accumulated48.Interpreting the ABN1314-103 SMB profile is more complicated than for ice cores drilled at dome summits because the ice sheet at the ABN drilling site is flowing horizontally at a rate of 16.2 m a11 , the region has abundant 0.5–1 m undulations in surface topography extending over horizontal extents of 3–10 km11 Fig. . The MARs48 Fig. . These sGPR) that can be directly compared to the SMBdensity and SMBδ15N reconstructions.Because ABN1314-103 is composed of snow that fell along this upstream transect, the ice core SMB record will not only reflect changes due to wetting or drying of the regional climate, but it will also reflect any spatial SMB variability caused by topographic features that existed along the upstream transect. Since the local surface topography has not significantly shifted or changed over the time period covered by ABN1314-103, we take the modern topography-driven SMB changes observed with GPR to be representative of past SMB spatial variability. As each position along the upstream transect is paired to a depth in ABN1314-103, we can transfer the GPR-derived SMB profile along the horizontal transect to ice core depths to produce a SMB reconstruction  and SMBdensity (r = +0.63) records  between SMBGPR and SMBδ15N, we find that the multi-decadal SMB values have been generally stable over the past 700 years  and that precipitation has increased in the most recent 100–150 years. This is generally consistent with what has been observed at other East Antarctic sites53 and for Antarctica as a whole18, but we recognize that this pattern is similar to the upstream topographic effect and that it might also arise if the SMBGPR record is excessively smoothed relative to true topographic-driven SMB variability (perhaps by the GPR data processing).To examine whether a secondary signal related to climate change was also preserved by the ars Fig. , with 50−2 a−1 around a common mean within 10–20 year periods. This pattern likely reflects the high interannual snowfall variability expected at sites like ABN14. Located at the transition between the coast and the interior East Antarctic Plateau, annual snow accumulation at ABN is sensitive to frequent intrusions of extreme precipitation events and atmospheric rivers45, and the observed sub-decadal SMBδ15N variability may represent the frequency of their stochastic occurrence at the site. Additionally, small scale surface roughness features like sastrugi may affect hyperlocal SMB through periods of enhanced accumulation and erosion as they migrate and evolve on the snow surface54. While the temporal evolution and possible life cycle cyclicity of surface roughness features are as yet poorly known, hyperlocal changes in SMB could also explain some of the short-term SMB variability observed in the ABN record if the sampling interval is shorter than the average duration of a surface feature at a given location.On shorter timescales, SMB values frequently change by ≈50 kg m2 of Antarctica having a SMB between 40 and 200 kg m−2 a−113 and over 70% of the ice sheet area modeled to have δ15NNO3 values markedly elevated by photolysis, the SMBδ15N proxy holds great potential for expanding our knowledge of Antarctic SMB variability over time and space and serving as an independent supplemental SMB reconstruction. Currently, regions with moderate SMB have only a handful of sites with SMB records older than 200 years, with the East Antarctic Plateau particularly poorly represented18. For ice coring projects in these regions, the SMBδ15N proxy can perform better at capturing the local effects of strong winds, irregular surface topography, and high interannual snowfall variability than water isotopic techniques while avoiding problems with layer thinning, density modeling, and core damage that affect density-based methods. As regional climate models still struggle to accurately simulate drifting snow and sublimation fluxes in the coast-to-plateau transition13, SMBδ15N can provide critical ground-based data for models predicting future contributions to sea level rise. The SMBδ15N proxy also holds particular value for helping to constrain and validate models of upstream flow effects in research targeting ice streams and broad-scale glacial flow patterns. The SMBδ15N approach may also be useful to estimate relative SMB changes for ice cores that lack robust age-depth models due to severe glacial deformation or discontinuities.With over 8 million kmδ15N proxy can save valuable time and cost compared to existing alternatives to expand current records of modern SMB. Obtaining new ground-based SMB measurements using existing techniques for sites without annually resolved layers requires either coring several meters to the increasingly buried Pinatubo volcanic horizon or repeated visits to newly installed stake transects. However, limited time and resources for research expeditions to remote areas precludes intensive SMB surveys with these methods. With the SMBδ15N proxy, a mean site SMB could be determined with only a series of shallow snow or firn samples extending deep enough into the archived zone to cover only a few seasonal cycles . After mixing snow well from multiple samples, only 15–75 g (0.3–1.5 kg if Δ17ONO3 results are desired) would need to be kept, transported, and analyzed for each sample, which logistically allows for the rapid collection of robust SMB site means in many locations. On-site melting and NO3− concentration could further reduce logistical requirements.Additionally, sampling for the SMBδ15N proxy promises to grow and adapt as studies on Antarctic NO3− dynamics continue. More NO3– samples coupled with quality environmental context data from East Antarctic will help us better constrain the uncertainty of SMBδ15N calculations and allow for more confidence in reconstructions. As additional ice cores are analyzed for δ15NNO3arc, we can better understand under which exact conditions δ15NNO3arc most accurately records SMB variability and if we can improve our reconstructions with a more complex model. Differences between calculated SMBδ15N values and well-constrained SMBdensity values may also prove useful in identifying periods of unusual environmental conditions that alter typical photolytic reactivity.The SMBδ15NNO3arc sampling is limited only by the minimum amount of NO3− needed for analysis, very finely-resolved δ15NNO3arc records can be obtained by increasing the mass of ice collected per depth unit  and with advances in NO3− isotopic analysis expected in the near future55. This may allow for more precise multi-annual aggregations for SMBδ15N reconstructions and permit a deeper examination of subannual NO3− dynamics that can improve the proxy. Given the potential of the SMBδ15N proxy to advance our understanding of the Antarctic environment and its sensitivity to climate change, we strongly recommend that potential ice coring projects incorporate NO3− analyses into their planning and urge continued studies on Antarctic NO3− dynamics.Because the resolution of δ15NNO3arc and the reciprocal of surface mass balance (SMB−1) has been previously observed and reported in Antarctica36. Here, we mathematically illustrate how this relationship between δ15NNO3arc and SMB arises through photolysis of NO3−. We focus solely on the characteristics of NO3− contained within a given horizontal plane of snow that is located at the snowpack surface at t = 0. We assume simplified conditions with a constant surface mass balance (SMB), clear sky conditions, no surface roughness, and no significant compaction with burial in the photic zone. Any NO3− that is photolyzed is immediately and permanently removed from the plane of snow, and NO3− recycling36 is assumed not to affect NO3− in the plane of snow during the burial process modeled here .A linear relationship between z is determined by the SMB :The time that it takes for a given horizontal plane of snow to be buried from the surface to a particular depth 3− within a plane of snow decays through time according to:J(z) is the photolytic rate constant at a given depth defined as: σ is the absorption cross section for NO3− photolysis (cm2), ɸ is the quantum yield for NO3− photolysis (molec photon−1), and I(z) is the actinic flux of ultraviolet irradiance (photon cm−2 s−1 nm−1) integrated over wavelengths that can induce photolysis of NO3−. However, this photolytic rate “constant” changes with depth because actinic flux exponentially decays with depth as:I0 is the initial actinic flux that strikes the snow surface and ze is the e-folding depth (cm) of the snowpack. Note that non-exponential decay of I in the top ~2 cm of snowpack32 is simplified here by assuming the decay to be exponential from the snow surface. Equation  to derive:In order to determine the NOAnd integrate to produce:Which simplifies to:t = 0, [NO3−](t) = [NO3−]0 and therefore:At And thus combining Eqs.  and 11)11):12\do3− concentration will decrease. However, the rate of decrease will lessen over time as the value of SMB × t approaches 3ze and 95% of the initial irradiance is gone. Here, below the photic zone , the NO3− concentration is largely stable and equal to ec.According to Eq. , as time3− archived below the photic zone (fNO3arc) as:Therefore, we can calculate the fraction of NOδ15NNO3arc of this NO3−, Rayleigh fractionation states that δ15NNO3 can be calculated with the fractionation factor ɑ by:To determine the fNO3arc in Eq.  is negative for nitrogen during photolysis of NO is negatδ15NNO3arc values. Thus, the non-SMB variables can be subsumed into two parameters A and B to function as linear regression coefficients, producing Eq.  ≈ x when x ≈ 0, a simpler relationship of Eq.  can be aδ15NNO3arc values in our database are taken from a mix of previously reported values from Antarctic research traverses and values newly reported here  1–2 m deep snow pit with continuous sampling at regular intervals from top to bottom, 2) single sample taken of a well-mixed 5–10 cm layer around the 1-m depth layer, and 3) drilled core later cut at desired intervals. For isotopic measurement of NO3– that included Δ17ONO3 analysis, 0.3–1.5 kg of snow or ice per sample were gathered to ensure a sufficient amount of NO3−. Generally, the multiple samples produced by the snow pit technique offered the best and most flexible results, but the 1-m depth layer technique was valuable for quick sampling during limited stops, and cores are necessary to collect samples deeper than ≈5 m.The ere Fig. . For allδ15NNO3arc results included in our database that have been previously reported, readers are directed to the original papers for specific analytical and sampling techniques. For the δ15NNO3arc data newly reported here, snow and ice samples were collected into clean sealed plastic bags or tubs and stored frozen until melted at room temperature for analysis. The NO3− mass fraction (ω(NO3−)) was determined on aliquots by either a colorimetric method or ion chromatography with detection limits <0.5 ng g−1 and precision of <3 %24. The remaining melted samples were passed through an anionic exchange resin , and the resulting trapped NO3− was eluted with 10 ml of NaCl 1 M solution.For 3− in these samples was converted to N2O with the denitrifying bacteria Pseudomonas aureofaciens (lacking nitrous oxide reductase), thermally decomposed into O2 and N2 on a 900 °C gold surface, and separated by gas chromatography with a GasBench II™. Oxygen and nitrogen isotopic ratios were then measured on a Thermo Finnigan™ MAT 253 mass spectrometer62. Isotopic effects from this analysis were corrected60, using the international reference materials USGS 32, USGS 34, and USGS 35 with ultrapure Dome C water used for standards and samples throughout the analyses to account for potential oxygen isotopic exchanges. Results are reported relative to Vienna Standard Mean Ocean Water (V-SMOW) for oxygen isotopes63 and N2-Air for nitrogen isotopes64.Isotopic analysis occurred at IGE-CNRS, Grenoble, France, where NOδ15NNO3arc values, a single δ15NNO3arc value was calculated as the aggregate of samples 30+ cm deep, weighted by the relative mass of NO3− per sample. Although the photic zone boundary can extend lower than 30 cm at some sites32, this cutoff was deemed an acceptable compromise to include more data from pits that stopped at 50 cm depth as the great majority of photolysis will have occurred within the top 30 cm due to exponential decay of actinic flux and ω(NO3−) with depth. Exceptions to this were made for three coastal pits from Cap Prud’homme (weighted-means of 3+ cm samples), where high accumulation greatly reduces photolytic impact, higher snow impurities reduce the photic zone depth, and a broader aggregation is necessary to smooth seasonal cycles. Additionally, two pits from Dronning Maud Land were aggregated with 15+ cm samples based on shallow 3ze values (2–5 cm) calculated on site during snow pit sampling31. For cores included in our database, a single δ15NNO3arc value to be considered representative of the site was calculated as the isotopic mean of samples extending from present back to no earlier than 1800 CE.For snow pits with multiple sequential δ15NNO3 values for 16 pits along the JARE54 and JARE57 transects28, but the sampling methodology for these pits took a single well-mixed sample of the entire pit depth which included the entire photic zone. In order to estimate the δ15NNO3arc values of these sites , we applied a correction factor calculated using data from other pits in our database that were taken on two similar transects spanning from the coast to other interior domes (Dome A and Dome C) of East Antarctica25. Because each of the pits on the Dome A and Dome C transects were continuously sampled at discrete intervals from the surface to a point below the photic zone, we calculated different weighted-mean δ15NNO3 values for selected depth spans that matched the three extents of the JARE pits: 0–30 cm, 0–50 cm, and 0–80 cm. Corrective factors were calculated through the linear regression of δ15NNO3arc vs. δ15NNO3.X from Dome A/Dome C transect pits  and applied to the JARE pit data through the appropriate depth correction  reported δ15NNO3arc samples are represented by 51 unique direct ground measurements of SMB (SMBground) values observed at or near the NO3− sampling site, with the numerical discrepancy due to some sites having replicate δ15NNO3arc samples. These previously reported SMBground values were determined by measuring the change in surface height on established stakes or poles, by measuring the mass between known volcanic or radioactivity horizons in an ice core, or by GPR identification of dated horizons71.In our database, 74 13, and we used the Modèle Atmosphérique Régional (MAR) version 3.6.4 with European Centre for Medium-Range Weather Forecasts “Interim” re-analysis data (ERA-interim) data as applied by Agosta et al. (2019) to model mean annual SMB at all database sites for the period 1979–201713. Because the MAR overestimates SMB at high elevation (>3000 m) interior sites of the East Antarctic plateau72, we calculated a correction factor through linear regressions of SMBground vs. MAR-estimated SMB (SMBMAR) for our 51 sites that have both values (Supplementary Table adjMAR) that match more closely with ground observations.Regional climate models can be used to estimate modern SMB rates for sites lacking ground observationsMAR < 175 kg m−2 a−1 and SMBMAR is >110 kg m−2 a−1), and a linear regression was calculated for each subset of sites. This regression for sites where SMBMAR < 175 kg m−2 a−1 is tightly constrained , and it performs well to align the SMBMAR estimates with the SMBground values at low SMB sites. The subset of SMBMAR is >110 kg m−2 a−1 has some samples where the difference between SMBMAR and SMBground are very large, particularly at lower elevation sites where intense aeolian erosion and deposition often produce highly variable local SMB rates that are difficult to accurately model14. As a result, this regression is weaker  than the first regression, but we apply it while acknowledging the possibility of wide deviations. The two regressions intersect at , and thus SMBadjMAR values were calculated by applying the first regression to all sites where SMBMAR ≤ 138 kg m−2 a−1 and applying the second regression to all sites where SMBMAR > 138 kg m−2 a−1. We constructed our final primary SMB dataset for the analysis of δ15NNO3arc samples by using the best quality SMB data for each site: SMBground if available and SMBadjMAR otherwise.These sites were then split into two overlapping subsets of roughly equal count (SMBδ15NNO3arc +1) and SMB−1 based on Eq. . With regression coefficients determined for Eq.  at a 35 km resolution13 that were converted to SMBadjMAR as previously described.We modeled linear relationships between ln based on seasonal ion and water isotope cycles and constrained by volcanic horizons that was originally developed for a longer core also taken at ABN. Each 1 m ice core segment was individually weighed prior to cutting, and the mass and volume were used to calculate a SMB profile based on dated ice density changes (SMBdensity).For reconstructing the ABN SMB49, isochronal internal reflecting horizons were identified to 220 m depth, digitized with ReflexW software, and dated by connecting to the ALC01112018 age-depth model. Using a density profile taken from a longer ice core simultaneously drilled at ABN, 2D fields (depth by transect distance) were calculated for age, mean accumulation rate, and local accumulation rate. The mean accumulation rate to the most shallow reflecting horizon was taken as the upstream topographical effect on SMB .To determine past topographical effects on SMB, a MALA GPR device towing a RTA antenna on the surface  was operated for a 65 km transect upstream of the coring site as part of the 2013–2014 campaign. Radar was triggered every 2 s  with a recording time window of 3000 nanoseconds that captured returns down to 300 m depth. After postprocessingggplot2, RColorBrewer, gridExtra, cowplot, and tidyverse and with Adobe Illustrator. QGIS was used for spatial analyses and map creation using data produced here or cited in image captions.Statistical analyses, regressions, SMB reconstructions, visualizations, and other statistical analyses were performed using the R programming language with packages Supplementary InformationPeer Review File


Pyrethrum cinerariifolium Trev. was identified, and this study confirmed that it binds to a novel allosteric pocket of furin through non-competitive inhibition. It exhibits a very favorable protease-selective inhibition and good cellular activity and specificity. In summary, permethrin shows a new parent nucleus with a new mode of inhibition. It could be used as a highly promising lead compound against furin for targeting related tumors and various resistant viral infections, including SARS-CoV-2.Furin is a potential target protein associated with numerous diseases; especially closely related to tumors and multiple viral infections including SARS-CoV-2. Most of the existing efficient furin inhibitors adopt a substrate analogous structure, and other types of small molecule inhibitors need to be discovered urgently. In this study, a high-throughput screening combining virtual and physical screening of natural product libraries was performed, coupled with experimental validation and preliminary mechanistic assays at the molecular level, cellular level, and molecular simulation. A novel furin inhibitor, permethrin, which is a derivative from pyrethrin I generated by  It isprotease  belongintivities .Furin is associated with a variety of diseases, such as cardiovascular diseases and endocrine system disorders, and is especially closely related to viral infections and tumors ,6,7,8. WPyrethrum cinerariifolium Trev. Permethrin is the most commonly used synthetic pyrethroid insecticide and is widely used due to its high activity as an insecticide and low mammalian toxicity [In this study, on the one hand, over 200,000 compounds were virtually screened using computer-aided drug design. On the other hand, inhibition of furin protein with high purity was analyzed by physical screening on 3000 compounds of natural products selected after virtual filters. Several compounds with furin inhibitory activity were obtained. Finally, permethrin was the most important compound found in this study, which has not been reported to have inhibitory activity against furin. Permethrin is a pyrethrin I derivative, which is the main active component of toxicity , meanwhitoxicity ,26,27.In addition to the selective inhibitory ability of permethrin on furin and its high activity at the cellular level, this research has found for the first time that permethrin can be used as a new type of inhibitor targeting the allosteric pocket of furin through enzymatic kinetic studies combined with extensive theoretical calculations, which will help us to better understand the relationship between the structure and function of furin. At the same time, this novel form of allosteric non-competitive inhibition will also provide inspiration for the development of novel inhibitors of furin.Expression of furin was identified and purification was achieved using SDS–PAGE and Western blot results with a target band at 52 KDa . Boc-R-V50 values were measured   B, indicaIn order to investigate this new interaction mode of permethrin with furin, allosteric site prediction, molecular docking, interaction energy calculation, and molecular dynamics simulation were utilized in the study. These results will help us to better understand the mechanism of the interaction of permethrin with furin, as well as be used to guide the structural modification of permethrin in future work.This study first used the allosteric site prediction program and found that the red sphere in This work docked permethrin into furin’s FuAP1 and FuCP, respectively. As shown in To further verify the interaction pattern of permethrin with furin, MD simulations of 100 ns duration were performed for furin, “permethrin–FuAP1 complex” and “permethrin–FuCP complex”. By comparing the MD simulation data of them, this study found that the total energy of “permethrin–FuAP1 complex” was lower than that of furin protein alone E, and thTo verify that the inhibitory ability of permethrin on furin is not only reflected at the molecular level, but also effective at the cellular level in this work we performed cytological studies using tumor cell lines strongly expressing furin (Hep-G2 and HeLa) and a control cell line (L-02). YJJ-122489, which had shown no inhibitory activity against furin in the previous drug screening, was also used as a control molecule. The cytotoxicity with increasing concentration of permethrin and YJJ-122489 was assayed by incubating cells treated with a gradient of compound concentration for 24 or 48 h . The resPyrethrum cinerariifolium Trev. ingredient derivative permethrin has obvious inhibitory activity against furin, it is still a long way from being a drug, and we will use it as a lead compound for structural modification and optimization to acquire derivatives with higher inhibitory activity and more stable structure in our future research. In In this study, although the Most of the existing furin inhibitors were developed based on furin-substrate peptide analogs, which have good binding to the catalytic pocket of furin but lack chemical and structural diversity ,37. AddiE. coli BL21 (DE3). After resuscitation of the transformed cells in LB medium containing kanamycin (100 mg/L) at 37 °C for 12 h, the cells were expanded at 37 °C (200 rpm) for 3 h until OD600 reached 0.6. Expression was induced with 0.1 mM IPTG, and the cells were harvested at 14 °C (200 rpm) after 16 h. Cells were collected using 6000 rpm for 10 min and resuspended in 50 mL of 25 mM Tris buffer . The cell suspension was sonicated (power setting 200 W) for 20 min and centrifugation at 12,000 rpm for 10 min. The precipitate with furin was collected, washed with 50 mM Tris buffer , then dissolved in 50 mM Tris buffer , filtered using a 0.22 μM microporous membrane , and subsequently used for chromatographic purification using a Ni-NTA column . After SDS–PAGE analysis to determine the effluent fraction containing the target protein, we used 50 mM Tris buffer  in a dialysis liquid system for 12 h at 4 °C, then the protein solution was loaded into a gravity desalination column  which was pre-balanced using 100 mM HEPES buffer . Then it was mixed with 10% glycerol and stored at −80 °C until use. Finally, the furin was identified using SDS–PAGE and Western blot.The commercial expression pET30a vector containing the furin gene  was transduced into + and Cl−, using GROMACS [In this project, the natural product libraries of Med Chem Expression and COCONUT , and the GROMACS  softwareBoc-Arg-Val-Arg-Arg-AMC (Boc-R-V-R-R-AMC) was used as a substrate for the detection of furin. It carries an AMC (7-methyl coumarin) moiety that fluoresces at an excitation wavelength of 370 nm and an emission wavelength of 460 nm.2) pre-incubated with the different inhibitors to be tested at 37 °C for 5 min. The reaction was then incubated for 90 min at 37 °C, supplemented with 40 μM substrate, quenched using 1% formic acid and the enzyme activity was monitored using a Thermo Scientific Varioskan Flash Multi-Mode Microplate Reader.Inhibitor screening was performed using 96-well plates with a 200 μL reaction system per well consisting of furin in 100 mM HEPES buffer , followed by different concentrations of the compounds to be tested, preincubated at 37 °C for 5 min. Different concentrations of the substrate were added; the sample was incubated at 37 °C for 35 min, and quenched with 1% formic acid. The initial rate of the enzymatic reaction of furin was tested and the curve was plotted.For the measurement of enzymatic kinetics and inhibition kinetics, the substrate concentration gradients were set to 0 μM, 2 μM, 5 μM, 10 μM, 20 μM, 40 μM, 60 μM, 80 μM, 100 μM, 120 μM, and the compound concentration gradients to 0 μM, 25 μM, 50 μM, 100 μM. Furin was added to 100 mM HEPES assay system buffer  was used to analyze the different state conformations of furin , and in consideration of the studies by Sven O. Dahms et al. [Based on the results of the enzymatic kinetics and structural calculation, this study found that the inhibitory model of permethrin was not a classical competitive inhibition, and this work speculated that it probably acted on another allosteric site. Via AlloSitePro (s et al. ,22, thisFurin is highly expressed in liver cancer cells and has specific effects on hepatocellular carcinoma. Therefore, human hepatocellular carcinoma cells Hep-G2 were selected as experimental cells, cervical carcinoma cells HeLa with similar furin expression in Hep-G2 were selected as control, and human permanent hepatocytes L-02 were selected as negative control. DMEM was used for HeLa, and 1640 medium was used for Hep-G2 and L-02. After incubation for 24 h with 100 μL complete medium in 96-well plates with 8000 cells per well, the medium was aspirated, 100 μL serum-free medium containing a concentration gradient of the compound was added and the samples were incubated. After 24 or 48 h the drug-containing medium was aspirated and 100 μL medium solution containing 10% CCK8 was added, subsequently, the absorbance was measured at 450 nm using a microplate reader after 1 h of incubation.In this study, furin with high purity and activity was obtained using recombinant expression, and the activity detection system was optimized. Next, a virtual screening of a natural product library containing 200,000 natural product molecules and a target-based physical screening at the enzyme level were combined and an effective potential inhibitor against furin, permethrin, was identified. The most important contribution of this investigation is the demonstration of a novel binding mode of permethrin to furin, and the discovery of this non-competitive inhibition phenomenon will contribute to a better understanding of the biochemical characteristics of furin and to the design of novel therapeutic drugs based on it. In addition, this study also demonstrated the good selective inhibitory ability of the pyrethrin I derivative permethrin against furin, as well as the inhibitory ability and anti-tumor-cell-proliferation activity of permethrin against furin at the cellular level. These findings may provide new insights and lead compounds for the discovery of drugs against furin.


Modifications to interventions can jeopardize intervention outcomes. Pre-existing perceived barriers and facilitators to the intervention arising in the implementation preparation phase may help explain why modifications to the intervention may occur during the implementation phase. This two-site comparative case study describes modifications made to a complex organizational-level intervention and examines how known implementation science factors may have enabled such changes to occur.TM Hispanic Kidney Transplant Program (HKTP) is a culturally competent transplant center-based intervention designed to reduce disparities in living donor kidney transplantation among Hispanics. In-depth qualitative interviews and discussions were longitudinally conducted with transplant stakeholders  at two kidney transplant programs with large Hispanic populations during implementation preparation and implementation phases. The Consolidated Framework for Implementation Research (CFIR) guided interview design and qualitative analysis, and Stirman’s Framework for Reporting Adaptations and Modifications-Expanded (FRAME) guided modification classification.Northwestern Medicine’sn = 29 versus n = 18). Sites differed in the proportions of delaying/skipping (Site-A 50% versus Site-B 28%) and adding (Site-A 11% versus Site-B 28%) but had comparable substituting (Site-A 17% versus Site-B 17%) and tweaking (Site-A 17% versus Site-B 14%) modification types. Across sites, the transplant team consistently initiated the most modifications . While individuals initiated slightly more modifications at Site-B (21% versus Site-A 17%), institutions instigated proportionately slightly more modifications at Site-A (17% versus Site-B 10%). CFIR inner setting factors  that prominently emerged during the implementation preparation phase explained similarities and differences in sites’ modification numbers, types, and agents in the implementation phase.Across sites, 57 stakeholders participated in an interview, group discussion, and/or learning collaborative discussion. Site-B made more modifications than Site-A (Organizations implementing a culturally competent care intervention made modifications. CFIR inner setting factors emerging in the implementation preparation phase largely explained similarities and differences in study sites’ modifications. Identifying factors contributing to modifications may help institutions become better prepared to implement an intervention by addressing known factors in advance, which may foster greater fidelity leading to desired outcomes.ClinicalTrials.govNCT03276390. We registered the study retrospectively on 9-7-17.The online version contains supplementary material available at 10.1186/s43058-022-00296-0. Contributions to the literatureResearch has shown that the CFIR explains why organizations modify interventions. However, research has seldom focused on complex, multilevel interventions with multiple components and strategies and has not examined the nature of those modifications.Applying Stirman’s FRAME typology of modifications to the study of implementing a complex intervention , we found that some CFIR elements are associated with different types of modifications.These findings demonstrate the groups of CFIR factors that influence modifications, an essential implementation outcome.Translating interventions into practice is challenging because intervention components may not fit within unique organizational contexts. The modifications made to better fit the intervention with the context can undermine intervention fidelity . ImplemeFollowing Stirman et al., we define “modification” as planned or unintentional “changes to the design or delivery of an intervention.”  We distiRelatively little is known about modifications made during intervention implementation. Studies have examined modifications by culturally adapting prevention interventions to improve fit with clients and optimize desired outcomes , 9–11. TIdentifying determinants of modifications may reveal which intervention components worked in achieving desired outcomes, the circumstances by which they worked , and helHowever, little research has examined how organizational factors, identified by FRAME or other implementation science theories and frameworks, explain intervention modifications. In one of the few exceptions, Lau et al. examined therapist and practice-level factors that predict different adaptation types. The researchers examined whether the practice influenced augmenting or reducing/reordering adaptations but did not examine the features of those practices that explain differences . RecentlWhile prior research on intervention modifications has focused primarily on simple interventions that intervene at the patient or physician level, few studies have examined modifications occurring at the organizational level . HealthcAlthough recently proposed by Damschoder and colleagues, studies have not yet evaluated how CFIR factors, identified in the preparation phase, engender modifications during the implementation phase . UnderstTM Hispanic Kidney Transplant Program. This paper uniquely examines the types and characteristics of modifications made to a complex, organizational-level, culturally competent care intervention. It describes how implementation science factors in the implementation preparation phase may have enabled modifications to occur during the first year of the implementation phase.This research is part of a large, multi-part 5-year study examining the implementation and effectiveness of Northwestern Medicine’sThe CFIR , 25 was structural characteristics, culture, self-efficacy, and compatibility.Stirman’s FRAME was used to classify and determine the intent of modifications . The FRAWe conducted a type-2 hybrid effectiveness-implementation study design with a pre-post intervention evaluation to assess the impact of the HKTP at two intervention sites (Site-A and Site-B) and two matched control sites. The pre-implementation period spanned from January 1, 2011 to December 31, 2016. The intervention period spanned from January 1, 2017 to March 15, 2020, and ended prematurely due to the COVID-19 pandemic. Our previous research  evaluateNorthwestern Medicine’s™ Hispanic Kidney Transplant Program (HKTP) is a complex healthcare organizational intervention  designedWe extend this previous work  by conduThe HKTP intervention was implemented at two U.S. kidney transplant programs: in the South (Site-A) and the Southwest (Site-B). Sites were chosen because they perform fifty or more LDKTs per year, have a Hispanic bilingual transplant physician, and serve a large Hispanic patient population. Both were non-profit hospitals with LDKT disparities for Hispanics, as compared to non-Hispanic Whites in 2016 . Site-A The CFIR guided implementation design . We usedSite visits were conducted in May 2016 and March–April 2017. In-depth, in-person, one-on-one and group interviews were conducted with transplant stakeholders by a trained female social scientist with a PhD, co-PI (EJG), using the CFIR Interview Guide . An addiFigure Transcriptions of 2016 data collected underwent a thematic analysis of barriers and facilitators to carrying out the HKTP during the pre-implementation phase, as described elsewhere . BrieflyWe performed a framework analysis using the FRAME by coding transcriptions of the audio-recordings and field notes from the implementation phase (2017) for the presence of modifications, their nature, initiator, intervention component, and intent. A codebook was based on Stirman’s FRAME. The research team  held multiple 1-h-long analytic retreats to review independently coded transcripts and revise the codebook for clarity, in an iterative process. The four-member coding team reached inter-rater reliability (kappa > 0.60), then resolved discrepancies between coders through discussion , 41, 42.During the second phase of analysis, axial coding techniques from grounded theory  were usen = 26, Site-B: n = 31; 100% recruitment rate) participated in one or more research activities, including 37 in-depth, one-on-one interviews , 34 group discussions (n = 45), and/or 6 learning collaborative discussions (n = 17)  (Table delaying/skipping (Site-A 50% versus Site-B 28%) and adding (Site-A 11% versus Site-B 28%), but were comparable in substituting (Site-A 17% versus Site-B 17%) and tweaking (Site-A 17% versus Site-B 14%) modification types.Site-B made nearly twice as many modifications than Site-A (8) Table . Sites dtransplant team consistently initiated most modifications . Individuals instigated proportionately slightly more modifications at Site-B (21% versus Site-A 17%). In contrast, institutions instigated proportionately slightly more modifications at Site-A (17% versus Site-B 10%). At Site-B, both the institution and individuals initiated two modifications (7%).Across sites, the The goals of making modifications slightly varied by site Table . Sites wSkipping and delayingskipping-type modifications, primarily due to their institutions’ structural characteristics. For example, both sites did not establish a direct, Spanish-speaking telephone line in the transplant division, per the protocol. Because Site-A worked in collaboration with a community nephrology organization that made and received all HKTP-related intake calls in which “everybody who answers the phone is bilingual,” Site-A did not perceive any problems in providing access to the HKTP to their Spanish-speaking patients. Site-B did not implement a Spanish telephone line because doing so would require a large infrastructural change that would challenge the institution’s “philosophy… [to] provide the same care at every site no matter what door you are walking into.” As a stakeholder from Site-B explained, setting up the Spanish line would be a “big ask for the institution” because “the Spanish portion of them having access to someone who speaks Spanish has never been an option at the institution”. Thus, if a Spanish-speaking telephone line were implemented in the transplant division, the institution would have to implement one in other clinical divisions.Both sites made similar structural characteristics. Site-A encountered delays in translating the HKTP website content because its merger with another healthcare institution posed other institutional priorities. Site-B encountered delays because it had not received approval from institutional enterprise leadership. As one interviewee explained, “Well, I know that our website needs to be translated and unfortunately I have no control over that. This is something that needs to be done by [the enterprise]”.Both sites experienced delays in publishing the Spanish HKTP information on their institutional websites due to available resources). As one interviewee from Site-B explained, “I mean we have international services that does translation for our patients, and I’ve asked them before if they would translate information. I think in the past when they are more heavily staffed they were able to, but now they’re short staffed, and they’re not able to.” Delays were also due to conflicts in coordinating with the transplant team, translation services, and marketing department. The intervention’s 16 components, involving different institutional departments and different organizations, made skipping and delays more likely to arise, given the challenges of coordination between these organizational units.Both institutions delayed the translation of HKTP patient-facing materials  into Spanish. Both institutions attributed these delays, in part, to their lack of Spanish-speaking staff or time available by such staff to dedicate to this task . Site-A had previously expanded their services to living donors, modeled after a program they adopted from another institution. “[This other institution has] a red phone and when donors call, it’s always answered. [So we implemented], a phone number that is always answered also, but the focus was, we value you as a donor, and we are going to take excellent care of you … I mean that project, we implemented and brought it in 2½ years ago.” Site-A’s previously successful implementation experience led them to make fewer overall modifications. The greater number of intervention modifications at Site-B was due to the HKTP being less compatible with existing workflows, structural characteristics, culture, and available resources. One interviewee explained, “I think that what it’s gonna make it hard to implement is that nothing happens at [Site-B] without 20 meetings and 20 people dotting the I and crossing the T. I think the biggest barrier is just kind-of going through the process, and then redoing the process, and making sure that everyone is part of the process and I think that it’s kind of like the nail in the hay.” For example, Site-B’s HKTP outreach staff had multiple work commitments, which prevented them from performing the minimum 16 h of outreach per week for a total of 832 h for the year, as outlined in the intervention protocol. Further, Site-B could not schedule the target number of patients to attend the HKTP education sessions because of limits imposed by the size of the education room.CFIR Inner Setting factors in the implementation preparation phase explained many differences in the number and types of modifications made across sites during the implementation phase. Details including illustrative quotations about each modification made by site are presented in the Supplemental File 3. Site-A’s prior experience and success with implementing other interventions increased the institution’s confidence in implementing the HKTP  on instAddingculture. One interviewee explained, “You don’t really have power. You don’t really go around telling people what to do. You just find ways to identify key people and stakeholders and help motivate them to do the job. We don’t really run an institution of authoritative dictatorship. It’s not like a traditional academic environment where the Chair says, 'Okay, this is what you all are going to do' and people say, 'Okay [the Chair] told me to do that.' It doesn’t work that way here.” The team-based approach to decision making placed a high value on obtaining input from all levels within Site-B’s social structure. Stakeholders involved in HKTP implementation behaved as though they felt empowered to make additions that they believed would improve the HKTP that bypassed the prolonged team-based approach to decision making. Additions included the bilingual outreach staff creating a flyer that was posted in dialysis centers to advertise the upcoming lobby days, and the bilingual/bicultural research staff creating a folder containing educational materials to give to potential living donors and family members attending the HKTP clinic. By contrast, decision making at Site-A was concentrated at the transplant division level, which facilitated approvals with implementing the HKTP with greater efficiency.Site-B added proportionately more intervention components than Site-A. Most of Site-B’s modifications involved adding elements to the intervention, which were related to the institution’s culture featuring strong leadership engagement by the transplant division facilitated approvals with implementing the HKTP with greater efficiency, leading to proportionately fewer components of the intervention being added. One interviewee explained, “We are organized in a fashion, so for us, we do whatever we want. There is no one who will oppose us. I mean no one will say no. If we say this is what we want to do, then everybody else says, 'Yes, sir.' That’s the way it works.” The strong leadership engagement from operation administrators at Site-A fostered momentum in intervention implementation.Site-A’s structural characteristics, culture, and absence of sufficient leadership engagement. As described above, decision making typically required multiple team meetings to come to a consensus. For example, the HKTP flyer developed for distribution to dialysis patients during outreach visits had to undergo an extensive chain of review before receiving authorization from the institutional enterprise’s “mothership.” Site-B’s team-based culture and the need to rapidly implement the intervention enabled individual stakeholders to expedite modifications by bypassing the typical lengthy approval process through “workarounds.” By contrast, decisions at Site-A were made internally by the transplant team. For example, the transplant team decided to host their usual Spanish Town Hall Question and Answer discussions for the public to promote the HKTP, adjusted the day and time of HKTP clinics to solve scheduling conflicts with healthcare providers, and cancelled HKTP clinics when too few patients were scheduled.The modifications made by individuals at Site-B were primarily related to the institutional In this study of a complex, culturally competent care intervention, we found that both institutions made numerous modifications. Modifications occurred after the intervention had been implemented and as new organizational issues emerged. By contrast, Stirman’s review found that most studies described modifications made proactively, early in the implementation process . Thus, ostructural characteristics, appeared to contribute to intervention delays/skipping in Site-A. By contrast, the lack of leadership engagement appeared to contribute to delays/skipping in Site-B. These examples illustrate how institutional-level factors are relevant to modifications made to complex interventions.This study is among the first to identify the CFIR factors that influence implementation outcomes, a new area of CFIR research . CFIR InModifying interventions is the subject of much debate because they potentially interfere with implementation fidelity . Our finculture, available resources, compatibility, and goals and feedback largely explain these modifications. The sites’ nested layers of institutional bureaucracy  promoted skipping and delaying modification types.Most modifications involved delaying/skipping, adding, or tailoring/tweaking intervention components, consistent with other research . Our finleadership engagement.Most modifications were made by the transplant team (64%), suggesting a unified or thoughtful approach. However, 19% of modifications were made by individuals, which highlights the need for greater oversight of the intervention implementation process by study champions. Modifications that originated from individuals were most common when there was an egalitarian culture, suggesting that such intervention sites require greater oversight than sites with greater structural characteristics), greater delays to implementation occurred. Practically, these findings can help prepare interventionists to expect certain modifications in certain settings.Our findings have practical implications for leaders intending to implement complex interventions. In particular, our study sheds light on Pawson and Tilley’s pivotal question, “What works, for whom, in what circumstances, in what respects and why?”  We foundOur study’s strengths include a prospective analysis of a complex intervention. We evaluated the implementation at the organizational level at two geographically distinct healthcare organizations. Given that the HKTP was devised as a culturally competent intervention, our evaluation of modifications to the HKTP largely controls for concerns raised by the cultural adaptation field within implementation science, modifications based on clients’ cultural backgrounds, and enables a broad analysis of organizational factors influencing modification. Involving the co-PI (EJG), who had an intimate knowledge of the intervention and what comprised minor versus moderate modifications, helped ensure appropriate modification classification in the coding and analysis processes.Our study has limitations. Detailed descriptions of modifications depended on self-report, which may have been limited by social desirability bias. However, triangulation through interviews with multiple stakeholders and member checking through weekly phone calls with Site-A and Site-B research staff and quarterly learning collaborative calls served to validate and clarify the nature of modifications. This analysis did not evaluate the impact of modifications on implementation fidelity and on HKTP outcomes. The relative weight of modifications for their impact on fidelity to different intervention components remains to be determined .We subsequently evaluated the intervention’s sustainability in light of modifications made over time , 51. SusComplex interventions require the coordination of multiple departments and individuals. The implementation of complex interventions creates many opportunities for modifications to occur in various locations within the organization. This research demonstrates that identifiable factors from the CFIR explain the frequency, type, and source of those modifications. In doing so, it guides how organizational actors are likely to modify the intervention, either to better fit the unique context or in ways that undermine intervention fidelity.Additional file 1. HKTP Implementation Components (same as protocol table). This file describes all 16 HKTP intervention components.Additional file 2. 2017 Site Visit Interview Guide for the Site PI and Administrators. This file provides the interview guide used for the 2017 site visits.Additional file 3. Modification Description, Reason, Illustrative Quotation, Modification Type, and Initiator by Study Site. This file presents a description of modifications, the reasons why they occurred, modification type, and illustrative quotations by study site.


Furthermore, comparisons reveal that neighbouring outlet glaciers can behave synchronously, but others show opposing trends, despite their close proximity. We link this spatial and temporal variability to changes in ice shelf buttressing and the modulating effect of local glacier geometry.Antarctica’s contribution to global mean sea level rise has been driven by an increase in ice discharge into the oceans. The rate of change and the mechanisms that drive variability in ice discharge are therefore important to consider in the context of projected future warming. Here, we report observations of both decadal trends and inter-annual variability in ice discharge across the Antarctic Ice Sheet at a variety of spatial scales that range from large drainage basins to individual outlet glacier catchments. Overall, we find a 37 ± 11 Gt year This imbalance has been caused by increased ice discharge5, particularly in the West Antarctic Ice Sheet (WAIS), outweighing longer-term trends of increased precipitation, particularly over the East Antarctic Ice Sheet (EAIS)6. Thus, in the context of predicted future warming7, it is important to understand the spatial and temporal variability in ice discharge from Antarctica and the likely drivers of recent and future dynamic changes, which remain a key uncertainty in future projections of sea level rise8.Since 1992, the Antarctic Ice Sheet (AIS) has contributed 7.6 mm to global mean sea level rise and this contribution is accelerating−1 between ~ 2008 and 20155, or by 48 Gt year−1 between 1999 and 2010 and 2010–20173. In the East Antarctic Ice Sheet (EAIS) there has been comparatively little change, with estimates suggesting − 1 ± 11 Gt year−1 decrease5 in ice discharge between ~ 2008 and 2015, and a 4 Gt year−1 increase in ice discharge between 1999–2010 and 20173. However, these studies mostly focus on decadal-scale changes in ice discharge from large regional drainage basins that sometimes average the contribution from several major outlet glaciers, thereby potentially masking both spatial and temporal variability. In contrast, few studies have focussed on the inter-annual variability in ice discharge within these basins or investigated changes at the scale of individual outlet glacier catchments. Establishing the magnitude of any inter-annual or spatial variability is important because it may enable an improved understanding of longer-term trends in ice discharge and the processes that are driving such variability. This is also relevant to numerical modelling studies that use modern observations to help constrain Antarctica’s future contribution to mean global sea level rise9.Several estimates of the change in ice discharge from Antarctica have shown that the increase over recent decades has been dominated by the WAIS, where ice discharge has increased by 30 ± 8 Gt year11 to create 12 time-stamped ice velocity mosaics spanning from 1999–2006 to 2018 to approximate ice discharge over both decadal and inter-annual time periods. We report changes in ice discharge at both previously determined12 regional scale drainage basins and individual glacier catchments. We show that the rate of change in ice discharge from Antarctica throughout our observational period has fluctuated through time, but also highlight considerable spatial and temporal variability where neighbouring catchments can simultaneously undergo opposing trends. We then explore the drivers of this variability, specifically analysing the role of changes in ice shelf buttressing and how feedbacks between ice discharge and geometry modulate the overall response of individual glaciers.In this study, we compile annual ice velocity products10 and ITS_Live11 velocity mosaics of Antarctica to create time-stamped composite velocity mosaics. The ITS_Live mosaics are available annually between 1999 and 2018 and have a 240 m spatial resolution. The mosaics are weighted averages of all Landsat-7 and Landsat-8 velocity image pairs with a centre date in each calendar year11. The MEaSUREs mosaics are available from 2005–2006 to 2016–2017 and have a 1 km spatial resolution. They are weighted averages of all velocity image pairs from a variety of sensors  with a centre date between July and June10. We first resampled the ITS_Live mosaics to a spatial resolution of 1 km to match the MEaSUREs velocity mosaics. To maximise spatial coverage, we then group the annual mosaics (ITS_Live and MEaSUREs) into epochs, before creating composite mosaics of both datasets by taking the average pixel value in all mosaics in each epoch. Prior to 2013, mosaics are grouped as follows: 1999–2002, 2003–2006, 1999–2006, 2007–2008, 2009–2010 and 2011–2012  meaning the discharge gate was previously located over the ocean.We produce a time series of ice discharge from 1999–2006 to 2018 for the EAIS and WAIS, for each of the 15 commonly used regional scale basins14. We do not correct for the vertical velocity gradient of ice at the grounding line or any dynamic changes in ice thickness that might have taken place over the study period. We justify this approach because our study is largely focussed on inter-annual variations in velocity that predominantly drive changes in ice discharge, rather than absolute changes in mass. As in most previous studies4, we do not correct for either ice surface elevation change or grounding line migration. Pan-ice sheet surface elevation time series are available15, but for most glacier catchments changes in surface elevation over our observational time period (1999–2018) make little difference to ice discharge  of these outliers are located on the glaciers that feed the Ross and Filchner-Ronne ice shelves. These glaciers are located closer to the South Pole meaning there is a much poorer image coverage, particularly earlier on in the time series, which also increases uncertainty. The remaining 83 outliers (26%) are typically located on other slower flowing regions e.g. Dronning Maud Land.We calculate ice discharge time-series at ice sheet, basin and catchment scales. At the ice sheet and basin scale, the time-series incorporates both reference data and time-stamped data. At a catchment scale we produce a filtered time-series. This time-series removes any data points where the spatial coverage of time-stamped data is less than 70%. This is done to make sure that any variations in ice discharge reflect time-stamped data as opposed to the reference data. In this time-series, we also remove any erroneous data points, which are classified as those data-points that fall outside of 1.5 standard deviations of the residuals of trendline for each catchment, calculated using a cubic spline. This timeseries is used to create Fig. 16 to extract time-series in ice shelf thickness change. This dataset has a spatial resolution of 10 km and has been corrected for changes in firn content. It spans from 1992 to 2018 and has a data point every 3 months. We extract the average ice shelf thickness change from all floating ice in our example catchments. The only exception to this is at Denman Glacier, where we only extract thickness change from the fast flowing Denman trunk and not the neighbouring Shackleton Ice Shelf. We then linearly de-trend the resulting time-series in ice shelf thickness change, before fitting a cubic spline  increase in ice discharge in basin G–H between 1999–2006 and 2018  increase in Marie Byrd Land (basin F–G), a smaller 4 ± 2% (2 ± 1 Gt year−1) increase in basin H–H  in basin E–F, which feeds the Ross Ice Shelf. This is in addition to a − 2 ± 4% (− 2 ± 6 Gt year−1) decrease in discharge at basin J–J, which feeds the Ronne Ice Shelf. In the EAIS, we observe increases in ice discharge in basin D–E  and J–K   in basin C–D and − 3 ± 2% (− 3 ± 2 Gt year−1) in basin D-D , Rennick (10 ± 7%) and Matusevich (7 ± 7%) glaciers Fig. b. In basIn addition to the marked spatial variability, we also observe temporal variations in ice discharge across individual catchments Fig. . In the We also observe substantial temporal variability across individual catchments in the EAIS. At the Rennick Fig. k and Mat−1 increase in ice discharge between 1999–2006 and 2018. Over a comparable time period, a recent study3 observed a larger (66 Gt year−1) increase in ice discharge. Much of this discrepancy can be explained by the Pope, Smith and Kohler catchments (referred to as the Dotson and Crosson Ice Shelves in Ref.3) where Ref.3 collectively observed a 51% (21 Gt year−1) increase in discharge, while we report a much smaller 15% (6 Gt year−1) increase. The reason for this difference could be a consequence of the complex velocity patterns over the Crosson and Dotson ice shelves where sections of floating and grounded ice have been both accelerating and decelerating  velocity mosaic and a velocity mosaic based on image pairs from 2013 to 2016. We report a smaller increase of 14 Gt ± 8 Gt year−1 between 2007–2008 and 2013–2016. The largest differences in discharge change between our results and Ref.5 come from basin J–J that feeds the Ronne Ice Shelf and basin F–G in Marie Byrd Land. In basin J–J we observe a decrease in discharge of − 3 Gt year−1, while Ref.5 observed a 2 Gt year−1 increase. This small difference could be related to the underlying data in the MEaSUREs velocity mosaic used in Ref.5. While most of the velocity measurements are from around 2008, velocities from the late 1990s and 2009 are used for glaciers that feed the Ronne Ice Shelf13. At basin F-G we observe a 6 Gt year−1 increase, while Ref.5 observed a 12 Gt year−1 increase in discharge. The reasons for this discrepancy remain unclear but we note that, over the same timespan (2008 to 2013–2016), Ref.3 reported only a 5 Gt year−1 increase in ice discharge at basin F-G, which is more consistent with our estimate. In the EAIS, our observations of limited change throughout the study period is consistent with the majority of previous studies5. The only exception to this is Ref.17 who reported a much larger increase in ice discharge in the EAIS (upwards of 50 Gt year−1) for the period 2008 to 2015. The underlying reasons as to why the ice discharge change reported by Ref.17 differs markedly to our results and other studies5 remains unclear.A separate study6. This further reinforces the notion that changes in ice discharge have been driving the observed changes in the mass balance of WAIS, as oppose to surface mass balance, at least over decadal time periods6. In the EAIS our observation of limited change in ice discharge is consistent with reconciled estimates of a mass balance that is close to zero, albeit with large uncertainties1. Indeed, there is a considerable range in mass balance estimates of the EAIS, typically depending on the methods used, with some studies estimating a positive mass balance6 and others a more negative mass balance3. The only regional exception where trends in mass balance do not appear to be consistent with trends in ice discharge is in Wilkes Land where we observe a decrease in ice discharge between 1999–2006 and 2018. However, multiple studies have confirmed that this region has continued to lose mass over roughly the same time period18, suggesting that the decrease in ice discharge in Wilkes Land has not been enough to reverse the trend of mass loss. The decrease is in ice discharge that we detect is focused at the Totten catchment and much of the decrease in ice discharge has occurred in recent years . We focus on nine examples: the Thwaites and Pope Glaciers in the Amundsen Sea; Land Glacier in Marie Byrd Land; Moscow University, Totten and Denman Glaciers in Wilkes Land; and Rennick and Cook Glaciers in George V Land. We justify our selection of these example catchments because their ice shelves are large enough to be captured in the ice shelf thickness dataset16 and they represent a selection of the both warm-water ice shelves  and cold-water ice shelves (George V Land). In general, we observe a clear pattern whereby periods of anomalous ice shelf thinning coincide with increases in ice discharge, while periods of anomalous ice shelf thickening coincide with decreases in ice discharge  and seasonal warming of the upper layers of the ocean near the ice front23. An example of this process is seen at the Rayner catchment in Oates Land, where modelling experiments have shown that its entire floating ice shelf is dynamically important23 and where the observed inter-annual variation in ice discharge can be explained by its calving cycle . However, at the neighbouring Frost and Holmes catchments, which also underwent large calving events in response to landfast sea-ice break-up44, we do not observe any obvious relationship with ice discharge variability, indicating that the glacial ice lost was passive. We suggest that the interaction between landfast sea-ice and ice shelves may become a more important driver of variability in ice discharge in the future if ice shelves weaken and retreat into confined embayments and/or if landfast sea-ice were to decrease52.The link between landfast sea-ice and ice shelf extent may also be important in determining ice discharge variability for glaciers whose ice shelves are both damaged and float in confined embayments that are favourable for persistent landfast sea-ice formation. A 5 ± 2% reduction in ice discharge between 2011–2012 and 2015 at the western section of the Cook Glacier, for example, can be explained by a multi-year landfast sea-ice promoting ice-front advance54. However, for outlet glaciers with ice shelves that are able to provide sufficient buttressing, the local bed slope becomes less important in determining grounding line stability55. Therefore, if ice shelves are weakened sufficiently, local bed slope can be an important factor in determining grounding line migration. Retreat of the grounding line can cause further feedbacks because the associated loss in basal traction can lead to further acceleration and thinning57, thus creating a positive feedback. The acceleration associated with a loss in basal traction, in addition to reduction in ice shelf buttressing, has been shown to be an important factor in explaining the longer-term observed accelerations of both the Denman58 and Pine Island Glaciers28. Therefore, whilst changes in ice-shelf buttressing are likely to be the primary driver of the high spatial and temporal variability in ice discharge that we observe, the local bedrock slope at the grounding line is an important secondary factor in explaining the precise rate of response of individual glaciers.The response of a glacier to an initial velocity perturbation associated with a change in ice shelf buttressing is strongly modulated by the geometry of the glacier in its topographic setting. One potentially important aspect is the local slope of the topography at the grounding line. This is particularly the case for outlet glaciers with unconfined or weak ice shelves, which may be susceptible to rapid grounding line retreat along retrograde slopes60. In contrast, there has been comparatively little grounding line migration in their respective neighbouring catchments, Rennick . Variable ocean forcing can be linked to anomalies in ice shelf thickness, while changes in ice shelf extent can be linked to periodic calving cycles and landfast sea-ice induced changes. However, the specific response of outlet glaciers is further modulated by their unique geometries, which can amplify or dampen the response through various feedbacks. Overall, our results demonstrate a highly sensitive and complex pattern of ice sheet discharge that is evolving rapidly in response to external forcing and feedbacks associated with glacier geometry.We have shown that much of the increase in AIS discharge between 1999 and 2018 took place in the first half of this period, with a 37 ± 11 Gt yearSupplementary Information 1.Supplementary Information 2.Supplementary Information 3.