The Pawnee M5.8 earthquake is the largest event in Oklahoma instrument recorded history. It occurred near the edge of active seismic zones, similar to other M5+ earthquakes since 2011. It ruptured a previously unmapped fault and triggered aftershocks along a complex conjugate fault system. With a high-resolution earthquake catalog, we observe propagating foreshocks leading to the mainshock within 0.5 km distance, suggesting existence of precursory aseismic slip. At approximately 100 days before the mainshock, two M ≥ 3.5 earthquakes occurred along a mapped fault that is conjugate to the mainshock fault. At about 40 days before, two earthquakes clusters started, with one M3 earthquake occurred two days before the mainshock. The three M ≥ 3 foreshocks all produced positive Coulomb stress at the mainshock hypocenter. These foreshock activities within the conjugate fault system are near-instantaneously responding to variations in injection rates at 95% confidence. The short time delay between injection and seismicity differs from both the hypothetical expected time scale of diffusion process and the long time delay observed in this region prior to 2016, suggesting a possible role of elastic stress transfer and critical stress state of the fault. Our results suggest that the Pawnee earthquake is a result of interplay among injection, tectonic faults, and foreshocks. Decades later, the central United States has seemingly replicated the 1960s experiment by accident: rapid increase in seismicity rates since 2009 that can not be explained by steady tectonic stress loading4. The mechanism is generally explained by the classic Coulomb stress view, where increased pore pressure reduces effective normal stress, and brings faults closer to failure. Induced earthquakes often occur in the form of swarm-like clustering with no clear mainshocks, and often exhibit spatio-temporal migrations that are regarded as the manifestation of fluid propagation5. Most previous studies focused on single injection well or wells that are directly linked to a localized sequence, where clear spatio-temporal correlation can be established7. However, recent studies suggest that induced earthquakes can occur as far as 20 km away from the injection zone with long-term fluid diffusion9. The larger spatial scale of pressure propagation makes it more challenging to understand the mechanism driving earthquake occurrence patterns, especially for large damaging earthquakes, as the expected pressure increase would be much smaller due to the spatial decay10.A well-established injection experiment in the 1960s demonstrates that human can influence earthquake occurrence by pumping water in the subsurface4. The increase in background seismicity is naturally expected due to increased external forcing 11, while the increase in aftershock productivity suggests that inter-event triggering can not be ignored. In Oklahoma, the Mw5.7 Prague earthquake may have been triggered by increased Coulomb stress from the M5.0 foreshock one day before12, suggesting that smaller earthquakes can trigger larger events.While it could be explained by critically stressed fault being re-activated by small amplitude of stress perturbation , the roles of earthquake-to-earthquake interaction and aseismic slip are often omitted. Statistical modeling to an induced sequence in Arkansas and a natural swarm nearby found that both background seismicity rate and aftershock productivity needed to be increased to match observations for the induced sequence14; however, it is rarely reported for induced seismicity until recently. Aseismic slip within highly pressurized zone was observed during a controlled fluid injection experiment on a natural fault15. Microearthquakes were triggered when the aseismic slip exceeded the pressurized zone; therefore, the seismic slip was only an indirect effect of fluid injection. Analysis of an earthquake swarm with two M5 earthquakes in southern California suggested that the M5 earthquakes were likely triggered by an injection-induced aseismic slip16. The aseismic slip started on a shallow normal fault following a rapid increase in injection rate two years before the M5 events occurred. Both of these observations suggest that aseismic slip initiates within highly pressurized zones close to injection zones, and triggers subsequent seismic slip.In addition to the direct Coulomb stress triggering from a large foreshock, increasing number of aseismic slip triggering mainshocks have been reported for plate boundary earthquakes16, but such direct measurement is often unavailable. Most of the studies infer aseismic slip through analysis of foreshock sequences17: the “swarm-like” foreshock sequences migrating within the mainshock nucleation zone is often regarded as a signature of aseismic slip. With improved detection and location techniques, increasing number of studies report foreshock migrations reflecting mainshock preparation processes21. However, as most potentially induced sequences occur as earthquake “swarms”, the role of foreshocks are often not discussed, and all earthquakes are assumed to be triggered by pore pressure.Some aseismic episodes are observed through direct measurement of ground deformationIn this study, we seek to better understand the nucleation processes of large earthquakes in Oklahoma, with the focus on the triggering process of the Pawnee earthquake. We begin by an overview of occurrence patterns of earthquakes in Oklahoma, and their relationship with injection zones. Then, we focus on the Pawnee County with a detailed analysis of the relationship between injection and precursory activities, as well as the stress interactions between the M3+ foreshocks and the mainshock through Coulomb stress analysis.22, and references therein. The major fault systems in Oklahoma include: the NW-SE trending Meers Fault, the N-S trending Nemaha Fault, the NNE-SSW trending Wilzetta Fault and the NNE-SSW trending Labette Fault . Some isolated patches of M3.5+ and M4+ events exist further away from the Nemaha fault .For M5+ earthquakes since 2011, they are all located at the edge of the injection zones as outlined by the contour line of injection rate based on the Arbuckle Group disposal wells  direction adjacent to the major regional faults.We first visualize the spatial correlation between injection activities and earthquakes by calculating the contour lines of average density for different sized earthquakes and injection wells . Key observations from Fig. History of injection in the Arbuckle Group shows two periods of injection Fig. : (1) 20130r is the distance from injection point to fault zone, D is the diffusivity (m2/s). With distances of 10 km and diffusivity ranging from 0.05 to 0.5 m2/s , we get the time delay range from 185 to 1850 days, and the 300 days would be a reasonable value for response to pore pressure changes due to fluid diffusion.The average time delay of 300 days statewide is consistent with the expected time delay from pore pressure diffusion process - the time scale of pressure diffusion is predicted to evolve according to the formulation32, and demonstrates that injection induced earthquake can be anthropogenically modulated, whether increase or decrease.For both periods, decrease in injection rate is followed by decrease in seismicity rate. At present, the injection rate has decreased to the 2012 level, and the seismicity rate has decreased to the 2014 level for M3+ earthquakes Fig. . The oveHowever, the four M5 earthquake sequences since 2011 appear to occur during periods with low or decreased injection rate and seismicity rate. The Prague earthquake occurred after the first peak injection and a few months of seismic quiescence in 2011, prior to the ramp-up of injection in 2012. The earthquake rate decreased from 3 in early 2015 to 2.5 events (M ≥3) per day in late 2015, until the Woodward/Fairview clusters started in northwest Oklahoma, which increased the earthquake rate slightly. The seismicity rate gradually decreased again since early 2016, from 3 to 2.6 at the time of the Fairview earthquake. Since the Fairview earthquake in early 2016, seismicity rate has substantially decreased from 2.6 to 1.6 events per day before the Pawnee and later Cushing earthquakes occurred. This means that Fig. 10. Calibrated geomechanical model using stochastic Coulomb stress triggering found that for models with spatial varying b-value and stress drop that match observations, the probability of larger (M ≥ 4) earthquakes is highest after shut-in, and at further distances away from the injection point10. The modeling results suggests possible scenarios for Oklahoma earthquakes that can be further tested with future higher-resolution catalogs : at the early stages of injection, highest pore pressure occurs near injection zones, which reduces the differential stress, and can trigger less critically stressed fractures with high b-value33; at later stages, the pore pressure distribution becomes more uniform with large scale diffusion, only critically stressed faults can be reactivated with normal b-values close to tectonic values33.Overall, the larger  earthquakes exhibit substantial differences in the spatio-temporal response to injection compared to smaller earthquakes. The delayed occurrence of larger earthquakes after decrease in injection and at further distances from injection zones, have been reported for hydraulic fracturing and enhanced geothermal system35, respectively. For the Pawnee sequence, using only early aftershocks, the b-value is estimated to be 1.06, close to normal tectonic b-values  preceding the mainshock in a relatively short time scale: the M5.7 Prague earthquake was preceded by a M5 earthquake less than one day before37. To better understand the seismicity evolution, we estimate precise locations for 950 earthquakes from 2014 to October 19th, 2016 based on double-difference algorithm combining analyst phase picks from the OGS, precisely measured differential-times via waveform cross-correlation and a 3D velocity model (see Method M5). The final catalog has a magnitude of completeness (Mc) of 2.0, and reveals several interesting observations. All the relocated earthquakes are located within the crystalline basement (the upper bound of the basement depth is between 1 km and 1.4 km) . The earthquake occurred near the intersection of three fault traces  Fig. . We alsoThe early aftershocks delineate a conjugate fault to the OOF.The previously umappped fault (SLF) delineated by aftershocks changes strike from 107°  to 98° (SLFe) at a structural bend Fig. .All the three major seimogenic fault segments  are nearly vertical, with dipping angles of 89.7° from earthquake locations (Method M5).Approximately 100 days prior to the mainshock, two clusters with similar magnitude events (M3.7 and M3.6) occurred two days apart near the PTJ  and further north along the OOF  Figs  and S4.Approximately 40 days prior the mainshock, two swarm-type clusters with mostly M2 earthquakes started two days apart  at similar locations as the previous two M3 events Figs  and S4. 38 , the SLFm mostly remained quiet at M2 level, except for the foreshock activities as described above Fig. –c1.Key observations summarized from the high-precision catalog . Figure 46. We apply a 30-day sliding-window analysis with 10-day smoothing window, and find that the two peaks in seismicity rate closely matches the peaks in injection rate with a short time delay (1–2 days) ys) Fig. . Differe45. The accumulated pore pressure amplitude is about a few tens of kPa from these two wells, and the coupled poroelastic stress is about a factor of two to three times larger at shorter time delay45.While a full scale reservoir modeling is beyond the scope of this paper, a pressure modeling demonstrated that the injection transient from two wells in 2012 and 2013 in the Osage county dominates the long-term stress changes on the mainshock fault52. The increasing deviation with time from the two catalog suggests that continuing weakening of the fault zone may facilitate earthquake-to-earthquake interaction, and that aftershock productivity may differ from natural earthquakes, e.g., the Arkansas induced earthquakes have higher productivity compared to a previous natural earthquake swarm4. Potential temporal changes in aftershock triggering parameters would warrant further study, and should be incorporated into hazard assessment for induced seismicity. This also indicates that in addition to the aseismic slip propagation, some degree of stress triggering due to foreshock themselves may exist, which we will investigate in the next section.During both T1 and T2, the declustered seismicity rate overlaps with the raw seismicity rate initially, but gradually deviates from the raw rate towards later stages for each period Fig.  and S7. For the Pawnee earthquake, SLFm had remained mostly locked throughout 2014 and 2015, while the surrounding areas have been active, including activities immediately east of the “bend” along SLFe see Fig. . For theThe earthquake clusters along OOF and near PTJ are nearly simultaneous both around 100 days and 40 days before mainshock (approximately two days apart) Fig. , suggest53. Given that this foreshock produced positive Coulomb stress on all subsequent foreshocks, it should also contribute to the triggering of the aseismic slip episode that drives the migration of foreshocks within mainshock nucleation zone, although these events were too small to have well-constrained focal mechanism solutions.The first M3.7 foreshock (denoted as F1) on June 6th is located at 0.3 km to the mainshock near PTJ. It is the last event of a five-day earthquake swarm that started following injection rate increase from a few nearby wells, including wells “Oldham” and “Scroggins”  produced Coulomb stress increase on the next M3 foreshock, and the M3.9 aftershock that occurred 4 days following the Pawnee mainshock. Event F2 triggered its own aftershock sequences on OOF. The M3 foreshock on September 1st, 2016 (denoted as F3) also promoted failure for the M3.9 aftershock. Both of these two foreshocks are located much further from the mainshock, and cause small but positive Coulomb stress changes at the mainshock The Coulomb stress analysis shows that all the foreshocks contributed to the triggering of the mainshock, and the first foreshock promoted cascading failure for all subsequent foreshocks for which we have focal mechanism solutions, and some early aftershocks. However, this event itself was not triggered by previous events in the same cluster, and is likely due to injection rate increases. The other two M3+ foreshocks contributed to triggering of other foreshocks and early aftershocks.The SLFm is a strong blind fault that can sustain the high pore pressure throughout the high injection period;All the seismogenic fault segments in this region  are critically stressed with continuing pore pressure increase due to long-term fluid diffusion and ready to slip with small stress perturbations;After a short period of quiescence in early 2016, operation from a few nearby wells led to small increases in injection rate, followed by rapid seismic responses on the conjugate fault system, and triggering of the first foreshock sequence, including a M3.7 earthquake near PTJ;The M3.7 foreshock caused Coulomb stress increase on most subsequent foreshocks and the mainshock, and promoted fault slip within the conjugate fault system, including a M3.6 earthquake along OOF, which also promoted failure for the next M3 foreshock, and a M3.9 a cks very well, and is subject to severer clipping problems ftershock along the same fault segment Fig. ;17, 54;The second stage of injection rate increase correlates with second stage of foreshock activities, which includes foreshocks near PTJ that appear to be migrating within 0.5 km of the mainshock, suggesting a possible aseismic slip episode - it should be noted that although the foreshocks appear migrating towards the mainshock, the relative locations between the foreshock sequence and the mainshock may subject to greater location uncertainty than within the foreshock themselves, as the waveform of the large mainshock does not correlate with the smaller foreshocks very well, and is subject to severer clipping problems due to strong ground motionThe second stage of foreshock activities also includes a second earthquake swarm along OOF, which culminated with a M3.0 earthquake just two days before the mainshock. The M3 event promoted failure for a M3.9 aftershock following the mainshock, and small positive Coulomb stress on the mainshock.The Coulomb stress on the mainshock from the first foreshock is significantly larger than the two later foreshocks (60 kPa versus about 0.5 kPa), likely due to its closer distance to mainshock (0.3 km versus 2 km).The aseismic slip propagation, stress loading from the foreshock activities, and the injection continues to increase stress in the mainshock nucleation zone, and eventually triggered the mainshock rupture.Combining the analysis of seismicity, injection, and stress interaction, we speculate the following scenario for the Pawnee earthquake occurrence:55. The physical parameters that determine the size of an earthquake are the macroscopic properties of earthquakes, such as the rupture size, duration, and total amount of slip56. Among them, the rupture size is limited both by the physical length of the fault and the rupture front propagation: larger faults are capable of generating larger earthquakes, e.g., the San Andreas Fault, and the Meers Fault; and the capability of the rupture front propagation along the fault, which is related to the dynamic interaction between the stress of rupture front and the friction parameters 59.Once the rupture initiates and propagates along the fault, the eventual size of the mainshock is limited by the physical properties of the fault zone and the earthquake rupture itself, as any earthquakes, regardless of the eventual magnitude, grows from a small rupture. Analysis of different sized earthquakes in Parkfield, found that the first 0.03 seconds of the rupture are indistinguishable for different magnitude events60. The estimated rupture extends about 6 km to the east from the mainshock epicenter, which roughly corresponds to the distance from the mainshock epicenter to the structural “bend” between SLFm and SLFe. It is possible that the structural complexity may serve as a “barrier” to the mainshock rupture. Further aftershock analysis may better constrain the faulting complexity.The estimated rupture length from the directivity analysis is about 6 km (Method M7) assuming a unilateral rupture along 107°, which is consistent with a recent finite slip model of the Pawnee earthquake45, but would depend on specific model assumptions in both Coulomb stress calculation and pore pressure modeling. The aseismic slip induced stress amplitude is difficult to assess due to the lack of absolute slip rates, however, it has been suggested to play an important role in triggering large plate boundary earthquakes, e.g., subduction zones13. The rapid response to small perturbations in injection rates during T2-N suggests that the fault is every sensitive to external stress perturbations, and would probably be triggered by any process that causes stress changes. Similar to the Prague M5.7 mainshock that was likely triggered by the M5 foreshock12, the Pawnee earthquake was plausibly triggered by precursory seismic and aseismic slips on the conjugate fault system. In both cases, the mainshocks ruptured previously unmapped basement faults, for which prior earthquake hazard assessment was not possible.The overview of earthquakes and injection well distributions in Oklahoma suggest that the spatial distributions of the M5+ earthquakes are controlled by regional tectonic faults. Detailed analysis of the Pawnee earthquake precursory activities shows that the nucleation process of the Pawnee mainshock is a result of the interplay among injection rate increase, earthquake interactions and aseismic slip. Will the mainshock occur without either process? Which process is more dominate in the triggering process? These questions are difficult to address given the simplified model assumptions in a heterogeneous environment. It appears that Coulomb stress from the M3.7 foreshock (about 60 kPa) is comparable to or larger than the injection induced stress changes from long-term injectionThe small magnitudes of the precursory activities for the Pawnee earthquake highlights the importance of high-resolution monitoring of microearthquakes. In this case, the “foreshocks” and the changes in the response to injection rate during T2-N would not have been recognized if we only focused on M3+ earthquakes and did not have a high resolution relocated catalog. As most of the high-resolution relocation is usually performed retrospectively, it is challenging to recognize the spatial-temporal pattern in real-time.61. Systemic analysis of foreshock occurrence patterns in California for M ≥ 5 earthquakes suggests that an important diagnostic feature of foreshocks is the increased seismic activities within the “Mogi” zone of a large seismogenic fault, especially those that are associated with fault zone discontinuities62. The “Mogi” zone is defined as a seismic quiet zone surrounding the mainshock, within a radius that is approximately consistent with mainshock rupture length63. So for an M6 earthquake, this would be about 5 km to 7 km. In this case, most of SLFm has been quiet (at least 6 km in length), except the 0.5 km area immediately surrounding the mainshock, well within the expected “Mogi” zone , increased “swarm” activity near major fault segments may suggest an increased probability of a larger earthquake 67 with much higher location resolution via waveform cross-correlation69. The observation of potential aseismic slip leading to the mainshock suggest that geomechanical analysis of the frictional behaviors of the fault zone would be very important to better understand the mainshock rupture process70. The rapid response to injection rates indicates a possible role of poroelastic stress responses: if this proves to be significant with further detailed reservoir modeling, it would suggest that we should probably consider injection to all formations in addition to Arbuckle Group for specific study areas. The detailed analysis of precursory activities for the largest earthquake in Oklahoma suggests that we need to look beyond fluid diffusion, and consider the full spectrum of triggering processes, fault slip, and stress transfer mechanisms to obtain a complete view of the nucleation process of large earthquakes. Partnership between industry, government and academia to investigate the cause and mitigation of the potential earthquake hazards will be the best way forward with mutual understanding of the importance of a fault database, pressure monitoring and earthquake monitoring.Thus, the detailed understanding of earthquake triggering processes and possible early recognition of damaging earthquakes would require high-quality fault map and high-resolution monitoring of microearthquakes, preferably down to much lower magnitude levelM1: Spatial density analysis of events and injection ratesM2: b-value estimationM3: Calculation of correlation coefficients and confidence limitsM4: Matched filter detectionM5: Earthquake relocation and fault parametersM6: Catalog declusteringM7: Waveform inversion using CAP methodM8: Coulomb stress analysisThe method section includes:We use the earthquake catalog from the Oklahoma Geological Survey (OGS). All earthquakes between 2011 and 2016 are spatially binned in a 0.025° latitude/longitude (approximately 3.6 km) grid. For each grid, the number of events above magnitude 2.5, 3, 3.5, 4, 4.5, and 5 were counted. To obtain the final image, we apply a Gaussian smoothing filter within a square area of 5 grids for each grid (approximately 18 km). For each magnitude range, the average number of events for all grids with seismicity is selected and contoured Figure . Each avFor injection data, we organize a complete database for all wells injecting into the Arbuckle Group since 2011. The wells are spatially binned in the same 0.025° latitude/longitude grid as earthquakes. For each grid, the average daily injection rate between 2011 and 2016 is calculated. Similar Gaussian smoothing filter is applied to all grids with non-zero injection rates. The average injection rate for grids with active injection are selected and contoured. The contour line is plotted together with the contour lines for each magnitude range in Fig. 71. The Mc is estimated through maximum curvature in the histogram for earthquake number per magnitude bin. The bin size is 0.1. The b-value estimation follows the maximum likelihood method72:For b-value and Mc estimations, we use the software “zmap” subroutinesMmin of 3  and seismicity (S), we compute the normalized correlation coefficients for each time lag following Matlab function “crosscorr”. At each time lag The normalized cross-correlation is:73. 1000 cross-correlations are obtained with each assigning different random phase shifts. The 95% confident limit is obtained from the 95% percentile limit at each time lag. All the maximum correlation coefficients at preferred time lags for both the statewide analysis and Pawnee county at different tiem periods are significantly above the 95% confident limit, suggesting that the correlation is not by random chance , then for each day (Ti) during the study period, we calculate the correlation coefficient using “corrcoef” function in matlab with injection and seismicity rate between Ti − Tw/2 and Ti + Tw/2. Because the “corrcoef” function would produce positive correlation between low injection rate and low seismicity rate (which may confuse the interpretation to search for positive correlations between increased injection rate and seismicity rate), we further calculate moving-average of the correlation results using the same window length Tw. Figs To perform the sliding-window analysis to identify short-term correlations, we preset a fixed window length , and resample the data at a 20 Hz uniform sample rate. The matched-filter technique computes the normalized cross-correlation coefficient (coefficient between −1 and 1) at each sample point for each individual template. We then shift each of the normalized cross-correlation functions for each individual component relative to the traveltime of each component and stack. Initial detection occurs when any point within the stacked cross-correlation function exceeds at least 9 times the median absolute deviation (MAD) of the daily stack46.Based on prior experience with regional network cross-correlation75. Then, we apply an auto-picker76 to pick around the predicted time. Only new picks with signal-to-noise ratio greater than 2.5 are saved for further use. All the traces band-pass filtered between 1 and 10 Hz. To measure cross-correlation, we select a time window 0.5 sec before and 1 sec after the picked arrival time  for both P and S waves. The final differential time has 0.001 second accuracy with sub-sampling around the peak correlation, and only pairs with CC ≥0.6 from at least four stations are used for relocation.312 earthquakes in our study area (last accessed: 10/19/2016) have analyst phase picks. To relocate all events systemically, we measure precise differential times through waveform cross-correlation between each event and all other events. We first compute predicted arrival time at each station for each event using 1D travel time table based on statewide 1D velocity model77 that incorporates 3D ray-tracing from a 3D tomography model22. This allows us to obtain precise locations for 950 earthquakes.In total, we obtain 1,566,713 P wave differential times from cross-correlation, and 50,628 from catalog, 972,388 S wave differential times from cross-correlation, and 50,394 from catalog. Overall, the amount of cross-correlation derived differential times is a factor of 25 larger than catalog. For relocation, we use the double-difference algorithm, with the hypoDD3D versionTo estimate location uncertainty, we apply a bootstrap approach. We use the final locations from the relocated catalog as input. Then we generate 50 sets of arrival times with 80% of randomly selected cross-correlation and catalog differential times. We run the same program for all resampled datasets. The final location error for each event is set to the 95% of the location differences between resampled dataset and the original catalog, following standard approach to estimate 95% confidence limit for each event. The relative location accuracy is estimated to be 35 m horizontally and 200 m vertically Figure . The ver79, and references therein, where we find the eigenvalues and eigenvectors for the covariance matrix of demeaned hypocentral coordinates of the events along each fault segment. The eigenvector of the largest eigenvalue defines the longest axis of an ellipsoid fit to the epicenters, while the eigenvector of the smallest eigenvalue defines the shortest axis of the ellipsoid. The strike and dip angles are found from the orientation of the largest eigenvector. All the three faults are nearly vertical with dipping angles close to 90°, consistent with the mainshock nodal plane solutions from waveform fitting , focal depth, and moment magnitude to best fit the waveforms bandpass filtered between 5 s and 20 s. We use the Frequency-Wavenumber (FK) method81 to calculate the Green’s functions with the CUS velocity model. To accommodate inaccuracies in the 1-D velocity model, we also allow the Pnl waves and the surface waves to shift with respect to each other80. The time windows for Pnl part and surface waves are 20 s and 60 s, respectively. And the frequency range is 0.2–0.05 Hz (5–20 s) for both Pnl and surface waves. The inversion results show that the mainshock is a strike-slip event with a moment magnitude of 5.73, and a depth of 6 km , and apply the Cut-And-Paste (CAP) technique km Fig. . The twom Figure , consist84. The method determines ruptured fault plane via measuring the difference between centroid and hypocenter location, which are straightforwardly derived from the time shifts in the CAP source inversion of the mainshock and a reference earthquake. We first determine the relative hypocentral location of the mainshock with repsect to a M4 event, then perform source parametrer inversion for both earthquakes. We test the cases of rupture along either strike, and the time shift against azimuthal variation can be fitted with a cosine curve, which indicates the rupture direction and rupture length. Both Rayleigh wave and Love wave suggest rupture to southeast along the 107° strike, and the estimated rupture length is 6.2 km and 5.8 km, respectively (Fig. To estimate rupture directivity, we apply the relative centroid location methodely Fig. . As unil85, available from USGS website. The software implements an elastic half-space model to calculate the stress changes in space and time. In this study, we use individual nodal planes as receiver faults for each earthquake that has focal mechanism solution53. For each foreshock, we use the default setting to calculate length and width for “strike-slip” faults with the corresponding magnitude. We assume that the location from the relocated catalog is the center of the fault plane. The friction coefficient is assumed to be 0.4, consistent with analysis of the Prague sequence that considers the effect of pore fluid pressure by assuming Skempton’s coefficient of 0.7553.For Coulomb stress analysis, we use the software Coulomb 3.4Injection wells and earthquakessupplemental materialrelocated earthquakes


The Project P.A.T.H.S.  is a positive youth development program in Hong Kong. After completion of the program, program implementers were required to draw five conclusions based on the subjective outcome evaluation findings collected from the program participants and implementers as reported in the evaluation report. Secondary analyses of the data collected from 48 schools that had joined the Secondary 3 program showed that most of the conclusions concerning perceptions of the program, instructors, and effectiveness of the program were positive in nature. There were also conclusions indicating strengths and possible improvement of the program. The present findings are consistent with the previous findings that suggest that the Project P.A.T.H.S. is well received by the stakeholders and the program is beneficial to the development of Chinese adolescents in Hong Kong.


Objective To evaluate the implementation process of a workers’ health surveillance (WHS) program in a Dutch meat processing company. Methods Workers from five plants were eligible to participate in the WHS program. The program consisted of four evaluative components and an intervention component. Qualitative and quantitative methods were used to evaluate seven process aspects. Data were gathered by interviews with stakeholders, participant questionnaires, and from registries of the company and occupational health service. Results Two recruitment strategies were used: open invitation or automatic participation. Of the 986 eligible workers, 305 participated in the program. Average reach was 53 %. Two out of five program components could not be assessed on dose delivered, dose received and fidelity. If components were assessable, 85–100 % of the components was delivered, 66–100 % of the components was received by participants, and fidelity was 100 %. Participants were satisfied with the WHS program (mean score 7.6). Contextual factors that facilitated implementation were among others societal developments and management support. Factors that formed barriers were program novelty and delayed follow-up. Conclusion The WHS program was well received by participants. Not all participants were offered the same number of program components, and not all components were performed according to protocol. Deviation from protocol is an indication of program failure and may affect program effectiveness. Several workplace health promotion (WHP) programs have demonstrated effectiveness , 2. ReceDue to an aging workforce and rising retirement age, effective WHP programs for older workers should be developed , 4. CompFor a WHS program to be effective, two aspects are important: the program must be based on sound rationale, and the program must be implemented and executed according to protocol . InadequThe objective of this study was to evaluate the implementation process of a WHS program at a large Dutch meat processing company. To structure the evaluation we used the process evaluation framework recommended by Linnan and Steckler . Furtherwww.trialregister.nl): NTR3445.This process evaluation is part of the FLESH study , a stepped wedge trial evaluating a comprehensive WHS program in the largest Dutch meat processing company . The WHSBetween February 2012 and March 2014 a total of 986 employees from five plants were eligible to participate in the POSE program. The POSE program was implemented at different time points at the involved plants, because of the stepped wedge design we applied, so invitation occurred separately at each plant.The POSE program has been elaborately described elsewhere . In shorQuantitative data were collected at baseline and at 3 and 9 months follow-up. At baseline employees enrolled in the POSE program. Various work-related, health-related, and personal characteristics were assessed by questionnaire and measurements. After 3 months, participants were called by the OHS and asked whether they had followed-up on the advice from the POSE program. At 9 months, participants received a questionnaire which evaluated satisfaction with the program, parts of the process, contextual aspects, and program advice  ranging from 0 to 10. In addition to the questionnaires, three participants from each plant were interviewed to gain more in-depth insight in reasons for participating, satisfaction with the program (short-term and long-term), and recommendations for future implementation.Context refers to factors in the organization, community, social/political context, or either situational issues that could potentially affect either intervention implementation or intervention outcome (barriers and facilitators). Context was evaluated by interviews with WHS participants, company and plant management, and OHS. Interviewees were asked to describe the entire process of preparation, implementation, and follow-up of the POSE program, and to highlight barriers and facilitators that could have affected implementation. Context was also addressed in the follow-up questionnaire which was distributed among participants, 9 months after the POSE program.Quantitative data were analyzed using descriptive statistics. Furthermore, Fisher’s Exact test was performed to compare advice on follow-up between two age groups, under 50 years of age (n = 116) or 50 years and older (n = 189). The age distinction was based on recruitment strategies and on age distribution. In all analyses, SPSS for Windows version 22.0 was used . Interviews were audio recorded, with permission from interviewees, and transcribed verbatim. Subsequently, transcripts were read and reread by the first author and investigated on pre-specified themes. The analyses of the interviews with HR and OHS focused on contextual factors within and outside the organization that could have affected the implementation and execution of the POSE program. The interviews with participants focused on recruitment, dose received, satisfaction, and context.Out of 986 eligible employees at the start of the study, 305 (31 %) participated in the POSE program. During the study two initially participating plants were closed due to economic reasons. A second group of employees from an already participating plant was enrolled in the study. Baseline characteristics of the participants are presented in Table Different recruitment strategies were used between and within plants and different reach was attained Table . At threAn overview of the dose delivered, dose received, and fidelity is presented in Table Although it is unknown whether all advices were delivered to and received by POSE program participants, the advices themselves were registered Table . Five ouOn a scale from 0 to 10 the participants appreciated the POSE program with a mean score of 7.6 (SD 1.1). The information that was provided to participants before the start of the POSE program was appreciated with a 7.4, ranging between plants from 6.9–7.8. The POSE program itself was awarded a 7.6 (range 7.3–7.8). The advice from the program was awarded an average of 7.7 (range 7.3–8.2). And the follow-up on the program received and average score of 7.7, ranging from 7.1 to 8.0. The majority of participants would recommend the POSE program to colleagues. Ninety-five percent of the questionnaire respondents (n = 135) indicated this by giving a grade of 6 or higher .” Reasons for not participating were fear of bad outcomes, a feeling of the program being useless, or lack of interest. Two interviewees: “I think that some people knowingly did not participate because of a bad lifestyle, overweight, smoking, etc.” “Some colleagues said it was nonsense: if something is wrong with me I’ll go see a doctor.”POSE program participants were satisfied with the program and indicated that they felt it added value to their own health and employability. Main reasons for participation were strong interest in health, getting an update of one’s health status, but also because the employer stimulated participation. Two participants: “First I was a little skeptic, but when you start to think about it you realize that it might be valuable, mainly because you normally don’t consider things like this.” “Creating some awareness about lifestyle, that’s what they [the company] want to promote more or less.In the questionnaire 114 participants indicated what they found the most important outcome of the POSE program. Awareness of one’s health status was mentioned most frequently , followed by the measurement results , confirmation of one’s own perception , and advice .POSE program implementation started in February 2012, which was during economic recession in the Netherlands. The company closed two plants that were initially enrolled in the study. Those employees who were relocated to other plants were still eligible to participate in the POSE program.An important motivator to implement the POSE program was the fact that Dutch law requires large employers to offer suitable occupational healthcare to employees. HR managers indicated that some difficulties were encountered during implementation at the first plants, which was partially caused by novelty of the POSE program, even though a pilot program already solved some teething troubles. Employees were still anxious about the consequences of the results. One manager suggested that more and better communication about the purpose of the program could have helped take away the anxiety. At that time, implementation of the POSE program was supported but enforced by company management and plant management was expected to execute the program. As one interviewee explained: “We actually forced it [the POSE program] to be deployed at the plants. It’s not the way we wanted to do it, but in this way we did give it a head start.”Implementation of the POSE program resulted in some resistance among work floor supervisors who had to adjust planning. Not only because employees were away from work for some time, but also because the program took more time than they had anticipated. The long time between program execution and presentation of results at company level was considered a barrier for smooth follow-up of the POSE program. During that time participants were left unaware about follow-up at company level, for instance whether they were going to be invited to see an occupational physician, or were invited to participate in a company health program. And even afterwards it remained a vague process, because at the company no one was made responsible, costs were unknown, etcetera. One HR manager also mentioned that plant management did not receive feedback from the OHS regarding individual follow-up.The POSE program was provided at a location near the workplace, during working time, which facilitated implementation and probably resulted in higher participation rates as well. Implementation became easier along the way. One interviewee indicated that over the past years societal influences created corporate responsibility and helped raise awareness among employees about responsibility for their own health. Both employer and employee became aware that they share responsibility regarding health and employability. Over time, the POSE program has been embedded in company policy and has even been expanded with other activities aimed at sustainable employability. Where personal employability was considered as something new and ‘scary’ to talk about, it is now a normal issue to discuss at the workplace and people want the employer to help them with their health problems. An employee confirmed this: “Well, at first people were a little distrusting towards the POSE program. Why is the company doing this, are they unsatisfied, do they want to change company culture? But then again I think it is a good sign towards employees that they want to listen to them.” And as another employee put it: “I believe it is a positive signal that the company makes employees aware and offers employees the opportunity to participate in the POSE program, and gives the opportunity to improve. Even though it is quite basic, you show corporate involvement.”This study is one of the first to investigate the implementation process of a workplace health promotion program. Our evaluation showed that the quality of program implementation varied. Different recruitment strategies were used which both seemed to be effective in attracting employees. POSE program questionnaire and biometrics were delivered and received as planned and were implemented according to protocol. However, FCE was not entirely delivered according to protocol, registration of counseling and follow-up was lacking and fidelity of specific components was not assessable. Nevertheless, participants were satisfied with the POSE program.A number of other studies have reported on process evaluations of occupational healthcare. Among those studies two were conducted in the construction industry , 18, twoA particular strength of this study is the integration of quantitative and qualitative methods which provided us with information on the implementation process of the POSE program from different perspectives. Data were collected from organizational decision makers, participants in the study, and program suppliers. The quantitative approach provided insight into the amount and quality of program implementation and the qualitative approach allowed an in-depth view on contextual factors and satisfaction. Another strong aspect is the long time period between POSE program implementation and the interviews, which allowed follow-up and interventions to come to effect. On the other hand, this long period may have caused recall problems which may have led to the overlooking of some program elements during participant interview. This may have affected program results, but this did not affect program implementation. A limitation is the low response to the participant questionnaire, which might have been caused by low satisfaction with the POSE program or so called respondent fatigue. This may limit the validity of the results. A second limitation is that we developed our own process evaluation questionnaire. Although other validated questionnaires have been used to construct the questionnaire, several aspects had to be amended to suit the current research needs, and therefore may limit generalizability. Furthermore, purposive sampling, based on individual risk profiles, was applied to select POSE program participants for interviews. This strategy was followed to gain insight in different types of follow-up trajectories. It is unknown whether data saturation was reached, although the impression was that later interviews minimally added new information. It is possible that the applied sampling strategy did not result in a representative perspective of the WHS program, which may limit generalizability of the study results. A last limitation is that fidelity was only assessed during interviews. Although it did become clear that not everything was performed according to protocol, objective measures could have provided more detailed information on fidelity and hence the quality of program implementation.Knowledge on the performance on several process outcomes provides insight in reasons for success or failure of the implementation of a WHS program in the meat processing industry. The results of this process evaluation have shown that participants were satisfied with the POSE program and that the program raised awareness about health and employability. Furthermore, this study has shown that several contextual factors should be taken into account when implementing a WHS program. Organization at the workplace during paid working time facilitates participation, just as a positive attitude from company management. Even though the protocol was established before the study, not everything went according to plan. This study demonstrated that program implementation was sufficient regarding the online questionnaire and biometric screening. Delivery of FCE and delivery of the counseling session failed to some extent and could not always be evaluated due to absence of registration. These registration failures apply to follow-up measures as well. If the program is not effective on primary outcomes this can thus be attributed to program failure. Whether it might  be due to theory failure will be impossible to distinguish. Therefore, whether complete program compliance would lead to the intended effects cannot be foretold, but complete program compliance would be the first step. Some aspects can be improved, not only regarding implementation but also regarding evaluation. For instance, better administration and monitoring of program implementation might provide more insight in process aspects like fidelity. These findings show the relevance of performing a process evaluation in order to be able to adjust and improve program implementation in the future. New studies should take this into account.


Although the restorative benefits of nature are widely acknowledged, there is a limited understanding of the attributes of natural environments that are fundamental to restorative experiences. Faced with growing human populations and a greater awareness of the wellbeing benefits natural environments provide, park agencies and planners are increasingly challenged with balancing human and ecological outcomes in natural areas. This study examines the physical and experiential qualities of natural environments people referred to when describing their connection to their most valued natural environments in an online questionnaire. Recruited primarily via a public radio program, respondents were asked to identify their favorite places and explain what they loved about those places. Favorite places are considered exemplars of restorative environments and were classified based on an existing park typology. Reasons people liked particular sites were classified into three domains: setting, activity, or benefit. Content analysis was used to identify the attributes most commonly associated with favorite places. These attributes were then related to the four components of restorative environments according to Attention Restoration Theory. In contrast to previous research, we found that “fascination” was the most important component of favorite places. Possible reasons for this contrast, namely, respondents' median age, and the likelihood of a high degree of ecological literacy amongst the study population are discussed. South Australians' favorite environments comprise primarily hilly, wooded nature parks, and botanical gardens, in stark contrast to the vast arid areas that dominate the state. Micro-variables such as birds, plants, wildlife, native species, and biodiversity appear particularly important elements used to explain people's love of these sites. We discuss the implications of these findings and their potential value as an anchor for marketing campaigns seeking to encourage contact with nature, as well as education programs designed to improve people's understanding of important but intangible concepts such as biodiversity. The findings have clear, practical implications for park managers given the modifiable nature of many of the attributes identified as being most important to our respondents, and we believe attention to such elements has the potential to simultaneously enhance people's nature experiences, optimize restorative outcomes, and improve environmental stewardship. For many people contact with nature is no longer a by-product of everyday life. For the vast majority of human history, we relied upon the natural environment for food, water, and shelter in very direct and unambiguous ways, as all species do. Today, although we are equally dependent upon the environment to sustain us, the majority of the world's population now resides in towns and cities  it allows for a feeling of “being away” by being geographically and/or psychologically distant from the daily hassles of life and the sources of attentional fatigue; (2) it has sufficient “extent” and scope to allow for an immersive experience; (3) it is able to offer “compatibility” with the intentions/needs of the person experiencing the environment; and (4) it provides “soft fascination” to catch one's attention without cognitive effort. As opposed to fascination in general, which may be derived from stimuli such as car accidents or violent scenes, settings that are rich in soft fascination—such as “the play of light on foliage” , compared to the other 11 weeks. This should be taken into consideration when viewing the results.In total, 447 people completed the questionnaire. The majority of respondents were female (65.7%), mature aged , and highly educated (53.66% with a bachelor degree or higher), as shown in Table Participants' favorite places and demographic data were analyzed using SPSS® software to calculate descriptive statistics such as frequencies and means. Participants' responses about why they loved particular places were coded in QSR Nvivo® using inductive content analysis. Directed content analysis was used to examine the relative importance of the four ART components in Australian “favorite places.” The two procedures are explained in the following sections. Similar to Irvine et al.'s  study, wFavorite places were initially grouped by name so that we could ascertain which favorite places were shared amongst multiple respondents. This process resulted in 241 unique locations across South Australia. These favorite places were then classified using a modified National Recreation and Parks Association (NRPA) park typology  and “botanical gardens and arboreta” (14.5%). The apparent popularity of botanical gardens is particularly interesting, given the number of these green spaces in the State is considerably lower than any other type of green space, i.e., 14.5% of favorite places were comprised of 11 botanical gardens and arboreta, whereas “private green spaces”  were comprised of hundreds of different gardens and backyards. It should be noted that one of the radio segments promoting the study did discuss one of the State's 11 botanic gardens, however, three botanic gardens featured in the 20 most popular parks in the State Table . The leaExcluding private green spaces and ranked according to frequency of mention, the 20 most popular favorite places in South Australia are shown in Table Interestingly, despite 87% of South Australia being classed as arid ; 20.7% referred to a personal benefit derived from the place ; and 14.5% of statements referred to an activity conducted in the favorite place, e.g., “…a wonderful gift to be able to visit for picnics or tennis or parties.”Given our interest in providing usable information for park management and nature conservation in Australia, we then identified that 84.6% of loved “setting attributes” referred to natural features of the environment, and 15.4% referred to human-made features such as toilets and walking trails. We further categorized the natural features into elements we believed park managers could modify  and those we considered were beyond reasonable human control . Under this classification system, 70% of statements referring to a “setting attribute” concerned a modifiable natural feature, 15.4% concerned a human-made feature, and 14.6% concerned an unmodifiable natural feature.In regards to responses lending support to conservation objectives, references to terms such as “biodiversity” and “native species” were surprisingly frequent . Although explicit references to biodiversity were fairly common, there were also many comments about the diversity of plant and animal species written in participants' own words, such as “…many trees of various varieties with different heights, colors and textures” and, “…to see a koala now and then, the kangaroos we've seen on many days, but especially the birds! So many different kinds!” As a result, nativeness, and biodiversity featured in the top 20 “loved” aspects of favorite places.To explore the relative importance of the four components of restorative environments in personal descriptions of favorite places, we re-coded responses to the question “What do you love about your favorite outdoor places?” We used a directed approach to content analysis, using words and phrases from previous restorative environments research, including the PRS  are essential to restorative experiences Kaplan, . ResearcIn the present study, statements associated with the idea of fascination featured prominently in the “loved aspects” of favorite places, particularly those referring to micro-variables such as birds and plants. References to “setting attributes” accounted for 65% of responses, which we believe could be suggestive of a difference between the relative importance of ART components in South Australian favorite places and those in Finland and the United States. The great value placed on fascination in our study may reflect the high level of ecological literacy in South Australia (Pitman and Daniels, Care should be taken when comparing our results to those of previous research. One of the criticisms of restorative environments research is that most studies have been performed on undergraduate university students in Western Countries (Joye and Van Den Berg, In the present study, “extent” was found to be the least important component of favorite place experiences. The reason for the apparent difference between our results and those of previous researchers (Korpela and Hartig, Unlike previous research, the present study assumed that experiences of natural favorite places would be restorative, and did not directly measure restorative outcomes or perceived restorativeness. This is a limitation of the study, but we felt it was reasonable to assume most favorite places were indeed restorative environments based on previous research (Korpela et al., how we can attract people to nature, we might also ask why, i.e., are the attributes of nature that are “lovable” also those that provide health benefits? Further research exploring the ability of different types of environments and environmental features to facilitate psychological benefits, as well as the influence of environmental knowledge on individual perceptions of these environments is warranted. Understanding why people love landscapes is crucial to global efforts to connect people with nature and ultimately improve population health, environmental stewardship and conservation outcomes.Consistent with European research, the most frequently reported types of favorite places in the present study were “nature parks” such as conservation areas and National Parks. Natural micro-variables such as birds and plants were the most frequently reported “loved” attributes of favorite places, and in general respondents paid much more attention to the physical attributes of their favorite places, rather than their ability to facilitate personal benefits and activities. Accordingly, we found much greater importance was placed on “fascination” in Australian favorite places than in previous research that identified fascination as the least important component of restorative experiences in favorite places. The possible reasons for this contrasting result include the focus on outdoor spaces, the comparably much higher mean age of our respondents, as well as their high level of education. Further, they were sampled from a population likely to have a reasonable knowledge of the natural environment and ecological processes. This is reflected in the personal importance respondents placed on the ecologically valuable attributes of their favorite places, such as the habitat they provide, as well as their species diversity and nativeness. We believe these findings can provide an anchor for marketing strategies aimed at increasing the public's use of parks, and assist in the development of education programs aimed at improving people's understanding of important but intangible concepts such as biodiversity. The findings of this study offer support for interventions that encourage people to take notice of and appreciate nature without overtly seeking to educate them. Beyond exploring This study was carried out in accordance with the recommendations of the Australian Code for the Responsible Conduct of Research, the National Statement on Ethical Conduct in Human Research and the UniSA Framework for the Responsible Conduct of Research. All subjects gave written informed consent in accordance with the Declaration of Helsinki. The protocol was approved by the University of South Australia Human Research Ethics Committee.All four authors designed the study and were involved in the collection of data and the coding of responses. Data analyses and interpretation were carried out by MS. The initial and subsequent drafts of the article were written by MS, and critical edits were made by DW, KL, and CD. All authors have approved the paper for publication.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


The treatment of Philadelphia chromosome-positive Acute Lymphoblastic Leukemia (Ph+ ALL) patients who harbor the T315I BCR-ABL1 mutation or who have two or more mutations in the same BCR-ABL1 molecule is particularly challenging since first and second-generation Tyrosine Kinase Inhibitors (TKIs) are ineffective. Ponatinib, blinatumomab, chemotherapy and transplant are the currently available options in these cases.We here report the case of a young Ph+ ALL patient who relapsed on front-line dasatinib therapy because of two independent T315I-positive subclones, resulting from different nucleotide substitutions -one of whom never reported previously- and where additional mutant clones outgrew and persisted despite ponatinib, transplant, blinatumomab and conventional chemotherapy. Deep Sequencing (DS) was used to dissect the complexity of BCR-ABL1 kinase domain (KD) mutation status and follow the kinetics of different mutant clones across the sequential therapeutic approaches.This case presents several peculiar and remarkable aspects: i) distinct clones may acquire the same amino acid substitution via different nucleotide changes; ii) the T315I mutation may arise also from an ‘act’ to ‘atc’ codon change; iii) the strategy of temporarily replacing TKI therapy with chemo or immunotherapy, in order to remove the selective pressure and deselect aggressive mutant clones, cannot always be expected to be effective; iv) BCR-ABL1-mutated sub-clones may persist at very low levels (undetectable even by Deep Sequencing) for long time and then outcompete BCR-ABL1-unmutated ones becoming dominant even in the absence of any TKI selective pressure.The online version of this article (doi:10.1186/s12885-017-3511-2) contains supplementary material, which is available to authorized users. First and second-generation Tyrosine Kinase Inhibitors approved for the treatment of Philadelphia-chromosome positive Acute Lymphoblastic Leukemia have Achilles heels that the BCR-ABL1 target oncoprotein may exploit to escape from inhibition: point mutations in the kinase domain may be selected that impair TKI binding . Particu9/L, a normal hemoglobin value and a moderate thrombocytopenia. A bone marrow aspirate showed 88% lymphoblasts, expressing the CD19, CD10, CD22, CD34, CD58, and CD45 antigens. Chromosome banding analysis of bone marrow revealed a normal karyotype; however, polymerase chain reaction revealed the BCR-ABL1 e1a2 fusion transcript. BCR-ABL1 transcript level assessed by real-time quantitative RT-PCR (RQ-PCR) was 111.09%. No involvement of central nervous system was detected, since all lumbar punctures performed showed the absence of leukemic cells in cerebrospinal fluid. Thus, a diagnosis of BCR-ABL1 (p190)-positive B-ALL was made. After informed consent was obtained, treatment was initiated according to the GIMEMA LAL1509 clinical trial that included a steroid-based pre-phase, followed by dasatinib induction therapy at 140 mg/daily for 84 days. After 52 days of dasatinib therapy, the patient obtained a complete hematological response with a mild decrease of the BCR-ABL1 transcript levels (1.22%). At day 85 the patient unfortunately progressed. Conventional Sanger Sequencing analysis showed evidence of a C to T nucleotide substitution at position 1091 of the ABL1 sequence in a proportion of BCR-ABL1 transcripts, resulting in the dasatinib-resistant T315I mutation. According to protocol schedule, the patient was treated with one course of standard chemotherapy, consisting of clofarabine 80 mg/daily, for 5 days and cyclophosphamide 800 mg/daily, for 5 days. The patient achieved complete hematological remission, but persistence of the BCR-ABL1 fusion transcript at the molecular level was observed (1.69%). A severe cardiac toxicity contraindicated the administration of an additional course of consolidation chemotherapy. Therefore, because of the minimal residual disease persistence, the patient was enrolled in the MT103–203 clinical study of blinatumomab, an anti-CD19 T cell engager antibody, as continuous intravenous infusion for 28-days cycles. After one course of treatment with 15 mcg/sqm/daily, which was well tolerated, a brilliant response was observed: the BCR-ABL1 transcript level significantly decreased down to 0.008% and the T315I mutation disappeared at conventional sequencing analysis. In consideration of the persistently suboptimal heart function, which would have seriously compromised the outcome of a transplantation procedure, a second course of therapy with blinatumomab was then started two weeks after the end of the first one, as required by protocol schedule. Unfortunately, the patient suddenly and unexpectedly relapsed after 10 days, with a remarkable hyperleucocytosis and a high percentage of lymphoblasts, with the same immunophenotypic signature detected at diagnosis. Conventional Sanger Sequencing showed that the T315I mutation had reappeared in a proportion of BCR-ABL1 transcripts. Salvage therapy with ponatinib at the dosage of 45 mg/daily was immediately started, but despite a very good tolerance to the compound, only a hematological improvement was observed, without significant changes in BCR-ABL1 transcript levels. At this timepoint, conventional Sanger Sequencing analysis displayed an unusual pattern of nucleotide substitutions: a C to T substitution at position 1091 and a T to C substitution at the adjacent 1092 position, suggesting the presence of two clones that could not be further characterized. Deep Sequencing was then performed as detailed in Soverini et al. [8/kg nucleated cells were infused, including 7.4×106/kg CD34+ cells. No signs or symptoms of graft-versus-host disease occurred, and a full recovery on peripheral blood was observed after 16 days from transplantation. After one month from this procedure, the bone marrow evaluation showed a complete morphological remission. FISH analysis revealed an almost complete full donor chimerism; BCR-ABL1 transcript level was 0.48%. Although the mutation analysis performed by conventional sequencing did not show evidence of mutations, the greater sensitivity of Deep Sequencing allowed to identify, again, both the T315I-positive subclones at very low levels . After 3 months from allogeneic stem cell transplantation, despite good clinical conditions and in the absence of symptoms of leukemia progression, the patient developed hyperleukocytosis, with mild anemia and thrombocytopenia. Bone marrow analysis showed a full hematological relapse, confirmed by a marked increase in BCR-ABL1 fusion transcripts (65.3%). The Deep Sequencing analysis performed at this time point showed the quick regrowth of both T315I-mutated subclones . Unexpectedly, the first clone was found to harbor additional point mutations: the F359V (16.34%) and H396R (9.47%). The rapid worsening of peripheral hematological values required an immediate therapeutic intervention. Therefore, after a brief and ineffective course of steroids and 6-mercaptopurine and hydroxyurea as cytoreductive agents, the patient received salvage chemotherapy according to HAM schedule with high dose of cytarabine and mitoxantrone. Treatment was well tolerated, but subsequent iatrogenic bone marrow aplasia was complicated by a severe pulmonary infection, with microbiological and radiological images diagnostic for an invasive fungal infection. Therefore, the patient received dual antimycotic therapy with voriconazole and liposomal amphotericin b, achieving a significant improvement of imaging reports after 3 weeks of treatment. Bone marrow examination, which was performed one month after the end of chemotherapy, showed the persistence of a relevant amount of CD19+ lymphoid blast cells and BCR-ABL1 transcript level had further increased (87.8%). Deep Sequencing analysis showed again all the sub-clones previously identified T315I act>att (17.93%), T315I act>atc (67%), F359V (3.17%), H396R (0.73%). At this time point we observed the emergence of the Y253H point mutation, with an abundance of 5.05%. Two T315I-inclusive compound mutations were observed: T315I act>att + F359V (0.67%) and the T315I act>atc + Y253H (3.98%)  of codon 315 were identified in the Sanger Sequencing chromatogram and the resulting amino acid substitution(s) could not be resolved. (PDF 209 kb)


Multivariate analyses pointed to vascular involvement as a strong and independent predictor for PSA failure (p = 0.023), and reduced biochemical progression-free survival (p = 0.019). LVI in radical prostatectomy is an adverse prognostic finding that must be recorded in the pathology report.Whether lymphovascular invasion (LVI) is an independent prognostic factor in prostate cancer is still controversial. We retrospectively investigated its predictive role in disease progression following radical prostatectomy. The histological sections of radical prostatectomies from 71 clinically localized, prostatic adenocarcinoma patients were reviewed for LVI. Pre- and postoperative follow-up data were collected. LVI was identified in 15.5% of cases. Univariate analysis showed a significant association between LVI and advanced pathological stage, higher Gleason score, positive surgical margins, extraprostatic extension, seminal vesicle invasion, and lymph node metastasis (each


About 80% of endometrial cancer survivors (ECS) are overweight or obese and have sedentary behaviors. Lifestyle behavior interventions are promising for improving dietary and physical activity behaviors, but the constructs associated with their effectiveness are often inadequately reported. The aim of this study was to systematically adapt an evidence-based behavior change program to improve healthy lifestyle behaviors in ECS.n = 16). An intervention mapping protocol was used for the program adaptation, which consisted of six steps: a needs assessment, formulation of matrices of change objectives, selection of theoretical methods and practical applications, program production, adoption and implementation planning, and evaluation planning. Social Cognitive Theory and Control Theory guided the adaptation of the intervention.Following a review of the literature, focus groups and interviews were conducted with ECS  contains supplementary material, which is available to authorized users. The high prevalence of obesity and suboptimal lifestyle behaviors render the increasing population of endometrial cancer survivors a high-risk group for both mortality and morbidity , 2. ObesThere is, therefore, a need for effective lifestyle behavior change interventions that can help this high-risk group to adopt and sustain health-protective behaviors . HoweverApplying an intervention to a different population requires adaptation. Some of the evaluated lifestyle programs in cancer survivors have used adapted versions of evidence-based programs. For example, the LEAN  study used an adaptation of the Diabetes Prevention Program . HoweverAn existing evidence-based weight management behavior change program is currently used across the UK in health and community settings. Developed by Weight Concern, “Shape-Up” is an eight-week, group-based program comprised of a self-help manual for participants  and a maShape was adapted using the six-steps within the IM Adapt approach Table . This enFollowing an assessment of organizational capacity and goals (1a), the adaptation process included a needs assessment examining the health and HRQoL issues in endometrial cancer survivors and their association with lifestyle behaviors (1b). These were conducted through a literature review and a qualitative study that took place in London, UK. All constructs of SCT  were included in the model as determinants of healthy eating and physical activity, because a comprehensive use of theory is associated with intervention effectiveness .Subsequently, a logic model of the problem linked the behaviors with health problems and HRQoL. This formed the basis for the development of the logic model of change that illustrates how the theoretical change methods influence the behavioral determinants that, in turn, affect the behaviors and, subsequently, health and HRQoL (1c). The performance objectives represent observable subsets of the targeted behaviors and the change objectives describe what participants must learn or change to meet or maintain the performance objective. Given the organizational capacity, the models were only focused on shaping the behavioral aspects of the problem. Lastly, the detailed program goal was established (1d).While the “Shape-Up” program was the initial choice, a retrospective search for other evidence-based interventions (2a) was run to confirm that no better option existed  and the selected program and evaluated the fit of the determinants and the theoretical methods of the original program for the new setting (3b). Additionally, it assessed the design, delivery and cultural fit (3c), considered its implementation fit (3d), and derived the essential elements of the original program that should be retained (3e).The behavioral change techniques used in the original intervention were retrospectively coded using the behavior change technique taxonomy v1 (BCTTv1) . The assThe content update was based on (i) current guidelines for cancer survivors , and , pretesting of the adapted materials (4b), and production of the final versions (4c). The drafted documents were reviewed in an iterative process ensuring they appropriately resembled the matrices of change objectives. Time constraints prohibited the originally planned pretesting of the materials.In the fifth step, facilitators, facilitation behaviors, and outcomes were specified (5a). The scope, sequence, and instructions for facilitation were developed (5b). The matrices of change objectives for facilitators were retrospectively created based on the original facilitator’s manual and were matched to SCT and CT constructs. These followed the rationale of the matrices in Step 3. A modified version of the original facilitator’s manual was created to reflect the content changes in the adapted version. These were followed by planning training and motivation activities for implementers (5c), and planning of logistics (5d).The final step consisted of the development of the evaluation questions (6a), selection of indicators and measures (6b), selection of the evaluation design (6c), and planning of the collection, analysis, and data reporting (6d).University College London (UCL) initiated the program planning focused on developing a healthy eating and physical activity intervention for endometrial cancer survivors to improve their HRQoL. To do so, it collaborated with the charity Weight Concern and the final team involved all authors.The needs assessment highlighted the high disease burden and need for an intervention , 8. The In this step, the logic models of changes for both the original and the adapted programs were developed. The main difference between the two was the removal of weight loss in the latter model. The adapted model is presented in Fig. Given the above, the goal of the program was to produce small clinically significant improvements in the overall HRQoL of participants in the first 6 months of program implementation .The retrospective search of the Internet, PubMed, and databases for effective evidence-based interventions did not return any intervention that would be a good fit for the current population. As the correlates of behavior appear to be similar for endometrial cancer survivors and the general population , the seaThe targeted behaviors  were the same for the general population and endometrial cancer survivors. Additionally, the organizational capacity could support the program, as the intervention did not require specific equipment or space but could be run in local places, such as community centers. Finally, its acceptability based on the initial thoughts of the participants was high and this was further reinforced through the telephone interviews detailed below.Details on specific changes on the manual content are presented below. Specific adaptations for each of the 3a, 3b, 3c, and 3d categories are listed in Table The original “Shape-Up” manual was developed in line with the recommendations in “The Eatwell Plate” and UK physical activity guidelines. The only major change in the adapted version was the shift of focus from weight loss to healthy eating and physical activity, given the lack of strong evidence for the benefits of intentional weight loss in cancer survival outcomes . This alThe targeted behaviors, behavioral determinants, and performance objectives remained the same except the performance objective “Cut down on quantity” which was rephrased to “Keep an eye on portion sizes” with respective changes in food portion recommendations. Based on the content-specific changes, change objectives and practical applications targeting weight management were removed while information on late-treatment effects management, and resistance exercises were added Table . These aMost participants found the manual useful, yet detailed and bulky. They were particularly keen on tailoring the information to endometrial cancer survivors. The delivery of the intervention remained unchanged, given the high preference of endometrial cancer survivors for face-to-face contact with the intervention facilitator. Retaining the duration, intensity, and frequency of the program to eight weekly meetings aimed to balance the lack of agreement among survivors for the optimal intervention delivery time.The program is currently used within the National Health Service. Its most recent service evaluation demonstrated positive results in terms of adoption of health behaviors. For example, 89% of participants reported higher physical activity, and 90% described being better able to manage ‘triggers’ that may lead to unhealthy behaviors .The implementation fit was considered adequate given the conservation of the initial delivery method. Nonetheless, disease-free endometrial cancer survivors are a very specific segment of the population widely dispersed across the country. Thus, program implementation might be more challenging in local centers, such as community centers, whereas treatment hospitals, and Macmillan Cancer Support Centers might serve this purpose well.Furthermore, clinicians and researchers participating in the NCRI gynecology workshop were supportive of the program, indicating its future potential acceptability. The dietitian involved, who might represent potential program implementers, was familiar with the original program. Additionally, the intervention is in accordance with the self-help and personalized support envisioned in the National Cancer Survivorship Initiative .Based on the intensity of the BCTs used, those considered essential included self-monitoring of behavior, behavioral goal setting, self-incentives, social support, and problem solving. These were also the core BCTs for facilitating health behavior change identified in the literature , 27–29. It could be argued that the combination of BCTs make the program effective rather than specific individual ones. Furthermore, all BCTs identified in the literature and coded against the BCTTv1 were included in both the original and adapted versions of the program. Therefore, the theoretical methods of the program remained largely unchanged. Examples of the adapted matrices for change objectives for diet and physical activity are shown in Tables ClinicalTrials.gov identifier: NCT02433080 [The production of the materials was based on the planned changes. The iterative review process ensured an optimal match between program goals and materials. A pilot evaluation of the program has recently been carried out  pilot trial  were trained to follow a scripted manual for delivery of the intervention. While one facilitator was considered sufficient, the presence of a second was also thought appropriate in case of unexpected circumstances. From the facilitators’ perspective, the original implementation protocol was deemed sufficient for adoption in the new setting. This also followed the suggestions from the qualitative work . TherefoAs geographical proximity was a significant barrier for participation, the pilot intervention took place in one of the recruitment hospitals in central London aiming to provide a location easily accessed by transport. Based on the areas covered by the two recruitment hospitals, it was anticipated that most participants would need to commute less than 45 min each way to attend the face-to-face program.The service evaluation of the original “Shape-Up” is primarily based on attendance rate and weight measurements. However, weight tracking was deemed inappropriate for the adapted version. Depending on resources, other criteria such as assessments of health status and HRQoL might determine program sustainability at program completion and at least 6-month follow-up. Quality control visits at random sessions was used as a measure of protocol fidelity. The implementation outcomes were expected to be 90% protocol fidelity and at least 60% adherence, as defined by attendance of sessions. These closely matched the observed fidelity and adherence rates of 85% and 61%, respectively.The above similarities between the two program versions led to identical matrices of change objectives for effectively facilitating a group  [The intervention has recently been evaluated within the DEUS (Diet and Exercise in Uterine Cancer Survivors) pilot trial in disease-free survivors within 3 years of diagnosis (2433080) .The current study presents the adaptation process of an evidence-based program focusing on healthy eating and physical activity for endometrial cancer survivors. The use of the IM systematic framework for its adaptation, implementation, and evaluation increases the potential for intervention effectiveness. The systematic process ensured all potential intervention aspects were considered. It described comprehensively the link between theory, BCTs and practice, helping interventionists understand the unique value of each essential intervention element and their interrelationship.As, it is currently unclear which interventions are most effective, use of theory for the development and implementation of behavior change interventions has been proposed as a means of increasing their effectiveness, and provide insights into the mediators of behavior change that can, subsequently, translate to successful interventions . SCT is If successful lifestyle interventions are to shape practice, they require suitable characterization methodology and connection to an analysis of the behavior. The IM framework has been used widely for the development of health promotion programs, including nutrition and physical activity . This isLimitations of this study include the retrospective evaluation of the original “Shape-Up”, and, potentially, the use of many BCTs that have not been identified in systematic reviews . (DOCX 112 kb)Full matrices of change objectives for healthy eating and physical activity, program structure, and additional methodology. Methodology for searching for evidence-based interventions; Methodology for the qualitative interviews;