ATM/GAFF2-AM1BCC/TIP3P/HREM) had RMSE less than 1.75 kcal/mol. The work discussed here also highlights several important lessons; for example, retrospective studies of reference calculations demonstrate the sensitivity of predicted binding free energies to ethyl group sampling and/or guest starting pose, providing guidance to help improve future studies on these systems.The SAMPL series of challenges aim to focus the community on specific modeling challenges, while testing and hopefully driving progress of computational methods to help guide pharmaceutical drug discovery. In this study, we report on the results of the SAMPL8 host–guest blind challenge for predicting absolute binding affinities. SAMPL8 focused on two host–guest datasets, one involving the cucurbituril CB8 (with a series of common drugs of abuse) and another involving two different Gibb deep-cavity cavitands. The latter dataset involved a previously featured deep cavity cavitand (TEMOA) as well as a new variant (TEETOA), both binding to a series of relatively rigid fragment-like guests. Challenge participants employed a reasonably wide variety of methods, though many of these were based on molecular simulations, and predictive accuracy was mixed. As in some previous SAMPL iterations (SAMPL6 and SAMPL7), we found that one approach to achieve greater accuracy was to apply empirical corrections to the binding free energy predictions, taking advantage of prior data on binding to these hosts. Another approach which performed well was a hybrid MD-based approach with reweighting to a force matched QM potential. In the cavitand challenge, an alchemical method using the AMOEBA-polarizable force field achieved the best success with RMSE less than 1 kcal/mol, while another alchemical approach (The online version contains supplementary material available at 10.1007/s10822-022-00462-5. Quantitative modeling done with molecular simulations can be used to estimate thermodynamic and/or physical properties, with the goal of aiding and directing small molecule drug design for therapeutic development –8. SimulFor well-behaved protein–ligand systems, free energy methods can achieve agreement with experiments within about 1–2 kcal/mol –22. HoweSupramolecular host–guest complexes have been used as simpler surrogate binding systems, instead of protein–ligand systems, to assess modeling errors and test computational methods and force fields. Host–guest systems feature hosts, or ”mini-receptors”, which are smaller and often more rigid, hence eliminating some challenges associated with the modeling of proteins. Since hosts are smaller  simulations can be run quicker and longer. These hosts can bind guest molecules  with protein–ligand-like affinities , 25, 26.SAMPL  is an NIH-funded project consisting of a series of blind crowdsourcing challenges which serve to test and improve computational methods as reliable predictive tools for rational drug design , 30, 31.Over the course of SAMPL, by focusing the community on specific modeling difficulties with well designed systems, host–guest challenges have driven progress in many areas and advanced our understanding of sources of error , 32–46. Although host–guest systems are ”simpler”, they still pose several modeling difficulties. For example, guests bearing a formal charge can be especially difficult to treat. Indeed, charged guests were shown to affect the accuracy of many methods in SAMPL7 . PolarizSeveral SAMPL iterations have helped identify obstacles that need to be addressed and further studied, and are described in the literature , 24, 30.SAMPL host–guest datasets involve hosts such as cyclodextrins , 48, cucKashift of titratable groups, treating the wrong protonation state (or even only a single protonation state) may lead to large errors in binding free energy estimates uril (CB[n]) families were chosen for the SAMPL8 host–guest challenge. We aimed to study modeling implication(s) of tetra-endo-methyl Octa-acid (TEMOA) and a variant tetra-endo-ethyl Octa-acid (TEETOA), with flexible ethyl side-chains in the presence of mostly rigid guests. In addition, SAMPL8 also revisits the cucurbit[8]uril (CB8) host, with a series of guests which are addictive and commonly abused drugs .The first dataset developed was for the CB8 host Fig. . The hosCB[n]–guest complexes are well known to have very high affinity, especially for cationic ammonium and diammonium guests like those featured in SAMPL8. The high affinity measurements from these systems have been attributed to an enthalpic driving force provided by the lack of host hydrogen bonds with intracavity waters . Upon biPrevious studies on cucurbiturils have provided some highlights and important factors to consider , 30, 60.Kavalue was near the experimental pH of 7.4. However, it was possible that alternative protonation states were accessible for other guests, thus necessitating their consideration. In such cases, close attention to the geometry of certain trivalent nitrogen centers would be required because if protonated, computationally they can act as a chiral center and all guest geometries might need to be sampled. If geometric sampling is inadequate, the selected geometry may impact the binding estimates for some methods.For this challenge we hoped participants would submit multiple methods which varied by only changing a single simulation parameter, such as a force field or an aspect of the simulation protocol, since such variations would allow us to directly probe the sensitivity of results to particular choices. Thus for our reference calculations the goal was to compare and test different force fields. At the same time, several protonation states needed to be considered for one guest. In particular, ketamine (G5), since its pThe second dataset featured two hosts in the GDCC family, TEMOA and TEETOA, commonly referred to as Octa-Acids. GDCCs are low-symmetry hosts, fairly rigid, and have a basket-shaped binding site with eight carboxylate groups appended to the host to enhance solubility , 66. FouIn this study we employ the attach–pull–release (APR) methodology, using the pAPRika toolkit , for theIn this section we give challenge organization details, a general overview of methods used by participants’ for their submissions, describe the details of reference calculations, summarize experimental details and methodologies , and deThe SAMPL8 host–guest challenge was organized similar to SAMPL7, allowing participants to submit their “top” predictions as a ranked submission for any or all of the datasets (CB8 and GDCC), but a submission for either dataset was required to include all guests. Only ranked submissions were considered for the main analysis of the challenge. Additional submissions were allowed, but needed to be denoted as non-ranked. Non-ranked submissions gave us an opportunity for benchmarking and provided additional methods for cross comparison, while still allowing each participant only one opportunity to formally compete in the challenge. All participants formally submitted blind predictions prior to the challenge deadline. In addition, two members of our team (MA and JS) conducted blind reference calculations which were submitted informally in the non-ranked category.https://github.com/samplchallenges/SAMPL8/tree/master/host_guest).Pre-prepared host and guest structure files  and SMILES strings were provided to participants. Where applicable, host and/or guest structures were provided with reasonable protonation states. However, we advised participants to exercise caution in the choice of protonation state, particularly for CB8–G5, TEMOA–G2, and TEETOA-G2. All files described above, data, and instructions are available on the SAMPL8 GitHub repository .A prescribed submission template was provided for participants to follow and included an example submission with all needed information. Participants were required to follow the template, since we would use automated scripts to parse and run the statistical analysis. Each submission required: predictions, participant name, participant organization, name of their method, list of used software, detailed method description, method category, and a ranked or non-ranked classification. In the predictions section, we required a predicted free-energy, free-energy SEM, and free energy model uncertainty. Predicted binding enthalpy values were optional. Participant and reference calculation submission files are available in relevant host submission directory in the SAMPL8 GitHub repository , respectively. Submissions for CB8–G8, CB8–G9, and TEMOA–G3 were optional since these binding values have been reported in literature.The statistical analysis of the challenge was performed using Python scripts adopted from SAMPL6 and SAMPL7, and deposited in the SAMPL8 GitHub repository. Thus, for SAMPL8 we use statistical metrics as used in previous SAMPL iterations , 18, 20 https://github.com/samplchallenges/SAMPL8/tree/master/host_guest/Analysis).The statistical analysis was separated into ranked and non-ranked categories. For the non-ranked category, all submissions (ranked and non-ranked) were considered, while in ranked category  only ranked submissions were considered. For datasets with optional systems, analysis was done with and without those guests, where the latter was denoted as “no optional” in the respective directories. All data, plots, and tables for ranked and non-ranked analysis subsets are available in the SAMPL8 GitHub repository , and OpenMM 7.4.2 as the simulation engine. In total, 15 windows were used for the attach and release phases, and up to 46 umbrella sampling windows (depending on the size of the guest) during the pull phase.Our in-house reference calculations were performed using the APR method , 87 withThe starting structures were obtained by docking using OEDock (with the Chemgauss4 scoring function) from OpenEye Toolkits (release 2019.4.2). AM1-BCC partial atomic charges were generated with oequacpac function oequacpac.OEAssignCharges as implemented with OpenEye Toolkits (release 2019.4.2). Each host–guest system was solvated with 2500 TIP3P water molecules in a rectangular box whose dimensions were approximately Cheatham ) were adCheatham .z-axis. Three non-interacting particles, called dummy atoms , were added to the system along the z-axis below the guest molecule at distances of 6, 9, and 11.2 Å, respectively. The third dummy atom (D3) was also offset by 2.2 Å, in the y-axis.The attach–pull–release windows were prepared using pAPRika 1.0.4, which consists of: adding three non-interacting anchor particles, defining host and guest anchor atoms, configuring Boresch-style restraints , the addAs described elsewhere , 91, sixr and 2; (b) angle and torsional restraints = During the attach phase, three restraints were applied to the guest molecule; two for the translation . In addition, guests G3 (morphine) and G4 (Hydromorphone) have at least one additional hydroxyl group for which the deprotonated form could possibly be relevant . Only three protonation states are likely populated for G3 and G4 at pH 7.4  and G6 (2 states) are predicted to be populated near 0.15In the GDCC dataset, guests G1 and G2 had at least 2 accessible/populated protonation states at the experimental pH of 11.5.  The guests protonation states were generated using an in-house script with OpenEye toolkits. The script also ordered the generated protonation states from the most likely state to least. The most likely state was then cross referenced with ChemAxon Chemicalize and used as the protonation state of the guest to model for free energy calculations.https://github.com/samplchallenges/SAMPL8/tree/main/host_guest/Analysis/ExperimentalMeasurements). If there are any updates or changes to experimental data, the GitHub repository will provide the authoritative source.The experimental labs of Lyle Isaacs and Bruce Gibb conducted Isothermal Titration Calorimetry (ITC) and/or Nuclear Magnetic Resonance (NMR) spectroscopy to obtain binding measurements for SAMPL8 host–guest challenge. All experimental binding data for host–guest systems are listed in Table Briefly, ITC and/or NMR experiments were performed at 298 K. The CB8–G2 host–guest 1:2 binding value is also available in Table Binding constants for the GDCC dataset were measured in 10 mM sodium phosphate buffer at pH For the SAMPL8 host–guest challenge, we find that binding free energy predictions are more accurate for GDCC hosts compared to CB8. This was also the case in previous SAMPL iterations despite CB8 and TEMOA being featured in those iterations. Then, we discuss the results for ranked methods and identify the top performing methods, compare ranked methods with each other, and discuss success and/or failures of methods. Separately, we also compare all methods  to probe the sensitivity of results to changes in protocol and/or method.First, we break down participation and submission statistics for SAMPL8. We received a total of 51 submissions from 11 different groups, with 34 for CB8 and 17 for GDCC. The challenge involved 18 ranked submissions total, 10 of which were for CB8 and 8 for GDCC, and which constitute our primary focus in analysis . However, both methods performed particularly poorly at predicting binding free energies.Most of the participants generated the initial host–guest complex for their calculations by docking, using various docking software. Methods also differed in how they modeled the buffer conditions, with some using an experimental ionic strength with sodium and chloride ions, while others using only neutralizing counter ions.Performance statistics for most ranked methods in CB8 and GDCC were relatively similar. The similarity in the results is likely due to these methods using the same energy model (GAFF and TIP3P). There were a few methods with slight differences in the chosen energy model (such as using GAFF and TIP4P rather than GAFF and TIP3P) or use QM/DFT based approaches, yet have similar results to those with GAFF/TIP3P. However, a couple methods stand out as clear top performers or perform particularly poorly Figs. , 7.Fig. DDM/FEP/MBAR/FM/RW[pm6s6], with RMSE, MAE, and RSILCS/LGFE/TIP3P/GCMC-MD method with RMSE, MAE, and RDDM/FEP/MBAR/FM/RW[pm6s6] and SILCS/LGFE/TIP3P/GCMC-MD methods achieved the best error metrics, however, they did not have the best correlation, which will be discussed shortly. Ordered by the RMSE error metric, the next six methods had values ranging from 3.77 kcal/mol to 4.68 kcal/mol while the lowest two methods ranged from 5.72 to 6.64 kcal/mol  method, Different metrics can be used to rank methods, and the ranking can be different depending on the metric chosen. For example, the MAE can be used to rank the submissions for SAMPL8, since this error metric is not as sensitive  entropy-enthalpy based method EE-MCC/GAFF2-AM1-BCC/TIP3P/MD/. Although the EE-MCC/GAFF2-AM1BCC/TIP3P/MD method yielded poor binding free energy predictions, binding enthalpy predictions were within 2 kcal/mol for 4/7 systems. On the other hand, the ABFE/Parsley-GAFF-BCC/TIP3P/MD/NoBuffer1 predicts 1/7 systems within 2 kcal/mol. The correlation was modest with a few outliers for the entropy-enthalpy method, while there was a larger error and there appeared to be some systematic errors for the ABFE/Parsley-GAFF-BCC/TIP3P/MD/NoBuffer1 method . The EE-MCC/GAFF2-AM1-BCC/TIP3P/MD/ and ABFE/Parsley-GAFF-BCC/TIP3P/MD/NoBuffer1 methods used the same energy model, but the ABFE/Parsley-GAFF-BCC/TIP3P/MD/NoBuffer1 method did not model the buffer concentration. These modeling differences indeed seem to affect results substantially, with the RMSE differing by about 1 kcal/mol. The effect of buffer conditions on the binding enthalpy appears to be more significant for specific systems, and these observations warrant further studies.It is worth noting that two sets of binding enthalpy predictions were submitted for CB8, but this was too few to allow statistical analysis. The methods were the DDM/AMOEBA/BAR, which had the best RMSE and MAE values of 0.88 and 0.72 kcal/mol, as well as ATM/GAFF2-AM1BCC/TIP3P/HREM method came in second overall for the GDCC dataset. Although we observe that computational predictive power is higher overall for the GDCC dataset, there are still methods which have very poor predictive power with RMSE and MAE values as high as 4.91 and 3.95 kcal/mol and coefficients of determination as low as 0.01 .In SAMPL8, methods were surveyed for their ability to correctly predict the tightest and weakest binders in each dataset. The tightest binders across host–guest datasets were CB8–G6, TEMOA–G2, and TEETOA–G2. As expected, methods that predict the tightest binders correctly are typically the top performing methods in each host–guest dataset (such as DDM/AMOEBA/BAR and ATM/GAFF2-AM1BCC/TIP3P/HREM) predicted TEETOA–G5 correctly as the weakest binder. Overall, most methods do a better job predicting binding of tight binders but perform poorly for particularly weak binders.The weakest binders of SAMPL8 were CB8–G1, TEMOA–G3, and TEETOA–G5. For TEETOA, here we default to TEETOA–G5 as the weakest binder since TEETOA–G3 was not detected and it’s uncertain if this is a binder at all. No method predicted CB8–G1 or TEMOA–G3 correctly as the weakest binders for their respective datasets, while only two methods  for comparison to one another and for cross validation of the newer ATM method. The methods differ in that the ATM method is alchemical while the PMF method is path-based, and each utilizes a different sampling approach , and outliers between the methods highlight the current limitations and advantages of these models.The top two methods, APR/GAFF2-AM1BCC/TIP3P/US/TI  with the top performing PMF/GAFF2-AM1BCC/TIP3P/MD-US method also using GAFF2, we observe an RMS difference of 2.97 and kcal/mol for TEMOA and 3.32 kcal/mol for TEETOA. As indicated by these RMS differences, the predictions of the two methods indeed vary more for TEETOA systems . One way in which the methods differ is that in reference calculations conformational restraints were applied on the TEETOA host cavity, so the fact that these methods yield different results suggests a binding mechanism involving TEETOA conformational change(s), likely of the ethyl side chains. In addition, the methods differed in their computed binding free energies for TEMOA–G2 and TEMOA–G3 by more than 4 kcal/mol in each case, while the remaining systems  were all within 0.13 kcal/mol of one another. The discrepancy for TEMOA–G2 is likely due to modeling differences of G2, where the reference had a deprotonated (charged) hydroxyl while in the PMF approach both protonation states of the hydroxyl form were considered. The use of conformational restraints of TEMOA may play a role rendering G3 particularly sensitive to this, though the reason for the discrepancy between TEMOA–G3 predictions with these two methods is not obvious.Comparing predictions of Many participants included additional binding free energy predictions as “non-ranked” submissions. For the most part, the difference between additional submissions is a single change such as using a different force field, a different sampling technique, or a different charging scheme. The submissions have also been analyzed and included in Table DDM/FEP/MBAR/FM/[pm6pm6]), and yielded an RMS error of 2.46 kcal/mol. This suggests that hybrid approaches involving MD-based simulations with QM reweighting may now be able to achieve some measure of success.One group provided a total of 13 different CB8 prediction sets based on MD free energy calculations with parameters from a FM protocol as previously applied in SAMPL6; some of their prediction sets, including their best ranked set of predictions, then used reweighting to re-evaluate free energies with a quantum mechanical energy function. The best approach  in this case used force-matched PM6-D3H4 parameters for the CB8 guests (SILCS/LGFE/TIP3P/GCMC-MD/rew) was not ranked. This seems to further illustrate that empirical corrections to computed binding free energies can improve accuracy, at least in some cases.Three different SILCS methods were applied to CB8 and achieved reasonable success; the top-performing method was a non-ranked submission which included empirical weighting factors applied to the computed grid free energies in order to improve agreement with experimental results for CB8 in SAMPL6. This empirical tuning resulted in better performance here than for the other two SILCS-based methods , though this submission  contribute to the larger error in predictions.It’s worth briefly speculating as to why GDCC binding affinity predictions may be more accurate than those for CB8. We speculate that methods achieve greater predictive power for GDCC systems because the guests are typically more rigid and “simpler” as opposed to guests in the cucurbituril datasets in this challenge, though also the availability of empirical data from prior CB8 studies may be helpful to tune methods . Sampling of water displacement and rearrangement has been reported to be a separate issue as well, or possibly the origin of problems in CB8. The binding of guests to CB8 also involves water displacement, but it is possible that additional complications not explicitly accounted for , and in each of these challenges, CB8 binding affinities have been more difficult to predict accurately compared to those for other host families. As discussed above, previous experimental work reported protonation state modulation of guests upon binding to CB8, thus we thought that this could play a role here for guests with multiple protonation states potentially accessible at pH 7.4. Indeed, when we modeled the guests in different protonation states compared to our initial predictions, the binding Our reference calculations encountered particularly severe problems for some host–guest complexes. For example, the TEETOA–G1 prediction for reference calculations was unfavorable at 2.79 kcal/mol, whereas experimentally binding was favorable. In the analysis of the initial simulation the guest leaves the TEETOA pocket, due to the ethyl groups remaining oriented towards the cavity. We tested how the host conformation affected binding by restraining the host ethyl groups to keep them oriented towards the cavity, and found that in this conformation the predicted free energy was We also examined two different small-molecule force fields and observed similar performance. Particularly, we compared our two sets of reference calculations which differ only in the force field used (GAFF2 or OpenFF Parsley v1.2.0), and found that the force fields have similar performance . However, for certain systems  there is disagreement in the calculated values between GAFF2 and Parsley. The RMS difference between the two force fields were 3.00, 1.14, and 1.17 kcal/mol for CB8, TEMOA, and TEETOA, respectively.https://github.com/MobleyLab/blues. Here, we used BLUES moves to enhance sampling of the host ethyl groups in particular.The GDCC TEETOA host has some degree of conformational flexibility which can be modulated by binding and by the guest orientation and identity. Thus, we performed additional calculations in which we applied the BLUES approach  to bettem MD steps  using the L-BFGS optimization algorithm . Then 1 sing PME , 109 witWe initialized BLUES simulations with five replicates. For each iteration, 1 NCMC move and 1000 MD steps were executed with hydrogen mass repartitioning scheme with 4 fs integration time step . Each NC3900 Iterations BLUES simulations were performed for each replicate. After checking collected data, we found (1) the ethyl groups orientations changed with the guest orientation in the pocket and (2) the guest unbound in in all 5 replicates. These results indicated the difficulty of adequate sampling of these ethyl groups and restraints were needed for both efficient sampling and keeping the host–guest in the bound state.k-centers clustering method. The distance was computed between two carbon atoms  that can represent different orientations of the guest and the distance between the guest and host sampled in the simulation. We picked four states of which three  were the most populated and represent different orientations of the guest in the cavity. The remaining one  was a conformation where the guest is right at the entrance of the host pocket. Position restraints with a spring constant of 20 kcal/mol/ÅTo seed more simulations, we clustered the trajectory where the host–guest was maintained in the bound state during the simulation using a distance based The additional BLUES simulations show that these four ethyl groups are very sensitive to the orientation of the guest in the cavity. Figure S17 shows the distribution of dihedral angles of the four ethyl groups sampled in BLUES simulations started from different conformations shown in Fig. S16. The position restraints on the guest and host ensure the orientation of the guest maintained the same in the context of simulations. Our results show that the ethyl groups’ preferred orientations are dependent on the orientation of the guest Fig. D. Since The SAMPL8 host–guest challenge provided a platform to test the reliability and accuracy of current computational methods and tools to predict absolute binding free energies. As part of this challenge, hosts CB8 and TEMOA were revisited with new guest libraries, including a new host in the Gibb deep cavity cavitand family , TEETOA.Similar to previous iterations of SAMPL, judging by the performance of submissions the CB8 systems posed a bigger challenge for participants. Five CB8 systems  all had an RMSE greater than 4 kcal/mol  followed by SILCS/LGFE/TIP3P/GCMC-MD. For this challenge, performance was variable with RMSE metric range from 2.43 to 6.64 kcal/mol, while correlation metrics for all methods were relatively poor. Only two methods achieved a coefficient of determination over 0.50. The few methods that achieved high correlation still had low binding free energy accuracy, which was a strong indicator of systematic errors. The FM method had a measure of success with its hybrid approach (MD-based with QM reweighting) method using force-matched PM6-D3H4 parameters for the CB8 guests.The best ranked methods for CB8 were a free energy method based on force-matching  had slightly better performance for the CB8 dataset. The SILCS based approach utilized an empirical approach, and illustrated that such corrections to binding free energy predictions did improve accuracy in many cases. When we consider all submissions (including non-ranked methods), a SILCS based approach  submission included predictions for these for the CB8 dataset, which were within 2 kcal/mol of experimental values for four of seven cases. Historically, accurate binding enthalpy/entropy predictions have been seldom seen, so this is exciting. However, since the challenge was based on predicting binding free energy, we must comment that binding free energy accuracy for this approach was low.Experimental binding DDM/AMOEBA/BAR method was the top performing method for the GDCC dataset (like in SAMPL7), followed by the ATM/GAFF2-AM1BCC/TIP3P/HREM. Although methods were generally more accurate on this dataset, there were some methods with limited predictive accuracy with RMSE values over 5 kcal/mol and coefficient of determinations as low as 0.01.The TEETOA is symmetrical and has four chemically equivalent ethyl groups. Based on our retrospective studies of TEETOA–G1, we conclude this symmetry is broken when G1 is bound because the guest (G1) has a particular orientation. So instead of all ethyl groups being oriented symmetrically, we find the preference is highly sensitive to the orientation of the guest. Our data suggests a specific orientation of the guest in the bound state  predominates. With this binding mode, the host has one ethyl group pointing inward whereas the other three point outward. Our results show details of the ethyl groups’ orientations and enhance our understanding of the likely bound conformation of TEETOA host–guest complexes. In addition, submissions for methods that used enhanced sampling techniques  performed with greater accuracy than methods using classic MD or US techniques, showcasing the success and perhaps the necessity of enhanced sampling methods for adequately sampling host–guest bound conformations.Supplementary file 1 (pdf 7554 KB)Below is the link to the electronic supplementary material.


MRI and Met-PET/MRICR findings were completely concordant in five patients, partially concordant in nine patients, and non-concordant in four patients. In five patients Met-PET/MRICR identified lesion(s) that were retrospectively also visible on MRI. Met-PET/MRICR was false negative in one patient, with a cystic adenoma on conventional MRI. Thirteen patients underwent transsphenoidal surgery, with nine achieving full biochemical remission, two clinical improvement and near normalized prolactin levels, and one patient clinical improvement with significant tumour reduction. Hence, nearly all patients (94%) were considered to have a positive outcome. Permanent complication rate was low. Three patients continued DA, two patients have a wait and scan policy.Met-PET/MRICR can provide additional information to guide multidisciplinary preoperative and intraoperative decision making in selected cases of prolactinoma. This approach resulted in a high remission rate with a low rate of complications in our expert centre.Met-PET/MRIThe online version contains supplementary material available at 10.1007/s11102-022-01230-2. Prolactinomas account for approximately 40% of all pituitary tumours . HyperprCurrent standard care is medical treatment with dopamine agonists (DA), but long-term remission rates are lower than previously suggested and some patients experience intolerable mental or physical side effects. Surgery has traditionally been considered a rescue treatment for patients with drug intolerance, resistance, or mass-related complications. Recently, surgical indications for prolactinoma have been revisited, particularly for those tumours amenable to gross total resection (GTR) . If GTR 11C-methionine to enable more accurate localization of functioning pituitary adenomas. This tracer is preferentially taken up by the adenoma and to a lesser extent by the normal pituitary with relatively low uptake by the surrounding brain. Co-registration of 11C-methionine positron emission tomography-computed tomography with MRI (Met-PET/MRICR) allows the site of maximal 11C-methionine uptake to be more accurately defined and addresses the important question of whether a possible lesion detected on structural imaging coincides with functional activity.For small prolactinoma (remnants) and those in close proximity to the cavernous sinus, conventional imaging has limitations to reliably identify the precise localization and invasion of surrounding structures, and to discriminate between normal gland and adenoma. Hence, in order to improve the prediction of chances for remission and to minimize surgically induced pituitary insufficiency there is an unmet need for better tumour localization. Therefore, we initiated a structural collaboration with the Cambridge pituitary multidisciplinary team, which has developed and optimized functional imaging using CR for treatment decisions in selected patients with Cushing’s disease and persistent acromegaly after primary therapy , and as (2) permanent complications . A priori estimation of chances for remission and complications: Before and after Met-PET/MRICR an estimate was made of the chance of remission and risks by the neurosurgeon and endocrinologist. The estimated chance of remission was divided into 5 classes: very unlikely (~ 0 to ~ 20%), unlikely (~ 21 to ~ 40%), possibly (~ 41 to ~ 60%), likely (~ 61 to ~ 80%), and very likely (~ 81 to ~ 100%). The estimated chance of long-term risks, mainly determined by the risk of permanent pituitary deficiencies, was divided into 3 classes: low (< ~ 2%), moderate (~ 2 to ~ 5%), and high (> ~ 5%).11C-methionine PET imaging for registration purposes) an additional post-contrast axial 3D T1w FFE with whole brain coverage was acquired  in the same frame of reference as the pituitary sequences.All MR imaging acquired at our institution was performed on an Achieva 3.0 T TXMR system  using a commercial 32-channel head coil, according to our local MR pituitary protocol. On initial presentation the protocol consisted of coronal and sagittal T1-weighted, turbo spin echo , and coronal T2 weighted, TSE  imaging of the sella region before intravenous (i.v.) contrast administration, dynamic coronal T1 weighted fast field echo  imaging of the sella during i.v. administration of 0.1 mmol/kg gadoterate meglumine , and coronal and sagittal T1w TSE imaging of the sella after i.v. contrast administration. On follow-up imaging no pre-contrast sagittal T1w TSE and coronal dynamic T1w FFE images were acquired. In addition, when appropriate (i.e. before 11C]-methionine (11C-methionine), was synthesized in compliance with good manufacturing practice at the Radionuclide Centre of the Amsterdam University Medical Centre (Amsterdam UMC) location VU University Medical Centre (VUMC), Amsterdam, the Netherlands, as described previously . Besides transient disturbances in fluid balance no complications occurred. In subject 10, Met-PET/MRICR showed two lesions, which were retrospectively also identified on previous MRI. Likelihood of remission remained possibly with a high estimated risk for complications due to previous surgery and medical treatment and localization of the pituitary gland. Given intolerance and resistance for DA, however, revision TSS was advised. Nevertheless, for now, the patient preferred a wait and scan policy without DA.In subjects 8, 10 and 14, functional imaging was used to localize a remnant of an initially clearly visible prolactinoma that had shrunk after long standing medical treatment and/or surgery and was less clearly visible on current MRI. All three patients had been treated with DA with accompanying side effects with a treatment duration of 72–74 months, and one patient had also been operated (subject 10). Met-PET/MRICR as compared to likelihood based on MRI only. The distribution before vs. after Met-PET/MRICR was: very unlikely 22% vs. 17%, unlikely 17% vs. 11%, possibly 44% vs. 17%, likely 6% vs. 33%, very likely 11% vs. 22% (p = 0.005) . Complication rate was low: 6/13 patients (46%) had transient complications (i.e. mild transient DI or SIADH) , and only 1/13 patients (7%) , complex surgery with estimated moderate risk) had long-term complications ). Looking per risk group, all nine patients in the estimated low risk group were operated, of which three had a transient complication (33%). In the estimated moderate risk group three of five patients (60%) were operated, of which three had a transient complication (100%) and one (subject 6) had long-term complications . In the estimated high-risk group only one of four patients  was operated with an uncomplicated course.Estimated complication risk for the complete group did not change significantly following Met-PET/MRICR Fig. . The disThis paper concludes that combined structural and functional imaging with a more accurate visualization of the size and extension of the adenoma and iterative MDT discussions provides added value in selected cases for prediction of surgical success and so clinical decision making. For patients with prolactinoma with drug intolerance or resistance, surgery is the next step in the treatment algorithm. Based on recent evidence, surgery is now increasingly considered as a first line treatment option for microprolactinomas and circumscribed macroprolactinomas in which complete resection can be anticipated , 14–30. CR) in guiding management in pituitary adenomas has previously been reported by several groups [CR) to localize sites with abnormal tracer uptake varies from 67 to 100%, depending on the type of pituitary adenoma and setting. Recent studies from the Cambridge group correlating imaging findings with subsequent treatment decisions and clinical outcomes in patients with specific functional pituitary adenomas  have shown clear added value of Met-PET/MRICR for treatment decision making [The potential utility of Met-PET prolactinomas, with clear difference from MR imaging . After reassessment, five Met-PET/MRICR identified lesion(s) could retrospectively also be identified on MRI. Operative findings were compatible with Met-PET/MRICR in 92%. In this complex case series, all but one patient had a positive outcome as defined by normalization of prolactin level and/or clinical improvement, with a low long-term complication rate.Met-PET/MRI11C-methionine uptake is a useful tool in complex prolactinomas cases because uptake is higher than in normal pituitary tissue in most cases. A single case without increased uptake had less clear findings during surgery and postoperatively.Assessment of CR in prolactinoma provides additional information on the anatomical relationship of the tumour with the cavernous sinus, which can help inform the likelihood of complete surgical resection.Met-PET/MRICR provides reliable information in the following situations: confirmation of functionality of small intrasellar recurrent adenoma also seen on MRI, and confirmation and exclusion of multifocality in cases with several possible small remnants of a previous macroadenoma in an enlarged, partly empty sella.Met-PET/MRICR is associated with additional costs, not only with respect to performing the scan, but also in terms of the time and expertise required to critically interpret the result. Therefore, the indication for this additional scan after protocolled MRI should be thoroughly discussed in the MDT before being requested.Met-PET/MRIIt is important to distinguish the different subgroups of patients preoperatively because they have different challenges.The multidisciplinary discussion for complex cases associated with the implementation of this new technique is another factor that may be associated with the high remission rates.Based on our findings in this study we conclude that:CR. These include (i) a cystic lesion , (ii) when serum prolactin is low , (iii) technical issues , (iv) hyperplasia instead of adenoma. In contrast to somatostatin analogue withdrawal in acromegaly patients [CR, but based on the half-life of cabergoline, the dose, and its biological effects, a period of 4 weeks is recommended, which can be extended if there is insufficient elevation of prolactin. In our cohort, prolactin levels at the time of Met-PET/MRICR varied between 1.4 and 161 times ULN. In our series, all patients with mildly elevated prolactin levels (between 1.4 and 2.5 times ULN) had positive Met-PET findings and achieved biochemical remission after surgery, suggesting that even in prolactinoma cases with mild prolactin elevation Met-PET can be diagnostic. Finally, availability and quality of pituitary MRI at diagnosis (i.e. pre-treatment) may be essential for optimal interpretation of Met-PET/MRICR.It is important to acknowledge that there are several potential situations in which functional imaging may fail to identify and localize a  adenoma with Met-PET/MRIpatients , currentCR indications for the particular clinical situations in our centre as subdivided in our paper:Based on our experiences and this evaluation we suggest the following guidance for Met-PET/MRICR (group 1), but in individual cases it may be requested when there is a particular high need to weigh surgical chances against alternatives. In patients with clear intrasellar remnants following previous surgery (group 1), Met-PET/MRICR was helpful in confirmation, however, in time, with the obtained increase in our learning curve, we feel that an increasing subset of this group may also be operated without Met-PET/MRICR guidance.Surgery naive patients referred for surgery with an obvious and well-defined adenoma on MRI have a high pre-test likelihood of remission and low risk of complications, and therefore we recommend against routine Met-PET/MRICR in cases with close relation or potential CSI, to broaden the preoperative scope on surgical perspective for a more accurate assessment of the benefit-risk ratio of TSS. This would include both for counselling on first surgeries and reoperations. The advice obtained after Met-PET/MRICR can be used to balance surgical need, against chances for remission (group 2).We would certainly recommend Met-PET/MRIgroup 2), we recommend functional imaging to distinguish suspected remnant from post-treatment changes (e.g. sella remodelling due to scar tissue) and to screen for multifocality. This is clearly the most difficult group, but with potentially the greatest added value of Met-PET/MRICR. For patients with complex macro-giant adenomas with a high need for treatment because of DA intolerance and/or resistance with a low a priori chance of remission, we have used Met-PET/MRICR in order to delineate the most active sites of residual adenoma that are potentially amenable to Met-PET-guided debulking surgery or targeted radiotherapy (group 2). We deemed this strategy helpful to counsel and plan the surgery, however, still, these surgeries appear to be highly difficult and visualization is limited by different layers, lamelles and/or pockets. Therefore, the intraoperative judgment is impaired and although Met-PET/MRICR may guide the plan, the extent of resection is dependent on the situation encountered during surgery. We will proceed with Met-PET/MRICR evaluations in those cases to collect more data to correlate with postoperative findings. Consequently, at present we cannot draw meaningful conclusions on the potential added value of Met-PET/MRICR in this group.For patients with a difficult remnant after surgery or tumour shrinkage after long-term medical therapy . This is considered a difficult group, with a potentially different type of prolactinoma, requiring further study as to whether these cases are candidates for surgery or not due to multifocal disease or hyperplasia rather than adenoma. Our results warrant further analysis and until then we will continue to perform scans but will be restrictive with proceeding for surgery—only in case of a very high need—since the outcomes of this particular group are less certain than for clearly visible lesions.Finally, in CR in the management of prolactinoma in particular for the indications specified above. An important drawback of Met-PET/MRICR is the short half-life of 11C-methionine (approx. 20 min), which means that the scan can only be acquired in centres with an adjacent cyclotron. Use of alternative tracers might be a solution. Radiolabelled amino acid ligands such as 18F-Fluoro-Ethyl-Tyrosine (18F-FET) have not yet proven efficacy in pituitary adenomas but exhibit a comparable uptake mechanism and pattern in brain tumours and have logistic benefit over 11C-methionine because of the longer half-life of Fluor-18 enabling transportation to centres without a cyclotron. Any functional imaging requires the MDT setting for dedicated evaluation of added value.This study has several limitations. The sample size is small, and the clinical indications vary. Larger cohorts, from several centres in different countries/continents are required to further delineate the role of Met-PET/MRICR is highly sensitive in (1) all patients with a well-defined non-cystic prolactinoma (remnant) and so this group is a suitable group to “test” and gain experience with functional imaging and the multidisciplinary collaboration. Met-PET/MRICR can provide clear added value in the clinical decision-making process for prolactinoma considered for surgery to assess chances and risks in: (2a) with recurrent or persistent disease after surgery and an adenoma suspected on MRI (to discriminate postoperative remodelling from a remnant), (2b) remnant prolactinoma tissue after drug induced volume decrease (to confirm location of remnants in enlarged sella and exclude other spots), and (2c) prolactinoma with uncertain extension/invasion to the cavernous sinus (more accurate benefit-risk ratio of TSS). Met-PET/MRICR can provide potential added value in: (2d) patients with (previous) large and giant prolactinoma without certain invasion , (3) patients without clear adenoma, or only somewhat asymmetrical enlarged pituitary (similar to Cushing disease cases without clear adenoma). Both indications require further evaluation and at present therefore should only be considered when there is a high need for surgery.In summary see Fig. : Met-PETSupplementary file1 (PDF 192 KB)Supplementary file2 (PDF 205 KB)Supplementary file3 (PDF 696 KB)Below is the link to the electronic supplementary material.


Medical talent development has its own characteristics, which means that political-ideological education in medical colleges must establish a development model that reflects these characteristics. In a methodological sense, research on the development of politico-ideological education in medical colleges should adhere to the coordinated development of politico-ideological education in medical colleges, which follows the requirements of the current situation and the three laws of politico-ideological education in medical colleges, namely, the requirements of the law of politico-ideological education, the law of teaching and educating people, and the law of study. In practice, in view of the practical contradictions in the politico-ideological work of medical colleges and universities at the present stage, explore the collaborative education mechanism of medical colleges and universities, constantly enrich the ways and methods of politico-ideological work in medical colleges and universities, improve the affinity, pertinence, and effectiveness of politico-ideological education, and constantly open up a new situation of politico-ideological education in colleges and universities. This work offers a path exploration approach based on deep learning for cultivating the political-ideological, and humanistic qualities of medical students' curriculum, and the model's performance is proven by simulation trials. The Communist Party of China has always attached great importance to politico-ideological work. The discipline of politico-ideological education was established in the early 1980s, and the politico-ideological work in colleges and universities began to be highly valued in the late 1980s , includiIt is of great significance to fully implement the party's education policy, policy, and line, continuously strengthen and improve politico-ideological education, always adhere to the correct direction of educating people, and comprehensively improve the politico-ideological work of colleges and universities . It is cCompared with the traditional politico-ideological education mode, the “great politico-ideological” education mode has its own characteristics . First oThe arrangements of the paper are as follows: Medical students' humanistic education needs to go through two stages: the classroom learning stage and the clinical practice stage. Similar to the current situation the biomedical model is still dominant in clinics, China's medical education has not gotten rid of the traditional biomedical education model. In the classroom learning stage, whether it is basic medical courses or clinical courses, teachers only pay attention to the explanation of medical knowledge . IgnorinMost of the teachers in clinical teaching units have been used to the disease-centered biomedical model. They believe that medical knowledge and technology are the most important. Students with solid clinical knowledge and skills can be competent for clinical work. Most of the clinical teaching teachers are frontline clinical doctors. They are nervous and do not have enough time to lead students to communicate with patients on the spot . HoweverIn fact, in clinical work, we often find that some patients are resistant to interns and unwilling to cooperate with their diagnosis and treatment activities, so they cannot master doctor-patient communication skills well . The lacThe coordinated development of politico-ideological education in medical colleges can learn from various educational media, educational subjects, and other favorable factors and operate in a coordinated and orderly manner . Thus, tHow to transfer the input data from the original space to the high-dimensional space, which can distinguish two types of complicated sample data without requiring any implicit mapping kernel function , is a prAmong them, the key is that the neural network has ushered in its spring again after a long cold winter. Although deep learning can automatically obtain features of different scales from simple to abstract when using the extracted features for classification or recognition, a deep neural network uses the feature of the last hidden layer for classification, that is, using the feature of a single scale for classification . This isBased on deep learning, this paper focuses on the kernel mapping structure and spanning structure model of the deep neural network, in order to effectively solve the shortcomings of the original method, improve the performance and generalization ability of the deep neural network, and finally promote the improvement and development of deep neural network model. This research plays a positive role in promoting the development of deep neural networks, especially multilayer perceptron and convolutional neural network models. Combined with the research focus of this paper, some representative works in multicore learning and cross-connected convolution neural networks are introduced in detail. Among them, the research of multicore learning is mainly divided into the research of learning methods of multicore learning and the research of training methods of multicore learning. The three representative models of cross-connected convolutional neural networks are fast track network, residual network, and densely connected network. When the compound nucleus is applied to the task of gene function classification, the classification accuracy is higher than that of a single nucleus. The mathematical expression is as follows:Then, the combination coefficient is directly calculated through a heuristic process, and its mathematical expression is as follows:The weight in the classification function leads to the combination kernel function with worse performance. Therefore, the kernel matrix is obtained first. Then, calculate the combination coefficient as shown below, and a more reasonable combination kernel function can be obtained. The optimization method also expresses the composite kernel function as a nonnegative linear combination of a set of basis kernels. The difference is that it calculates the combination coefficient through some optimization criterion. By solving the programming problem represented by the above formula, the combination coefficient can be obtained. Moreover, the optimization method can also express the composite kernel function as the nonlinear combination of the base kernel. The mathematical expression of its objective function is as follows:Kernel functions can have a variety of forms, commonly used for the following mathematical expressions:The depth method is to stack multiple basis kernels in depth to obtain the composite kernel function and then use some criteria to solve the parameters. The structural block diagram of the composite kernel function of the depth method is shown in j-layer can be expressed asThe optimization problem of multilayer and multicore learning of Specifically, the mathematical of the decision function can be expressed asAt this time, the mathematical expression of the objective function isFirstly, the base core is selected, and then, the selected base core is combined in a linear or nonlinear way to obtain the composite core. However, research shows that the composite kernel generated by multicore learning is not always better than the base kernel, one possible reason is that the network structure of multicore learning is shallow and has certain limitations, which is not enough to express relatively complex composite kernel functions through the linear or nonlinear combination of base kernels. Most of the current multicore learning methods convert the problem to dual space and use a two-step method to solve the parameters. This will cause misunderstanding among readers to a certain extent. For solving the kernel learning method, we must convert it to dual space for the solution. The cross-layer connection structure of the residual network is shown in The traditional deep neural network only allows the structure connected by adjacent layers, which limits its integration of multiscale features for classification or recognition. In the fast-track network, information can flow across layers directly behind layers without obstacles, and its mathematical expression is as follows:By multiplying element by element, the fast tracklayer can be simplified toAnother treatment is to change the dimension of the ordinary layer first and then stack the fast track layer. Based on these two processes, a similar fast tracklayer can be constructed by using the idea of shared weight and receptive field in a convolutional neural network. Once convergence begins, degradation problems may also occur. The degradation problem is that as the depth increases, the accuracy quickly reaches saturation and then degenerates rapidly. Unexpectedly, this degradation is not caused by overfitting, because increasing the number of layers will lead to a higher error rate. The introduction of identity transformation can make the adjustment of network. Parameters more effective, i.e., the mapping is more sensitive to output change after the introduction of residual. In terms of back-propagation, identity mapping allows for direct propagation and the addition of the error term to the front layer, removing gradient reduction and explosion issues. In short, residuals allow you to remove the same main part while highlighting minor differences. According to research on residual networks, even networks with hundreds of layers can be trained reliably and successfully provided cross-layer connections are added between levels. Broadly speaking, a dense network refers to a convolutional neural network containing one or more dense modules, as shown in This control of growth rate cannot only reduce the parameters of the dense network but also ensure the performance of the dense network. However, dense networks simply splice features of different scales, which may lead to feature redundancy. In addition, the dense network consumes a lot of memory during training. The usual approach is to design a cross-connect structure carefully for a given task. This approach usually achieves good results but does not provide people with the difference between the results of different cross-connect methods. To sum up, this paper proposes a deep neural mapping support vector machine model. The model uses a deep neural network to explicitly represent the kernel mapping and maps the input from the original space to the feature space. In fact, kernel mapping is an explicit function represented by a deep neural network.In order to accurately understand the current situation of the implementation of curriculum politico-ideological education, a questionnaire survey was conducted on the teaching front-line teachers of the teaching part of 8 medical colleges in Shandong and some students in freshman, sophomore, and junior grades, and field visits were conducted to investigate the politico-ideological classroom of relevant schools. The teaching records of politico-ideological education were included in the scope of this study, so as to master the specific implementation of curriculum politico-ideological education such as students' cognitive status and teachers' cognitive status. Starting with the current situation of curriculum politico-ideological education, this paper deeply explores and analyzes the bottlenecks and reasons encountered in the implementation process, puts forward reasonable solutions for the implementation of curriculum politico-ideological education in the classroom, and puts forward measures to improve the quality of curriculum politico-ideological education, so as to integrate teaching with politico-ideological education and improve the ideological and moral level of medical students. The current situation of politico-ideological integration is shown in The results show that in the implementation of curriculum thought and politics, the integration of physical education in sophomore is the best, followed by the freshman, and the integration of junior is slightly worse. On the one hand, it may be related to the learning pressure of students. Compared with freshmen and sophomores, junior students are facing great pressure of graduation. The focus of learning is on the subjects of cultural courses, which requires a lot of time to study and review cultural courses. On the other hand, some politico-ideological courses may be replaced by other teachers, resulting in the reduction of students' politico-ideological courses. At the same time, in order to serve other courses, teachers only complete teaching tasks in class, only pay attention to the teaching of skills and ignore the guidance of values, which makes it difficult to implement curriculum politico-ideological education in the third grade. In contrast, freshmen and sophomores face less pressure. Sophomores have adapted to the school environment, have a certain sports foundation, and have stronger autonomy in choosing learning content, so it is easier to implement curriculum thought and politics. Through the investigation, it is found that in terms of the ways to receive politico-ideological education, students believe that politico-ideological course is the main way to carry out politico-ideological education, followed by the infiltration in various disciplines, indicating two problems: one is that high school students lack ideological education at present, and the other is that the school does not pay attention to carrying out ideological education. The statistics of politico-ideological elements in the end part are shown in From the results of teachers' questionnaire statistics, first, in terms of teachers' cognition, teachers believe that the current way for students to receive ideological education is through the penetration of various disciplines. Secondly, most teachers affirmed the suitability and necessity of curriculum politico-ideological infiltration into the classroom and said that they would implement it in the follow-up classroom, but on the whole, teachers' understanding of curriculum politico-ideological is not enough.People benefit from political-ideological education. The work of being a man is difficult, and the ideological work of being a man is even more difficult. In general, political-ideological education integrates individual differences with society's mainstream values. Individuals have subjective initiative, and there are still some distinctions among them. Medical colleges and universities should be transformed into model places of stability and unity in order to cultivate a pleasant and welcoming environment. The politico-ideological education in medical colleges and universities should proceed from reality and integrate theory with practice. Based on this, this paper proposes a path exploration method for the cultivation of politico-ideological, and humanistic quality of medical students' curriculum based on deep learning, and the effectiveness of the model is verified by simulation experiments.The research on the coordinated development of politico-ideological education in medical colleges is a research focusing on practice and application. In the future, we should continue to think about how to do a good job in the politico-ideological education in medical colleges and improve the affinity and pertinence of the politico-ideological education in medical colleges. Politico-ideological educators should have strong theoretical literacy and actively make use of the collaborative resources of Politico-ideological education with the characteristics and advantages of medical colleges. Finally, we should constantly improve our comprehensive ability to obtain and process information and be good at using new media. Other fields' mature theoretical and practical experience have been incorporated by the subject of political-ideological education. At home and abroad, dialectically treat and absorb ideological culture, science, and technology, and the discipline of politico-ideological education is expected to grow by leaps and bounds only via continual learning.


This study can provide a feasible method to determine the dynamic parameters of rate-dependent constitutive relation of concretes. This method has good applicability, especially in the study of the dynamic behavior of multicomponent composite materials with large-size particle filler.The paper presents a new method to study the dynamic mechanical properties of concrete under low pressure and a high strain rate via the inversion of spherical wave propagation. The dynamic parameters of rate-dependent constitutive relation of elastic concrete are determined by measured velocity histories of spherical waves. Firstly, the particle velocity time history profiles in the low stress elastic region at the radii of 100.6 mm, 120.6 mm, 140.6 mm, 160 mm, and 180.6 mm are measured in the semi-infinite space of concrete by using the mini-explosive ball and electromagnetic velocity measurement technology. Then, based on the universal spherical wave conservation equation and the fact that the accommodation relationship in state equation satisfies linear elastic law, the inverse problem analysis of spherical waves in concrete  is proposed, which can obtain the dynamic numerical constitutive behavior of concrete in three-dimensional stress by measuring the velocity histories. The numerical constitutive relation is expressed in the form of distortion, and it is found that the distortion law has an obvious rate effect. Finally, the rate-dependent dynamic parameters in concrete are determined by the standard linear solid model. The results show that the strain rate effect of concrete cannot be ignored with the strain rate range of 10 Concrete is widely used in engineering, and these concrete engineering facilities are often subjected to various effects, such as earthquakes, weapon strike explosions, and engineering blasting. There are usually spherical wave problems such as point explosion and point impact. Then, it is necessary to deal with the propagation of spherical waves in concrete ,2,3. TheMeanwhile, researchers have carried out many studies on rate-dependent materials of spherical waves ,14,15,16i , it is still difficult to solve the other two unknowns from the two constitutive equations with unknown dynamic parameters (Equations (1a), (1b), and (2)), which is different from the rate-independent elastic problem for parameters of constitutive equations, which are constant. In the work outlined in this paper, a series of particle velocity wave profiles of concrete in the far-field or low-pressure region under spherical impact loading is measured. Then, based on the universal spherical wave conservation equation and the fact that the volumetric part of constitutive relation satisfies linear elastic law, the Lagrangian inverse analysis of spherical wave problems and particle velocity history measurements  are carried out to obtain the numerical constitutive relation, expressed in the form of distortion. Furthermore, it is found that the rate-dependent characteristics of spherical wave distortion is different from the rate-independent case and therefore an appropriate rate-dependent constitutive model is chosen to describe this problem. Finally, the dynamic parameters in constitutive relation of concrete with high strain rates are obtained by the standard linear solid model.In order to solve the above-mentioned difficulties and deal with the coupling problem, people have developed WPT to study the dynamic properties of materials subjected to dynamic loads . In vari−3, and the behavior of concrete under one-dimensional and multidimensional stress under static load also shows great differences. Therefore, the concrete can be regarded as a linear viscose-elastic material, not just a linear elastic material.Many materials have significant rate correlation characteristics under the loading of short-duration explosion and impact ,29,30. CFirst, the description system of spherical wave propagation is established in the spherical coordinate system a. The goThe linear viscose-elastic constitutive equation in differential form based on the standard linear solid model can be effectively used to describe the dynamic constitutive properties of concrete (3a) , and FigThe relevant material parameters are characterized as a linear elastic response (3b), volume deformation (3c), linear bulk modulus (3d), linear Young’s modulus (3e), and linear shear modulus (3f). According to conventional considerations, it is assumed that Poisson’s ratio u is constant, and the elastic stage is independent of other strains and strain rates.In this way, in order to describe the linear viscose-elastic spherical wave propagation problem, based on the standard linear solid constitutive relation, the governing equation reflecting the linear and high strain rate effect of materials is established. i,t) at different radii distance ri from the center of the sphere is measured by a series of embedded magneto-electric velocimeters.In order to understand the propagation characteristics of spherical waves in concrete, an experimental method is developed to measure the particle velocity histories of spherical waves. The experiment adopts the electromagnetic method, and the sample is a cylinder with a diameter equal to the height. Because the arrangement of particle velocimeters have accurate representative characteristics, the method has strong advantages in studying the dynamic properties of multicomponent composites containing fillers, such as polymer–matrix composite materials, concrete, and rock in 3-D stress. In the spherical wave experiment, the characteristic size of the sample can be meters, which is more than ten times larger than the size of concrete coarse fillers, so that the information of wave histories can accurately reflect the wave propagation characteristics. A group of particle velocity waves v and the particle velocity is established by the conservation equation. Now, the initial condition t = 0, v=0 is known, and v at different positions ri  is also known. So, the time numerical integration operation can be performed to determine εθ. Then, the first derivative ∂v/∂t can be obtained by numerical differential operation. Similarly, the strain εr can be determined by integrating time.The differential relation of strain  and is independent of the rate. Then, it is easy to determine this relationship under quasi-static conditions. The calculation process related to quantity εr and εθ, ∂σθ/∂t, and ∂σr/∂t can be expressed in Equations (4) and (5b).However, the stresses σi,t) at multiple Lagrangian radii r=ri are provided, and their related other time and position differential components ∂v/∂t can be easily determined.r/∂t can be expressed as (5b).In order to establish the magnitude relationship at each radius, the path-line processing method can be used to define the total derivative of a certain magnitude on the path-line , and the path-lines P1, P2, P3…Pi… Pm can be established as shown in the figure. In this way, when the spherical particle velocity histories v, and the stress σr at different radius r=ri along the path-line P2 /∂t by using the constructed path-lines (5). Then, ∂σθ/∂t is known from (4), and the circumferential stress at different positions r = ri on the path-line P1 σθ|P = j can be calculated by integrating ∂σθ/∂t. Similarly, the stress σr|P = j + 1 and σθ|P = j + 1 on all path-lines can be determined by cycling in sequence. Note that this method can be used to load the whole process, which is called “NV + T0/SW” for short.The zero initial condition is known at different positions of wave propagation .An advantage of “NV + T0/SW” is that there are no assumptions of the constitutive equation of materials, directly giving the stress–strain numerical relation. However, now there is a next step to take when the dynamic properties of materials are known. So, its description with a known standard linear solid constitutive model is provided in future work, and the dynamic shear modulus Based on the experimental method as described in the previous section, the particle velocity profiles  in the l0/SW”. Since the constitutive relation of materials is often described by volume deformation and shape deformation with multidimensional stress state, it is convenient to reflect the stress characteristics under 3-D stress. The results are expressed as spherical profiles of volumetric part and distortional part, such as stress histories σr + 2σθ, strain histories εr + 2εθ, stress histories σr − σθ, and strain histories εr − εθ .The numerical results are shown in In the series of measured particle velocity histories shown in the M can be determined from Equations (6) and (7), and the concrete static parameters and the numerical distortion relations of stress σr − σθ and strain εr − εθ are taken as the known conditions using the inverse method. The concrete static parameters used in the inverse analysis are the results of our experimental research on concrete under one-dimensional stress, and ρ and ν are measured from concrete samples, as shown in According to the above theory, the dynamic parameters G and θM can be obtained through Equation (7), and the values of θM are also listed in a and decreases with the reducing of strain rate (M increases with a reducing strain rate and is in the magnitude range of 10−6 s.Note that Equation (6) is suitable for the series numerical distortion relations with different strain rates at each radius, so the average value of dynamic parameters G can be calculated easily with Equation (6), as shown in ain rate b. At thei,t) of the spherical particle velocity wave of concrete, the Lagrangian “NV + T0/ SW” inverse analysis is carried out using the path-line method, and the wave propagation information of each physical quantity of the spherical wave is obtained. The numerical constitutive relation is expressed in the form of distortion and has an obvious rate effect. The results shown in 2 1/s. The numerical constitutive relation is deduced directly from the measurements and analyses of wave propagation signals, which should be more appropriate for the coupled effects between wave propagation and rate dependency, are considered. Next, the rate-dependent dynamic parameters in concrete are determined by the standard linear solid model, which is a typical and useful model for analyzing stress relaxation and creep behaviors of viscoelastic solids. The results of dynamic parameters show that the dynamic shear modulus G is larger than the static modulus Ga and decreases with the reducing of strain rate .The inverse problem is solved by the newly proposed “NV + T0/SW” Lagrangian analysis method, with the measured series velocity profiles as known conditions. The results provide a basis of a further study on how to determine accurately and effectively rate-dependent constitutive relation of concrete at high strain rate. When the numerical constitutive relation is expressed in the form of distortion, it is found that the distortion law has an obvious rate effect.M increases with the reducing strain rate and is in the magnitude range of 10−6 s.Based on a series of numerical constitutive relation with different strain rates at each radius, the rate-dependent dynamic parameters in concrete are determined by the standard linear solid constitutive model. The dynamic shear modulus G is larger than the static modulus and decreases with reducing strain rate. The dynamic relaxation time θThe goal of this research was to expand the knowledge about the possibilities of studying rate-dependent constitutive relation and the determination of dynamic parameters based on spherical waves in concrete. According to the former, the main conclusions drawn from the above results are as follows:It should be emphasized that, if more experimental data in the strain rate range and more continuous particle velocity profiles are measured through the improvement and development of experimental loading and data acquisition technology, the results obtained by this method will be enriched into a series. This method has good applicability, especially in the study of the dynamic behavior of multicomponent composite materials with large-size particle filler for the characteristic size of specimens in spherical wave experiments could be in the order of meters.


For many, including military veterans and their families, support between individuals with shared lived experiences, or peer support, has long been utilized as a way to support each other through many different challenges. Building on other reviews and guided by the seven domains of well-being in the Canadian veteran well-being framework, the objective of this paper is to describe and catalogue the nature of peer support activities and related outcomes in the veteran, serving member, and family member populations. A scoping review following the five stages outlined by Arksey and O’Malley was conducted; it was guided by the question: What is currently known about peer support activities for veterans, serving members, and their families that has been evaluated in the literature? In total, 101 publications from 6 different countries were included in this review and catalogued based on publication characteristics, participant information, peer support activity information, and peer information. Peer support activities have the potential to positively influence the well-being of veterans, serving members, and their families on a holistic level across multiple domains. This scoping review highlights the existing gaps in the literature and provides an important foundation for future research on peer support for these populations, specifically in the Canadian context. For many, including military veterans and their families, peer support has long been utilized as a way to support each other through many different challenges, health-related or otherwise ,2. WhileA clear definition of well-being and its components, however, currently seems to lack consensus ,12,13,14Currently, the peer support literature is quite heterogeneous, which may be contributing to the lack of empirical support on effectiveness ,17. AlthRecognizing the increase in peer support activities for veterans, serving members and their families and the lack of empirical support for these activities, Ramchand et al.  attempteThe authors conducted a scoping review following the five stages outlined by Arksey and O’Malley, and expanded on by Levac, Colqunhoun, and O’Brien ,29. ThisWhat are the characteristics of the veterans, serving members, and their families participating in these peer support activities?What are the types and characteristics of the peer support activities evaluated in the literature for veterans, serving members, and their families?Which domains of well-being are these activities aiming to improve?What are the gaps and limitations in the literature on peer support activities for veterans, serving members, and their families?Keeping a broad approach to the search, the scoping review was guided by the question: what is currently known about peer support activities for veterans, serving members, and their families that has been evaluated in the literature? Considering the wide scope of the research question, the following sub-questions were developed to further refine the review:The search strategy was created in consultation with a research librarian and advisory group consisting of individuals with lived and living expertise, as well as professional and academic expertise. Six electronic databases were searched in July 2020: Medline, Embase, PsychInfo, Cochrane, CINAHL, and Web of Science. A search of other credible electronic sources outside of peer-reviewed journals was also completed in January 2021 in order to capture the full spectrum of publications. These included Google, Veterans Affairs Canada’s website, National Institute for Health and Clinical Excellence, Centre for Disease Control and Prevention, Department of National Defence Canada’s website, and RAND Corporation’s website. The searches were conducted with a combination of terms related to peer and social support in military, veteran, first responders or other public safety personnel (PSP), and family member populations. The search terms chosen were used to capture the broad extent of peer support activities, and serving members were added as a population of interest, considering the MCT period begins while individuals were still serving. The search was limited to English or French publications from January 2000 or later. Limitations due to language were added due to translation capacity, with the timeframe chosen to be large enough to capture the breadth of the relevant literature. No limitations were added in relation to the outcomes. The search was re-run across all sources and databases in December 2021 using the same strategy to update the results. The full search strategy is available in the A team approach was utilized for the publication selection process . Prior tUsing a data extraction form initially created in consultation with the study’s advisory group and guided by Cochrane’s data collection forms for qualitative and quantitative studies, two reviewers were responsible for the independent data extraction from the included articles. A third reviewer provided consensus on any data extraction conflicts. After an initial extraction of a sample of studies, the data extraction form was revised. The final data extraction was then completed using the revised form.Publication characteristics: including year of publication, country, journal, and design of the publication;Participant information: including group , health condition, phase of the life course, and sex and gender;Activity information: including name, format, modality, timing, duration and intensity, supervision, cost, reported adverse effects, and measured outcomes;Peer information: including main role of peer, integration in a clinical team, training, and category related to remuneration. A ‘yes’ or ‘no’ approach to the training component was used, due to the varied nature of training described in the literature.The final data, presented in the results section, was collated based on four categories:p < 0.05) between-group differences were included. For uncontrolled studies, only outcomes with a statistically significant (p < 0.05) improvement were included. Lastly, for qualitative studies, an outcome was included if the authors identified it as a theme commonly mentioned by participants. In the timing category, activities for which peer support was provided in real time were categorized as synchronous, and those for which it was not, such as recorded videos, were categorized as asynchronous.For the activity information category, all evaluated outcomes from publications were identified and categorized under the related domain of well-being. To identify if peer support activities were associated with an improvement in well-being, outcomes were also categorized as positively associated with the peer support activity, or not. The identification of positive association varied by study design. For controlled studies, only statistically significant  . The publications also came from the United Kingdom , Australia , Iran , Canada , and Israel . The details on the years of publication are available in Combinations of many different study designs were utilized in the included publications. The most common designs were experimental , mixed-method , quasi-experimental , and qualitative  . Of all Although the inclusion criteria for the search included peer support activities for veterans, serving members, and their families, most of the included publications reported on activities for veteran participants only  . LookingThe majority of the publications reported on activities for participants with particular health conditions . Specifically, 50% of all publications included participants with mental health conditions (n = 51) .To be included in the analysis, the publications had to relate to specific peer support activities. Some of the included publications reported on the same activity, and the counts presented reflect those of individual publications, not of unique activities. Of the 101 publications, 59 unique activities were identified and 24 activities were not named .The publications were categorized based on the format of the evaluated activity, modality, timing, activity supervision, and measured outcomes. The publications evaluated activities that were mostly delivered in-person , with the format for all activities almost evenly divided between one-to-one support , and group-based support .The activities were also categorized based on the timing of the delivery. In total, 93 publications (92%) related to a peer support activity being delivered synchronously. All six publications evaluating asynchronous peer support were in relation to online or remotely delivered activities; however, not all publications reporting on activities delivered online/remotely were asynchronous (n = 4 synchronous).Although separate, peer support activities can occur in conjunction with other care. Some publications used a peer support activity not as the main intervention but adjunctively to enhance the main intervention (n = 12). This included using peers to help reduce attrition with therapist-delivered prolonged exposure therapy and to support engagement with online programs and mobile applications. The complete results of all characteristics are available in In terms of peer roles, relating to the aforementioned categories highlighted by Ramchand et al. , peer suThe publications on peer support activities were further categorized based on the measured outcomes related to the domains of well-being and the phases of the life course. All measured outcomes from publications were categorized into the corresponding domain of well-being, with publications evaluating most frequently the association between the peer support activity and the outcomes related to the health domain . Other outcomes evaluated included those related to life skills , social integration , purpose , housing and physical environment , and culture and social environment . Twenty publications explored outcomes which could not be categorized under any of the domains of well-being, most of which were related to the program evaluation.Once all measured outcomes were categorized within the related domain of well-being, those reported by the publications’ authors as being positively associated with the peer support activity were identified. The outcomes positively associated with a peer support activity were most frequently related to the health domain (n = 34) . This trAn attempt was made to categorize the publications according to the phase of the life course of the participants; however, the ability to do so was limited because the time since discharge was only rarely presented. Lastly, an analysis was conducted to identify the trends in the role of the peer supporter by associated well-being domains for positively associated outcomes. Considering each associated domain by publication, peer supporters were more frequently involved as informal support for both the health domain (35%) and the social integration domain (62%) when a positive association was identified . The detThis scoping review identified 101 relevant publications about peer support activities for veterans, serving members, and their families, demonstrating the breadth of peer support activities evaluated in these populations. With the vast majority of publications coming from the United States, it was not possible to compare activities between countries, therefore, all publications were grouped and analyzed together. Some authors have indicated a gradual increase in peer support publications from Europe and other countries, however, the findings from this review were unable to verify this trend in relation to veterans, serving members, and their families .This review found that peer support activities in the literature are evaluated using various designs, many based on pilot studies. The presence of many pilot studies should be considered when interpreting the results of this review, as findings from these types of publications could differ with larger sample sizes. The increase in the number of publications from the last two years, as well as the presence of many pilot studies, emphasizes the emergent nature of the literature in this area and the increased attention that peer support activities are receiving in the veteran, serving member, and family member populations.The wide scope of this review allowed the authors to identify the myriad of components currently being utilized and evaluated in the delivery of support from peers to veterans, serving members, and their families. While the majority of identified publications evaluated synchronously delivered programs for male veterans with a mental health condition, a vast heterogeneity was present in relation to the other catalogued characteristics of activities and participants. Additionally, the successful categorization of peer roles using types of peers described by Ramchand et al.  supportsRecognizing the limitations in the current method of identifying positive associations between measured activity and well-being, a strength of this review is the categorization of outcomes by well-being domain. Although some publications did not report an improvement, this study found that positive associations between peer support activities and six of the seven domains, excluding finances, were identified by at least one publication. Considering this, it can be concluded that peer support may have the potential to positively influence the well-being of veterans, serving members, and their families holistically.Categorizing the evaluated outcomes by domain of well-being also revealed that the main interest of evaluated peer support activities lies in three of the seven domains. In the identified publications, the outcomes related to health, life skills, and social integration were more frequently mentioned or evaluated. On the other hand, the outcomes related to purpose, housing and physical environment, and culture and social environment were only rarely included, with no identified studies including measures categorized to the finance domain. Although more research evaluating peer support activities and their association to improving all domains of well-being is needed, it would be important for future research to consider including measurements for the latter four domains, as well-being is considered by VAC as being made up of all seven domains . A true Although evaluation of the alignment between the well-being framework and published peer support activities was not an objective of the current review, it was found that 80% of publications (n = 81) evaluated at least one outcome that aligned with a domain presented in the framework. This categorization was meant to test this method for future peer support studies in this population, while aligning with the recommendations of select authors suggesting the need to look beyond measures of clinical recovery to better assess the effectiveness of peer support activities .The findings from this review allowed the authors to identify gaps in the current literature. First, only two Canadian publications were identified, limiting the generalizability of the results within the Canadian context. Furthermore, only a few, or no, publications were found to be specifically evaluating peer support activities for serving members or family members, for individuals who have experienced military sexual trauma (MST), in 2S/LGBTQ+ populations, in Indigenous populations, or in women veterans. Considering the heterogeneous nature of Canadian serving members and veterans, unique sex- and gender based-differences, and recent developments with regards to individuals who have experienced MST and the LGBT Purge in the Canadian Armed Forces, future research should be conducted to evaluate the use of peer support activities for a more representative spectrum of veterans, serving members, and their families ,35,36,37Finally, the included publications rarely considered the time since discharge when evaluating the peer support activities for veterans. Considering the differing nature of needs and well-being during different phases of the life course, identifying and reporting time since discharge could prove useful in expanding knowledge on peer support activities and their outcomes, and should be considered in future research .Though this scoping review can be used as a foundation for future research in the area of peer support for Canadian veterans, serving members, and their families, some limitations should be considered when interpreting the results beyond the ones already mentioned. The first relates to the descriptive nature of the analysis. Based on the purpose and nature of this review, no critical appraisal of individual sources was conducted and many study designs were considered. This limits the authors’ ability to confirm the benefits of the peer support activities on each domain of well-being and future research should aim to reach more definitive conclusions by establishing the strength of the available evidence, considering research designs and effect sizes. Another limitation is related to the categorizations of outcomes to their respective well-being domain. The well-being framework used is composed of seven domains, however, not all of them are mutually exclusive and some overlap may exist between domains. For this study, the authors categorized outcomes based on subjective best fit, which may have led to misclassification. A final limitation is related to the search criteria used. Although the search for publications was kept as wide as possible, some relevant articles may have been missed due to search terms used.The purpose of this review was to describe the nature of peer support activities specific to veterans, serving members, and their families and to align their outcomes within VAC’s Canadian veterans’ well-being framework. Already utilized by some government departments, peer support activities in these populations are receiving increased attention in the literature and have the potential to improve well-being across all domains. This scoping review provides an important foundation for future research related to peer support in Canadian veterans, serving members, and their families. Utilizing a consultative approach with an advisory group of varied expertise, this review builds on existing research and is another step towards standardizing the peer support vocabulary, as well as the way these activities are designed, evaluated, and presented in the Canadian context.