The spatial distribution of large earthquakes in slowly deforming continental regions (SDCR) is poorly documented and, thus, has often been deemed to be random. Unlike in high strain regions, where seismic activity concentrates along major active faults, earthquakes in SDCR may seem to occur more erratically in space and time. This questions classical fault behavior models, posing paramount issues for seismic hazard assessment. Here, we investigate the M7, 1967, Mogod earthquake in Mongolia, a region recognized as a SDCR. Despite the absence of visible cumulative deformation at the ground surface, we found evidence for at least 3 surface rupturing earthquakes during the last 50,000 years, associated with a slip-rate of 0.06 ± 0.01 mm/year. These results show that in SDCR, like in faster deforming regions, deformation localizes on specific structures. However, the excessive length of return time for large earthquakes along these structures makes it more difficult to recognize earthquake series, and could conversely lead to the misconception that in SDCR earthquakes would be randomly located. Thus, our result emphasizes the need for systematic appraisal of the potential seismogenic structures in SDCR in order to lower the uncertainties associated with the seismogenic sources in seismic hazard models. Slow-slip faults show a variety of earthquake behaviors ranging from periodic seismicity to complex behavior alternating periods of clustered activity with seismic quiescence (e.g.3). In fact, it has been suggested that for some of the slowest slipping faults a single earthquake could occur with no distinguishable repeat pattern nor cumulative scarps1. These drastically different fault behaviors have been previously related to differences in loading rate, strength, healing rate, and interactions with external stressing rate, including the effects of lithospheric response to surface loads (e.g.7) and fault interactions within a spatial cluster of events. (e.g.9).The seismic behavior of faults in slowly deforming continental regions (SDCR) is a major source of uncertainty for seismic hazard assessment . In most cases, only one or two events are preserved, making it difficult to examine the behavior of faults over multiple seismic cycles (e.g.11).One major limitation in ascertaining which seismic behavior model might be most appropriate for SDCR is the limited number of paleoseismological sites recording a period long enough, from 10Here, we report a long paleoseismological archive in a SDCR by documenting a paleoseismic trench across the 1967 Mogod earthquake surface rupture that occurred in the low strain region of Mongolia. This surface rupture is exceptionally well preserved due to permafrost and low erosion rate.12. Based on geologic and geodetic records, the slip rate on these different faults is estimated to be in the range of 1–3 mm/year (e.g.14). The stress build up related to this deformation is released by some moderate background seismicity, in addition to unusually large M8 strike-slip earthquakes, which seem to happen in temporal clusters triggered by postseismic viscoelastic stress transfer9. These large earthquakes have left spectacular surface ruptures scars along the principal fault systems including the Bolnai, Hovd, and Gobi-Altai systems18 . In contrast, the deformation appears more distributed in the Hangay dome22, a region where faults are sometimes only evidenced by their seismic activity24.To the west of Hangay dome , Mongo25. Fault slip rates, localization and recurrence time for large earthquakes remain mostly unknown in this part of Mongolia, usually described as a part of the Amurian plate, and recognized as a SDCR26. Indeed, the boundaries of the Amurian plate remain controversial due to the low seismicity rate, distributed faulting (e.g.30), and very low rates of deformation, ≤ 2.10–8 year−1 (Ref.32).The areas of central and eastern Mongolia, east of the Hangay dome Fig. a, are ch35. The earthquake surface ruptures are about 40 km-long in total, with numerous co-seismic displacements larger than 1 m38. The surface trace comprises three principal fault sections and dozens of secondary structures. Waveform inversions revealed that the earthquake could be decomposed in three seismic sub-events, which focal mechanism, magnitude, and location are consistent with the three surface rupture sections35. The northernmost fault section is mainly a North–South dextral strike-slip fault that ruptured along the western edge of the Mogodyn Nuruu mountain ridge . The morphology of the ruptures at the junction between the central strike-slip section and the southern thrust section is complex, including two parallel reverse faults, which have clear surface rupture expression, in addition to many secondary ruptures. At the junction between the strike-slip and the thrust sections, the southernmost reverse scarp is located at the base of a large slope, facing up-slope and blocking sediments that go down the subdued drainage colleting surface wash .Locally, the different units of the footwall are dragged and folded and include some gouge reworked by the fault, such as at the southern end of U1 to U3 can be found on both sides of the backthrust. South of the backthrust, in the hanging wall, the three units thicken gradually away from the scarp, following a growth strata geometry. Closer to the scarp, units onlap unconformably on top of each other along erosional contacts marked by coarser material  are consistently separated by a few cm-thick red layer that is interpreted to be some gouge-derived clay washed away from the fault zone along what was at that time the ground surface. This red clay is also found on top of the two channels, although stratigraphy has obviously been locally perturbed during emplacement of channels, and it is likely that the red clay that currently overlays the two channels has been remobilized one or several times, yielding complex depositional facies.North of the backthrust, in the footwall, the top layers are formed by fine sediments U1S to U3S is interpreted to relate to rejuvenation of the flexural scarp during successive earthquakes that would dam the incoming sediments. Concomitantly, more gouge-derived clay would be washed away northward soon after the backthrust break to the surface. Thus, as detailed further down, our trench exposure suggests that there is evidence for at least three ground-breaking events at the Tület Uul trench site, including the 1967 Mogod earthquake.Eventually, the emplacement of each sedimentary unit UThe earthquake horizon that corresponds to the most recent earthquake in 1967 is the current ground surface, where surface ruptures are still visible, suggesting that under the current climatic conditions both sedimentation and erosion rates are very low. Dating older units has proved difficult, as sediments are mostly devoid of any organic material usable for radiocarbon dating. Thus, 7 samples were collected in order to perform Optically Stimulated Luminescence (OSL) dating on sandy material.40 and analytical approaches as in Ref.41 . The seven dates distribute over a period from 17 to > 81 ka, spanning the last glacial period  and close to the age of OSL1 and OSL2, sampled at the base of U2S. Thus combining these observations we could bracket the age of EQ3 which event horizon is located between U3 and U2. Surprisingly, OSL4 that was sampled shallower and closer to the fault, in U2N, yields an age older (> 65 ka). Although we could not totally disregard this age (similarly to OSL3) this sample was far from ideal, as it was sampled in a rather heterogeneous drag fold hinge. Several factors might have biased age determination such sample saturation, or partial bleaching issues . Hence, in addition to the typical diffusion process that dominates erosion of scarps everywhere throughout Asia44, local erosional processes have likely been temporary emphasized by climatic changes. Eventually, given the very long time interval between successive earthquakes along the Mogod fault, and the small size of the co-seismic fault escarpment, these processes resulted in eroding evidence of previous surface ruptures and prevented the building of obvious significant cumulative scarps.The 45). This trench, however, demonstrates that even in SDCR with low rates of deformation, the deformation could localize on specific structures where deformation is accommodated through successive earthquake cycles despite the absence of visible cumulative scarps. In fact, absence of cumulative topography makes it difficult to assess the actual length of the fault structure beyond the section that did rupture most recently. Hence, it suggests that in SDCR a special attention should be paid in localizing such fault zones and trying to describe longer paleoearthquake time series (e.g. Refs.48), as they bear special significance in term of assessing seismic hazard.This is not specific to the Mogod earthquake area, and similar difficulties to find well-preserved Quaternary cumulative deformation have been reported elsewhere in central and northern Mongolia , about 6 times what is actually measured by geodesy across Mongolia13. Thus, it has been proposed that this unusual sequence resulted from specific fault interactions and visco-elastic relaxation effects of one event that would lead to trigger the next one9, ending up in a major spatio-temporal cluster of events. The question of existence of similar earthquake clusters earlier in time remains unsolved yet. At best, it has been shown that return time for M8 earthquakes along the Bulnai fault is on the order of 3 ka to 4 ka15. Similar time scale has been suggested for the Fuyun fault48 although timing is poorly constrained. Our trench shows that Mogod-style earthquakes follow a different pattern with a repeat time of the order of several tens of thousands of years. The XXth century earthquake cluster in western central Mongolia, however, has certainly contributed to the loading the Mogod fault and might have hastened the Mogod earthquake. Hence, it emphasizes that for active faults with low loading rate, the contribution to fault loading of far seismic sources could be more significant than in faster deforming regions, where long-term tectonic loading dominates, and should therefore be considered thoroughly in SDCR seismic hazard assessment.In the case of Mongolia, the Mogod earthquake came in 1967, at the end of an earthquake sequence that ruptured 4 major faults during 4 magnitude M8 earthquakes, between 1905 and 1957Supplementary Information.


ABL1 is a proto-oncogene encoding a nonreceptor tyrosine kinase, best known in the somatic BCR-ABL fusion gene associated with chronic myeloid leukaemia. Recently, germline missense variants in ABL1 have been found to cause an autosomal dominant developmental syndrome with congenital heart disease, skeletal malformations and characteristic facies. Here, we describe a series of six new unrelated individuals with heterozygous missense variants in ABL1 (including four novel variants) identified via whole exome sequencing. All the affected individuals in this series recapitulate the phenotype of the ABL1 developmental syndrome and additionally we affirm that hearing impairment is a common feature of the condition. Four of the variants cluster in the myristoyl-binding pocket of ABL1, a region critical for auto-inhibitory regulation of the kinase domain. Bio-informatic analysis of transcript-wide conservation and germline/somatic variation reveals that this pocket region is subject to high missense constraint and evolutionary conservation. Functional work to investigate ABL1 kinase activity in vitro by transient transfection of HEK293T cells with variant ABL1 plasmid constructs revealed increased phosphorylation of ABL1-specific substrates compared to wild-type. The increased tyrosine kinase activity was suppressed by imatinib treatment. This case series of six new patients with germline heterozygous ABL1 missense variants further delineates the phenotypic spectrum of this condition and recognises microcephaly as a common finding. Our analysis supports an ABL1 gain-of-function mechanism due to loss of auto-inhibition, and demonstrates the potential for pharmacological inhibition using imatinib. ABL1 is a proto-oncogene encoding a nonreceptor tyrosine kinase with diverse roles in cytoskeleton remodelling and the DNA damage response [BCR-ABL1 fusion gene in the Philadelphia chromosome, associated with chronic myeloid leukaemia (CML) and acute lymphocytic leukaemia (ALL) [ia (ALL) .ABL1 spans 170 kb of chromosome 9q34.12, comprising 11 exons. It has two isoforms owing to use of alternative first exons. The longer transcript (NM_007313), encodes 19 additional N-terminal residues involved in auto-inhibition of the ABL1 kinase.ABL1. Clinical features included congenital heart disease, skeletal malformations, dysmorphic facies, and failure to thrive. More recently, the clinical spectrum of the ABL1 malformation syndrome has been expanded to include hearing impairment, renal hypoplasia and ocular abnormalities [Recently, Wang et al.  describemalities .Tyr245 lies in the SH2-kinase linker domain of ABL1 essential for the “docking” of the Src homology SH3) domain in the inactive conformation of the protein . Phospho domain iAla356 lies within the myristoyl-binding pocket of the ABL1 kinase domain. In isoform 1b (NM_007313) a myristoyl group bound to the N-terminal glycine of ABL1 occupies this pocket to stabilise the inactive conformation of the protein . This doAbl2 mice harbour a targeted insertion-deletion in which exon 5 and part of exon 6 are replaced by the neomycin resistance gene [Ablm1 mice have a large targeted deletion of approximately one third of the ABL1 protein from the c-terminus [Ablm1 homozygotes of a C57BL/6J background also develop cardiac abnormalities [ABL1 does not display haploinsufficiency, and supporting the possibility that the human germline missense variants act through a gain of function.The developmental significance of ABL1 is illustrated by animal models. nce gene . Homozygnce gene . Ablm1 mterminus . Homozygterminus . Interesmalities . HeterozABL1 variants and have modelled the effects of these variants in vitro. We find that all but one of the variants identified in this cohort cluster in the myristoyl-binding pocket of ABL1, and that these variants increase the tyrosine kinase activity of ABL1 in vitro. These results are consistent with a gain-of-function effect, in which the variants disrupt the crucial auto-inhibitory binding of an N-terminal myristoyl group to its binding pocket. We find that variants in this myristoyl-binding pocket are a common cause of the ABL1 cardiac and skeletal malformation syndrome.In this study, we have collected clinical and molecular details of six patients with deleterious ABL1 variants were contacted and requested to make assessments of variant pathogenicity in their patients.Patients 1, 3 and 5 were identified through genetic variant results returned via the Deciphering Developmental Disorders (DDD) study  . Plasmid mutagenesis of the ABL1B transcript (NM_007313.2) was carried out for each variant following a modified version of the QuikChange Site-Directed Mutagenesis method  using PfuUltra II Fusion HotStart DNA Polymerase (see https://www.chem.agilent.com/store/primerDesignProgram.jsp) or using a partially overlapping primer design [E. coli . Individual clones were isolated and ABL1 fully sequenced to confirm the correct sequence and presence of the required variant.A pCDNA3.1/V5-His A plasmid vector containing the r design  . After 48 h, cells were serum starved for 1 h before preparation of protein lysates. Phosphorylation of ABL1 and the ABL1-specific substrate STAT5B was measured by western blotting using the following antibodies: ABL1 (clone OP20) ; Phospho-ABL1 (Tyr245) ; Phospho-ABL1 (Tyr241) , STAT5 ; phospho-STAT5 ; Phosphotyrosine , Actin . Imatinib was purchased from Stratech . To assess effect on phosphorylation activity, 1 µM imatinib was added during the 1 h serum starvation before lysis.To investigate ABL1 kinase activity in vitro, HEK293T cells were transfected with plasmid constructs encoding wild-type or variant ABL1 in patients with abnormal phenotypes were collated from the DECIPHER database [ABL1 missense variants in healthy population controls were identified through the gnomAD [Non-pathogenic missense variants of database . ABL1 mie gnomAD  and EVS e gnomAD  databasee gnomAD  for evere gnomAD . Missense gnomAD . Pathogee gnomAD , SIFT [2e gnomAD , Mutatioe gnomAD , and CADe gnomAD .The clinical features of our cohort are summarised in Table ABL1 variants are dysmorphic facies (18/18), finger/toe abnormalities (17/18), congenital heart disease (14/18), failure to thrive (14/18), developmental delay (11/18), IUGR (10/18), ear abnormalities (9/18), palatal deformity (9/18) and microcephaly (9/18)  Table .ABL1. Four of these variants have not been previously described. Our findings are summarised in Fig. We identified six individuals with five deleterious de novo missense variants in The molecular characteristics of each variant are shown in Table ABL1 variants cluster within and adjacent to the ABL1 kinase domain, non-pathogenic ABL1 variants in the DECIPHER cohort largely lie outside this region . This variant was identified through the DDD study in a patient with a likely pathogenic de novo variant in another gene.The c.731T > C p. construct caused an increase in phosphorylation of STAT5B and of overall tyrosine phosphorylation, with reduced autophosphorylation at Tyr245 compared to wild-type. Alteration of Val244 to alanine therefore appears to result in loss of phosphorylation of the adjacent Tyr245 residue. This result is surprising, as phosphorylation of Tyr245 is thought to potentiate ABL1 kinase activity .Finally, as expected, imatinib abolished phosphorylation of ABL1-Tyr245 and STAT5B in all of the constructs Fig. .ABL1, which in five cases are confirmed as de novo. All but one of these variants cluster in a myristoyl-binding pocket within the kinase domain, suggesting a gain-of-function effect due to loss of auto-inhibition. We present functional data consistent with this mechanism and reaffirm that the clinical phenotype of the ABL1 syndrome includes conductive hearing loss.We describe six additional patients with a skeletal and cardiac malformation syndrome caused by heterozygous missense variants in ABL1 transcript, and yet suggests a self-evident mechanism by which they can exert a deleterious gain-of-function effect. We predict that other amino-acid substitutions within the myristoyl-binding pocket, particularly those which disrupt hydrophobic interactions or introduce bulky amino acids, will also be deleterious in the germline. We also predict that missense variation or in-frame deletion of the N-terminal glycine of ABL1, which carries the myristoyl modification, will be deleterious.A distinctive feature of the variants we describe is their close spatial relationship to one another in the three-dimensional crystal structure of the protein, and specifically their position within the myristoyl-binding pocket. This close spatial relationship is not immediately apparent from the position of these variants in the ABL1 developmental syndrome [We also describe a novel c.731T > C p. variant which lies in the SH2-kinase linker domain, immediately adjacent to a previously described c.734A > G p.(Tyr245Cys) variant. Other variants in this linker domain are known to disrupt the inhibitory docking of the SH3 domain to the SH2-kinase linker domain, and thereby constitutively activate the ABL1 kinase [syndrome , but no ABL1 is best known as a proto-oncogene. In CML and other haematological malignancies, a somatic translocation between chromosomes 9 and 22 produces the Philadelphia chromosome [BCR-ABL fusion gene. As the N-terminus of ABL1 is lost in the fusion product, the auto-inhibitory binding of the myristoyl group to the kinase domain is abolished, and ABL1 gains constitutive tyrosine kinase activity which drives cellular proliferation [romosome , carryinferation .Tyrosine kinase inhibitors (TKIs) specific to ABL1, such as imatinib, are the mainstay of treatment for CML. However, resistance to TKI therapy is strongly associated with somatic missense variants in the ABL1 kinase domain, particularly in the ATP-binding loop (P loop) and at TKI-specific binding sites .ABL1 developmental syndrome or its complications, for example in limiting aortic root dilatation or reducing the tendency for dilatation to occur. However, given that this condition appears to affect embryonic and fetal development, any more complete therapeutic effect would require as early treatment as possible and entail long-term therapy, potentially risking adverse drug effects. While imatinib is used to treat paediatric CML cases, it is expected to be teratogenic in pregnancy. Further work is therefore required to ascertain whether therapeutic scope exists for use of imatinib or similar TKIs in this condition.It is noteworthy that none of the activating germline variants we describe have been associated with somatic TKI resistance. If, as we argue, germline variants in the kinase domain sterically hinder myristoyl binding, they will functionally mimic the loss of the ABL1 N-terminus in BCR-ABL. We therefore expect that TKIs effective against BCR-ABL should be similarly effective against these variant proteins. Indeed, TKIs may potentially in some way be therapeutically beneficial for the ABL1 have not been found to independently cause haematological malignancy, although both isoforms of ABL1 are ubiquitously expressed. Disruption of myristoyl binding alone may not activate ABL1 sufficiently to drive malignancy. Two other “linchpins” of ABL1 auto-inhibtion  may prevent its excessive activation [ABL1 skeletal and cardiac malformation syndrome described here or elsewhere are reported to have haematological malignancy, but longitudinal follow up of these patients will be required to better determine this.It is also noteworthy that activating somatic missense variants in tivation . Indeed,ABL1 be borne in mind in such cases. The high prevalence of hearing impairment makes audiological assessment advisable. Furthermore, assessment of the aortic root diameter at the time of diagnosis may also be appropriate in individuals found to have pathogenic ABL1 variants. Evidence is currently lacking as to the true risk of aortic aneurysm and dissection in this condition. We are not aware of any affected individuals having had rapid progressive aortic dilatation requiring surgical intervention and this may therefore suggest a more indolent course. However, a precautionary approach of ongoing aortic root screening similar to that used for Marfan syndrome may be appropriate until such time as more accurate natural history data are available.From a clinical perspective, we believe this condition to be a phenotypically distinctive and recognisable syndrome based on affected individuals’ dysmorphology and associated clinical features. Phenotypes such as skeletal malformations, aortic root dilatation and pneumothorax point towards an overlap with genetic connective tissue disorders and we recommend that Supplementary information


Although specific anti-phospholipid antibodies (aPLs) have been used in the diagnosis of the antiphospholipid syndrome (APS) for years, new biomarkers are required to increase its diagnostic and risk-predictive power. This study aimed to explore the value of several non-criteria aPLs in a Chinese cohort.A total of 312 subjects, namely, 100 patients diagnosed with primary APS, 51 with APS secondary to SLE, 71 with SLE, and 90 healthy controls, were recruited. Serum anticardiolipin (aCL) IgG/IgM/IgA, anti-β2-glycoprotein I (aβ2GPI) IgG/IgM/IgA, anti-phosphatidylserine/prothrombin antibodies (aPS/PT) IgG/IgM, and anti-annexin A5 antibodies (aAnxV) IgG/IgM were tested using ELISA kits.Of the total number of patients, 30.46% and 6.62% with APS were positive for aCL or aβ2GPI IgA, respectively, while 39.07% and 24.50% were positive for aAnxV or aPS/PT for at least one antibody (IgG or IgM). The addition test of aCL IgA and aAnxV IgM assists in identifying seronegative APS patients, and IgG aPS/PT was linked to stroke.Detection of aCL IgA, aβ2GPI IgA, aAnxV IgG/M, and aPS/PT IgG/M as a biomarker provides additive value in APS diagnosis and would help in risk prediction for APS patients in medical practice. The antiphospholipid syndrome (APS) is a systemic autoimmune disease characterized by thrombosis and/or pregnancy morbidity with the persistent presence of medium or high titer of antiphospholipid antibodies (aPLs). The 2006 APS classification criteria (Sydney criteria) have been widely accepted in APS diagnosis, where at least one of the clinical criteria, as well as one of laboratory criteria including lupus anticoagulant (LA), high level of anti-cardiolipin (aCL), and anti-β2 glycoprotein-I (aβ2GPI) immunoglobulin isotype G (IgG) or M (IgM), should be present . DespiteMore specifically, numerous studies have been conducted to investigate the diagnostic value of aCL/aβ2GpI IgA for APS, which received contradictory results . NeverthProthrombin is another phospholipid-binding protein that forms a complex and is often co-detected of antibodies together with phosphatidylserine (aPS/PT). An international multicenter study confirmed the contribution of aPS/PT IgG in APS diagnosis IgG . ConcernStudy design, including detection method, patient stratification, population heterogeneity, and other factors, may lead to contradictory results in different studies. Regarding the Chinese population, a previous study indicated an increase of both IgG and IgM aAnxV in primary APS patients and APS associated with other diseases. Significant associations were also observed between IgG aANxV and thrombotic events . AdditioThis was a single-center, prospective cohort study conducted at Peking Union Medical College Hospital (PUMCH) from May 2017 to January 2020. A total of 152 consecutive APS outpatient cases were included in this study, of which 100 patients had been diagnosed with primary APS (PAPS group) and 51 with APS secondary to SLE (SAPS group). A total of 71 SLE patients (SLE group) and 90 healthy controls (HC group) were also included and matched with APS groups for gender and age. Diagnosis of APS was defined by clinicians according to the 2006 Sydney revised classification criteria. Upon diagnosis, sera samples were collected at the outpatient clinic and immediately profiled of aPL antibodies at the Key Laboratory of Department of Rheumatology, Peking Union Medical College Hospital (PUMCH). Besides aPL serology, history of clinical manifestations was recorded for PAPS, SAPS, and SLE groups, including thrombosis , pregnancy morbidity, microangiography , and history of adverse pregnancy. For the HC group, only aPL serology information was present. The study was approved by the ethics committee at PUMCH and fulfilled the ethical guidelines of the declaration of Helsinki. All subjects gave written informed consent.® ELISA Test Kits provided by Aesku. Diagnostics GmbH & Co. KG . Cutoff value was defined as 18 U/ml as recommended by the manufacturer. Lupus anticoagulant was detected and evaluated at the Key Laboratory according to the ISTH recommendations measuring Dilute Russell viper venom time (dRVVT)/activated partial thromboplastin time (>1.20 as positive)  . Diagnosχ2 test or Fisher’s exact test was used for comparison of categorical variables, and Wilcoxon test was used for continuous variables after normality was explored with the Shapiro–Wilk test. Sensitivities, specificities, and accuracies in APS diagnosis were compared in the McNemar test. Youden Index, positive and negative predictive values (PPV and NPV), and odds ratio (OR) with 95% confidence interval (95% CI) were also shown. Receiver operating characteristic (ROC) curves of individual aPL as well as logistic regression analysis of aPLs profile were used to calculate the area under the curve (AUC), with 95% CI shown. Associations between aPL isotype positivity and clinical manifestation in patients with APS were explored and displayed in 95% CI. Two-tailed values of p less than 0.05 were considered statistically significant.Statistical analysis was performed using SPSS 26.0 or R (version 3.6.2). The χ2 = 10.560, p = 0.001). Clinical manifestations were recorded for both APS and SLE patients and were selectively shown. Thrombosis was most commonly present, with 80 (80.0%) for PAPS and 74.5% for SAPS, but not in the SLE group. Patients were recorded for history of arterial or venous thrombotic events, pregnancy morbidity, microangiopathy, history of adverse pregnancy, and LA. Of all the clinical manifestations, prevalence of adverse pregnancy history was significantly different between the PAPS and SAPS group .Among 151 APS patients, there were 63 (63.0%) females for PAPS, 45 (88.2%) for SAPS, and the mean age for each was 36.3 and 32.9 years (p < 0.001), while specificity was lower (p = 0.031). A similar result was observed for aCL or aB2GpI IgG or IgM or IgA compared to aCL or aB2GpI IgG or IgM. As for aAnxV, the sensitivity and accuracy of aAnxV IgG or IgM were significantly higher than that of aB2GpI IgG or IgM (p < 0.001). In addition, a combination of aCL, aβ2GpI, or aAnxV IgG or IgM had significantly higher sensitivity (p = 0.016) compared to that of aCL or aβ2GpI IgG or IgM.The diagnostic power of aPLs positivity (>18 U/ml) was evaluated for sensitivity, specificity, accuracy, Youden Index, PPV, NPV, and ORs in APS diagnosis from HC group in As illustrated in Among 151 APS patients, cross-positivity of IgG, IgM, or IgA for aCL or aβ2GpI (a and b), as well as IgG or IgM for each of the four aPLs (c and d) were demonstrated with the Venn diagram in For APS patients, 43 (28.5%) were positive for more than one non-criteria aPLs. Besides, the number of patients positive only for one of the five non-criteria aPLs was also calculated. A total of 11 patients positive only for aCL IgA, 9 for aAnxV IgG, 5 for aAnxV IgM, 3 for aPS/PT IgM, 1 for aPS/PT IgG, and 1 for aβ2GpI IgA were observed among these patients.p = 0.029) and aβ2GpI IgA for SAPS (p = 0.043). Compared to HC, levels of IgG and IgA were significantly higher for four aPLs in both PAPS and SAPS group. However, IgM results varied for different aPLs.The distribution of all criterial or non-criteria aPLs among different patient groups is shown in Correlations between different aPLs and LA or clinical manifestations are shown with odds ratios in APS is an autoimmune disease featuring thrombosis and/or pregnancy morbidity, which may lead to severe consequences. Detection of aCL and aβ2GPI as the golden standard in APS diagnosis is not satisfactory in the clinical scenario, and various potential aPLs have been extensively explored.In this study, the diagnostic value of IgA for aCL or aβ2GPI and of IgG/IgM for aANxV or aPS/PT was evaluated in APS patients. In brief, 45.70% and 6.62% of patients with APS were positive for aCL or aβ2GPI IgA, respectively, while 30.46% and 24.50% were positive for aAnxV or aPS/PT for at least one antibody (IgG or IgM). Adding IgA to criterial aPLs could increase the sensitivity in APS diagnosis. Detection of aANxV or aPS/PT, especially aAnxV IgG, could add value to diagnosis. IgG of aANxV or aPS/PT was significantly associated with LA, and IgG aANxV was linked to stroke.p < 0.001). The sensitivity  and accuracy  of aAnxV IgG or IgM were both significantly higher than that of aβ2GPI IgG or IgM. Moreover, combination of aCL, aβ2GpI, or aAnxV IgG or IgM had significantly higher sensitivity  than that of aCL or aβ2GpI IgG or IgM. Statistical results suggested that adding aAnxV IgG or IgM to aCL or aβ2GpI IgG or IgM would both increase diagnostic value besides criterial antibodies. Meanwhile, there was no significant decrease in specificity (96.67%).Analysis of the predictive power indicates that although aCL IgA had relatively low specificity, adding IgA to aCL IgG or IgM/aCL or aβ2GpI IgG or IgM test could increase test sensitivity (The result was further illustrated with ROC curves for each aPL and their combination. AUC of aCL IgA and aAnxV IgG ranked second and third (0.853 and 0.728) among individual aPLs. Statistical analysis showed that the addition of IgA to aCL IgG/IgM would significantly increase diagnostic power . The addition of aAnxV or aPS/PT to aCL/aβ2GpI IgG/IgM would also significantly increase diagnostic power .The Venn diagram indicated the additive value of new aPLs from another perspective. Positive only for IgA isotype could point out an extra number of patients for both aCL  and aβ2GPI . Additionally, the number of patients positive for aAnxV IgG, aAnxV IgM, and aPS/PT IgM outperformed those of aβ2GPI, indicating their importance in APS clinical diagnosis. The result suggested that additional tests for non-criteria aPLs may provide a unique value in the identification of SNAPS patients.p = 0.029) and aβ2GpI IgA (p = 0.043). Between PAPS and SLE, significantly higher titer of IgM aCL, IgA aCL, IgM aPS/PT, IgG AnxV, and IgM AnxV was observed (p < 0.001). As for SAPS and SLE, only IgM aPS/PT showed a significant difference (p = 0.015). The results implied that both criterial and non-criteria aPLs had difficulty in distinguishing APS from SLE or APS secondary to SLE. Indeed, baseline information suggested little difference between PAPS and SAPS patients in age and most clinical manifestations , the National Natural Science Foundation of China (81771780), and the CAMS Initiative for Innovative Medicine (2017-I2M-3-001 and 2019-I2M-2-008).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.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


Metro systems are gradually becoming more and more crucial in promoting the economy and society in cities. However, various challenges such as financial resources and the efficiency of utilizing these metro plans bring difficulties for metro construction. Hence, accurately evaluating the urban metro system’s development condition seems significant for the sustainable development of the urban metro system. Therefore, a comprehensive evaluation indicator system of metro development conditions containing 25 indicators from dimensions of demand and supply is established in this study, and a coupling coordination degree model combined with the entropy weight method and Technique for Order Preference by Similarity to an Ideal Solution (TOPSIS) method is proposed to analyze the level of metro development conditions and coupling coordination conditions of 35 cities in China. According to the calculation results, 35 cities are divided into six categories, and radar charts are constructed to promote the sustainable development of the metro system. As the most critical component in urban infrastructures, the metro system plays a crucial role in promoting a city’s economy and society development. Compared with other modes of transportation, such as buses, taxis, and private cars, the metro system has many advantages and benefits, such as environment protection, better travel safety and efficiency, and high travel punctuality ,2, whileHowever, it is possible that these ambitious metro plans will encounter many challenges, such as financial resources and the efficiency of utilizing these metro plans. It is appreciated that considerable investment is needed to build the metro system. For example, it is reported that the average cost of metro construction rose to 800 million CNY per kilometer in urban areas in China , indicatAccording to the definition of sustainable development, it emphasizes the ability to meet society’s current needs without compromising the capacity to satisfy future generations’ demands . In addiTherefore, there is a need for coordinated development between supply and demand conditions for developing the metro system. It is considered very important to plan the scale of metro systems properly. Suppose the scale of the metro system is too small compared to the population scale of a city. In that case, it will not meet the transportation demand of the urban population . On the Although previous studies have paid attention to the supply and demand of the metro system by using various transport system models from different perspectives, few studies focus on the coordination problem of the demand and supply. In fact, the coupling coordination degree model has vast advantages in studying the coordination problem. Coupling, a concept in physics, refers to the phenomenon that several physical systems interact with each other through internal connection, so coupling degree is proposed to describe the degree of interaction among systems . In addiThe above discussions demonstrate a small existing study assessing the coupling coordination degree of metro systems from a perspective between supply and demand conditions. Therefore, in this study, an assessment model is developed to evaluate the coupling coordination degree between the supply and demand conditions for developing the metro system. And then, the coupling coordination conditions of 35 cities in China are analyzed. The contributions of this paper are as follows. First, while some scholars have researched demand or supply conditions of the metro system, previous studies mainly concern the factors affecting development conditions from the perspective of demand or supply ,14,15,16Demand can be defined as the amount of all services and products currently utilized, consumed, or expected to be obtained by the human society in a particular area . SimilarSupply refers to the capacity to provide services and goods for human society . SimilarIn order to measure the coupling coordination degree of metro systems, three procedures are proposed in D) to evaluate the interaction between demand and supply systems and reflect the dynamic trend of coordination and transverse comparison between demand and supply systems [This study uses coupling coordination degree ( systems . Couplin systems  and urba systems .C) and coordination degree (T) is used to calculate the coupling coordination degree (D), and the basic equation of coupling coordination degree can be presented as follows:C represents the coupling degree of the metro system, and T represents the coordination degree of the metro system.According to Zhang et al. , couplinC) comes from physics. It can be defined as a phenomenon in which the systems under investigation influence each other through different links [C) can be presented as follows [x denotes the number of systems and xu represents the comprehensive development value of x-th system.In Equation (1), coupling degree  can be simplified as:du represents the comprehensive development value of the demand system, and su represents the comprehensive development value of the supply system.In this study, there are two systems of the metro system: the demand system and the supply system. Therefore, in Equation (2), the value of T) refers to the degree of benign coupling in the coupling interaction relationship, which reflects the quality of coordination among systems [T) can be presented as [x denotes the number of systems, and xu represents the comprehensive development value of x-th system. In addition, α, β and γ represent the degree values of the importance of systems. In Equation (1), coordination degree ( systems . The basented as :(4)T = αx is 2. Meanwhile, the same importance of the demand and supply system is considered. Therefore, in Equation (4), the value of α and β is 0.5. The Equation (4) can be simplified as:du represents the comprehensive development value of the demand system, and su represents the comprehensive development value of the supply system.In this study, there are two systems of the metro system: the demand system and the supply system. Therefore, in Equation (4), the value of By substituting the results Equation (3) and (5) into Equation (1), the coupling coordination degree is presented as follows:According to the relative research, the coupling coordination degree is divided into 4 levels and 12 types in this study, as shown in The comprehensive evaluation includes three main steps: selecting the indicator system, calculating indicators’ weights, and selecting evaluation methods. The selection of evaluation methods is the core stage in the whole process, which is also a significant way to obtain the conclusion. Generally, these evaluation methods are classified into parametric and non-parametric. Moreover, Data Envelopment Analysis (DEA) and Multi Criteria Decision Making Methods (MCDM) are the most commonly used methods in recent years. DEA is a non-parametric method that concentrates on evaluating decision-making units’ efficiency ,44, and du) and supply system (su) in this study, which constructs the positive and negative ideal solutions of multi-index problems, considering the proximity to the positive ideal solution, and the distance from the negative ideal solution as the basis for evaluating feasible solutions [The TOPSIS method, proposed initially by Hwang and Yoon , is usedolutions . Moreoveolutions , city ecolutions , and smaolutions . The speolutions ,47:Step 1. Establishment of an evaluation matrixn indicators to measure the development of metro systems in m cities, the evaluation matrix can be expressed asijy represents the evaluation value of the j-th evaluation indicator in the i-th city.With Step 2. Normalization of all indicatorsThe evaluation indicators are divided into positive indicators and negative indicators. For those positive indicators, that is, a larger value indicates a better result. The normalized value can be calculated as follows:j. And y′ij represents the evaluation value of the j-th evaluation indicator in the i-th city after normalization.For those negative indicators, a smaller value indicates a better result. The normalized value can be calculated as follows:Step 3. Construction of a weighted decision matrixijz represents the weighted evaluation value of the j-th indicator in the i-th city after normalization. And j-th evaluation indicator.The weighted decision matrix can be obtained through the product of the matrix after normalization and the entropy weight as follows:Step 4. Calculation of the positive ideal distance and the negative ideal distancej-th evaluation indicator in the i-th city should be calculated as follows:Before calculating the positive ideal distance and the negative ideal distance, the positive ideal value i-th city should be calculated as follows:Then, based on the positive ideal value and the negative ideal value, the positive ideal distance Step 5. Calculation of relative closenessiR) of the i-th city is used to sort the evaluation objects. A larger relative closeness value represents a smaller distance between the evaluation object and the ideal sample. The specific equation is as follows:The relative closeness value  and supply system (su) are represented by the relative closeness values (iR), respectively.Therefore, in this study, for the jω) in this study. Entropy is a measure of the degree of disorder of the system. Suppose the entropy of the indicator is small. In that case, more information is provided by the indicator, which means the role of this indicator in the comprehensive evaluation is bigger. Therefore, the indicator should be given a higher weight [The entropy weight method is used to determine the weight of each indicator  of j-th indicator in i-th city should be calculated as follows:As for the evaluation matrix after normalization, firstly, the contribution value  for each indicator can be calculated as follows:Then, before obtaining the entropy weight of jω) of j-th indicator can be calculated as follows:Finally, the entropy weight value  and (9). After that, the contribution value, the entropy value and the entropy weight of each indicator of demand and supply systems are calculated by the Equations (17)–(19). The entropy weights of the two systems are presented in From From Next, the weighted values of the two systems are calculated by the Equation (11), and each indicator’s maximum and minimum values in the 35 cities are identified. Therefore, the positive ideal distance, the negative ideal distance, and the relative closeness value of each city of two systems are calculated by the Equations (12)–(16). The results are presented in From From du in su in du in su in Finally, by combining the value of The calculating results for 35 cites are presented in From According to the coupling coordination degree levels and types in Furthermore, combining metro scales of each metro system, 6 categories of the coupling coordination degree are further analyzed in this study. And the metro scales of the 35 cities in 2019 are shown in As shown in As shown in There are seven metro systems in this category: Chongqing, Tianjin, Nanjing, Hangzhou, Qingdao, Dongguan, and Suzhou, as shown in Furthermore, for Chongqing metro system, its excellent supply conditions can suit the high demand well. Since 2005, Chongqing has made tremendous progress in building, facilities, and people satisfaction . Under tFrom The levels of Chengdu metro and Wuhan metro are lower than Shenzhen in most aspects. As for Chengdu, slightly weak environmental issues and adequate passenger supports make the evaluation value of the demand system a little bit higher than the supply system. Chengdu performs terribly in urban road emissions as one of the three Chinese cities with the most vehicles nationwide . But forAs shown in The population is the main reason why the low evaluation values of the demand system in the cities. The resident population and passenger flow of public transportation cannot offer the development of metro supports. Environmental issues and infrastructure situations perform relatively better. In the future, the cities should focus on developing demand conditions, for example, attracting more population by developing the economy and urban construction or improving metro to attract passengers. Meanwhile, not bringing burden to the local economy should taken into consideration when developing metro.As shown in Moreover, some metro systems performed a high demand situation, especially Harbin metro and Shijiazhuang metro, because of the large population and the worse environmental issues. In the future, metro systems in this category should pay more attention to the development of the economy. Only in a favorable economic environment can the metro make a significant development.The coupling coordination degree of 35 cities in China is measured by the indicator system and coupling coordination degree model established in this study. From the results and the discussion, firstly, the comprehensive evaluation indicator system of metro development conditions and the coupling coordination degree model can be well used to evaluate the coupling and coordination of the metro system. Secondly, the development conditions of the metro system among the 35 cities in China are quite different according to the calculation results due to the individual differences in the specific socio-economic condition in all the cities. Finally, the category of coupling coordination degree and the comparison of demand and supply conditions can offer specific suggestions for metro development in the future. For example, the metro systems of slightly unbalanced cities should put urban development first because only favorable demand and supply conditions will benefit the metro development. Moreover, cities’ metro systems in the types of barely balanced and highly balanced should improve the demand or supply conditions based on the results, keep harmony between the two systems, and finally realize sustainable development for the metro system.This study has yet to consider the availability of data for other countries in the constructed model, which is a limitation. However, suppose the constructed model is applied to other cases. In that case, the parameters of the model will be appropriately modified according to the data characteristics of other countries. This is also the following research focus of the research team, through optimizing the established model and collecting more data for analysis of more metro systems in the world. In addition, sustainable development for the metro system is not only the improvement in demand and supply conditions, but also the sustainability parameters regarding risk management, the environmental impacts of its construction, the comparison with other mass transport systems with lower emissions or fewer infrastructure requirements, and the damage from natural disasters. Hence, there is still considerable space for improvement for model parameters to analyze the sustainable development of the metro system.


We investigated decaying post-seismic deformation observed on the Korean Peninsula associated with the 2011 Mw 9.0 Tohoku-Oki earthquake using Global Navigation Satellite System (GNSS). The GNSS velocity vectors were estimated in five periods from 2005 to 2019. A co-seismic offset of the Korean Peninsula caused by the 2011 earthquake was inversely proportional to epicentral distances. According to the temporal variations of two components (magnitude and direction) of the GNSS velocity vector with the epicentral distance, the difference between the eastern and western regions for the two components becomes smaller over time. For approximately nine years after the 2011 event, the direction for the crustal movement in South Korea showed a recovery pattern returning to the pre-earthquake motion. In addition, the recovery patterns of the crustal movement were observed differently with the regional geologic structure  and each period. Our estimates of the decay in post-seismic deformation of the Korean Peninsula suggest that post-seismic relaxation will be complete within 5–20 years after the 2011 earthquake. The results suggest that the crustal movement on the Korean Peninsula is gradually recovering to its pre-earthquake motion. Many earthquakes occur somewhere on Earth every day. Most earthquakes are so weak that they rarely cause ground displacements, but some large earthquakes produce significant crustal deformation over large distances. Studies of major earthquakes with magnitudes exceeding 7.0 play a key role in improved understanding of crustal deformation, including co-seismic and post-seismic effects . Many stThe Mw 9.0 Tohoku-Oki earthquake, which struck northeastern Japan on 11 March 2011, is one of the most severe natural disasters ever recorded. It represents the fourth-largest earthquake to occur since 1900 ,6. OzawaThe Korean Peninsula is located near the margin of the Amurian microplate . It is tPrevious studies have reported that the 2011 Tohoku-Oki earthquake strongly affected the crust of the Korean Peninsula ,16,17. AKim et al.  suggesteIn this study, we calculate crustal velocity vectors in five periods  for 15 years from 2005 to 2019. In addition, we investigate the crustal movement recovery in post-seismic deformation of the Korean Peninsula following the 2011 Tohoku-Oki earthquake. More specifically, we process data obtained from a global navigation satellite system (GNSS) network in the Korean Peninsula to investigate the pre-, co-, and post-seismic deformation. As mentioned earlier, there was no significant crustal deformation on the Korean Peninsula before the 2011 earthquake. Therefore, we analyze the relative changes of the velocity vector after the Tohoku-Oki earthquake by referring to the pre-seismic motion. The velocity vector can be separated into a magnitude and a direction. As a co-seismic offset of the Korean Peninsula caused by the 2011 earthquake is inversely proportional to epicentral distances, we analyze the temporal variations of the two components, magnitude and a direction of a velocity vector, with the epicentral distance. In addition, the recovery patterns of the crustal movement were investigated with the regional geologic structure. We also estimate the post-seismic relaxation completeness using an exponential decay function.GNSS is an effective geodetic tool for investigating the movement of the crust. We use displacements captured by GNSS stations within a network operated by the National Geographic Information Institute of Korea (NGII) and Korea Astronomy and Space Science Institute (KASI); accordingly, we determine the crustal motion of the Korean Peninsula. GNSS data with a sampling interval of 30s were processed in the International GNSS Service (IGS) realization of the reference frame ITRF 2014 using a double-difference method in the Bernese 5.2 software . In thisWe processed the data to determine average velocity vectors for the GNSS stations over each of five periods; i.e., pre-seismic (1 January 2005 to 31 December 2010), co-seismic (4 March 2011 to 18 March 2011), post-seismic stage 1 (12 March 2011 to 31 December 2013), post-seismic stage 2 (1 January 2014 to 31 December 2016), and post-seismic stage 3 (1 January 2017 to 31 December 2019). In the Korean Peninsula, there have no records of earthquakes of magnitude 6 or greater, and only two earthquakes of magnitude 5 or greater in the 30 years before the 2011 earthquake [Some studies suggested that the earthquake-induced significant effects lasted for 2~2.5 years after the 2011 mainshock ,9,20. HoY  as a function of one independent variable X . The general equation for a simple linear regression can be expressed by the following Equation (1). This model can also be represented in matrix form as Equation (2).α, β, and ε are the intercept, slope, and error, respectively. The coefficient confidence intervals for the slope are calculated using the Wald method expressed in Equation (3) [α/2) percentile of t-distribution with n − p degrees of freedom that leaves a probability α/2 in the upper tail and (1 − α/2) in the lower tail. n and p are the number of observations and the number of regression coefficients, respectively. Here, we use the 95% confidence intervals . The supporting information We consider the linear regression fitting approach to estimate the velocity vectors during each time period. In this study, we use a simple linear regression model that describes the relationship between a dependent variable tion (3) .(3)β^±tOnly the horizontal components of velocity were used in the analysis of crustal motions caused by the earthquake; vertical displacements in the region were comparatively insignificant ,26. We sIn addition, we investigate the post-seismic deformation associated with the 2011 Tohoku-Oki earthquake. Post-seismic deformation is observed in GNSS time series following a large earthquake. In general, post-seismic GNSS time series can be fitted by a logarithmic, exponential, or combined decay function ,8. In thWe investigated any changes in average velocities over five periods, as summarized in The horizontal co-seismic displacements reached about 35 mm on the eastern coast of the Korean Peninsula, approximately 1150 km away from the epicenter. In contrast, the crustal displacement on the western coast area was approximately 10 mm on average. When the distance increases from the epicenter, the displacement amplitudes tended to decrease. The co-seismic movement for all stations is summarized in the supporting information As mentioned in the previous section, there was a difference of about 25 mm in co-seismic deformation between the east and west regions of the Korean Peninsula. Therefore, we analyzed the variation in the magnitude component of vectors over each of the five periods depending on the epicentral distance. 2) values, the coefficient of determination for best-fit lines, become smaller. This means the weakness of the relationship between the epicentral distance and the magnitude over time. The overall magnitude of the velocity vector became more similar to that of the pre-earthquake. However, it has not fully returned, indicating that post-seismic deformation is ongoing.For the pre-seismic period, the best-fit line has a positive slope, which means that the crust of the western regions (far-field) moves a little more rapidly than that of the eastern regions (near-field) before 2011 a. In Fig2 = 0.17) than the variation in velocity magnitude  in each stage during each time period. To understand the displacement characteristics of the Korean Peninsula after the earthquake and to estimate the duration of post-seismic deformation, we applied a curve-fitting algorithm based on an exponential function using the GNSS time series. In addition, the time series datasets after the 2011 event are subtracted by the secular motion of tectonic plates. The applied exponential function for post-seismic deformation is given by Equation (4) ,28.(4)uu(t) is the horizontal displacement of the GNSS station, t is the time after the 2011 earthquake, c is the co-seismic offset, a is the amplitude associated with the estimated final cumulative displacement, and τ denotes the decay time. From Equation (4), we compute the unknown parameters  associated with the site displacements for the GNSS stations.In Equation (4), a is the amplitude associated with the estimated cumulative displacement. We estimate the post-seismic relaxation completeness using the amplitude a. The relaxation completeness is defined as follows:Among the unknown parameters of the function, The relaxation completeness with the epicentral distance for each station is summarized in The 2011 Tohoku-Oki earthquake caused significant crustal deformation in the Korean Peninsula. After the megathrust earthquake, the crustal movements were different from those before the 2011 Tohoku-Oki earthquake. These variations in the velocity vector on the Korean Peninsula may be due to the complex effect of the post-seismic deformation and the regional geologic structure. To further analyze the crustal movement changes before and after the earthquake, we depicted the velocity vectors in five periods.After the 2011 Tohoku-Oki earthquake, the crustal movement in the Korean Peninsula seems to be recovering to the pre-earthquake direction. However, this movement does not coincide with the direction of the pre-earthquake. During the post-seismic stage 1  marked by orange arrows, the crust moved in the direction of 106 degrees on average from the north. This direction shows a difference of about 13 degrees compared to the pre-earthquake. The crustal movement was counterclockwise compared to the pre-earthquake motion during this period. In the next post-seismic stage (2014–2016) represented by the pink arrows, it moved in the direction of about 111 degrees on average from the north. This direction shows a difference of about 8 degrees from the pre-earthquake. Interestingly, the direction of the crustal movement is getting close to the pre-earthquake.The direction of crustal movement from 2017 to 2019 was about 115 degrees on average from the north. This movement is marked by the blue arrows in The recovery patterns for the post-seismic deformation can be explained by viscoelastic relaxation, i.e., the crust deforms to return to its previous level. Tormann et al.  presenteThe steady-state lower crust viscosity has a good correlation with crustal thickness . The movUsing the post-seismic relaxation completeness, we investigated the average relaxation completeness in areas ‘A’ and ‘B’, as summarized in Ansari and Bae  showed tIn conclusion, after the 2011 Tohoku-Oki earthquake, different recovery patterns for the crustal movement of the Korean Peninsula can be directly associated with the crustal thickness. In addition, the complex structure of the Korean Peninsula’s crust may have influenced different recovery patterns.In this study, we investigated decaying post-seismic deformation observed on the Korean Peninsula following the 2011 Tohoku-Oki earthquake. Using GNSS data for the 15 years from 2005 to 2019, the velocity vector of the Korean Peninsula was calculated over five periods of time. From 2005 to 2010, the crust of the Korean Peninsula moved toward the southeast in the direction of about 119 degrees with an average rate of approximately 30 mm/year. In 2011, the Tohoku-Oki earthquake caused large displacements of the crust throughout South Korea; the co-seismic offset tended to reduce with the distance from the epicenter. According to the analyzed results of changes in the magnitude and direction components of the crustal velocity vectors depending on the epicentral distance, there was a difference of a few mm/year in the magnitude between the eastern and western regions in the post-seismic stage 1 (12 March 2011 to 31 December 2013). However, in the post-seismic 3 (1 Januray 2017 to 31 December 2019), the difference in the magnitude was less than 1 mm/year between the two regions. In contrast, there was an obvious difference in the horizontal direction between the eastern and western regions before and after the 2011 earthquake. There was also a change in the average direction of the velocity vector during each time period. However, the correlation between the variation of the velocity vector and the epicentral distance decreased with time.Additionally, we analyzed the velocity vectors for 20 GNSS stations with the crustal thickness during each time period. The crustal velocity vectors displayed different azimuths in the five periods. In the post-seismic stage, the vector direction tended to recover to the direction of the pre-earthquake. It is shown that a crustal movement recovery in the area with a thick crust is faster than in the area with a thin crust. In addition, the relaxation completeness of post-seismic deformation in the thick area is higher than in the thin area. From these results, the crustal movement recovery may be associated with the regional geologic structure . Our estimates of the decay in post-seismic deformation of the Korean Peninsula suggest that post-seismic relaxation will be complete within 5–20 years after the 2011 earthquake. We suggest that the movement characteristics of the crust in the Korean Peninsula after the earthquake are gradually recovering to their pre-earthquake motion. However, it is unclear whether the crustal movement will be recovered to the same motion as before the 2011 Tohoku-Oki earthquake after post-seismic relaxation fully completeness.


While disparities in educational outcomes for Aboriginal children have narrowed in early childhood education and for Year 12 completions, these positive trends are not replicated in the intervening years where attendance, reading, writing, and numeracy targets have been missed. Erratic attendance in the primary years has the greatest impact on achievement; literacy and numeracy scores decline as absences increase. Family functioning and health, caregiver expectations, past encounters with the education system and socio-economic disadvantage are all implicated in poorer rates of attendance. In response to community concerns, an Aboriginal/mainstream partnership was forged in 2011 and began work in 2016 to address patterns of attendance and achievement among Aboriginal primary students in a regional city in Western Australia. This paper describes the innovative, community-led “More Than Talk” program and presents findings from teaching and support staff interviews two years after implementation. Qualitative methods were employed to analyse the data, develop themes, and ensure rigour. Findings highlighted the cascading impact of erratic attendance and the role of strong relationships, respect, and investment of time with children as critical elements in student engagement and wellbeing. Community-led, collaborative educational programs have the potential to positively impact Aboriginal students’ engagement and contribute to culturally responsive environments. If sustained, such efforts can enable learning to flourish.  Australia’s annual “Closing the Gap” report charts progress made on government commitments to address disparities in health and life expectancy for Aboriginal and Torres Strait Islander peoples . Since iAboriginal/mainstream partnerships have been the cornerstone of numerous, successful, community-based programs aimed at improving health outcomes and are recommended to guarantee Aboriginal participation in decision making ,4,5,6. IWith awareness of these factors in mind, and intent upon building a strong relationship with the local Aboriginal community, a partnership was forged between the Midwest Aboriginal Organisation Alliance (MAOA) and the Western Australian Centre for Rural Health (WACRH), University of Western Australia, both located in Geraldton, 420 kilometres north of Perth. The collaborative health promotion project entitled, “More Than Talk: An Aboriginal, non-Aboriginal partnership for action” aimed to support the delivery of better health and wellbeing for Aboriginal people residing in Western Australia’s Midwest region and identify and strengthen Aboriginal/mainstream partnerships . MAOA’s housing and education were identified by MAOA as their priorities for research; important social determinants of health which require greater attention, both in terms of research to better understand the impediments to achieving better outcomes, and action to implement community-led initiatives . WhThe additional resources and activities provided by the program were valued by all participants; they recognised that team members brought specific skills to their interactions with children and families. These skills include socio-cultural knowledge that arises from immersion in community, capacity to connect with children through creative activities, and the application of social work professional skills to address children’s social and emotional needs. School staff benefited by having “more hands on deck” including students on placement, the provision of advice that is locally informed, and children who are often more engaged with learning and happier. While areas for fine-tuning were identified, it was considered that the program achievements, including an influx of Aboriginal parents during NAIDOC Day celebrations, outweighed any limitations.Teachers and support staff involved in the “More Than Talk” program made frequent reference to the culturally responsive, welcoming, and community-focused nature of the school leadership team; indeed, without these attributes the program may not have been implemented in the first place. Parallel initiatives addressing Aboriginal children’s educational outcomes existed within the school, with some successes evident. A consistent theme among participants was that despite setbacks, the attendance and achievements of many children is sound, and improvements that occur should be celebrated more often. The whole school approach was positive and supplements those programs commonly focussed on problematic or at-risk children. It aligns with the strength-based approaches favoured for improving Aboriginal outcomes and provides a platform on which to build further achievements . An examAnother strengths-based pedagogical approach that has been trialled among Aboriginal primary school children is the innovative “on country learning” project in Whadjuk Noongar country in south-west Western Australia. Designed collaboratively with Aboriginal community members including Elders, the project aims to imbue students with local cultural knowledge, deepen their cultural connections with land and “foster a robust sense of cultural identity and well-being”  (p.86). A recent systematic review of school-based programs that aim to build resilience and coping skills among primary students found that teacher involvement in program delivery, and teacher and program adaptability characterise successful intervention programs . While tParticipants in this study were receptive to fresh approaches and keen to build upon the positive legacy of the “More Than Talk” program. Recent discussions with staff revealed interest in adopting further innovations and becoming better informed about ways to improve school experiences for Aboriginal children. Positive suggestions offered include culturally designed yarning areas in the playground, regular invitations to Elders to conduct culture and language yarning sessions with staff and students, weekly “Acknowledgement of Country” announcements, a more comprehensive approach to celebrating Aboriginal culture within the school, and the inclusion of more culturally appropriate educational resources. While still in the implementation stage, these suggestions support the school’s aims to be inclusive, welcoming, culturally responsive, and connected to the local community it serves, likely a key to students’ future patterns of attendance and achievement. The study findings were drawn from interviews conducted with teachers, support staff, and the leadership team two years after the implementation of the “More Than Talk” educational program. Interviews with staff not directly involved in the program or from team members who participated in its delivery were not sought, as the focus of this study is upon how the program was received. The “More Than Talk” educational program was designed as part of a wider Aboriginal/mainstream partnership because educational outcomes were recognised as poorer for Aboriginal children and education was valued by Aboriginal leaders. The program was implemented in a high-needs primary school where the attendance and achievement of some students was identified as a community concern. Interviews with school staff revealed numerous strategies employed to improve student engagement. Staff were very receptive to the program; they appreciated its collaborative nature, the additional resources provided, especially program members with specialised skills and strong community ties, and the time invested in children with complex needs. While some fine-tuning was recommended, the program was highly valued, left a positive legacy and encouraged further initiatives in the school, with many aspects continuing in some form. While the short duration of the program was a limitation, further research on similar longer-term initiatives will build the evidence-base around Aboriginal-mainstream educational partnerships. Findings from this study, however, suggest that community-led, collaborative educational programs have the potential to positively impact Aboriginal students’ engagement and wellbeing, and contribute to culturally responsive environments where learning can flourish.


Inflammatory bowel disease (IBD) which includes Crohn’s disease (CD) and ulcerative colitis (UC), is a chronic relapsing-remitting or progressive inflammatory condition. In addition to physical symptoms, individuals with IBD experience uncertainty about their future, social isolation, and increased psychological stress. Conventional medical and surgical IBD treatment does not adequately address the the impact of psychological stress. Online stress reduction interventions may therefore be useful adjuncts to standard medical therapies for IBD. The Peace Power Pack (PPP) trial was a 12-week RCT testing a stress reduction intervention with two core components: (i) a yoga, breathwork and meditation video, and (ii) a behavior-change facilitation informed by cognitive behavioral therapy.The aims of this qualitative study, which was carried out alongside the PPP trial was to: (i) explore the experience of living with IBD, (ii) understand the impacts of the PPP program, and (iii) identify potential improvements to the program.Upon completion of the 12-week RCT, all intervention participants were invited to participate in semi-structured interviews. A qualitative descriptive approach was used. Interviews were analyzed through a theoretical thematic analysis process, whereby transcripts were coded, and codes then grouped into larger categories and themes.Of the 56 participants interviewed, 52% had CD and 48% had UC. Participants ranged in age from 23 to 73 years, were predominantly female (70%) and had been diagnosed with IBD 14.3 years ago. Three main themes (Table 1) were identified: (i) IBD as a source of stress and uncertainty, (ii) understanding the positive impacts of the stress reduction program, and (iii) suggested strategies to enhance program desirability. IBD was described as causing uncertainty, significant disruptions to daily activities, and stress. The online program was associated with a perceived reduction in IBD symptom burden, an increased ability to manage daily and disease-associated stressors, and a more positive mindset. Variation in program content and fostering connections with others in the IBD community were identified as potential strategies to enhance future programming.This study highlights the power of the patient voice to deepen our understanding of the impact of IBD, and the potential benefit of an online stress reduction program including suggestions for iterative refinement.Table 1. Themes identified with sample quotationsUniversity of Alberta Hospital Foundation, the American College of Gastroenterology and the Inflammation, Microbiome, and Alimentation: Gastrointestinal and Neuropsychiatric Effects (IMAGINE) Network CIHR grant


Population growth and general practitioner workforce constraints are creating increasing demand for health services in New Zealand (NZ) and internationally. Non-medical prescribing (NMP) is one strategy that has been introduced to help manage this. Little is known about the NMP practice trends in NZ. The aim of this study was to provide a current overview of the scale, scope, and trends of NMP practice in NZ.All claims for community dispensed medicines prescribed by a non-medical prescriber were extracted from the NZ Pharmaceutical Collection for the period 2016–2020. Patient demographics were retrieved from the Primary Health Organisation enrolment collection. These national databases contain prescription information for all subsidised community pharmacy medicines dispensed and healthcare enrolment data for 96% of New Zealanders.The proportion of prescriptions written by all NMP providers and patients receiving NMP prescriptions increased each year from 1.8% (2016) to 3.6% (2019) and 8.4% (2016) to 14.4% (2019) respectively. From 2016 to 2019, the proportion of NMP patients who had at least one NMP prescription increased from 26% to 39% for nurse prescribers, from 1% to 9% for pharmacist prescribers, from 2% to 3% for dietitian prescribers, and decreased from 47% to 22% for dentists, and from 20% to 12% for midwives. The most commonly prescribed medicines were antibiotics , and analgesics . While some NMP providers were prescribing for patients with greater health needs, all NMP providers could be better utilised to reach more of these patients.This study highlights that although the NMP service has been implemented in NZ, it has yet to become mainstream healthcare practice. This work provides a baseline to evaluate the NMP service moving forward and enable policy development. Improved implementation and integration of primary care NMP services can ensure continued access to prescribing services and medicines for our communities. As in other countries, non-medical prescribing (NMP) was introduced in New Zealand (NZ) to address the increased demand for healthcare services and diminishing access to prescribing services and medicines –3. NMP iNMP is still a relatively new practice in NZ and is changing significantly with the number of non-medical health professional groups gaining prescribing rights increasing. NZ non-medical prescribers include dentists, midwives, nurse prescribers (nurse practitioners and registered nurse prescribers), pharmacist prescribers, optometrists and dietitian prescribers . In NZ dcontribution and trends of all non-medical prescribing to overall prescribing from 2016 to 2020;contribution and trends of each NMP health professional group to all non-medical prescribing from 2016 to 2020;demographics of patients who receive prescriptions from non-medical prescribers;most frequently prescribed therapeutic groups and medicines by non-medical prescribers.This study aims to provide a current overview of non-medical prescribers’ prescribing trends in NZ with specific objectives to determine the:This retrospective nationwide observational study used the NZ Ministry of Health Pharmaceutical Collection and the Primary Health Organisation (PHO) Enrolment databases , 14. TheMedicines and therapeutic products that are publicly funded in NZ are listed in the NZ Pharmaceutical Schedule , which is managed by the Pharmaceutical Management Agency, PHARMAC . PHARMACThe Pharmaceutical Collection was searched between 1 January 2016 to 30 June 2020 (4.5 years) using the distinct provider type codes to identify dispensed medicines prescribed by: dentists, nurse prescribers (which includes nurse practitioners and registered nurse prescribers), optometrists, midwives, pharmacist prescribers, and dietitian prescribers. The number of distinct enrolled patients who were dispensed a medicine from a NMP and the number of original prescriptions dispensed were also determined. The distinct original prescription dispensing refers to each single item prescribed by a prescriber on a prescription form to a patient, and does not include any repeat dispensing that occurred from a prescription. The distinct patients were identified using the encrypted National Health Index (NHI) number, which is unique for each patient and remains the same in each health-related database across a patient’s lifetime and allows the linking of collections. The following patient sociodemographic details were also retrieved from the PHO Enrolment Collection: age, gender, ethnicity, NZ Deprivation Index (NZDep2013 score), and District Health Board (DHB) provider. Data for the 100 most dispensed medicines by therapeutic group and medicine chemical name  [Descriptive statistical analyses, using Excel 2016®, were conducted on the aggregated data set, to determine NMP contribution to overall community dispensed medicines in NZ, NMP by non-medical prescriber provider type , the demographics of the patients who received prescriptions from non-medical prescribers, and summarise the types of medicines prescribed by non-medical prescribers in NZ.The study analysed patients’ DHB, deprivation and self-reported ethnicity data. The following Statistics New Zealand reporting standards for ethnicity were used: Asian, Māori, MELAA , NZ European/European, Other, and Pacific Peoples. The NZDep2013 score combines census data relating to income, home ownership, employment, qualifications, family structure, housing, access to transport and communications . The NZDThis study was approved by the University of Otago Human Ethics Committee (reference HD20/029).The number of dispensed prescriptions written by all healthcare prescribers  increased by 10.8% from 2016 to 2019 . The number of patients who had a prescription issued by all healthcare prescribers  increased by 4.7% from 2016 to 2019   (Table Nurse prescribers were the largest NMP contributors 1.40%) to all prescriptions  dispensed between 2016 and 2020, followed by dentists (0.64%), midwives (0.39%), and pharmacist prescribers (0.25%). Optometrists and dietitian prescribers were the smallest contributors equally (0.06%). Nurse prescribers increased their proportion of all NMP prescriptions from 35% (2016) to 56% (2019), and they contributed 50% of all NMP prescriptions for the four-and-a-half-year period (2016–2020) , dentists and dietitian prescribers prescribed for almost equal proportions of female and male patients Table . During The NZDep2013 score was recorded for 1,017,132 NMP patients with a median score of 6 (IQR 3–8). In total, 466,393 NMP patients (42.8%) were living in the more deprived areas (i.e. NZDep2013 decile 7–8 and above). During 2016–2020, optometrists saw patients living in the less deprived areas  and nurse prescribers saw patients living in more deprived areas .For all NMP providers overall, 171,882 (15.8%) patients self-identified as Māori and 54,011 (5.0%) as Pacific peoples. Nurse prescribers prescribed for the highest proportion of Māori patients ) and optometrists for the lowest proportion of Māori patients (2676 (5.8%)). Midwives prescribed for the highest proportion of Pacific patients ) and optometrist prescribers prescribed for the lowest proportion of Pacific patients (1284 (2.8%)). Twelve percent of pharmacist prescribers’ patients self-identified as Māori and 3.5% as Pacific.The five DHBs with the most patients receiving a prescription from a NMP provider were: Counties Manukau ), Waitematā ), Canterbury ), Waikato DHB ), and Auckland ). Most rural DHBs had lower numbers of NMP patients  and South Canterbury 12,500 (1.1%)), and included the two DHBs with the least NMP patients which were West Coast (9227 (0.8%)) and Tairāwhiti ).Based on the 100 most frequently prescribed therapeutic groups by NMP providers, we ascertained the top five therapeutic products that were most prescribed by NMP providers during the period from 1 January 2016–30 June 2020. For all NMP providers, the two most frequently prescribed therapeutic groups were antibacterials with 1,802,812 dispensings (23.4%), followed by analgesics ). Antibacterials were also the most prescribed therapeutic group by dentists ), and the second most prescribed therapeutic group by nurse prescribers ) and optometrists (5320 (2.5%)). Analgesics were the most prescribed therapeutic group by nurse prescribers ), and the second most prescribed therapeutic group by dentists ) and midwives ). The analgesic therapeutic group included medicines such as paracetamol, codeine phosphate, and tramadol, but excluded ibuprofen and diclofenac, which are categorised as non-steroidal anti-inflammatory agents in the Pharmaceutical Collection data.The top five most prescribed therapeutic groups by pharmacist prescribers were contraceptives-hormonal with 159,013 dispensings (17.9%), followed by vaccinations ), treatments for substance dependence ), lipid-modifying agents ), and agents affecting the renin-angiotensin system ). Unsurprisingly, the eye preparation therapeutic group was most prescribed by optometrists (95.6%), and all the top five therapeutic groups prescribed by dietitian prescribers related to nutrition.Based on the 100 most frequently prescribed medicines by NMP providers, Table This study reported the first data describing all NMP in New Zealand providing an important baseline for future comparisons. The increasing contribution trend of nurse prescribers towards NZ NMP could be due to their new ‘registered nurse prescriber’ scopes of practice , a suppoOnly nurse prescribers and midwives prescribed for a higher proportion of Māori patients (21.6% and 17.6% respectively) than in the general New Zealand population (16.5%) . HoweverAntibacterials and analgesics  were, on average, the most prescribed therapeutic groups by NMP providers. These two therapeutic groups were also in the top five groups prescribed by NZ GPs in the most recent statistics (2018) . There iIt is difficult to compare the prescribing practice of the NZ NMP providers in this study as there a scarcity of published work about NMP providers’ practice in NZ and internationally. The number of original prescriptions written by non-medical prescribers in NZ is increasing and has surpassed the 1 million NMP prescriptions reported in earlier NZ research , with thSimilar to NZ, UK research reported that nurse prescribers are the biggest contributor to NMP prescriptions in the UK, however UK nurse prescribers accounted for a much higher proportion (94.4%) of NMP prescriptions dispensed in primary care  for the 5 year period January 2011–December 2015 . It is nWhile pharmacist prescribers contributed modestly (0.25%) to all NZ prescribing, they were the fourth largest contributors to NMP prescriptions (9.0%) from 2016 to 2020 , however, that study only focused on nurse practitioner prescribing practice . This prNZ research found three antibiotics  in the top ten most prescribed medicines by nurse practitioners in 2013–2015 . UK reseThe larger urban DHBs account for 48.3% of NZ NMP patients as they have bigger population bases. Based on current prescribing practice of the overall NMP service, there is a great opportunity for NZ NMP providers, including pharmacist prescribers, to contribute to communities with greater health needs, including Māori and Pacific communities , 33. RurThe high prescribing of analgesics and antibiotics by non-medical prescribers suggest that they are dealing with a high number of acute conditions. These examples could signal that non-medical prescribers are prescribing within their scope such as dentists treating oral/dental infections and conditions that required pain relief. It also suggests that non-medical prescribers could be taking some of the burden from GPs and be helping to improve medicines access equity for acute conditions. UK research has indicated that NMP has made better use of health professionals’ skills (including nurse and pharmacist independent prescribers) to reduce workload pressures of GPs –38.NZ pharmacist prescribers prescribed more preventative agents (nicotine replacement therapy), and immunisations (influenza vaccine). UK pharmacists are also increasingly prescribing the influenza vaccine  and in 2Understanding NMP practice in NZ identifies areas that require sufficient initial and continuing education. NZ is a relatively high user of antibiotics , 45, andA strength of this study is the large data set available for analysis, with dispensing, prescriber, patient, and medicines details. The data set contained comprehensive sociodemographic details for each patient and captures > 96% of the New Zealand population. It is acknowledged that dispensing may not fully reflect prescribing, as patients who had a prescription issued but did not take it to a pharmacy for dispensing, are not captured in this study. The Pharmaceutical Collection data did not differentiate between pharmacists prescribing funded medicines as registered pharmacist prescribers and via the pharmacist only medicines classification. This study captured both nurse practitioner and registered nurse prescribing within the ‘nurse prescribing’ umbrella term.All the NMP professions in NZ appear to be prescribing medicines within their usual practice. While there is modest growth in this service, NZ NMP still makes very small contributions to overall prescribing in primary care. Nurse prescribers are the largest contributor to NMP, and other NMP providers including pharmacist prescribers have the potential to contribute more to this service.There is some indication that NMP providers could be alleviating the prescribing burden on GPs and improving access by prescribing for acute conditions that require pain relief or antibiotics. However, overall all NMP providers could be better utilised to provide prescribing services to our communities with greater health needs and improve access to these healthcare services. NMP providers have the potential to improve healthcare service delivery to cope with unmet health needs in rural NZ, a sector that struggles to meet health needs due to workforce constraints and inequity of access. The variation of NMP service provision across the different DHBs in NZ indicates that the NMP service has been well integrated in certain geographic areas, and this variation could be due to better support and funding in some DHBs compared to others. This study highlights the importance of identifying what medicines NMP providers are prescribing, to ensure adequate education and continuing professional development to support best practice and appropriate prescribing decisions. Further research is needed to determine the impact of NMP on patient outcomes and access to healthcare.As NZ seeks to cope with the increasing demand for health services, factors such as workforce constraints have the potential to affect the availability of the usual GP prescriber in primary care. NZ has to make better use of the skills of other health professionals, and must consider new models of care and service delivery to meet these increasing healthcare needs. This study highlights that NMP has been implemented in NZ, but it has not yet become mainstream healthcare practice. This work provides a baseline to evaluate the NMP service moving forward and contribute to policy development. Improved implementation and integration of primary care NMP services can enable continued access and reduce inequity to prescribing services and medicines for our communities.