Supraorbital rim fracture is a rare sports-related injury encountered by craniofacial specialty and great challenge to the surgeons because of their anatomical location and relation with vital structures in close relation. Currently, in the literature, no classification system or treatment protocol exists for the supraorbital rim fracture. Supraorbital rim fracture forms a small proportion of sports-related injuries. Here we present a case with supraorbital rim fracture by sports injury diagnosed by computed tomography and treated surgically by open reduction methods using mini plates. Fractures of the supraorbital region are rare and are frequently associated with high-energy cranio-maxillofacial trauma. Orbital rim fractures are challenging to manage because of their close proximity to the eye, ocular muscles, underlying frontal sinus, and ultimately the brain. Therefore, during the process of assessment and treatment planning, it is mandatory to evaluate the extent of involvement of the various anatomical structure that lies in close relation to the affected area that includes nerves, eye muscles and cranial base in the anterior cranial fossa . Moreover, due consideration should be given to the possible morbidity risk associated with different types of operative approaches while selecting the management approach .Most common etiological factors associated with trauma to the supraorbital region include blow out injuries, personal assault, and road traffic accidents. Overall, one-third of the injuries to human bodies are the result of sports injuries. Facial fractures can involve the supraorbital rims and the anterior table of the frontal sinus in approximately 1 to 9% of cases, and many supraorbital rim fractures are associated with other forms of craniomaxillofacial injury . HoweverA 19-year-old male patient reported to the department with the chief complaint of pain and discomfort above the left eyebrow area after sustaining a head impact from a co-player’s elbow while playing cricket. The pain started two days after the impact. The medical history of the patient was unremarkable, and he was up to date with his tetanus immunization. The patient did not show any sign of head injury or neurological deficit on examination. The extra-oral examination did not show any asymmetry or swelling other than the depression that was noted on the left supraorbital region. Local examination of the left supraorbital margin revealed bony depression measuring 2 x 1.5 cm that was extending 1 cm medial to the midline, laterally till 2 cm from external eye canthus and superiorly 2 cm from the supraorbital margin  and ocular movements were normal on eye examination. Based on the patient’s history and clinical examination, a provisional diagnosis of left supraorbital margin fracture was made.Paranasal sinus projection with open mouth revealed discontinuity in the left supraorbital margin at the medial 1/3rd and junction of middle and lateral 1/3rd. Also, the haziness was noted in the left frontal sinus suggestive of fluid collection. Computed tomography (CT) scan confirmed the involvement of the frontal sinus Figures , 3.The patient was informed about the diagnosis with an explanation of possible treatment options. Subsequently, after obtaining consent, the patient was treated surgically by open reduction, and mini plates were fixed with screws. Consequently, the facial aesthetic was restored to normal without any postoperative complication Figure .Sports injuries account for 4-18% of the facial trauma and facial bone fractures occur in 11-40% of cases . The incIt is of foremost importance for the healthcare professionals that are supporting athletes to familiarize themselves with the anatomy of the facial region. Moreover, they should be well aware of the common type of facial injuries, their assessment, and initial management. The most common type of sports-related facial trauma is soft tissue injuries and dentoalveolar fractures and minor facial bone fractures of the nose, zygoma, mandible, and orbital fractures -8. The oThe diagnosis of facial fractures is accomplished by the clinical examination and the use of imaging modality. More often, facial deformity from trauma is initially concealed by overlying edema and soft tissue injuries. Therefore, it is important to take a proper history of gauging the severity and mechanism of injury ,9. When Supraorbital rim fractures usually present with cosmetic deformity consisting of depression or flattening of the supraorbital ridge that can be visualized like in the current case. Later the patient may present with soft-tissue edema, lacerations, and periorbital ecchymosis. If the supraorbital and supratrochlear nerves are involved then paresthesia can occur . PresentThe treatment of supraorbital rim fractures should be directed by the functional and esthetic needs of the patient. Open reduction is the treatment of choice in the current case and in most of the displaced supraorbital fracture cases. When there is the displacement of the fractured segments then, surgical exploration, reduction, and stabilization are indicated ,10. SuprLastly, the use of protective equipment is the key to prevent facial injuries in sports. It was reported that orbital fracture can almost always be prevented with the use of protective eyewear during sports. The risk of injury to the eye is highly related to the type of sport ,6. HenceOrbital rim fractures constitute a small, but significant, number of sports-related facial injuries. This case report highlighted the impact of elbow hit while playing cricket resulting in a supraorbital fracture. There is a need to educate all youths regarding the use of personal protective equipment and adherence to the rules of sports to reduce the incidence of maxillofacial injuries from sports. Analysis of fracture patterns and concomitant injuries is imperative to develop effective management strategies and prevention techniques.


BACKGROUND: Traditional models of geriatric medicine and health system reimbursement structure often force ambulatory care teams to function as high-volume delivery programs, thereby dis-servicing our most vulnerable and frail older patients. This “high cost and high needs” labeled demographic requires uniquely adapted plans from medical and social work providers. METHODS: To better examine opportunities for improved framework for geriatric ambulatory care, the Acute Life Interventions, Goals & Needs (ALIGN) Program has launched several inter-professional pilot programs, each with intention to explore components of health care service to older patients, and feasibility of implementation in other health care systems. Three current models include the ALIGN Program itself, a telemedicine community paramedicine program, and a geriatric surgery co-management program. RESULTS: Preliminary results are forthcoming, with initial promising findings. For the first 126 patients enrolled, mean emergency room (ED) visits 6 months prior to ALIGN enrollment were 1.7 visits per person, reduced to 0.7 ED visits/person 6 months post-graduation from the program, and 126 fewer ED visits. Mean hospitalization 6 months prior to enrollment was 0.32 per person, whereas 6 months post-graduation was 0.2 hospitalizations/person, totaling 40.32 hospitalizations saved. Mean length of stay in the hospital 6 months prior to ALIGN enrollment for the 22 patients admitted was 7.7 days, reduced to 7.3 days post-graduation, and 32 fewer hospital days in the small subset of patients requiring hospitalization despite program interventions. CONCLUSION: The ALIGN Program’s multi-professional and flexible modularity highlights promising innovative frameworks for ambulatory geriatrics care, warranting further exploration and collaboration.


Overall, these results agree well with values from other sources. The advance that is provided by our method compared to other research is the ability of determining earthquake epicentres with magnitudes ≤7.5 based upon GRACE observations. However, the approach is of limited use for very deep earthquakes.Investigation of regional and temporal variations in Earth’s gravitational field that are detected by the Gravity Recovery and Climate Experiment (GRACE) twin-satellites may be useful in earthquake epicentre determinations. This study focuses on monthly spherical harmonic coefficients that were extracted from GRACE observations, which were corrected for hydrological effects to determine earthquake epicentres. For the first time, we use the concept of deformation of Earth’s gravity field to estimate invariant components of strain tensors. Four different earthquakes  were analysed that occurred between 2003 and 2015 and under different hydrological regimes. Wavelet analysis was explored as a means of refining and reconstructing tectonic signals forming the disturbance gravitational potential tensor in the GRACE gravity field models. Dilatation and maximum shear were extracted from these tensors and used to map earthquake epicentre locations. Both components reached their maxima during months of the earthquakes . For the aforementioned earthquakes, we estimated their respective epicentres in the ranges:  The accumulated energy that is released suddenly in the rupture is propagated as seismic waves. These waves spread outward through the surrounding crust from its initiation point or focus. When the waves reach the surface of the crust, they result in the shaking motions that we associate with an earthquake. The focal point at which the rupture occurs deep within the Earth is called the hypocentre, and the point on the Earth’s surface, which is located immediately above the hypocentre, is referred to as the epicentre of the earthquake.Earthquakes are natural geophysical processes that occur in certain locations across the surface of the globe. These seismic disturbances are found at the boundaries between tectonic plates (inter-plate) and in rift zones within plates (intra-plate). The rigid crust  and upper mantle constitute lithospheric or tectonic plates, which are cooler solid slabs of rock that ride on the hotter, more fluid deeper mantle. The surface tremors that characterise earthquakes result from gradual accumulation of strain and stress that is incurred when friction retards the movement of deeper rock strata from sliding against one another along a fault plane in opposing directions. When opposing fault faces are locked together, the continued movement of the surrounding lithosphere materials will continue to exert shear strain, i.e., energy that is stored, given that fractures can no longer extensively propagate along the fault to release the pressure. Given that the rocks cannot move freely, they deform , which is based upon gravimetric measurements. In fact, an earthquake generates a redistribution of mass and, consequently, causes localised variation in Earth’s gravity field. GRACE satellites are capable of detecting these changes due to earthquakes. Sun and OkuboIn contrast to existing studies, the use of gravimetric data to aid the determination of an earthquake epicentre is a new idea. Hence, our motivation is to investigate its first-time implementation using GRACE observations. Two main questions are of interest: Is it possible to determine an earthquake epicentre using GRACE data? If yes, how do the magnitude and depth of the earthquake influence the process? Our objective is to propose an alternative method for locating lower magnitude earthquake epicentres based upon the deformational strain in gravity space that can be easily observed from satellite gravity data. Therefore, we propose a new and innovative approach for determining the invariant components of strain tensors of earthquakes using gravimetric observations.18) with an updated dataset (version 2.1) to remove hydrological effects from signals containing changes in mass distribution, thereby revealing tectonic signals in the remaining mass changes. First, GRACE data contamination from seasonal variations was reduced to improve tectonic signal extraction. We computed wavelet coefficients of the gravity signals from both hydrology and GRACE observations to filter and localise the desired signals based upon expansions of a Legendre polynomial in the frequency domain. The desired signals then were inserted into the gravity strain tensor to calculate dilatation and shear values. By considering two long periods before and after the earthquake, we determined the epicentre point of four different earthquakes. Last, the effect of earthquake depth on the estimated gravity strain components was considered. We added data from four other events, including two severe earthquakes (> 7 in magnitude) with great depth, to test the sensitivity of our model to the geometric depth parameter of the earthquakes.We used the Global Land Data Assimilation System  in Fig. Four different major earthquakes that were characterised by great depth and magnitudes greater than 7, and which were located in Iran, Pakistan, and Turkey, were selected to better understand effects of earthquake depth on our proposed approach. Their locations are numbered 5 to 8 (green colour) in Fig. 19. In deformation analysis, the Earth’s properties are usually compared under two situations: the reference or Lagrangian state (before deformation) and the current or Eulerian state (after deformation). The Earth-fixed three-dimensional Cartesian coordinate system of points on the ground is described as 20:One of the most important areas of research in geodesy is modelling of Earth’s deformation at local and global scales. Together with the study of causative factors that are involved in deformation and the provision of various computational methods for determining crustal displacements21 introduced this concept to Earth surface deformation analysis by exploring variations in the geometry of the surface through displacement fields that were computed from space mission measurements. This method is referred to as deformation of the gravity field of the Earth. A straightforward way of defining deformation in the gravitational field is to compare two different gravitational vector fields near a fixed point in space. Consider such a point, T (before deformation) and t (after deformation), with the corresponding gravity disturbance vectors that are assigned to each: 22 is:In the literature of continuum mechanics, the theoretical concept of strain analysis is well known for its lack of dependence on the coordinate system. Grafarend and VoosoghiIn this study, we used the Lagrangian strain formulation in numerical computations. These gravity strain tensors may be formulated using second-order space derivatives of the disturbing potential (gravity gradient disturbances). Let:According to Eqs. 23.24. These coefficients also contain mass variation due to seismic and hydrological effects25. Therefore, the removal of hydrological effects is an integral part of the process to obtain refined signals that are related to the earthquake. Hydrological variables were derived from the Noah Land Surface Model process level-426, which was obtained from GLDAS-2.1 model simulations for the study period . The simulations contained 36 land surface fields from 2000 to present27. They include the most effective hydrological variables, such as surface runoff, subsurface runoff, soil moisture content from surface to 2 m depth, canopy water content, and surface snow amount. No data for groundwater were provided in the GLDAS model. Yet, we assumed the effects of this component are negligible. The correction process consisted of converting the hydrological signals from their space (water layer thickness) to gravity space. This conversion is performed by applying Love numbers28. All of these were transformed, in turn, to coefficients through harmonic analysis, to maintain consistency with GRACE observations. The corresponding coefficients were subtracted from GRACE coefficients to obtain data that were corrected for hydrological effects:The GRACE satellite is able to recover the gravity changes in terms of spherical harmonic coefficients. Indeed, spherical coefficients are the solution to the partial differential equation of the disturbance potential that satisfies the Laplace equationet al.30 introduced localised wavelet analysis to reconstruct regional spatiotemporal potential changes in the form of GRACE coefficients. In comparison with Fourier transformations, wavelet functions decompose the main signal to extract its regional behaviour at different frequencies by transfers in time and expansion or compression  in amplitude. Spherical wavelets are a special type of wavelets that form radial base functions over the sphere by increasing the signal-to-noise ratio over the region. In this regard, their scaling properties are described by a scaling function. In this study, a non-orthogonal cubic polynomial was considered as a scale function  Before the earthquake, each target month would be considered the current disturbing potential (t), whilst the mean of the two years prior to the earthquake would be considered as the reference disturbing potential (T). ii) After the earthquake, each target month would be considered the current state disturbing potential (t), whilst the mean of the two years following the earthquake would be considered as the reference disturbing potential (T).Then, with 31:Since the strain is a symmetric tensor, only six components are required to specify it at a given pointD) and shear (SH) are respectively computed such that:In general, 32. To analyse mass change details that are induced by an earthquake, we need to consider a long period of time. Therefore, we assumed that considering changes over two years would be reasonable to acquire these details. By constructing a gravity strain tensor from GRACE observations, as explained above, the maximum shear appears at the earthquake’s epicentre. Generally, the best results are achieved when the reference year is considered as a year in which a large mass change  has not occurred in and around the study area. We tested our method on four different seismic areas with various hydrological disturbances to provide a more comprehensive analysis surrounding the computation of the location of the earthquake’s epicentre.To determine an earthquake’s epicentre using GRACE data, we introduced the following method. The average two years prior to the year of the earthquake are considered as the current state, whilst the average of the two years after the year of the earthquake can be considered as the reference state. The decision to use two years may be explained by signal processing concepts. As previously mentioned, dilatation and shear can be computed from the gravity gradient changes that are extracted from GRACE data. Taking the second derivative of the data, however, weakens the signalTo investigate uncertainties in epicentre results, we proposed a method for estimating the contributions of errors that are induced by the GRACE observations in the computation of dilatation and maximum shear. More precisely, we defined upper/lower and right/left bounds of the errors for the maximum shear values. In each case, the interval size between the bounds depends upon the location of the maximum shear in the earthquake’s region, and its changes in surrounding areas. In order to define these bounds, we examined the changes in maximum shear using different window sizes. In all cases, a size of 1° was found to be sufficient. Outside this 1° range, changes in maximum shear appear to be either negligible or nonexistent. To illustrate the process, let us consider the case of the Bam earthquake. According to the position of the epicentre, two profiles of maximum shear were computed in the longitudinal direction. The first one was for the lower bound situated at 28.5°N, while the second was for the upper bound at 29.5°N. The difference between the maximum shear values of the two profiles indicates the uncertainty in the north-south direction. The same process was used to compute the profiles in the latitudinal direction. The profiles were computed for the left and right bounds, located respectively at 58°E and 59°E. The difference that was found between their maximum values was considered as the uncertainty in the maximum shear in the east-west direction.In practice, in mathematical geodesy, a region will be defined in terms of the uncertainties, which normally is an error ellipse. This region is a confidence area that is based upon maximum errors according to coordinate axes. This assumption does not hold in this study, since the maximum shear is an invariant parameter of the strain tensor, and is not dependent on a coordinate system. Under these circumstances, defining an error ellipse does not make sense. The solution is to use an alternative approach that produces similar uncertainties in all directions.33 introduced an algorithm for the true determination of positioning and navigation. He determined the probability of having the true position inside a confidence circle. We used this idea here to calculate the radius rcc of that confidence circle, the centre of which corresponds to the estimated epicentre position for a given earthquake, and radius to maximum error of the shear in all directions. Let us consider respectively ash and bsh as the errors on maximum shear values in the east-west and north-south directions, as explained above. The ratio Csh between these errors can be computed from the following equation:In this regard, HooverK) in Eq. rcc of the confidence circle , as a first step, we computed long-term mean gravity changes due to the hydrological effects for a period of about 4 years over the study regions (i.e. 2 years before the earthquake occurrence and 2 years after). Differences between each month and a mean of the whole period (4 years) were considered to compute these anomalies. The time series of these gravity variations for each earthquake are shown in Fig. 2). This highest value was found for the Chinese earthquake. From the literature, the maximum gravitational changes that have been recorded for the most severe earthquake in the 21st C. are about 10 µGal for both the Sumatra earthquake in 2004 (M 9.2) in Indonesia, and the Tohoku-Oki earthquake 2011 in Japan (M 9.0)35. Other severe earthquakes, such as Maule earthquake 2010 (M 8.8) in Chile, recorded a gravity change of about 5 µGal36. Accordingly, the values of gravitational changes that were introduced by hydrological effects, which were computed in this study for the four earthquakes considered . Gravity variations were computed after these corrections. The results are shown in Fig. Using the monthly gravity variations computed after the hydrological effects corrections Fig. , the inv37. As no earthquake event occurred between February and June 2004 in the Bam area, dilatation and shear remained constant, as shown in Fig. As shown in the time series for each earthquake in Fig. 38. Both areas were very active during the time period studied here, and this is well reflected in the GRACE-based approach that we proposed. Yet, Fig. Although the maximum value of dilatation and shear occurred in the month of earthquake for the other two earthquakes, the process is not linear. This behaviour can be affected by the occurrence of small earthquake events. For the Sichuan-Gansu border and Banepa earthquakes, Fig. As dilatation and shear reach their maximum values at the earthquake occurrence time, determining the epicentre could be possible. Therefore, we applied our method, as explained in Section 3. Accordingly, we considered an average two years before and after the earthquake year as the reference and current states, respectively, to form gravity strain tensors and compute maximum shear and dilatation for each earthquake. Figure 39. Unfortunately, due to the altitude of GRACE, retrieval of reliable gravitational changes is only feasible in the low-to-medium frequency bands, because of an aliasing problem with higher wavelengths40. Therefore, applications of spaceborne gravimetry to earthquake studies are seriously limited by the satellite’s current spatial resolution (1° by 1°). To smooth the decay speed of the spectrum in the gravitational and gradient changes that were observed by GRACE, together with the deformation that was associated with the earthquake, we implemented wavelet analysis to localise our data and improve the resolution (see Section 3). In the localisation method, we assumed that the preferred location of the epicentre of the earthquake corresponds to the centre of the main cell that has been identified with the maximum shear value. Yet, the epicentre could actually reside anywhere inside the cell. As a result, the method is not able to determine a definite position for the epicentre. Alternatively, the result is given in terms of ranges of latitude and longitude comprising the point. In general, Fig. It must be noted that large deformations caused by earthquakes are typically highly localised, with associated signals residing in high frequency bands41. This pattern yields the direction of the dominant fault line in the region, which is in south-north direction in this case. Moreover, this rate change can be also seen in the Chinese earthquake area, showing that the Sichuan fault line is oriented in a southwest to northwest direction.With a little greater focus on Fig. The comparison between the locations that were determined in this study and the epicentre coordinates that were provided by three different sources is presented in Table 8. Therefore, the most reasonable method for validating the results is to consider ranges of differences in terms of distance. The approximate differences between our method for computing the longitude and latitude of each earthquake epicentre and other sources are displayed in Table We used the only available authoritative sources  to validate our computed results for the epicentre of each earthquake. As mentioned above, the spatial resolution of the GRACE dataset makes it impossible to accurately determine the location of the epicentreAs explained in Section 3, the profiles of maximum shear were computed using bounds located at 0.5° apart from the epicentre, in order to estimate the uncertainties both in north-south and east-west directions. Figure Table 42. In this study, we wanted to understand whether the earthquake depth could affect the epicentre location determined by the proposed approach. As indicated in Section 3, we applied the method to four different earthquakes cases with depth varying from 12 to 80 km , φ = 32.5°–33°, λ = 105.5°–106° for Sichuan-Gansu border earthquake (China), φ = 38.5°–39°, λ = 39.5°–40° for Elazig earthquake (Turkey), and φ = 27.5°–28°, λ = 85°–85.5° for Banepa earthquake . All the results are in good agreement with authoritative referenced sources, with distance differences less than the spatial resolution of GRACE; indicating thus the potential of the approach. The correction of hydrological effects from GRACE data is important for a better computation of tectonic signals in the approach presented. The resulting gravity strain tensor components showed a clear linkage with earthquake event. Even small magnitude earthquakes (5 to 6) manifest themselves with slight variations in maximum dilatation and shear values. Therefore, according to the cases tested, GRACE seems able to detect earthquakes with a magnitude of less than 7.5. However, most accurate results were found for only shallow depth earthquakes (less than 15 km). The effects of depths and other geometric parameters of the earthquake should be further addressed in forthcoming studies to better define the domain of applicability of the method. The coarse spatial resolution of GRACE data constitutes a limitation for accurately determining epicenter location, as it falls somewhere inside the identified cell with maximum shear value. Downscaling approaches may eventually improve GRACE spatial resolution and help to have a better location of earthquakes epicenters using the approach.Our approach brings new findings in the use of invariant components of gravity strain tensor, including dilatation and shear, extracted from GRACE satellite gravimetric observations to determine earthquakes epicenters location. The approach is based on the second derivatives of potential changes as gravitational gradient changes of monthly geophysical coefficients of GRACE data along with the GLDAS model and localised wavelet analysis. The results showed that the values of dilatation and shear increase by approaching the earthquake time and reach their maximum at the occurrence of the earthquake. Due to GRACE data structure and spatial resolution, epicenter location can only be expressed in terms of range of latitudes and longitudes. Hence, for the four different earthquakes considered to demonstrate the applicability of the approach, epicenter was estimated in the range of


Immunoglobulin Fc receptors are cell surface transmembrane proteins that bind to the Fc constant region of antibodies and play critical roles in regulating immune responses by activation of immune cells, clearance of immune complexes, and regulation of antibody production. FcμR is the IgM antibody isotype-specific Fc receptor involved in the survival and activation of B cells. Here we reveal eight binding sites for the human FcμR immunoglobulin (Ig) domain on the IgM pentamer by cryo-EM. One of the sites overlaps with the binding site for the transcytosis receptor pIgR, but a different mode of FcμR binding explains its antibody isotype specificity. Variation in FcμR binding sites and their occupancy reflects the asymmetry of the IgM pentameric core and the versatility of FcμR binding. The complex explains engagement with polymeric serum IgM and the monomeric IgM B cell receptor. Although IgM is a primordial Ig isotype present in all vertebrates, FcμR has a relatively late appearance during early mammalian evolution2. Full-length human FcμR has 390 amino acids (aa). 251 aa are extracellular, including a 17-aa signal peptide, a 107-aa immunoglobulin (Ig)-like domain, and a 127-aa stalk. The rest of the receptor consists of a 21-aa transmembrane region and a long 118-aa cytoplasmic tail at the C-terminus3. The Ig-like domain is responsible for ligand binding3 and shares about 40% sequence identity with the first Ig-like domain of the polymeric immunoglobulin receptor (pIgR-D1), which is encoded by a gene located in the same chromosomal region in mammals2. However, rather than binding to both polymeric IgM and IgA as pIgR does7, FcμR exclusively binds to IgM8, indicating its specific binding mechanisms as well as functional roles. Potential residues responsible for the binding between IgM and FcμR have been proposed but the structure of the FcμR/IgM complex is currently unknown11. In this study, we image a complex of the ectodomain of human FcμR and the IgM-Fc pentameric core using single-particle cryogenic electron microscopy (cryo-EM). The analysis reveals multiple binding sites for the N-terminal Ig domain of FcμR on the Cμ4 domain dimers within the IgM constant region and provides a framework for understanding FcμR’s role in immunoglobulin recognition and signalling.Immunoglobulin Fc receptors are effector molecules expressed on the surface of immune cells, which can generate a wide range of protective functions crucial in immune responses after engaging with the Fc domains of the immunoglobulins. FcμR  is a high-affinity Fc receptor specific for IgM12  identical to the subunits of the IgM pentamer at Cμ4 domains and two signalling chains Igαβ, shows that mIgM-BCR can accommodate binding of two FcμR Ig domains  and the back of subunit Fcμ1 (position 1b) though extremely low occupancy at position 5f may be suggested by features near the noise level in unsharpened cryo-EM maps. The tip of the hairpin-1 region in the J chain may prevent the addition of an FcμR at position 5f by marginally blocking FcμR at Ser55-Thr57. Position 1b seems available for binding, but access to this site may be blocked by the hairpin-2 region in the J chain, a highly flexible loop containing 30 residues that remains unstructured in the cryo-EM map.d for FcμR binding to immobilised IgM10 and is therefore unlikely to be saturating for all binding sites. As a result, our maps indicate a diversity of FcμR affinity for the potential binding sites. Focused 3D classification at individual IgM subunits was also conducted to quantify the occupancies at each subunit  of 1.64 Å2 on Cα atoms (Two binding sites (position 1f and 3f) which have highest occupancies of FcμR, reached high-resolution (3.5 Å and 3.1 Å) in the cryo-EM maps -7, thus Cα atoms , with se6, but in a slightly lifted position relative to the IgM  in subunits Fcμ1 and Fcμ3 respectively , Fig. 5a9. The same residue Arg112 in FcμR at position 1f, on the other hand, interacts with Thr571 and Thr574 at the tailpiece in subunit Fcμ5 (chain B) extended from the other side of the IgM-Fc core  on the Cμ4-2B domain in the neighbouring IgM subunit , which i-Fc core . Met108 -Fc core , consistThe interactions observed between the CDR loops in FcμR and the IgM-Fc core provide a structural basis for IgM specificity of FcμR. The CDR1 loop in FcμR is four residues shorter than the same region in pIgR-D1. Only Arg45 at the tip of CDR1 of FcμR is conserved (Arg34 in pIgR-D1), whereas the other key CDR1 residues in pIgR-D1 which have multiple interactions with the J-chain are missing in FcμR. Therefore, FcμR binding on IgM is predominantly stabilised by CDR2 and CDR3 loops. On the other hand, CDR1 contributes significantly to pIgR binding to both Ig isotypes , more so1 likely reflects high-avidity binding of IgM to multiple FcμR molecules, the potential for which has been shown in the structures of the complex. Multivalent engagement of IgM facilitates the capture of soluble IgM or IgM immune complexes by FcμR anchored on cell surfaces, leading to FcμR clustering and signalling18. Clustering has been found to be essential to induce phosphorylation at the serine and tyrosine residues in the immunoglobulin tail tyrosine (ITT) motif within the cytoplasmic region of FcμR1. The complex provides a structural basis for the observed colocalisation of FcμR and IgM-BCR on membranes of mature B cells that promote B cell survival19 and on the trans-Golgi network (TGN) in developing B cells that regulates the transport of IgM-BCR from TGN to the B cell surface20.We determined the structure of FcμR Ig-like domain at multiple FcμR binding sites on the IgM pentamer, where the Ig-like domain binds to Cμ4 dimers though can make additional interactions with either the adjacent subunit Cμ4 or tailpiece. The subnanomolar binding affinity of pentameric IgM to immobilised FcμR reported here and by others21, and its long and flexible nature potentially enhances capture of IgM or IgM immune complexes by surface-anchored FcμR. More structural details of the stalk regions will be required to see if they can interact with the stalk of adjacent FcμR or other molecules.The stalk region of FcμR, although disordered and largely indiscernible in the cryo-EM map, may indicate flexibility of the stalk region mediating membrane attachment. The stalk of FcμR contains several O-linked glycosylation sites22. pIgR-D1 alone binds with sub micromolar affinity (Kd ˜300 nM) to IgA23 at a site similar to the IgM binding site consisting of Cμ4 and the J chain. These similar interactions depend on CDR1 in D1 and are absent in FcμR and therefore explain the specific binding of FcμR to IgM. Comparison of the IgM-Fc core with and without the SC of pIgR bound suggests that SC binding does not induce significant changes in the IgM-Fc core13. Because SC only occupies a single site on IgM with the D1 domain and the other four Ig domains (D2-D5) do not occlude the remaining FcμR binding sites, seven positions are available (positions 2f-4f and 2b-5b) for FcμR binding on the IgM/SC complex, so potentially FcμR could work in concert with pIgR in mucosal immunity24.We describe structural similarities and differences between FcμR Ig domain and pIgR-D1, and one of the FcμR binding sites overlaps with the single IgM binding site observed for D1 in the context of the five-domain secretory component (SC), where D1 is necessary and sufficient for IgA binding15. Overall, our structures reveal the binding and isotype specificity of FcμR for IgM and promote the understanding of the functions of FcμR in the BCR signalling pathway.A key common feature of the FcμR binding sites is that only the Cμ4 domains are involved in the interactions. They therefore recognise an invariant region, whereas other parts of IgM, including Cμ3, may vary in conformation2, pH 8.1). The IgM sample was then concentrated to around 2 mg/mL and ultrapure trypsin  with equivalent 4% weight of IgM was added to the sample for proteolysis. The reaction was kept at 56°C for 30 min. The proteolysed sample was then run again on HPLC column again using the same Superose column above with PBS as running buffer to isolate the correct IgM-Fc fragment, and fractions were double-checked by visualising on 3-8% Tris Acetate protein gels. The IgM-Fc sample was diluted to 2μM in PBS. Lyophilized human FcμR  was suspended in PBS to 20 μM.Full-length IgM  was HPLC purified using Superose 10/300 column with running buffer  operating at 25 °C. The anti-FcμR antibody (Toso Antibody (RR-16)) was purchased from Santa Cruz Biotechnology (cat no. sc-101253). Octet AMC (anti-mouse IgG-Fc capture) biosensors were loaded with anti-FcμR antibody (2 μg/ml) and then FcμR (20 μg/ml) in two subsequent steps. The sensors were then exposed to different concentrations of full-length or proteolysed IgM (0.08-10 nM). Two technical replicates were conducted for each form of IgM.25. Apparent equilibrium dissociation constants (Kd) were determined from the instrument response against IgM concentration using a 1:1 binding model using least squares non-linear regression. In control experiments, sensors with immobilised anti-FcμR antibody (2 μg/ml) were exposed to varying IgM concentrations.Association and dissociation curves were recorded for each concentration. Data were analysed as previously describedμM) were mixed with the resuspended human FcμR (20 μM) with the same volume. The solution was incubated at room temperature for 10 min, and then diluted 10-fold just before plunge freezing to final concentrations of 0.1 μM for IgM-Fc and 1 μM for FcμR. Quantifoil  was washed by chloroform, dried in air, and glow discharged (EMITECH K100X) with air . 4 μl of diluted sample was pipetted to the grid in the environmental chamber of a Vitrobot Mark IV (FEI/Thermo) at 4 °C and 100% humidity. The grid was blotted for 4 s before plunged into liquid ethane kept at liquid nitrogen temperature.The proteolysed human IgM-Fc (2 2 fractionated over 40 frames (dose rate 5.06 e-/Å2/s) with a 1.08 Å pixel size and a defocus range between -1.2 to -3.5 μm. 16,713 additional movies were recorded with the same imaging conditions but with the sample stage tilted by 20° to increase the particle orientation distribution.The IgM cryo grids were first screened on Talos Arctica microscope (FEI/Thermo) at 200 kV and the best ones were transferred to a Titan Krios microscope (FEI/Thermo) at 300 kV equipped with a Gatan Imaging Filter (GIF) using EPU software (v 2.11). The slit width of the energy filter was set to 20 eV. 17,835 movies were recorded on a K2 camera in counting mode with a total dose of 50.6 electrons per Å26, followed by Relion’s own motion correction and CTF estimation 27. For the tilted dataset, patchCTF in CryoSPARC (v 3.2.0)28 was also conducted in parallel on the aligned micrographs to obtain a better estimation of the defocus values. 5.9M particles in total were picked by a trained model in CrYOLO (v 1.7.5)29 from both datasets and extracted in Relion with a box size of 100 pixels . The original CTF values of the particles in the tilted dataset were then substituted by the results from patchCTF by using the patchCTF extraction function in CryoSparc, and the particles were re-extracted in Relion with the same box size and binning as the non-tilted particles. The particles were then combined and subjected to 2D classification in CryoSPARC, with 2.08 M particles selected based on the populations and resolutions of the class averages. Typical 2D class averages are shown in The workflow of the Cryo-EM data processing is shown in To address problems caused by the quasi-two-fold symmetry of IgM pentamer and different occupancies of FcμR binding, particle subtraction was conducted to remove the signal of FcμR from the IgM-Fc core  in μR was predicted by trRosetta online server30, and the cryo-EM model (pdb id 6KXS) was used as the initial model for IgM-Fc core.The initial atomic coordinate model of Fcμ1 32. Iterations between auto- and manual-refinements were conducted for optimisation. N-Acetylglucosamine (NAG) molecules on the four IgM Fcμ chains at Asn563 were built and refined in Coot.For the map refined using the particles selected by the focused 3D classification at subunit Fcμ1 , all tenμ3 34 as shown in All three cryo-EM maps were sharpened with corresponding models in LocScale35 in CCP-EM. The data table for Cryo-EM data collection, processing, and validation statistics are summarised in 36. The figures are made with UCSF Chimera (v 1.13.1) and UCSF ChimeraX (v 1.4)37.A series of validation steps were conducted on the maps and models, shown in panel c to f in Extended Data Fig. 1


N = 692). We assessed the program’s effect on mindful experiencing, perceived stress, emotion regulation strategies, self-compassion, negative affect, and quality of life. The results of the presented pilot study confirmed that eMBP is a feasible and effective tool in university students’ mental health support. The students who completed the eMBP reported a reduction of perceived stress with a large effect size (pη2 = 0.42) as well as a decrease of negative affect experience frequency and intensity (pη2 = 0.31), an increase of being mindful in their life , and a higher rate of self-compassion (pη2 = 0.28) with a medium effect size. A small effect size was found in the frequency of using a cognitive reappraisal strategy (pη2 = 0.073). One new result is the observation of an eMBP effect (pη2 = 0.27) on the decrease in attributed importance to the quality-of-life components replicated in two consecutive runs of the program. The study affirms that mindfulness-based interventions can be effectively delivered in an eHealth form to university students.University study can be a life period of heightened psychological distress for many students. The development of new preventive and intervention programs to support well-being in university students is a fundamental challenge for mental health professionals. We designed an 8-week online mindfulness-based program (eMBP) combining a face-to-face approach, text, audio, video components, and support psychotherapy principles with a unique intensive reminder system using the Facebook Messenger and Slack applications in two separate runs ( Current research and clinical experience show that the time of university study can be a life period of heightened psychological distress for some students . ResearcIn this context, the development of new approaches to preventive and intervention programs to support well-being in university environments is a fundamental challenge for mental health professionals.In the last two decades, information and communication technology have been rapidly incorporated into traditional physical and mental healthcare practices . The terWhile most eHealth programs for students are based on cognitive–behavioral therapy e.g., , there iThe effectiveness of face-to-face mindfulness-based interventions on improving mental and physical health has been repeatedly documented in healthy people  and in peMBPs have the potential to deliver the benefits of mindfulness-based programs to previously inaccessible large groups of participants. eMBPs (1) are easily accessible, (2) are anonymous, (3) are available 24/7 to people during the course of their daily life, (4) do not necessarily require the involvement of a therapist educated in mindfulness, (5) are less expensive; and (6) save time . In termeMBPs have been documented as effective in supporting mental health in healthy subjects , in patiThe new skills obtained in mindfulness-based programs are broad, and they are not associated with any particular syndrome . The theThere are important differences in the construction, length, and delivery modes of eMBPs . These pThis study aimed to evaluate the feasibility of eMBP, incorporating some of the most effective eHealth program components such as an introductory lecture, a reminder system, text, audio, and video, social support by peers, and lectors in a university setting. We designed an 8-week mindfulness-based program with an innovative intense reminder system incorporating supporting psychotherapy principles  to foster a therapeutic alliance with a team of lectors behind the eMBP and to promote mindfulness practice. In this study, we examined the effect of the program on perceived stress, negative affectivity, self-compassion, quality of life, basic emotion regulation strategies, and mindfulness skills in university students. We hypothesize that participants completing an 8-week eMBP will report significantly lower levels of stress and negative emotional experience and higher levels of mindfulness facets and self-compassion than they report at the start of the intervention. We also hypothesize that the completion of the eMBP will induce a significant change in the frequency use of cognitive reappraisal (higher) and suppression (lower) in the process of emotion regulation in comparison to its measure at the start of the program. In the context of the observed value clarification induced by mindfulness training, it could also be assumed that the importance attributed to the quality of life components could be lower at the end of the intervention than its level at its start.Mindfulness: A Practical Guide to Finding Peace in a Frantic World (We developed an 8-week eMBP based on MBCT . eMBP waic World . The proThe program was divided into three parts: (1) face-to-face introductory lecture, (2) eMBP according to the book program mentioned above, and (3) the reminder system. The introductory lesson lasted 120 min and had eight parts: (1) introduction of the program team, (2) assignment to program run , (3) motivation section explaining the positive effect of mindfulness on mental and physical health, (4) introduction to the attitudinal foundation of mindfulness practice (The course was organized into eight modules. Each week’s module started on Monday morning with a pdf file sent through the mobile application that described the program plan for the whole week. The first week started on Tuesday because of the introductory lecture on Monday. The pdf files ranged from three to seven pages. The program structure was based on The Mindfulness Solution: Everyday Practices for Everyday Problems (Full Catastrophe Living (Revised Edition): Using the Wisdom of Your Body and Mind to Face Stress, Pain, and Illness  on YouTube.com, with each attitude presented by Jon The students were encouraged to download audio recordings recommended in the program sourcebook  at the “via reminders aimed at helping the participants get social support from the group. The participants also had the opportunity to exchange messages with the lecture team regarding any questions or difficulties with formal and informal practice. Participation in the program was completely free.Moreover, the students had the opportunity to share their experiences and questions with others within the Facebook group or separate Slack channel, respectively. Sharing was repeatedly encouraged All subjects were students at Masaryk University recruited through advertisements on the website and the Facebook page of the Department of Psychology and Psychosomatics of the Faculty of Medicine. The advertisement was also posted on the web news portal of the university 1 month before the program started. The opportunity to participate in the program was also announced during lectures at the department and on notice boards at the university faculties. The inclusion criterion was that the participants were students at Masaryk University. No exclusion criteria were applied.In total, 227 students participated in the first run of the program delivered through Facebook messenger , and 465 students participated in the second run of the program delivered through Slack . The Facebook group program ran in the period between March and May 2018, and the Slack group program ran in the period between October and December 2018. The participants were not randomly assigned to the Facebook and Slack groups.Both samples consisted of students of medicine (40.4%), humanities (35.8%), and natural sciences (23.8%). No differences in measured variables such as age, gender, and questionnaires were found among these subgroups.The university ethics committee approved the study (application number 18/2017), and all participants signed informed consent forms at the introductory lecture at the start of the program. Every participant got two matching stickers with a unique number. One sticker was put on the informed consent form and outcome measure questionnaires, and the participant kept the other. This unique code was used as the control measure at the end of the program in a Google Forms version of the outcome measures to anonymize data.The participants completed the outcome measures questionnaires before the introductory lecture (pen-and-pencil method). The control measurement at the end of the program was created in Google Forms. The link to the questionnaires was sent individually through email to each participant. The notification was sent three times, with 3-day spacing between each notification. Mindfulness, negative and positive affectivity, perceived stress reactivity, self-compassion, emotion regulation, and quality of life were assessed as outcome measures using the following questionnaires.The Five Facet Mindfulness Questionnaire FFMQ;  is a widThe Subjective Emotional Balance Questionnaire SEBQ;  assessesThe Perceived Stress Reactivity Scale PSRS;  is a quer ≥ 0.97; The Self-Compassion Scale SCS-SF;  measuresThe Emotion Regulation Questionnaire ERQ;  measuresThe Subjective Quality of Life Analysis SQUALA;  measurespost hoc tests with program as a within-subject variable (before vs. after the program) and group as a between-subject variable (Facebook group vs. Slack group). The Pearson correlation analysis was utilized to determine the relationships between the variables.Data analysis was conducted with IBM SPSS, version 25, and Jamovi 1.1.0. A dropout analysis by 2 (Facebook group vs. Slack group) × 2 (dropout vs. completed) ANOVAs was calculated for both groups to ensure that dropouts did not differ from completers in baseline outcome measures, gender, or age. The effect of the program was analyzed by 2 × 2 repeated-measures ANOVAs with Bonferroni The dropout rate was 97 (43.7%) students  in the Facebook group and 262 (56.3%) students  in the Slack group. These subjects dropped out during the program or did not complete the post-program test battery (program-dropout group).The 2 (Facebook group vs. Slack group) × 2 (dropout vs. completed) ANOVA was performed to check for possible initial differences between the participants who completed the program and those who dropped out. For this analysis, we looked at whether the dropout factor effect  was significant; differences between group 1 and group 2 were not examined. No significant effects of dropout were found in the questionnaires, age, or gender.post hoc tests with program as the within-subject variable (before vs. after the program) and group as the between-subject variable (Facebook group vs. Slack group). The results are displayed in The descriptive statistics of all questionnaire scores are displayed in 2 in The pre- and post-program comparison in both experimental groups showed that the eMBP led to a decrease of the perceived stress reactivity  decreased significantly. A significant effect of group only was found in satisfaction with life (SQUALA), driven by a borderline significant difference in satisfaction between the groups before the program, but not after the program. However, none of the groups improved significantly in satisfaction after the program.The correlation analysis revealed a significant negative association between mindfulness as measured by all subscales of FFMQ and perceived stress and prevailing positive and negative emotional experiencing at the start of the program see . The higInterestingly, a significant correlation was found between the FFMQ subscales Acting Aware, Non-judging and Non-reacting, and Importance attributed to the quality of life components . The association between these variables is even closer at the end of the eMBP . Self-coThe analysis also revealed a significant positive association  between reported mindfulness experiencing and cognitive reappraisal and a negative association with suppression before and after the program. At the same time, this association is stronger for suppression at the end of the program . A signiCognitive reappraisal is associated with positive emotivity, and suppression is related to negative emotivity , 5.via the messaging application  survey was sent to the dropout group to get information about how long they followed the program and if they finished it. One hundred sixty-one students from the dropout group answered. One hundred fourteen of them did not complete the eMBP. The average time of the attrition rate was 2.78 ± 1.62 weeks . Even though they dropped out of the program, 46 of them reported that eMBP had influenced their life positively .Forty-seven students of the 161 who dropped out and answered the short version of the survey completed the program, but they did not have enough time or will to complete the final battery of questionnaires. The open question concerned the reasons for dropout. The reasons of the 161 drop-out students were very heterogeneous, and there were usually combinations of several reasons. The most prevalent reasons were as follows: (1) lack of time for formal and informal practice (56.7%), “If I can’t do it for one hundred percent, I won’t do it at all”, (2) realizing that the program was not suitable for them in its content or form (7.2%), (3) loss of motivation (42.3%), (4) dissatisfaction with Facebook or Slack that requires being online , and (5) too intensive reminder system . These respondents often explained that the reminder system was not too intense in its content. They appreciated it; however, the higher frequency of the reminders reminded them that they were not fulfilling the program tasks according to the recommendations, and it was stressful for them.A correlation analysis was performed to find any evidence of a relationship between the self-reported percentage of adherence to the eMBP formal and informal practices and the positive psychological outcomes. Small significant correlations, presented in In the partial adherence analysis in the Slack group , we were interested in how many students react to each reminder on different days, what the average reaction time to it was, and the total number of participants who confirmed all the daily reminders on each particular day . Each reThe pre–post completer analysis indicates the large eMBP intervention effect on the decrease of perceived stress and a medium effect on affect experience, self-compassion, and mindful approach to the entire experience. These results were observed in both runs of the program repeatedly. The effect sizes detected in our study are comparable with the mean results of other studies conducted on university students using mindfulness-based interventions and participants from the non-clinical population in eHealth version  and in fr = 0.41, Our study presents the finding that students who underwent the eMBP significantly increased the use of cognitive reappraisal with a small effect size. Although increased emotion regulation induced by mindfulness probably involves a mix of the many implicit and explicit regulation strategies and processes comprehensively described by We found some supportive data showing that the importance attributed to the quality of life components would be lower at the end of the program, with an unchanged satisfaction with partial components of quality of life proposed in SQUALA. The decrease of importance, with a medium-sized effect, while maintaining unchanged components of life satisfaction, represents a specific shift induced by the program, and it is a new result in this area. These results were replicated in two consecutive runs of the same program. Mindfulness techniques, as part of the “third wave” of cognitive and behavioral therapies, help to target contexts and functions of psychological phenomena, not just their form . Unlike Of the 227 subjects who participated in the first run of the program and the 465 who participated in the second run, 51.95%  completed the eMBP in that they completed the post-program test battery. This rate of attrition corresponds approximately to the findings of similar studies. Thanks to the short-version survey addressed to the dropout group (359 students in sum), we obtained additional partial information from 161 of them. We found out that still 47 students completed the program without completing the final questionnaire. In this context, the attrition rate is a little bit lower (45.1% in sum). One possible explanation is that the program ends before the exam period, and many students may have decided that they did not have time for it. This finding documents that there is a discrepancy in some subgroups of participants between adherence to the program and the motivation to complete a relatively time-consuming test battery. The common methodological problem is that programs are effective for people who stayed in them , but whoAccording to a partial analysis of reactions to reminders in the Slack group , the steThe partial results from Previous studies raised expectations that high mindfulness traits at the start of the program would predispose the participants to adherence , but ourAlthough we did not conduct any mediational model among monitored variables, our results indirectly support that the effect of eMBP on the decrease of stress and negative affect experiencing could be mediated by mindfulness and self-compassion see , 5. Mindvice versa with positive affectivity), an increase of being mindful in their life, and a higher rate of self-compassion. A significant change in the frequency of using some adaptive emotion regulation strategies and feelings of life satisfaction was also observed. Our study provides a new result in the observation of a significant decrease in attributed importance to the quality of life components. The study documented that mindfulness-based interventions can be effectively delivered via eHealth form to university students. In our study, we introduced an online eMBP based on MBCT, combining a face-to-face approach (introductory lecture) with text, audio, video, and e-learning components integrated into a unique intensive reminder system using support psychotherapy principles. The study used Facebook as a popular tool for social networking and also the less widespread tool for team communication Slack, which offers many options and benefits for use in eHealth intervention settings.The results of the presented pilot study confirmed that eMBP is a feasible tool in university students’ mental health support. It revealed that the students who completed the eMBP reported a reduction of perceived stress, a decrease of negative affect experience frequency and intensity  and informed consent was obtained from each participant before participation. The patients/participants provided their written informed consent to participate in this study.MS designed and executed the study, prepared the online program, assisted with data analysis, and wrote the manuscript. PL collaborated in analyzing the data, wrote part of the “Results” section and edited the final manuscript. TK, BK, JK, VH, KJ, and KL converted the program to Facebook and Slack and executed the study. AS and RŠ collaborated in the writing and editing of the final manuscript. All authors contributed to the article and approved the submitted version.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.


One of the Sustainable Development Goals is to reduce the global maternal mortality ratio to less than 70 per 100,000 live births by 2030. In South Africa, the flagship National Department of Health MomConnect program was launched in 2014 to strengthen the quality of maternal and child health (MCH) services and improve mortality outcomes. MomConnect was rapidly rolled out with a limited understanding of how and why the program was expected to work even though studies had shown the effectiveness of the MomConnect program in improving the uptake of MCH services. This study aimed to unearth the initial program theory of the MomConnect program based on explicit and implicit assumptions of how the program was organized and expected to work.We conducted a document analysis using design- and implementation-related documents of the MomConnect program guided by the principles of Theory of Change (ToC) and Realist Evaluation (RE). Content and thematic analysis approaches were deductively applied to analyze the documents toward constructing ToC and RE-informed models. Abductive thinking and retroduction were further applied to the realist-informed approach to link program context, mechanisms, and outcomes to construct the initial program theory.ToC and RE-informed models illustrated how the MomConnect program was organized and expected to work. The process of constructing the ToC provided the platform for the development of the initial program theory, which identified three critical elements: (1) the central modalities of the MomConnect program; (2) the intended outcomes; and (3) the tentative causal links indicating, in a stepwise manner of, how the outcomes were intended to be achieved. The RE approach ‘enhanced’ the causal links by identifying relevant programmatic contexts and linking the postulated mechanisms of action  to program outcomes.The application of ToC and RE provided an explicitly cumulative approach to knowledge generation in unveiling the initial program theory of MomConnect rather than delivering answers to questions of program effectiveness. Target 3.1 of the Sustainable Development Goals (SDGs) aims to reduce the global maternal mortality ratio (MMR), defined as the number of maternal deaths attributed to pregnancy-related complications per 100,000 live births, to less than 70 deaths per 100,000 live births by the year 2030 [With an institutional MMR of 133.3% per 100,000 live births in 2013/2014 . HoweverAlthough SA’s MMR has improved from 2014 to 2019, complications of hypertension in pregnancy and obstetric hemorrhaging are still the main issues causing maternal mortality, which can be prevented through early uptake of antenatal care (ANC) and postnatal care (PNC) services . The firIn keeping with the SDG 3 target, SA developed a strategic plan to reduce maternal and child mortality by improving the uptake of maternal and child (MCH) services. To achieve this goal, mobile health technology  was integrated into the healthcare system as a strategy to overcome barriers to universal health coverage and promote MCH . The NatThe MomConnect program is a digital health communication program , which wThe MomConnect program was also guided by an emergent body of work around the use of mobile phones to enhance MCH programs –21. EvidThe program aimed at (i) registering all pregnant women using the public health sector; (ii) sending targeted health promotion messages during pregnancy and up until the first year of age to encourage healthy and health-seeking behavior ; and  material . Our docToC and RE are members of the theory-driven evaluation (TDE) or theory-based evaluation (TBE) family. TDE/TBE are regarded as key to untangling the multiple processes between policy intent and outcomes by investigating program implementation, and the causal link processes that trigger outcomes , 26. TraAccording to Taplin et al. , ToC makWhile ToC illustrates ‘how’ change occurs through program implementation, RE goes deeper by establishing ‘why’ through a mechanism-based generative causal framework. Blamey and Mackenzie  propose RE focuses on providing a ‘causation-based explanation’ – depiction of cause-effect relationships among elements  – to proThere are multiple definitions of ‘mechanism’. In RE terms, a mechanism (M) relates to a combination of intended and unintended resources provided by the program and the response to those resources by stakeholders . A mechaBy combining the ToC and RE approaches we intended to unearth, in a systematic manner, the assumptions underlying the MomConnect program and speculate the changes likely to take place as a result of the intervention . Our intWe performed a document analysis of MomConnect-related documents in South Africa, adopting three search strategies: (1) an electronic search of Google Scholar, (2) purposive search of the NDoH website, and (3) requesting relevant stakeholders’ meeting minutes and reports related to the design and implementation of the MomConnect program.The Google Scholar search covered the period 2014–2019, i.e. from the year that MomConnect was implemented until the year the document review was initiated. Using the terms ‘MomConnect intervention’ OR ‘MomConnect program’ resulted in 266 hits. Combining the terms (‘MAMA South Africa’ AND ‘MomConnect program’) resulted in 86 additional documents, resulting in 352 documents. Eighteen documents relating to the MomConnect program were found by searching the NDoH website. Ten meeting minutes and reports were retrieved from key stakeholders resulting in a total of 380 documents , reading (thorough examination), and identifying themes within the documents associated with the elements of ToC and the concepts of RE theory formulation. This iterative process combined elements of content and thematic analyses . ContentInductive coding and deductive categorizing were performed to uncover and align themes related to the ToC framework Fig. . After oFigure The process of constructing the ToC provided three critical features toward developing an initial program theory of the MomConnect program. Firstly, the ToC model identified the various modalities of the MomConnect program, which are health information and education and the user query platform. Secondly, it clearly articulated the intended outcomes (short-term and long-term) of the MomConnect program. Finally, the ToC provided tentative causal links in a stepwise manner to show how the outcome is to be achieved Fig. .Fig. 5TOur ToC underpinned the process of developing the initial program theory, which is based on the RE methodological approach. As highlighted in Fig. Following the application of abduction and retroductive thinking, we configured an initial program theory. Table A key component of the program consists of sending pregnancy-related stage-based messages (I) to pregnant women and mothers (A), facilitated by health systems conditions such as facility readiness to provide care (C), and intervention-related resources and mobile connectivity (C). The pregnancy-related stage-based information was envisaged to encourage and empower (M) users through knowledge acquisition to motivate them (M) thus improving their health-seeking behavior (O).Interaction with the health system (service rating and feedback) (I) is influenced by health system conditions such as facility readiness to provide care (C) and health care worker availability and buy-in (C). By rating the services received at the facility level, women and mothers are expected to feel empowered (M), which in turn would result in improved quality of health care delivery (O) and improved uptake of MCH services (O).We aimed to glean an initial program theory of the MomConnect initiative to understand how and why the program works (or not). We used the ToC and RE approaches to elicit the initial program theory . Using tFindings from the study revealed that if pregnant women and mothers receive pregnancy related information by ‘SMSs’, they will become sensitized about existing MCH services tailored to the stage of their pregnancy. Being sensitized can encourage and motivate them to attend clinic appointments, ultimately decreasing maternal and child mortality. We also found that the interaction with the health system (service rating and feedback) provided by the MomConnect program is likely to empower users, since they feel that it can improve the quality of services offered at healthcare facilities, thus improving the perceived quality of MCH services and, in turn, the uptake of health services.These findings are consistent with the work by Ruton et al.  in whichOur findings are also supported by the mHealth FrontlineSMS-based application that provided women with information in Ethiopia  and the A study conducted by Hategeka et al.  in RwandOur initial program theory is consistent with some existing models such as the Elaboration likelihood model (ELM) and the extensive Elaboration likelihood model (eELM) , and theThe Theoretical Domains Framework (TDF) was developed to assess implementation problems, support intervention design, and investigate the fidelity of intervention delivery . TDF posWe contend that applying the ToC approach and then moving on to the RE approach facilitated the process of developing the initial program theory. The ToC was used to explicate the implementation theory for program planning, improvement, and the development of robust monitoring systems at a macro program level . The RE The formulation of the ToC and initial program theory was achieved in an iterative process – moving back and forth between the data, the ToC, and developing the initial program theory. All authors held discursive weekly meetings to conceptualize and finalize the ToC and initial program theory.Overall, our study has established theoretical foundations and comprehensive requirements for the development of program theory in mHealth interventions (MomConnect), to support decision making, and decision support capabilities. Our study contributes to the cumulative theory development activities, mHealth, MCH services, and decision support. The program theory and connection between mHealth, improved MCH services, and decision making is highlighted in our ToC and RE, and the implications for developers of mobile-based interventions are that the model provides a holistic approach to system thinking, systems analysis, and design. This assisted in actualizing the next phases of our study, which is the development of a program theory using a scoping review and stakeholders’ interviews.The study has several limitations as both ToC and RE have their challenges. For instance, the ToC model tends to be linear and lacking detail, particularly around causality. The model can be too descriptive and ignore issues of power and conflicting theories. ToC is also time and resource-intensive and has some difficulties in dealing with multiple perspectives, unexpected outcomes, and critical analysis. In RE, on the other hand, it can be difficult to identify and conceptualize mechanisms and separate context from mechanisms. RE lacks substantive theory in some fields, multiple and conflicting theories in others, and uses inaccessible jargon. Like ToC, RE is also time and resource-intensive. A final limitation is that this study only included document reviews and excluded studies such as RCTs and systematic reviews.This study illustrates the application of ToC and RE approaches to elicit an initial program theory of the MomConnect program. Because both approaches take an explicitly cumulative approach to knowledge generation, they have been usually applied in isolation. Based on the experience from our study, we concur that ToC and RE approaches can be practically employed together and that their synergism can partially overcome the critiques of each methodology. We found that the application of both ToC and RE enhances learning and the unveiling of the initial program theory rather than delivering answers to questions of program effectiveness.Additional file 1 List of documents containing clauses for MomConnect program (n = 22) the Document was ordered by date of publication.


With the passage of the Deficit Reduction Act of 2005 and the Patient Protection and Affordable Care Act in 2010, Medicare's Inpatient Prospective Payment System (IPPS) began a transition to value-based purchasing (VBP) that rewards or penalizes hospitals based on patient satisfaction, clinical processes of care, outcomes, and efficiency metrics. However, hospital-level volatility vs. persistence in value-based payments year-over-year could result in unpredictable cash flows that negatively influence investment behavior, drive underinvestment in community benefit/population health management initiatives, and make management of the factors that drive the VBP adjustment more challenging. To evaluate the volatility and persistence of hospital VBP adjustments, the sample includes VBP adjustments and the associated domain scores for the 2,547 hospitals that participated in the program from 2013 to 2016. The sample includes urban (74%), teaching (29.1%), system affiliated (46.5%), and not-for-profit (63.6%) facilities. Volatility was measured using basic descriptive statistics, relative risk ratios, and a fixed effect, autoregressive, dynamic panel model that robust-clustered the standard errors. There is substantial change in a given facility's total VBP score with an average standard deviation of 10.74  that is driven by significant volatility in all metrics but particularly by efficiency and outcomes metrics. Relative risk ratios have dropped substantially over the life of the program, and there is low persistence of VBP scores from one period to the next. Findings indicate that if hospitals receive a positive adjustment in 1 year, they are almost as likely to receive a negative adjustment as a positive adjustment the following year. Furthermore, using a fixed-effect dynamic panel model that controls for autocorrelation, we find that only 13.5% of a facility's prior year IPPS adjustment (positive or negative) carries forward to the next year. The low persistence makes investment in population health management and community benefit more challenging. National healthcare expenditures have grown from $146 per person in 1960 to $11,172 per person in 2018. During the same time period, the percentage of the gross domestic product (GDP) devoted to healthcare has grown from 5% to over 17.7%. Healthcare spending projections from Centers for Medicare and Medicaid Services (CMS) continue to grow at rates that outstrip projected inflation rates and are projected to account for per person spending just under $17,000  in the next 7 years  is moving more Medicare fee-for-service (FFS) reimbursements to an alternative payment model (APM) basis and aims to grow that percentage to 50% , 9. To dThough voluntary in 2012, participation in the VBP program became mandatory in 2013 for hospitals receiving IPPS payments and meeting the minimum number of cases, surveys, or measures required to calculate the adjustment . The program works by adjusting the Diagnosis-Related Group (DRG) base rate up or down relative to performance on predetermined measures. Adjustments started at ±1% of IPPS hospital-specific base rates in 2013 and have increased by 0.25% per year. In 2017, the program put up to 2% of the Medicare IPPS at risk—the maximum at-risk percentage for the program. Because the program is revenue neutral, increases in the hospital base rate are equally offset by decreases at other hospitals with the average adjustment centered on zero. Those facilities that deviate the most positively or negatively from the mean receive the largest positive and negative IPPS adjustment.In an environment where profit margins are already thin, ranging from 3 to 5% depending on hospital ownership, location, and teaching status , 11, fluWhile some prior work has examined the magnitude of the VBP adjustments and the associated relationships with quality and hospital profitability –14, thisPrior literature on earnings persistence within the healthcare sector is largely absent. Outside of the sector, substantial efforts have been devoted to the relationship between measures of persistence and methods of improving security pricing –21, the The prior research on the effects of P4P programs, including systematic reviews, is more robust, but the findings are mixed . Some stDespite the potential for adjustments of up to 1.75% in 2016, early evaluations of the VBP adjustment indicate that over 74% of hospitals nationally experience a change in IPPS reimbursement of >0.50% , 13, 31.Unlike some prior P4P payment incentives that employ more targeted performance metrics and incentives, the VBP adjustment to the IPPS utilizes a wide variety of factors. In 2013, the first year of the program, the VBP adjustment was driven only by patient satisfaction and clinical process scores, with 70% of adjustment driven by the clinical process score. As the program matured, outcomes and efficiency metrics were added to the overall calculation and accounted for 40 and 25% of the overall adjustment, respectively. As detailed in VBP adjustments and the respective unweighted domain scores for all hospitals in the United States were gathered from CMS for years 2013–2016. For descriptive and analytic purposes, hospital characteristics were gathered from HCRIS data  and matched on the unique provider identification. Inclusion criteria required VBP adjustments for all 4 years of the program and resulted in 2,547 hospitals and 7,641 observations. Hospital characteristics of those in the analysis are included in The volatility of the IPPS adjustments was measured as the standard deviation and the relative standard deviation (standard deviation/mean) of their final VBP score (scored 0–100) prior to a financial adjustment being tied to a given score. The process was repeated for the associated VBP domains over the 2013–2016 time frame as long as the domain contributed to the final IPPS adjustment. Since unweighted domain scores are scored based on a 0–100 percentile achievement for all years in the study, they did not require standardization. However, the financial VBP adjustments increased from ±1 to ±1.75% over the 2013–2016 time frame and required standardization. To account for the change, every facility adjustment was standardized by the total potential adjustment in the respective year for a standardized adjustment of between−100 and 100% for every year in the sample. For example, a facility that received an upward adjustment of 0.75% in 2014 would receive a standardized score of 60% or (0.75/1.25). With an upward adjustment of 0.75, the facility received a total of 60% of the total potential upward adjustment for that time period.Relative risk measures were also calculated for the 2013–2014, the 2014–2015, and the 2015–2016 time frames as an additional volatility metric. These metrics measure the relative risk of receiving a positive VBP adjustment where receiving a positive adjustment in the prior year is treated as the exposure. All measures of volatility are presented in 1 coefficient associated with a lagged, standardized VBP adjustment in a time series analysis (a dynamic panel model with maximum likelihood estimation) where time-invariant hospital characteristics are fixed (Equation 1). The standardized adjustment for a given period t and facility i serves as the dependent variable. The standardized score from the hospital's prior period (t-1) and a vector of time-invariant, hospital-specific characteristics serve as the independent variables. Standard errors were clustered at the facility level to adjust for within-facility correlations after Durbin–Watson tests indicated some small autocorrelations , and our model estimated a β1 parameter of 0.135. On average, 13.5% of a hospital's prior VBP financial penalty or reward carries to the next period.The persistence measure associated with VBP adjustments reinforces the volatility metrics. In the fixed-effects model where hospital characteristics and autocorrelation are controlled for, a βWhen examined on a between-group basis, all of the time-invariant characteristics are significant predictors of the VBP adjustment persistence. Facilities that are affiliated with a system, designated as urban, and are teaching institutions have, on average, maintain slightly less of their VBP adjustments than peers. Not-for-profit firms maintain slightly more of their VBP adjustment. While all characteristics are significant at the <0.01 level, the adjustments are not operationally significant. The largest between-group difference is among urban and non-urban facilities where the parameter estimate is −0.0646. To put this in context, a −0.0646 parameter estimate indicates that urban facilities are able to maintain one-tenth of one percentage point  more of their VBP adjustment relative to non-urban facilities.Hospitals participating in the VBP program have experienced significant volatility in their total VBP score and a lack of persistence in the associated IPPS adjustments. Hospitals that receive a positive adjustment in 1 year are now almost as likely to receive a penalty in the next. The lack of consistency from one period to another makes both financial planning and process management more challenging.As discussed in earlier works , 39, becThe costs of compliance and metric improvement are also important to note. CMS expanded the VBP program to include 23 separate metrics and added a new safety domain  in 2017. As metrics and domains are added, there are at least two direct impacts on hospitals. First, the relative weight of any given metric and the impact it can have on the overall IPPS adjustment diminish. The financial weight and resulting adjustments are spread over more domains and metrics. Second, as items are added to the evaluation protocol, hospitals must implement methods of tracking and improving those metricsIt is not clear that each domain and metric reinforce each other. For example, to score well on the MSPB metric, a facility would be interested in cost control and utilization management tools. As suggested by Das et al. , those cFrom a community benefit perspective, the “two-canoe” problem of population health initiatives becomes more pronounced under the hospital VBP methodology. Providers have one foot in a canoe that is operating in the traditional volume-based system that incentivizes providing more frequent and more expensive care while the other foot is attempting to occupy a canoe operating in a value-based environment where there are efforts to constrain costs and reduce care that has little to no marginal benefit . As longThere is also a “wrong pocket problem” with a mismatch between investors and those who accrue the benefits of improved health. Providers and facilities may make significant investments of time and money to improve the health and well-being of the communities they serve and those benefits do not necessarily accrue to the investing providers. Efforts may be effective and even result in fewer patient visits or reduced facility occupancy, which has a negative impact on the bottom line. Not only is the healthcare provider incurring community benefit expenses, but they are also negatively impacted by a reduction of volume and frequency. It is also possible that the benefits of population health initiatives accrue to competing or nearby providers that did not make the investment.In cases of a shared-savings program, the reduction in volume may be offset by payouts from the program. The programs themselves transfer significant health status  and medical care (cost of providing care) risk without an associated risk premium. Of the 32 pioneer ACOs that pursued shared savings program with CMS, only 8 remain with only 6 receiving a positive payout at an average rate of 1.37% of benchmark expenditures . There aAlthough there was great interest in the initial years of the VBP program, each year there exists little financial reward for provider organizations  , and whaPayment adjustments continue to be tightly distributed around zero with the majority of hospitals receiving an adjustment of < The datasets generated for this study may be made available upon request to the corresponding author.All authors listed have made a substantial, direct and intellectual contribution to the work, and approved it for publication.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


On the other hand, in patients who underwent RC, ≥pT3, presence of G3 and LVI was significantly associated with OS and CSS in univariate analysis. Multivariate analysis identified inclusion of G3 as a significant predictor of OS and CSS. The concordance rate between LVI at first TURBT and RC was 48.0%. Patients with positive results for LVI at first TURBT and RC displayed poorer prognosis than other patients (p < 0.05). (4) Conclusions: We found that the combination of LVI at first TURBT and RC was likely to provide a more significant prognostic factor.(1) Background: This study aimed to evaluate the associations of lymphovascular invasion (LVI) at first transurethral resection of bladder (TURBT) and radical cystectomy (RC) with survival outcomes, and to evaluate the concordance between LVI at first TURBT and RC. (2) Methods: We analyzed 216 patients who underwent first TURBT and 64 patients who underwent RC at Toho University Sakura Medical Center. (3) Results: LVI was identified in 22.7% of patients who underwent first TURBT, and in 32.8% of patients who underwent RC. Univariate analysis identified ≥cT3, metastasis and LVI at first TURBT as factors significantly associated with overall survival (OS) and cancer-specific survival (CSS). Multivariate analysis identified metastasis (hazard ratio (HR) 6.560,  The presence of lymphovascular invasion (LVI) has been suggested to predict poor prognosis of bladder cancer, such as more advanced disease and recurrence, and has been reported as a poor prognostic factor even for other carcinomas ,7,8,9,10Further, LVI has been described as a risk factor in the guidelines of the American Urological Association. Those guidelines define high-grade and T1 tumors, recurrent high-grade and Ta tumors, high-grade Ta and large (>3 cm) tumor, multifocal high-grade Ta tumor, any carcinoma in situ (CIS), any Bacille de Calmette et Guérin failure in high-grade cases, any variant history, any high-grade prostatic urethral involvement, and any LVI as high-risk factors . HoweverAs noted above, LVI has been studied in case reports of small numbers of cases, in larger international collaborative groups, and in meta-analyses. In particular, an extensive body of literature exists regarding LVI at RC, which is strongly suggested to be associated with poor clinical outcomes. On the other hand, LVI at TURBT has also been increasingly reported recently, and is suggested to be associated with poor prognosis. TURBT is the first-line treatment for bladder cancer, and we considered first-time (first) TURBT as the most important for diagnosis and treatment. Although many investigations have examined TURBT and RC individually, few have looked into LVI at TURBT and RC.The present study aimed to evaluate the relationship between LVI on both TURBT and RC, as well as overall survival (OS) and cancer-specific survival (CSS). The present study also aimed to assess the concordance rate between TURBT and RC specimens with regard to the presence of LVI. Furthermore, we analyzed differences in prognosis due to the combination of LVI at TURBT and RC.n = 1); concurrent or recurrent bladder cancer with upper urinary tract urothelial carcinoma (UC) (n = 16); bladder Tis lesions only (n = 8); and missing values (n = 50). A final total of 216 patients were analyzed for prognostic factors of first TURBT, and to determine the utility of LVI . We identified 423 patients with bladder cancer treated by TURBT at Toho University Sakura Medical Center between January 2012 and December 2016. Moreover, a total of 291 patients underwent first TURBT for bladder cancer. Of those, 75 patients were excluded from the present study due to the following reasons: tumor of any other origin (y of LVI .n = 2); and missing values (n = 9). Eventually, a total of 64 patients were analyzed regarding prognostic factors for RC , presence of metastasis, urinary cytology, histological variant, CIS, and LVI. LVI was defined as the presence of tumor cells within an arterial, venous, or lymphatic lumen. Presence of LVI in specimens was assessed using conventional hematoxylin and eosin (HE) staining. If we encountered any difficulty in evaluations using only HE staining, we added Elastica van Gieson staining. Positive urinary cytology was defined as ≥class IV  according to Papanicolaou’s classification. Lymph node metastasis and distant metastasis were collectively defined as metastasis. Pathological evaluation was performed by two out of three pathologists each as a council system in Toho University Sakura Medical Center using the tumor, node, and metastasis classification system updated in 2009 and the new classification for grading non-invasive urothelial bladder carcinomas proposed by the World Health Organization and the International Society of Urological Pathology in 2004 ,8,9,10.t-tests. Non-parametric variables were compared using Mann-Whitney U tests. The Kaplan-Meier method was used to estimate OS and CSS following TURBT and RC, respectively. The log-rank test was used to compare statistical significances in each curve. After variables were selected in univariate analyses, regression analyses of Cox proportional hazards were performed to determine factors significantly associated with OS and CSS.Results are presented as median and range or mean ± standard deviation, as appropriate. Continuous parametric variables were compared using p < 0.05 were considered significant.These statistical analyses were carried out using JMP Pro version 13 . All statistical tests were two-sided, and values of n = 216). Mean patient age was 71.3 ± 9.3 years, and males represented 79.6% of the study population. G3 was present in 43.5% of patients, 22.7% of patients had LVI, and only 9.7% had CIS. We compared the LVI-positive and -negative groups (p < 0.001), pathological T stage (p < 0.001), non-papillary (p < 0.001), G3 (p < 0.001), and histological variant (p < 0.001), compared to the LVI-negative group. Subsequently, we analyzed prognostic factors from first TURBT . Multivariate analysis identified metastasis (hazard ratio (HR) 11.363, 95% confidence interval (CI) 3.968–32.285; p <0.001) as significant predictors of OS after first TURBT. According to univariate analyses, ≥cT3 (p < 0.001), metastasis (p < 0.001), histological variant (p < 0.001), and LVI (p < 0.001) were significantly associated with CSS (n = 167) displayed significantly better CSS than those in the LVI-positive group at first TURBT . Multivariate analysis identified metastasis  and LVI  as significant predictors of CSS.The clinical and pathological characteristics of patients who underwent first TURBT are shown in e groups . The LVIst TURBT . Univariwith CSS . Patientn = 64). Mean patient age was 68.2 ± 7.9 years, and males represented 79.7% of the study population. G3 was present in 53.1% of patients, 32.8% of patients had LVI, and 10.9% had CIS. Moreover, in 13 patients with lymph node metastasis, 9 patients had positive LVI at RC (p = 0.046). We analyzed the survival implications in 64 patients who underwent RC . Multivariate analysis identified presence of G3  as a significant predictor of OS. According to univariate analyses, ≥cT3, presence of G3 and LVI were significantly associated with CSS  (n = 43) exhibited significantly better CSS than those in the LVI-positive group at RC . Multivariate analysis identified presence of G3  as the only significant predictor of CSS.Clinical and pathological characteristics of patients who underwent RC are shown in rwent RC . In univctively) . PatientWe analyzed the concordance rate between LVI at first TURBT and LVI at RC . We analp = 0.006), and LVI was more frequently evident (p = 0.003) compared to the group not receiving NAC (NAC- group). On the other hand, patients in the NAC+ group at RC displayed significantly higher pT stage than those in the NAC- group (p = 0.044). No significant difference in the presence or absence of LVI was evident between NAC+ and NAC− groups at RC (p = 0.312). In patients showing LVI (LVI+) at first TURBT, but not at RC, pT stage was pT0 in 9 patients (42.9%). n = 14) and NAC− group (n = 17) in LVI+ cases at first TURBT (p = 0.252).We confirmed the effect of NAC on LVI in RC specimens. The clinical and pathological characteristics of patients according to use of NAC are shown in p = 0.016)  had the best prognosis, and patients with evidence of LVI at both first TURBT and RC (TURBT+/RC+) had the worst prognosis (= 0.016) . Five-yeThis study detected LVI in 22.7% of first TURBT specimens and in 32.8% of RC specimens. These rates were comparable to those described in the literature. The rate of LVI at TURBT has been reported as 6%–70%, and the rate of LVI at RC has been reported to range from 30% to 50% . Clinicap < 0.001, p = 0.47). On the other hand, LVI was found to be a significant predictor of CSS in multivariate analysis. Various studies have reported that LVI was associated with CSS, but not with OS. A meta-analysis of LVI at first TURBT has shown that the pooled hazard ratio was significant for CSS , but not for OS  [p = 0.049) [p < 0.001) [At first TURBT, ≥cT3, presence of metastasis, histological variant, and LVI were found to be significantly associated with OS and CSS in univariate analyses. However, in the patients with only lymph node metastasis, univariate analysis showed a significant difference in OS, but multivariate analysis did not about OS (< 0.001) . In addi< 0.001) ,25.Subsequently, at RC, factors of ≥pT3, presence of G3 and presence of LVI were found to be significantly associated with OS and CSS in univariate analyses. In multivariate analysis, inclusion of G3 was identified as a significant predictor of OS and CSS. High tumor grade is included as a high-risk factor in all guidelines, and it is also included as a factor in the nomogram that predicts risk of recurrence after RC . On the p = 0.282). However, in 14 patients who were diagnosed with LVI + at TURBT and underwent NAC, the RC LVI negative group had a significantly better prognosis than the RC LVI positive group (p = 0.03867)  . AlthougNext, we considered the concordance between LVI in first TURBT and RC specimens. A total of 10 patients 32.2%) with LVI at first TURBT showed the presence of LVI at RC. On the other hand, a total of 14 patients (73.7%) without LVI at first TURBT had negative LVI at RC. In other words, the concordance rate between LVI at TURBT and at RC was 48.0%. The concordance rate was about 60%–70% in some other reports, but was lower in this study 2.2% with,36. MoreLVI at first TURBT and RC were associated with OS and CSS. Specifically, LVI at first TURBT was suggested to represent an independent prognostic factor for CSS. Furthermore, we found that the combination of LVI at first TURBT and RC was likely to offer a more significant prognostic factor than either factor individually.