The BDI-II score of the patient group showed a moderate negative correlation with the tract volume value of the right (r =  − 0.33) and left (r =  − 0.41) DLPF-TT (p < 0.05). On the other hand, no significant correlations were detected between the BDI-II score of the patient group and the values of the other DTT parameters values for the three PF-TT regions (p > 0.05). Using DTT, depression was found to be closely related to a DLPF-TT injury in patients with mild TBI. We believe that evaluation of the DLPF-TT using DTT would be helpful when assessing patients with depression following mild TBI. These results can provide useful information regarding the proper application of neuromodulation in the management of depression.The prefrontal lobe has been considered to be closely related to depression. This study examined the relationship between depression and three prefronto-thalamic tract (PF-TT) regions  in patients with mild traumatic brain injury (TBI), using diffusion tensor tractography (DTT). Thirty-seven patients with depression following mild TBI were recruited based on Beck Depression Inventory-II (BDI-II) scores. Thirty-one normal control subjects were also recruited. The three regions of the PF-TTs were reconstructed using probabilistic tractography and DTT parameters for each of the three PF-TT regions were determined. The tract volume of the DLPF-TT and OF-TT in the patient group showed a significant decrease compared to that of the control group ( Among these, mild TBI is observed in 75–90% of all TBI patients. Moreover, up to 44% of mild TBI patients were reported to suffer from depression3. Depression, a risk factor associated with poor recovery, leads to a range of problems, such as mood , behavior , cognitive (memory and attention), physical (fatigue and headache), and sleep problems3. These problems can deteriorate a patient’s quality of life4. Therefore, it is important to investigate the pathogenic mechanism of depression. Previous studies related to the pathogenic mechanism of depression reported that depression is associated with multi-focal brain abnormalities including abnormalities in the cingulate cortex, amygdala, hippocampus, basal ganglia, thalamus, prefrontal cortex (PFC), and other brain regions6. In particular, the dorsolateral PFC (DLPFC), which manages the modulation and regulation of mood, is considered to play a key role in depression8. Many studies using various brain imaging methods, including positron emission tomography, functional magnetic resonance imaging (MRI), and voxel-based morphometry, have reported that injury of the DLPFC can lead to depression16. In addition, the DLPFC has been a primary treatment target region of repetitive transcranial magnetic stimulation used in the management of depression18.Traumatic brain injury (TBI) may be classified into three types  according to the level of injury severity19. This also has the advantage of being able to detect even subtle changes of the white matter in the human brain19. DTI is suitable for use in an investigation of depression because depression is associated with various brain regions. Of particular note, diffusion tensor tractography (DTT), which is a derivative of DTI, provides for three-dimensional visualization and localization of neural tracts in the human brain20. Previously, three regions within the prefronto-thalamic tract (PF-TT), the dorsolateral prefronto-thalamic tract [DLPF-TT], the ventrolateral prefronto-thalamic tract [VLPF-TT] and the orbitofronto-thalamic tract [OF-TT] were reconstructed using DTT in normal subjects21. Many studies have used DTI to examine the changes in various brain regions in patients with depression, including the PFC, cingulate cortex, and amygdala12. Regarding TBI, many DTI studies of patients with post-traumatic stress disorder or depression have been reported25. Regarding the DTT, however, only one case study incorporated DTT in its investigation of depression in a patient with TBI26.Recent developments of diffusion tensor imaging (DTI), which measures the diffusion of water molecules, has allowed an investigation of the entire microstructural features of white matter in pre-defined regions of interest (ROIs)27. In contrast, since the introduction of DTI, many DTI-based studies could demonstrate axonal injury lesions that are related to the presence of various clinical features such as central pain, memory impairment, or motor weakness in mild TBI patients29. Regarding depression, one case study reported that a DLPF-TT injury was related to the presence of depression26. On the other hand, the regions within the PF-TT that may be related to depression in mild TBI have not demonstrated. This study hypothesized that, among three PF-TT regions, depression in patients with mild TBI would be associated with injury of the DLPF-TT.Mild TBI is not usually associated with lesions that can be detected by conventional brain magnetic resonance imaging (MRI)In the current study, DTT was used to investigate the relationship between depression and tract injury in three PF-TT regions  in patients with mild TBI.30. Values of BDI-II were obtained by self-report. In addition, 37 healthy control subjects  with no previous history of neurological, physical, or psychiatric illness were recruited. There are no significant differences in sex, mean age, and whole brain volume between patient and control groups. All healthy subjects understood the purpose of the study and provided written, informed consent before participation. Because this study was conducted retrospectively, we could not obtain patient's consent and the study protocol without patient's consent was approved by the Institutional Review Board of a Yeungnam university hospital. (YUMC-2019-06-032). The study was carried out in accordance with relevant guidelines and regulations.Fifty-eight patients with mild TBI visited the rehabilitation department of a university hospital Table . Among t2; repetition time = 10,398 ms; echo time = 72 ms; parallel imaging reduction factor (SENSE factor) = 2; echo-planar imaging factor = 59; b = 1000 s/mm2; and a slice thickness of 2.5 mm (acquired voxel size 1.25 × 1.25 × 2.5 mm3). The head motion effects and image distortions due to the eddy current were corrected by applying an affine multi-scale two-dimensional registration using Functional Magnetic Resonance Imaging of the Brain (FMRIB) Software Library 31. One analyzer (Kwon HG) performed fiber tracking using probabilistic tractography and applied the default tractography option  of the Oxford Centre for FMRIB Software Library with BedpostX method32. For reconstruction of the PF-TT regions a seed ROI was placed on the known anatomical location of the mediodorsal nucleus of the thalamus on the coronal image of the b0 map on each subject’s brain and each of the target ROIs as follows21: (1) DLPFC as Brodmann areas (BAs) 8, 9, and 46 on the coronal image of the b0 map; (2) ventrolateral PFC as BAs 44, 45, and 47 on the coronal image of the b0 map; and (3) orbitofrontal cortex as BAs 47/12, 10, 11, and 13 on the axial image of the b0 map. Values of fractional anisotropy (FA), mean diffusivity (MD), and tract volume (TV) were determined for each subject using MATLAB™ .DTI data were acquired an average of 10.9 ± 11.5 months after the onset of head trauma using a six-channel head coil on a 1.5 T Philips Gyroscan Intera with 32 non-collinear diffusion sensitizing gradients . The imaging parameters were as follows: acquisition matrix = 96 × 96; reconstructed to matrix = 192 × 192; field of view = 240 × 240 mmt statistics were used to evaluate the differences between the DTT parameters  of the three types of PF-TT regions  in the patient and control groups. The r-statistic (Pearson correlation) was used to assess the relationships between the BDI-II score and the FA, MD, and TV values. The correlation coefficient (r) indicates the relative strength  and direction  of a linear relationship between the two values. The significance level of the obtained p value was set at 0.05.Statistical analyses were performed using SPSS software . The independent p < 0.05). In contrast, there were no significant differences in the FA and MD values of the DLPF-TT and OF-TT between the patient and control groups (p > 0.05). In addition, there were no significant differences in the FA, MD, and TV values of the VLPF-TT between the patient and control groups (p > 0.05).Table r =  − 0.33) and left (r =  − 0.41) DLPF-TTs (p < 0.05). On the other hand, no significant correlations were detected between the BDI-II score of the patient group and the other DTT parameter values of each of the three PF-TT regions  (p > 0.05).With regard to the correlation results, the BDI-II score of the patient group showed a moderate negative correlation with the TV values of the right  The TV values of the DLPF-TT and OF-TT in the patient group were lower than those of the control group. (2) The BDI-II score showed a moderate negative correlation with TV value of the DLPF-TT. Among the commonly assessed DTT parameters, the FA, MD, and TV have been used wildly to demonstrate the status of various neural tracts. The FA value indicates the degree of directionality of water diffusion. Consequently, it reflects the fiber density, axonal diameter, and white matter myelination, whereas the MD value indicates the magnitude of water diffusion16. These studies showed that the blood flow and gray matter volume of the DLPFC in patients with depression were lower than those in the control subjects14. Regarding DTI analyses, a few studies reported decreases in the FA value in the DLPFC area, which was measured using an ROI-based method, of patients with depression compared to those of the control subjects12. Specifically, Taylor et al. (2004) and Yang et al. (2007) demonstrated that the superior frontal gyrus including the DLPFC exhibited a lower FA value in patients with late-life depression than the normal subjects11. In addition, Blood et al. (2010) reported that DLPFC white matter in patients with major depressive disorder had a lower FA value compared to that of normal subjects12. With regard to DTT, only one case study has been reported. In 2016, Jang et al. reported the presence of DLPF-TT injuries in both hemispheres of a patient with depression26.Several studies have reported the presence of DLPFC injury in patients with depression35. Fourth, although DTT is a powerful anatomic imaging tool that can demonstrate gross fiber architecture, it can produce false positive and false negative results due to crossing fibers or the partial volume effect36. Therefore, further studies will be needed to overcome the above limitations.To the best of our knowledge, this is the first original study to demonstrate a relationship between depression and DLPF-TT injuries in patients with mild TBI by using DTT. However, some limitations of this study should be considered. First, only patients with depression who visited the rehabilitation department of a university hospital were recruited. Therefore, it is possible that among the patients with mild TBI, we recruited patients with a different level of severity of clinical manifestations than that of other patient populations. Second, regarding the results of significance of only TV (non-significance of FA and MD), we could not provide the apparent evidence why non-significance of FA and MD were shown. Third, their answer for BDI-II could have been exaggerating because it was self-reported. In addition, the generalizability of the results was affected by the spectrum bias, which refers to the differential performance of a test in different settings37.In conclusion, by using DTT, we observed that depression was closely related to the presence of DLPF-TT injury in patients with mild TBI. We believe that DTT-based evaluation of the DLPF-TT would be helpful for patients with depression following mild TBI. In addition, although these results can provide information that may be useful for determining the proper application of neuromodulation, such as repetitive transcranial magnetic stimulation or transcranial direct current stimulation, in the management of depression, TBI-related depression is different than from major depressive disorders in terms of the seizure risk


The application of pultruded glass fiber-reinforced polymer composites (PGFRPCs) as a replacement for conventional wooden cross-arms in transmission towers is relatively new. Although numerous studies have conducted creep tests on coupon-scale PGFRPC cross-arms, none had performed creep analyses on full-scale PGFRPC cross-arms under actual working load conditions. Thus, this work proposed to study the influence of an additional bracing system on the creep responses of PGFRPC cross-arms in a 132 kV transmission tower. The creep behaviors and responses of the main members in current and braced PGFRPC cross-arm designs were compared and evaluated in a transmission tower under actual working conditions. These PGFRPC cross-arms were subjected to actual working loads mimicking the actual weight of electrical cables and insulators for a duration of 1000 h. The cross-arms were installed on a custom test rig in an open area to simulate the actual environment of tropical climate conditions. Further creep analysis was performed by using Findley and Burger models on the basis of experimental data to link instantaneous and extended (transient and viscoelastic) creep strains. The addition of braced arms to the structure reduced the total strain of a cross-arm’s main member beams and improved elastic and viscous moduli. The addition of bracing arms improved the structural integrity and stiffness of the cross-arm structure. The findings of this study suggested that the use of a bracing system in cross-arm structures could prolong the structures’ service life and subsequently reduce maintenance effort and cost for long-term applications in transmission towers. In electrical power grid systems, transmission towers are implemented to grasp and hold conductor cables from power generators to substations in continuous line connections. Transmission towers are divided and grouped into two major types, namely, latticed steel towers and monopole steel tubes. Latticed steel towers have been installed throughout Peninsular Malaysia since 1929 .Neobalanocarpus hemii) were previously applied because they provided superior mechanical performance and arc quenching during lightning strikes [Wooden cross-arms made from Chengal wood , secondary (steady-state) and tertiary (accelerated) and end in structural failure. In the primary creep stage, the creep rate decreases at function of time due to strain hardening or mobile dislocations. For the secondary creep stage, the creep rate remains almost constant as a state of balance is achieved between the rate of dislocation generation and the rate of recovery. Tertiary creep stage is followed as the creep rate increases rapidly until the material ruptures after undergoing a total of strain within a time. Over the long term, creep causes shear yielding, void formation and growth, chain slippage and fiber breakage. These phenomena subsequently allow the material to become fractured ,26,27. TComposite cross-arms must be subjected to creep experiments to formalize, analyze and predict creep behaviors during long-time service systematically. In order to ensure better long-term durability of PGFRPC cross-arms, bracing systems are introduced in this research to compare and evaluate the long-term mechanical performance of the current design used in in 132 kV transmission towers. Important data can be collected and assessed by using a full-sized cross-arm in the creep test under actual load conditions in an external tropical environment. This approach will contribute to the comprehension and forecasting of the long-term mechanical durability of existing cross-arm structures incorporated with bracing arms. Furthermore, it will provide a highly holistic and intuitive perspective for evaluating the behavior of whole structures.PGFRPCs have only been recently applied in the cross-arm structures of latticed transmission towers to replace conventional wooden cross-arms. A literature survey revealed that no previous works have evaluated the creep behaviors of full-scale PGFRPC cross-arms in 132 kV transmission towers. This research aimed to analyze the influence of the bracing system on the creep behaviors and responses of PGFRPC cross-arms in transmission towers under actual loading conditions. Moreover, this work aimed to establish the baseline creep properties of full-scale PGFRPC cross-arms. Thus, the outcomes of this study are projected to provide a practical perspective to researchers and engineers for understanding the long-term mechanical behavior of PGFRPC cross-arms.The methodology of this research is divided into two stages: experimental works and numerical analyses. Further detail methods and steps of the research are discussed in the subsequent subsections. In general, 2) with a thickness of 7.8 mm. The total length of the cross-arm’s main member was 3651 mm and that of the tie member was 3472 mm. Each cross-arm member was assembled with bolts and nuts with their fastening brackets. After the assembly of the cross members, a whole set of cross-arm units were fitted inside the creep test rig with a constant load of 647 kg of bricks on the end side.The PGFRPC cross-arm was applied as the test subject in the preparation stage of the creep test. This cross-arm comprised one tie and two main members. The PGFRPC cross-arm for the 132 kV suspension tower was obtained from a local cross-arm manufacturer, Electrius Sdn Bhd, in Klang, Selangor, Malaysia. The PGFRPC cross-arm assembly members were fabricated via pultrusion by using unsaturated polyester resin as the matrix and E-glass as the reinforcement fiber. The physical size and dimensions of the cross-arm were determined in accordance with the actual standard of the Tenaga Nasional Berhad. Each member cross-arm was shaped in the form of a square hollow section  and three short members (joined at the middle to the middle of every member). The lengths of the long (tie–main), short (tie–main) and short (main–main) bracing members were 186, 50 and 40 cm, respectively. This study focused on the effect of the bracing system in a cross-arm assembly on creep properties. Thus, five additional beams were incorporated and connected to the main cross-arm structure. The bracing arms were fabricated with the dimensions of 50 × 50 mmA cantilever beam setup test condition implementing two-point bending application was executed to assess the creep properties of PGFRPC cross-arms. Dial gauges were positioned at five points of each main member of the cross-arm. As shown in The creep test was performed in accordance with ASTM D2990 with 1000 h of test operation. The dial gauge readings for deformation were taken at 0, 0.1, 0.2, 0.5, 1, 2, 5, 20, 50, 100, 200, 500, 700, and 1000 h intervals. The initial strain was evaluated at 15 s after the working stress was loaded and considered as an instantaneous strain. The environmental condition was maintained and was influenced by actual tropical weather because the test was conducted outdoors . At the end of the experiment, existing (without bracing members) and improved (with bracing members) cross-arm designs were subjected to creep strain and modulus comparison and creep numerical analysis. In this research, the cross-arm was assumed as a cantilever beam structure because it is horizontally extended from one end. Thus, cantilever beam equations and derivations were used to evaluate the cross-arm’s long-term mechanical properties. The cross-arm structure was exposed to constant tension and compression reactions on its upper and bottom sides during the application of a downward constant load. This condition created a series of strain patterns corresponding to the location of load implemented at the free end of the beam. Given that the displacement movement was maintained at a certain position for a period of time, the beam exhibited a stress response pattern across its length. In this pattern, stress gradually decreased from the fixed point to the free ends. This behavior showed that the viscoelastic beam responded to the material’s viscous characteristic; this response reduced the total stress ,32. Deflection could be assumed to occur in the cross-arm because the upper part of beam was in tension mode, whereas the bottom part is in compressive mode. Specifically, the cross-arm was exposed to non-uniform stress distribution in accordance with the beam’s length and thickness. Given that the cross-arm comprised PGFRPC material, the profile of the material could be assumed to display uniform density across its length.eE) of the cross-arm’s beam can be generated based on Equation (1):y is the deflection at the beam (m); eE is the static elastic modulus (N/m2); P is the force exerted on the beam (N); L is the total length (m) and b and h are the width and thickness of the beam (m), respectively.As shown in x = 0, whereas the minimum stress is exhibited at the loading end x = L. The maximum and minimum stresses of the beam can be formulated on the basis of Equation (2).Given that the y deflection is already known, the maximum bending stress can be predicted by using Equation (1) . In genetε is the creep strain at a specific time and location point across the beam, nσ is specific stress and eE is the static elastic modulus at the specific point on the cross-arm.Equation (3), which is based on the equation of Hooke’s law, can be used to calculate the creep strain at a specific time and location across the beam.The evaluation of creep trends and properties can be further extended by using established creep models, such as empirical and physical models. In the empirical model, the nonlinear Findley power law model is used to justify and clarify transient creep in accordance with stress factor and material constants. Moreover, the Findley model can remove any exaggerated data deviation because the empirical model is simple and straightforward ,35. HoweA and n are the transient creep strain and time exponents, respectively, and In Equation (4), The Burger model is a physical model that is usually applied to describe and visualize the creep pattern with a spring and dashpot diagram to examine the viscoelasticity of creep. Perez et al.  and ChanThe presented model is presented as Equation (5).eε, dε and vε, which are called the elastic strain, viscoelastic strain and viscous strain, respectively. The mathematical formulation in Equation (5) comprises σ is the applied stress; eE and dE are the elastic moduli of the springs and t is the time, and τ is the retardation time for the Kelvin element to produce 63.21% (or 1–1/e) of its total deformation [Equation (6) was derived on the basis of Equation (5) and the physical elements of Burger models, such as spring and dashpot elements.ormation .eE, dE, The The specific behaviors, such as elastic, viscoelastic and viscous moduli, of the creep properties of the PGFRPC cross-arm can be determined on the basis of the Burger model. In this work, this model was suitable because the creep period was valid only for primary and secondary creep. These outcomes were meaningful for predicting the improvement of long-term mechanical properties through the inclusion of a bracing system in composite structures.The braced cross-arm expressed a lower value of creep strain than the current cross-arm design. The beam laterally (buckling reaction) deflected at the middle of the beam as the force acted downward to the ground . OverallThe creep strain patterns in A and stress-independent material exponent n.As discussed in this section, Findley’s power law was implemented to visualize the steady-state creep experienced by PGFRPC cross-arms . SeveralA parameter of current and braced composite cross-arms were compared as depicted in A parameter of the current composite cross-arm design was higher than that of the braced cross-arm, accounting for the superior steady-state creep response of the existing design. This result indicated that retrofitting the PGFRPC cross-arm with additional braced arms would not influence the secondary stage of creep because the GFRP composite itself exhibited improved creep resistance performance [The transient creep or formance ,46,47. n value of the current composite cross-arm was 0.1366, whereas that of the current PGFRPC cross-arm was approximately 0.2697. The average n value of the braced composite cross-arm (0.2597) was within the acceptable range of 0.20–0.29 [n value of the current PGFRPC cross-arm was 0.1366, which was less than the common range of stress-independent material exponents. Moreover, the stress exponent n of the braced composite cross-arm was higher than that of the current composite cross-arm, showing that the braced composite cross-arm had a poorer hardening capability, which resulted in increased flow rate along each individual arm [As shown in .20–0.29 ,49,50. Hdual arm ,52.Adj. R2) values for Findley’s model for both cross-arms (current and braced designs) were close to 1, indicating that the Findley model fitted the experimental data very well. The braced PGFRPC cross-arm (0.997–0.862) exhibited higher Adj. R2 values than the existing design (0.964–0.890). This result demonstrated that the braced composite cross-arm followed the creep principles in the primary and secondary creep stage and that the creep data produced showed reduced exaggeration due to improved structural integrity.All adjusted regression (eE and kη) as shown in The Burger model was used to elaborate the elasticity and viscoelasticity parameters of the two configurations of the PGFRPC cross-arms in the current and braced designs. The computational software OriginPro 2016 was implemented to plot nonlinear curve fit functions to identify two estimation parameters (eE of the two arm configurations was plotted to visualize this phenomenon. Overall, the graph shows that the braced PGFRPC cross-arm had high elastic moduli at y1–y5, likely because the cross-arm was being supported by an additional bracing system, which subsequently increased the elastic critical moment of the beam as the force was exerted [The elastic phase occurred after instantaneous strain directly after the load was applied on the cross-arm. A graph  indicati exerted . This re exerted .The viscoelasticity modulus was another parameter that was evaluated by using the Burger model. This parameter is vital for analyzing the relaxation response over time of a beam inside an interconnected structure, such as cross-arms. This parameter is also called the irrecoverable creep strain, which accounts for the relaxation coefficient of the viscoelastic property . Figure 2Adj. R for each fitted model are tabulated in Adj. R2 coefficients for Findley’s power law model ranged from 0.860 to 0.997 and were better than those of the Burger model, which ranged from 0.416 to 0.985. The forecasted value of the Burger model diverged from experimental data because this model forecasted the relationship of viscosity and time linearly [The coefficients of determination or adjusted regression linearly . Hence, linearly ,59. The Each model was further evaluated and validated by comparing their instantaneous strain values with the experimental instantaneous strain. Instantaneous strain was obtained on the basis of Hooke’s law principles, which state that the value of instantaneous stress is linearly proportional to the applied stress. As seen in The time-dependent creep behavior of PGFRPC cross-arms implemented with bracing systems was reduced compared with that of the existing PGFRPC cross-arm design. Therefore, the bracing arms showed potential for installation in latticed transmission towers to grasp electric cables and insulators. Previous works have investigated the creep behaviors of coupon-scale PGFRPC cross-arms in the laboratory environment. This approach is typical for intended baseline characterizations. The creep behaviors of the braced and current designs of PGFRPC cross-arms under outdoor working conditions were compared. This comparison showed that the creep strain of the main member beams in the braced PGFRPC cross-arm had decreased by approximately 8–20% compared with those in the existing PGFRPC cross-arm design. Moreover, the incorporation of bracing systems in the cross-arm structure would increase the stability of the viscoelastic stage. This effect could reduce any failure potential within the structure. Further analysis with the Findley and Burger models revealed that the braced PGFRPC cross-arm had a higher elastic modulus than the current design of the PGFRPC cross-arm. The braced systems increased the viscoelastic modulus of the cross-arm, thus enhancing relaxation during creep. Retrofitting the PGFRPC cross-arm with braced arms would not influence the secondary stage of creep given that the PGFRP composite itself had improved creep resistance performance due to its high flexure strength and modulus. This characteristic could be advantageous for using bracing members inside cross-arm structures in the construction of transmission towers to prolong the structure’s service life.Findley’s power law model was a useful tool for describing and predicting the creep responses of braced and current PGFRPC cross-arm designs under their working loads. This model predicted that both PGFRPC cross-arm designs showed low creep rates under their actual working loads. Meanwhile, the Burger model was very practical for explaining the elastic and viscoelastic behaviors of the composite structures. In future works, fatigue and electrical capacity tests should be conducted to evaluate the dynamic load exerted by the wind and the electrical resistance of braced PGFRPC cross-arms. These works could broaden the views and perspectives of researchers and engineers of braced PGFRPC cross-arms.


In the recent decades, the use of computerized decision support software (CDSS)-integrated telephone triage (TT) has become an important tool for managing rising healthcare demands and overcrowding in the emergency department. Though these services have generally been shown to be effective, large gaps in the literature exist with regards to the overall quality of these systems. In the current systematic review, we aim to document the consistency of decisions that are generated in CDSS-integrated TT. Furthermore, we also seek to map those factors in the literature that have been identified to have an impact on the consistency of generated triage decisions.As part of the TRANS-SENIOR international training and research network, a systematic review of the literature was conducted in November 2019. PubMed, Web of Science, CENTRAL, and the CINAHL database were searched. Quantitative articles including a CDSS component and addressing consistency of triage decisions and/or factors associated with triage decisions were eligible for inclusion in the current review. Studies exploring the use of other types of digital support systems for triage  were excluded. Quality appraisal of included studies were performed independently by two authors using the Methodological Index for Non-Randomized Studies.From a total of 1551 records that were identified, 39 full-texts were assessed for eligibility and seven studies were included in the review. All of the studies (n = 7) identified as part of our search were observational and were based on nurse-led telephone triage. Scientific efforts investigating our first aim was very limited. In total, two articles were found to investigate the consistency of decisions that are generated in CDSS-integrated TT. Research efforts were targeted largely towards the second aim of our study—all of the included articles reported factors related to the operator- (n = 6), patient- (n = 1), and/or CDSS-integrated (n = 2) characteristics to have an influence on the consistency of CDSS-integrated TT decisions.To date, some efforts have been made to better understand how the use of CDSS-integrated TT systems may vary across settings. In general, however, the evidence-base surrounding this field of literature is largely inconclusive. Further evaluations must be prompted to better understand this area of research. The protocol for this study is registered in the PROSPERO database (registration number: CRD42020146323).The online version contains supplementary material available at 10.1186/s12911-021-01472-3. In the recent decades, telephone triage (TT) has become recognized as a promising tool for addressing rising healthcare demands and overcrowding in the emergency department –3. TT caAn innovative technique for advancing the quality of TT systems is the use of computerized decision support software (CDSS), which are systems that are specifically designed to support operators in the handling and managing of patient calls. Evidence suggests that the application of TT including CDSS may reduce general practitioner (GP) workload, the number of medical errors, and as well as unnecessary hospital costs , 11–13. Despite its large potential for success, the problem with CDSS-integrated TT is that the application and practical use of these methods are complex and may vary significantly from one setting to another. Many types of CDSS-integrated TT systems are available and a wide range of possibilities exist with regards to their inherent structure, where they are used, and how they are used by operators with different professional backgrounds . For insTo date, there is a lack of evidence summarizing the overall quality of CDSS-integrated TT, and scientific efforts describing the efficiency and effectiveness of TT services from a larger perspective are required , 15. In The present systematic review was conducted and was reported according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) Checklist  see Add. The proA literature search was performed in November 2019 using PubMed, Web of Science, Cochrane Central Register of Controlled Trials (CENTRAL), and the Cumulative Index to Nursing and Allied Health Literature (CINAHL) database. With the help of a librarian specialized in biomedical sciences, an exhausted list of MeSH terms and keywords related to “telephone triage” and “computerized decision support systems” were searched on PubMed. These terms were then adapted for use with other bibliographic databases in subsequent searches. The complete search strategy can be found in Additional file Articles that included a CDSS component in their TT methods and addressed either consistency of triage decision between operators and/or factors associated with triage decision were eligible for inclusion in the current study. Specifically, studies comparing agreement or disagreement of a triage outcome for a presented situation were included for analysis. Studies using a qualitative research methodology and those articles exploring the use of other types of digital support systems for triage  were excluded.Two authors (FI and PH) independently screened titles and abstracts to select those articles that meet the inclusion criteria. Each manuscript judged to be relevant by at least one reviewer proceeded to full text review. Full text articles were then reviewed by these authors and those judged to be irrelevant were further excluded from the review.Data was extracted by one author (FI) using a standardized excel database. Information regarding reference details , main objectives of study, triage disposition categories, methods , characteristics , and study results  were extracted. A second author (PH) reviewed accuracy of data extraction.The quality of included studies were independently rated by two authors (FI and MS) using the methodological index for non‐randomized studies (MINORS) . This isAll discrepancies regarding study inclusion, study selection, data extraction and/or quality assessment were resolved through discussion. In the case that a consensus could not be achieved, an additional author  was consulted to make a final decision.A flow diagram of the study selection process is presented in Fig. The included manuscripts were published between 1998 and 2019. Five of these articles were conducted in the UK , 22, 23,Scientific efforts investigating our first aim was very limited. Specifically, two of the seven articles were found to investigate the consistency of decisions that are generated in CDSS-integrated TT , 21. LarBased on our ratings, the risk of bias (ROB) for studies was found to be low for all included studies , 20–23 . It is iIn a prospective longitudinal study, Brasseur et al.  investigIn a cross-sectional analysis, O’Cathain et al.  examinedSeveral factors were found to have an influence on the consistency of triage decisions generated in CDSS-integrated TT. Specifically, six of the seven studies found operator-related characteristics to have a significant influence on the outcome , 22, 23.Associations between operator-related characteristics and TT decisions were studied by several authors. In a study by O’Cathain et al. , it was In another article, type of experience was also found to be an important factor. Monaghan et al.  comparedIn three studies, the consistency of TT decisions made by nurse-operators with different backgrounds was also assessed. Results showed that between operators, the consistency of triage decisions for referring patients presenting with the same or similar case was low to moderate , 15, 20.Furthermore, three articles , 21 alsoTwo of the included studies also looked at correlations between CDSS-related characteristics and TT decisions. Though the findings of Brasseur et al.  have beeOnly one of the included articles directly assessed patient-related characteristics (e.g. age and symptoms) that may be associated with CDSS-supported TT decision as part of the overall study objective. Dale et al.  showed tThe objective of our systematic review was to collate the available research on CDSS-integrated TT. Despite the growing use of these services, we found that the scientific evidence addressing this topic is largely limited. A small body of inconsistent research was found to address the consistency of CDSS-integrated TT decisions , 22. In Most of the available evidence-base addressed our second research objective which aimed to investigate key factors that influence the consistency of TT decisions , 20–23. Specifically, we argue that two key external domains associated with estimating level of triage urgency include system structures  and the local environment  Fig. . To bettA fairly low number of studies were included in the current review. Though this is largely related to the scare evidence base surrounding this topic, a broader research question using less stringent study inclusion/exclusion criteria may have illuminated a larger scope of relevant findings within the existing literature.Nonetheless, our review has highlighted some important discoveries in the field of CDSS-integrated TT. To date, only observational research efforts based on nurse-led TT have been prompted. The methodological quality of the included articles were found to have a low risk of bias , these possibilities continue to expand. Guidelines created by experts should be adapted to reflect the rapidly evolving capacities of TT techniques.From a scientific point of view, substantial efforts are required to further establish how remote- triage technologies can be used to successfully manage healthcare demands in the population. At the same time, the current pandemic situation has accelerated the growth and use of these systems exponentially, and it is imperative that research efforts catch up. Fruitful research endeavors should therefore seek to further identify and synthesise findings of widely used TT methods, better understand how different factors may influence CDSS-integrated TT (as well as other remote-based triage) using established criteria such as the GUIDES checklist , and cleCDSS-integrated TT has become a prominent instrument for managing unplanned care needs in the population. Our systematic review demonstrates that some efforts have been made to better understand how the use of these systems may vary across settings. In general, however, the evidence-base surrounding this field of literature is to date, very limited and largely inconclusive. Further scientific investigations must be prompted to make conclusive statements about the effectiveness of these systems.Additional file 1. PRISMA Checklist.Additional file 2. Search Strategy Used for Databases.Additional file 3. Complete Study Characteristics.Additional file 4. Quality Appraisal of Included Studies.


Groove pancreatitis (GP) is a rare form of chronic pancreatitis involving the groove area bound by the pancreatic head, the duodenum, and the common bile duct. The diagnosis of this entity is challenging since it can mimic pancreatic carcinoma. We herein report the case of groove pancreatitis diagnosed in a 37 year old men, with a past history of chronic alcohol consumption. The patient was admitted for several times over the past three years because of recurrent alcohol-induced pancreatitis. The diagnosis of groove pancreatitis was made on the basis of CT, MRI and EUS findings. A medical treatment was initially attempted. In the absence of improvement in clinical symptoms, a pancreatico-duodenectomy was performed with satisfying results at 24 months follow up. Pancreatico-duodenectomy is the treatment of choice in groove pancreatitis since it leads to total resolution of clinical symptoms. Groove pancreatitis (GP) is a rare form of chronic pancreatitis involving the groove area bound by the pancreatic head, the duodenum, and the common bile duct . It was We report the case of a 37-year-old man, with a past history of chronic alcohol consumption, presented with epigastric pain radiating to the back, intermittent vomiting and recent weight loss. He had a history of recurrent admissions with abdominal pain secondary to recurrent alcohol-induced pancreatitis over the past three years. The physical examination revealed mild tenderness in the upper abdomen and periumbilical region, while no abdominal mass was detected. Biochemistry tests showed high levels of lipase and amylase  and cholestasis syndrome . Tumor markers (CA 19.9 marker and carcinoembryonic antigen) were within normal limits. A CT of the abdomen was realized . It reveEndoscopic ultrasound (EUS) was performed, showing localized wall thickening in the second portion of the duodenum. The cephalic region of the pancreas was hypoechoic, heterogeneous, with fuzzy limits. It was slightly increased in size with an areolar appearance and some parenchymal micro-calcifications. It was the seat of a 2 cm cystic formation not communicating with the Wirsung duct . These fet al. in 1982 [Groove pancreatitis (GP) is a rare form of chronic pancreatitis, characterised by fibrosis of the paraduodenal groove, ananatomical section limited by the pancreatic head, the duodenum and the main bile duct .This ent in 1982 . In the  in 1982 . Because in 1982 . The exa in 1982 . Also, t in 1982 . Blood t in 1982 . Various in 1982 .et al. have obtained an accuracy diagnosis of 87.2% for groove pancreatitis, using 3 MRI criteria: focal thickening of the duodenum 2, hyper uptake of the second segment of the duodenum, and cystic alterations in the region of the accessory pancreatic duct [Magnetic resonance (MR) imaging usually presents a hypo-intense mass on T1-weighed MR images, and iso or slightly hyperintense on T2-weighed MR images, with delayed contrast enhancement after injection of the contrast material, reflecting its fibrous nature . Nowadaytic duct . Treatmetic duct . If symptic duct . A part tic duct .The pre operative diagnosis of groove pancreatitis is challenging. Despite the development the imaging technics, the differentiation between this entity and pancreatic head carcinoma is still difficult. Medical and endoscopic treatment may be helpful initially or in patients who are unfit for surgery, but the corner stone of therapy is pancreatico-duodenectomy since it leads to total resolution of clinical symptoms.


Interestingly, the dynamic parameters are irrelevant to the size of TDNs, while the larger TDNs rotated slightly during the transporting process. Meanwhile, both the results from single‐molecule force tracing and ensemble fluorescence imaging demonstrate that the different size TDNs transmembrane transporting depends on caveolin‐mediated endocytosis.DNA nanostructures have attracted considerable attention as drug delivery carriers. However, the transmembrane kinetics of DNA nanostructures remains less explored. Herein, the dynamic process of transporting single tetrahedral DNA nanostructures (TDNs) is monitored in real time using a force‐tracing technique based on atomic force microscopy. The results show that transporting single TDNs into living HeLa cells need ≈53 pN force and ≈25 ms duration with the average speed of ≈0.6 µm s DNA nanostructures with inherent biocompatibility have become a unique vehicle in drug delivery. The transmembrane process is the first and the most important step for drug delivery. Herein, the transporting of single tetrahedral DNA nanostructures (TDNs) is recorded by a force‐tracing technique based on atomic force microscopy, and the size effect of TDNs on the transporting dynamics is studied. Nevertheless, the recent critical issue for drug delivery systems is lack of efficient drug delivery carriers.Among the DNA nanostructures, tetrahedral DNA nanostructures (TDNs), self‐assembling from four DNA strands with high yield, are considered as one of the simplest nanostructures.Herein, the dynamic transmembrane process of TDNs is tracked by force tracing technique based on atomic force microscopy (AFM), the force and duration of the transmembrane transport process of single nanoparticles/molecules could be detected down to pico‐newton and milliseconds, respectively.22.1Figure−1, 2 million data points per second). To acquire clear force signal of the fast transporting process, the 20 kS s−1 sampling rate of data acquisition with a 100 low pass filter was applied. The transmembrane transporting of single TDN‐13 is first tracked, and the typical force tracing curve is shown in Figure HeLa cell line is selected as a model to study the dynamic transmembrane transporting process due to its higher activity of cellular uptake.2.2FigureTo explore the size effect, transmembrane transporting measurements of TDNs with different size  were performed, respectively, and the typical force tracing curves are similar. Interestingly, it is found that both the transporting force and duration were undifferentiated. As shown in D was calculated, which includes the bending distance of the AFM cantilever tip (d) and the extension length of the PEG linker (h)What about other dynamic parameters of TDNs in transmembrane transporting? the TDNs engulfment depth F)‐dependent stretching activity by the following equationkB is the Boltzmann constant, T is the absolute temperature, Lp is the persistence length, K0 is the enthalpic correction, h is the extension of PEG linker, and L0 is the contour length. Based on the previous literature,Lp is 3.8 ± 0.02 Å, and the enthalpic correction K0 is 1561 ± 33 pN. Given that the PEG unit length is 4.2 Å, the estimated contour length L0 to PEG linker is about 196 Å. Based on Equation h is calculated as 14.28, 14.43, 14.49, and 14.59 nm for TDN‐13, TDN‐17, TDN‐26, and TDN‐37, respectively. The bending distance of the AFM tip cantilever is calculated using the following Hooke's lawF represents the force of single TDNs transmembrane transporting on living HeLa cells that could be directly measured from the force tracing curves, and K is the spring constant of the AFM tip cantilever. According to Equations D is calculated as 14.89, 15.08, 15.15, and 15.28 nm for TDN‐13, TDN‐17, TDN‐26, and TDN‐37, respectively . Therefore, the average speed of single TDNs transmembrane transporting on living HeLa cells could be calculated as 0.586, 0.596, 0.592, and 0.613 µm s−1 for TDN‐13, TDN‐17, TDN‐26, and TDN‐37, respectively . These results further confirmed the statement that the single TDNs transporting on living cells is size‐independent.Using the extended worm‐like chain model, the stretched length of the PEG linker could be calculated, which characterizes the force  simulation of different size TDNs transporting was conducted based on a dipalmitoylphosphatidylcholine lipid bilayer model. When the length of DNA molecules is short, they are frequently treated as the rigid rods. Therefore, in the simulation, single TDNs is constructed by six rigid rods with the same length . Similar to the lipid model developed by Sunil Kumar et al.,FigureFigure3, and TDN‐37 is 280 nm3). Therefore, the dynamic process of TDNs transmembrane transporting is size‐independent in the range of several tens of nanometers. Comparing the experimental and simulation results, we found that the transporting duration from experiments was longer attributed to the complexity of real cell membrane. The complicated cell membranes have been described as the protein layer–lipid–protein Island model that the proteins at the ectoplasmic side of the cell membrane form a dense protein layer showing a smooth feature with a height of about 4 nm.2.4Figure−1) for 30 min at 37 °C, the probability of force tracing curves with force signal is 10.3%, 9.7%, 10.4%, and 10.1% for TDN‐13, TDN‐17, TDN‐26, and TDN‐37, respectively. The probability is similar to that of untreated HeLa cells . After inhibiting with M‐β‐CD (5 × 10−3m) for 30 min at 37 °C, the probability of force tracing curves with force signal decreased to 4.5%, 4.6%, 5.3%, and 4.9% for TDN‐13, TDN‐17, TDN‐26, and TDN‐37, respectively , the TDNs (red) still could be found inside the cells. However, after inhibition with M‐β‐CD , almost no TDNs was found inside the cells . The colocalization images of the YZ plane and XZ cross‐section confirmed that the TDNs with different sizes were located inside the cells, as shown in s Figure . The res3DNA nanostructures with inherent biocompatibility and biodegradability become a unique vehicle in drug delivery.−1. Meanwhile, the Z‐position of the different size TDNs relative to the middle line of the membrane changes in similar trend as time going  medium with 10% fetal bovine serum (FBS), 100 units mL−1 penicillin (Invitrogen), and 100 mg mL−1 streptomycin (Invitrogen) at 37 °C under the atmosphere 5% CO2. To remove cell debris and unattached cell, the cells were washed with phosphate buffer (PBS) for three times before performing all subsequent experiments.AFM Tip Modification: Modification of AFM tips (PPP‐BSI) need two steps. AFM tips were washed by Piranha solution (V(H2SO4):V(H2O2) = 3:1) for 1 h, cleaned with ultrapure water twice and absolute ethylacohol once then the AFM tips were dried by argon gas, and cleaned under O3 for 30 min to remove other impurities. After cleaning, the AFM tips were modified with 3‐aminopropyltriethoxysilane−1). After drying with argon, the tips were immersed in a mixture of 100 × 10−9m TDNs, 50 µL NH2OH‐reagent , and 50 µL buffer A . After functionalization for 1 h, the AFM tips were washed with PBS for three times and stored at 4 °C.Fluorescence Imaging of AFM Tips: Fluorescence imaging of TDNs modified AFM tips was carried out with Andorra Q3.6.2 confocal microscopy. Cy3 labeled TDNs were excited with a 561 nm helium–neon laser. The fluorescence images were collected with a NA = 1.40, 100 × oil immersion objective. The fluorescence imaging was analyzed by Image J.Force Tracing Experiments: As the sample of force tracing test, HeLa cells were seeded on glass slide in 35 mm petri dish for 1 or 2 d until 75% of the petri dish was covered by HeLa cells. Before performing force tracing experiments, the HeLa cells were washed with PBS for three times and then added to 2 mL DMEM without FBS. In block experiments, the cells were precultured with CPZ (ultimate concentration 10 µg mL−1) for 30 min and methyl‐β‐cyclodextrin  for 30 min at 37 °C, respectively.P = 0.001; I = 0.001; the error signal between the set point and the deflection of the cantilever is −2.0 V) would be turned off with the TDNs tethered AFM tip lightly contacting cell surface. The transporting of TDNs that attached on the AFM tip will cause the deflection changes of AFM tip cantilever, which were recorded by a 16‐bit DA/AD card  controlled by LabVIEW software, and the data were processed with MATLAB 7.9 software .Force tracing curves were obtained with AFM 5500 , and controlling the temperature at 37 °C with temperature controller 325 . The sensitivity and the spring constant of AFM tip was set right as reported previously.The Fluorescence Imaging of HeLa Cells and TDNs: For fluorescence imaging, HeLa cells were incubated with TDNs (100 × 10−9m) for 1 h at 37 °C, then washed by PBS for three times. Subsequently, the cell membranes were stained with lipophilic dyes DIO (1 mg mL−1) for 30 min at room temperature, washed by PBS for three times to remove extra dyes, and added 1 mL PBS to proceed fluorescence experiment. Finally, the cells were fixated with paraformaldehyde (4%), after washing with PBS. For block experiments, before incubation with TDNs, the HeLa cells were cultured with blocking reagents CPZ (ultimate concentration 10 µg mL−1) and methyl‐β‐cyclodextrin  for 30 min, respectively. Fluorescence imaging was performed using Andorra Q3.6.2 confocal microscopy. Cy3 labeled TDNs were excited with a 561 nm helium–neon laser. The fluorescence images were collected using a NA = 1.40, 100 × oil immersion objective. In order to present a good visual effect, all images were added false colors. All fluorescence images were analyzed using Image J.Molecular Simulation: DPD method was used to elucidate the transporting mechanism of TDNs with different size. To simplify the system, a model comprising a piece of cellular membrane and TDNs was constructed. The cellular membrane was formed by lipids and receptors that were a stable bilayer structure like Sunil Kumar et al. model.vij/dt = Fij/m, and the total force Fij applied on each bead i, because that bead j was given as a sum of five terms, i.e., conservative force (Fijc), dissipative force (FijD), random force (FijR), bond force (FijB) (including the harmonic bond force and bond angle force), and the LJ interaction between ligands and receptors. The details of the setup of the system and the interaction potential were listed in the simulation method.c x 80rc x 60rc with periodic boundary condition applied three directions. There are total 1 152 000 beads in the simulation box to keep the particle density. To avoid the distribution of the nanoplate to the equilibrium state of a pure membrane, a long time (≈300 ns) equilibrium simulation was preformed when the TDN was placed near the membrane surface. All simulations in this work were carried out by using the modified soft package Lammps.The simulation box is a cube of size 80rThe authors declare no conflict of interest.Supporting InformationClick here for additional data file.


Intraventricular neuroendoscopic techniques, particularly third ventriculostomy, are employed increasingly in the management of infantile hydrocephalus. However, surgical access to the ventricular cavities is associated with a risk of post-operative cerebrospinal fluid (CSF) leak. Here, we describe a structured, multi-layered approach to wound opening and closure which aims to maximise the natural tissue barriers against CSF leakage. We present a series of patients undergoing this technique and subsequently review the literature regarding opening and closure techniques in paediatric intraventricular neuroendoscopic procedures.We performed a retrospective case series analysis of patients under 1 year of age who underwent intraventricular neuroendoscopic procedures in a single institution over a 5-year period. Patients were identified from an institutional operative database, and operation notes and clinical records were subsequently reviewed.28 patients fulfilled the inclusion criteria for this study. The mean age at operation was 9 weeks. 27 patients underwent endoscopic third ventriculostomy whilst 1 underwent endoscopic septostomy, and all patients underwent our structured, multi-layered opening and closure technique. Follow-up ranged from 4 months to 5 years. There were no cases of post-operative CSF leak, infection or wound breakdown. 12 patients remained shunt-free at the last follow-up, with the remaining 16 requiring shunt insertion for progressive hydrocephalus at a mean of 24 days post-operatively.Various methods aiming to prevent post-operative CSF leak have been reported in the literature. We propose that our institutional technique may be of benefit in minimising this risk in infants undergoing endoscopic third ventriculostomy and similar intraventricular neuroendoscopic procedures. Intraventricular neuroendoscopic techniques are utilised increasingly in the management of hydrocephalus, including in infants. This is principally in the form of endoscopic third ventriculostomy (ETV), a minimally invasive technique which allows excellent visualisation of anatomical structures and can potentially delay or avoid the need for a cerebrospinal fluid (CSF) shunt –4. CSF lPrevious practice in our institution was a conventional approach for ETV in infants involving a linear skin incision with ventricular access either through an underlying burr-hole or via the open anterior fontanelle. Following endoscopy, the dura and scalp layers were closed. However, following three cases of CSF leak in such patients in our institution, we evaluated our practice and moved to a structured, multi-layered approach to opening and closure of the wound. This is one of the various published techniques to minimise the risk of post-operative CSF leak, and it aims to maximise the natural tissue barriers during closure. Here, we present a detailed description of the technique we employ in the context of a case series of 28 patients who underwent this technique. Following this, we review the methods previously published in the literature which aim to minimise the risk of CSF leak following intraventricular neuroendoscopic surgery in infants.We performed a retrospective case series analysis of patients under a year of age who underwent an intraventricular neuroendoscopic procedure in our institution between February 2015 and January 2020. Patients were identified from a departmental operative database, and operation notes and clinical records were reviewed.A U-shaped frontal incision is fashioned behind the hairline, centred on the midpupillary line. This is achieved by scoring the skin with a blade and then completing the incision with monopolar diathermy . The medial curve of the wound may cross the anterior fontanelle, so care is taken not to breach the dura. The pericranium is opened in the same pattern and peeled off the skull and fontanelle using saline-soaked gauze. This is used to maintain pericranial integrity and prevent drying out, which may impede closure. The bone is elevated away from the fontanelle and underlying dura, and either levered or broken as a greenstick-like fracture at the anterior limit of the operative site. The dura is opened in a reverse U-shaped pattern and also kept from drying out. The cerebral cortex, now exposed, can be entered via a small corticotomy with a Dandy cannula prior to endoscopic access to the ventricle.The goal of this technique is as watertight a closure as possible, and each layer opened is given individual consideration for this. The corticotomy edges are apposed and glued with a TISSEEL (Baxter®) fibrin sealant. The dura is closed as a continuous layer with 4/0 PDS. The bone is placed back in its original position, tacked with several interrupted 2/0 Prolene sutures and the edges sealed with TISSEEL. The pericranium is closed, ideally continuously with 4/0 PDS, but failing this then in an interrupted fashion. Again, TISSEEL is applied along the edges. The galea is closed with continuous 3/0 Vicryl and finally the skin with continuous 4/0 Monocryl. Post-operatively, the patient is nursed at 30° head up and standard neurological observations are employed.28 patients  were identified for this study, of whom 27 underwent ETV and 1 underwent endoscopic septostomy. Additional procedures performed included choroid plexus cauterisation (14), cyst fenestration (7), aqueductoplasty (3), septal fenestration (2) and evacuation of concurrent intraventricular haemorrhage (1). All patients underwent our multi-layered opening and closure technique. The mean age at operation was 9 weeks (range: 5 days–6 months). The length of follow-up ranged from 4 months to 5 years. There were no cases of post-operative CSF leak, infection or wound breakdown in this series. 12/28 patients remain shunt-free at last follow-up. Of the remaining 16, shunt insertion occurred on average 24 days following their neuroendoscopic procedure (range: 2 days–10 weeks). In all cases, the indication for shunt insertion was progressive hydrocephalus, with no evidence of CSF leakage.Given the potentially devastating effects of intracranial infection associated with post-operative CSF leakage, it is important to employ technical approaches that may reduce the risk of this complication. These can be considered according to management of each anatomical layer from the skin of the scalp through to the cerebral cortex, beginning with the planning of an appropriate technique for incision and opening. We would argue that the conventional placement of a linear incision immediately overlying a burr-hole generates a potential linear route for the post-operative leakage of CSF. This can be avoided by means of a curvilinear skin incision with reflection of a flap, which allows the bony defect to be spatially removed from the point of weakness in the skin , 8. In oThe approach to bony opening of the calvarium is likely to play an important role. Some groups advocate plugging of the burr-hole with absorbable gelatin sponge, or reinforcement of the burr-hole with a bone graft or metal covering . AlternaFinally, consideration must be given to the deepest anatomical layers involved: the dura mater and the site of the corticotomy following removal of the endoscope. The dura has not traditionally been closed in endoscopic procedures and indeed dural closure can be challenging if the procedure is carried out through a burr-hole only. Cinalli proposes this as one of the benefits of minicraniotomy and advocates continuous watertight dural closure . Yadav aWe feel that our institutional technique provides a structured, multi-layered approach to wound opening and closure that maximises the natural barriers against CSF leakage and has led to improvements in CSF leak rate in our institution. It incorporates some of the technical approaches previously described in the literature, although we believe that its utility also lies in its being anatomically well structured and technically reproducible. We acknowledge that the number of patients is relatively low; however, in the context of our experiences with a conventional approach, we feel that an absence of post-operative wound complications in this series is of value. The formal closure of multiple layers and the use of watertight continuous closures where possible are likely to have played an important role. We advocate the use of TISSEEL fibrin sealant at multiple stages in the closure process, as this appears to add downward pressure between layers and contributes to a water-resistant closure. Furthermore, using a greenstick-like fracture of the calvarium allows the free edge of the bone to be spatially removed from both the skin incision above and the durotomy below, which may help avoid a potential linear route for any CSF leakage. We hope that this technique may be useful to others aiming to reduce the rate of CSF leak in patients undergoing intraventricular neuroendoscopic surgery, and we continue to follow the pattern of our results.


Cerebrospinal fluid (CSF) biomarkers are useful in the diagnosis and the prediction of progression of several neurodegenerative diseases. Among them, CSF neurofilament light (NfL) protein has particular interest, as its levels reflect neuroaxonal degeneration, a common feature in various neurodegenerative diseases. In the present study, we analyzed NfL levels in the CSF of 535 participants of the SPIN (Sant Pau Initiative on Neurodegeneration) cohort including cognitively normal participants, patients with Alzheimer disease (AD), Down syndrome (DS), frontotemporal dementia (FTD), amyotrophic lateral sclerosis (ALS), dementia with Lewy bodies (DLB), progressive supranuclear palsy (PSP) and corticobasal syndrome (CBS). We evaluated the differences in CSF NfL accross groups and its association with other CSF biomarkers and with cognitive scales. All neurogenerative diseases showed increased levels of CSF NfL, with the highest levels in patients with ALS, FTD, CBS and PSP. Furthermore, we found an association of CSF NfL levels with cognitive impairment in patients within the AD and FTD spectrum and with AD pathology in DLB and DS patients. These results have implications for the use of NfL as a marker in neurodegenerative diseases. Thus, the quantification of these biomarkers in the CSF is currently being implemented in clinical practice either to confirm the biochemical AD signature in the evaluation of a patient with mild cognitive impairment (MCI) or dementia or to exclude it in other dementia syndromes, such as frontotemporal dementia (FTD) or dementia with Lewy Bodies (DLB)3. More recently, other CSF biomarkers, such as YKL-40, the soluble β fragment of amyloid precursor protein (sAPPβ), neurogranin, glial fibrillary acidic protein (GFAP) or Neurofilament Light (NfL), have been described to be potentially informative for the discrimination of various neurodegenerative conditions, such as AD, FTD, progressive supranuclear palsy (PSP), corticobasal syndrome (CBS), or DLB8.Biomarkers of neurodegenerative diseases are key for the evaluation, differential diagnosis and follow-up of patients with cognitive impairment or dementia. In particular, three cerebrospinal fluid (CSF) biomarkers , AD, FTD or vascular dementia among others17, which includes a variety of neurodegenerative disorders, such as AD, FTD, ALS, DLB, PSP, CBS and subjects with Down syndrome (DS). This is the first time to our knowledge that such different phenotypes can be compared through a monocentric cohort. We compared CSF NfL levels accross these disorders and studied its association with other CSF biomarkers, with the severity of cognitive impairment and with the presence of AD pathology in DLB (DLB-AD) and DS (DS-AD). This study highlights the potential role of CSF NfL for the early diagnosis  and follow-up of DLB patients.In the present work, we investigated CSF NfL in the SPIN cohortAPOEε4 allele was significantly higher in AD patients than in the other groups , and no differences were observed among the other groups. As expected, MMSE scores were lower in all clinical groups compared to control subjects .We included a total of 535 participants from the SPIN cohort, comprising 118 cognitively healthy participants and 417 patients with various neurodegenerative disorders  among the groups  compared to control subjects, Table There were differences in CSF core AD biomarkers  and were associated with sex  in the entire cohort. All group comparisons and correlation analysis were thus subsequently age and sex-adjusted. In addition, as shown in Table CSF NfL levels were elevated in all groups (with exception of DS) compared to control participants , Table . We found a gradient in NfL levels in the ALS-FTD spectrum  were comparable (data not shown). The AUC for CSF NfL comparing prodDLB and DLB patients was 0.694 (95% CI 0.564–0.805). Compared to control subjects, CSF NfL was increased in prodDLB and DLB groups, Fig. The DLB group showed higher CSF NfL levels compared to control participants p < 0.001), Table , Table 118, CSF NfL levels were increased in the DS-AD group compared to DS group (p < 0.001), Fig. As previously described19. We confirm that ALS and FTD-related syndromes show the highest CSF NfL levels followed by AD and DLB. We also confirm the positive correlation between CSF NfL and age, its association with gender 19 and its negative correlation with MMSE in various contexts, including control participants, AD and FTD patients16. Finally, we report that in DLB patients, CSF NfL levels are influenced by the existence of comorbid AD.In the present study, we extend previously published results that highlight the importance of CSF NfL in the evaluation of neurodegenerative diseases19. In agreement with a recent meta-analysis that included various neurological conditions, our study confirms the overlap of CSF NfL level between various clinical conditions19, which may limit its use as a diagnostic marker in the clinical routine of cognitive impairment. In line with other studies20, we found that ALS patients showed the highest CSF NfL levels. As ALS and FTD are associated in a proportion of patients, we evaluated the differential CSF levels of NfL in ALS, ALS-FTD and FTD. Our results show that CSF NfL levels were increased in the three groups compared to controls, with the highest levels for ALS, followed by ALS-FTD and FTD, in agreement with previously published data16. These results are discordant with the recent meta-analysis of Bridel et al. describing the ALS-FTD group to be the clinical group with the highest CSF NfL level19. This discrepancy may be related to the variability of CSF NfL values in these clinical groups or to the differences in sample size. Although our results suggest that high CSF levels of NfL may be indicative of ALS in the context of FTD, the ROC curves showed moderate diagnostic value and its implementation in clinical routine would therefore require further confirmation. Future studies are needed to determine whether longitudinal changes in CSF NfL meaurements are useful to predict the development of motor neuron disease in patients with FTD. We also found increased CSF NfL levels in patients with CBS and PSP compared to controls, which is in agreement with previous studies21. We did not find correlation between MMSE scores and CSF NfL in these two groups, similarly to previously published results16. However, such results may be due to the low number of patients in each group  or to the lack of sensitivity of MMSE to capture cognitive impairment in these disorders.Our results confirm that CSF NfL levels are increased in all neurodegenerative conditions studied compared to control participants19. Interestingly, patients with prodDLB within this group showed higher levels of CSF NfL compared to controls. Furthermore, patients in the dementia stage had higher levels compared to prodDLB, while levels of t-Tau, p-Tau and Aβ1–42 were similar between both groups. Thus, our results illustrate that CSF NfL levels increase early in DLB, even at prodromal stages, with a further increase in dementia stages. CSF NfL may be of potential value to diagnose prodDLB, as its diagnostic performance appeared higher than CSF core AD biomarkers. These promising results should be further confirmed in a larger cohort. In the present work, we also found higher levels of CSF NfL in DLB patients that had AD copathology compared to DLB patients with negative AD biomarkers. However, the potential added value of CSF NfL for AD pathology in the context of DLB was low .We also report high CSF NfL levels in patients with DLB compared to controls, in accordance with a previous study18, we found a clear and progressive increase of CSF NfL in DS patients with prodromal AD and DS-AD compared to asymptomatic DS participants. These results indicate that CSF NfL could be informative for the diagnosis of dementia in this population, where clinical assessment might be complex. Interestingly, despite the difference in age between DS-AD and sporadic AD patients, NfL levels were similar in both groups indicating a comparable degree in neuroaxonal damage in both types of AD. These results, together with the good correlation of CSF NfL levels with those in plasma found in previous studies18, highlight the potential of this biomarker in the diagnosis of dementia in the DS population.In participants with DS, CSF NfL levels were associated with clinical stages. As previously publishedOur work also has some limitations. First of all, the study is retrospective and the clinical protocols differed between clinical groups. Second, the work relied on clinical diagnosis and neuropathological confirmation was not available. Third, MMSE was the only cognitive scale included in this study, which may be less sensitive to capture changes in some groups, such as FTD. Finally, some groups were small and results should be validated in larger cohorts.In summary, the present work confirms the importance of CSF NfL in the evaluation of neurodegenerative diseases. The study highlights the influence of AD co-pathology on the levels of CSF NfL in DS and DLB and shows the potential interest of CSF NfL determination for early detection of DLB, at prodromal stages of the disease. Taken together, our data show that CSF NfL levels could be a useful addition to the core AD biomarkers in the diagnostic evaluation of neurodegenerative conditions.17 evaluated at the Memory Unit at Hospital de Sant Pau between January 2009 and October 2017. We included the following diagnostic groups: Alzheimer’s Disease , Down Syndrome, without or with dementia 18, dementia with Lewy Bodies 22, prodromal DLB 22, Amyotrophic Lateral Sclerosis , Frontotemporal dementia 20, corticobasal syndrome , and progressive supranuclear palsy . Cognitively normal control participants (n = 118) were also included in the present study. All controls had normal cognitive scores in the formal neuropsychological evaluation23 and normal core CSF AD biomarkers (see17 for further details of the SPIN cohort).We included 535 subjects from the SPIN cohort1–42 and high t-Tau or p-Tau) in the CSF based on previously published cut-offs24. FTD patients with an AD CSF profille (low Aβ1–42 and high t-Tau or p-Tau) were excluded from the present study.All AD patients had abnormal core AD biomarkers  met general criteria for mild cognitive impairment25 with at least one sign of α-sinucleinopathy )28 at the time of evaluation and had to meet criteria of probable DLB during the follow up29. Patients with DLB met consensus criteria for probable DLB29 and were evaluated using a previously reported clinical protocol, as previously described17,22. DLB patients with suspected AD copathology were defined according to the ratio tTau/Aβ1–42 considering values ≥0.52 as indicative of underlying AD pathology30. Patients with ALS fulfilled El Escorial revised criteria31 for probable, probable laboratory-supported or definite ALS, and were classified as ALS-FTD according to Raskovsky32 criteria.Classification of DLB patients was made according to previously published data33. CSF levels of core AD biomarkers  were measured using commercially available kits from FUJIREBIO-EUROPE , Ref 81579  and Ref 81581 (phosphorylated tau)), as previously described and following provider´s instructions. NfL levels were measured using a commercially available ELISA kit  as previously described20.CSF was obtained by lumbar puncture as previously described, collected and processed in polypropylene tubes following international recommendationsAPOE was genotyped accordingly to previously described methods34.DNA was extracted using standard procedures and 2 test was used to assess differences in APOEε4 allele frequency among groups. All tests and area under ROC curve (AUC) analysis were performed using MEDCALC (MEDCALC software ver 15.2.2).Because biomarker values were non-normally distributed, the nonparametric Kruskal-Wallis test and the post hoc pairwise Mann-Whitney-tests were used to assess differences between groups. Associations of NfL with other biomarkers and with MMSE score were calculated using Spearman rank correlation. All group comparaisons and correlation analysis were age and sex-adjusted. Alpha threshold was set at 0.05 and ccorrection for multiple comparisons was made with the Bonferroni procedure. XThe study was approved by the Sant Pau Ethics Committee following the standards for medical research in humans recommended by the Declaration of Helsinki and reported to the Minister of Justice according to the Spanish law for research in people with intellectual disabilities. The protocol of the SPIN cohort was approved by the Sant Pau Ethics Committee. All participants and their legally authorised representative gave written informed consent before enrolment; all controls gave written informed consent before enrolment for their medical information to be used for purposes of scientific research in accordance with the guidelines of the local ethics committee.


Pathogens has the timely honor to present a Special Issue on Classical Swine Fever collecting 14 publications. Readers can find that perhaps few swine diseases have such a comparable ancient history as CSF [Recent reemergence of classical swine fever (CSF) in previous CSF-free areas reminds the veterinary community of this old disease. At this difficult period, y as CSF ,3 as wely as CSF  transmisThe CSF world has been quiet for almost 20 years . It was The threat from CSF remains. The continual application of newer technologies, such as next generation sequencing coupled with meta-analysis, point-of-care diagnosis ,9, as weVaccination has been practiced for years with success. The question is: is the currently used modified live virus (MLV) vaccine really as safe as we thought ,13? The Colleagues in the CSF world are familiar with a recent “virus shift” from genotype 3 to genotype 2 in the field. We now know that genotype 2.1 has an in vivo replication advantage of 1.5–3 log over that of genotype 3.4, which partially explains the virus shift observed in the field , althoug+-T cell and interferon (IFN) -alpha responses to CSFV [The transplacental transmission and congenital form of CSF is always a concern, since it is a potential source of persistent infection in the herd. Indeed, experimentally infecting sows at mid-gestation showed newborn viremic piglets launching CD8 to CSFV , and fas to CSFV . These p to CSFV , and furThe CSF is a truly classical swine disease that will continue to pose a threat to pig production. Our fight against CSF is far from over, and it deserves our continual attention.