Hypotrichosis is an uncommon type of alopecia (hair loss) characterized by coarse scalp hair caused by the reduced or fully terminated activity of the Lipase-H (LIPH) enzyme. LIPH gene mutations contribute to the development of irregular or non-functional proteins. Because several cellular processes, including cell maturation and proliferation, are inhibited when this enzyme is inactive, the hair follicles become structurally unreliable, undeveloped, and immature. This results in brittle hair, as well as altered hair shaft development and structure. Because of these nsSNPs, the protein’s structure and/or function may be altered. Given the difficulty in discovering functional SNPs in genes associated with disease, it is possible to assess potential functional SNPs before conducting broader population investigations. As a result, in our in silico analysis, we separated potentially hazardous nsSNPs of the LIPH gene from benign representatives using a variety of sequencing and architecture-based bioinformatics approaches. Using seven prediction algorithms, 9 out of a total of 215 nsSNPs were shown to be the most likely to cause harm. In order to distinguish between potentially harmful and benign nsSNPs of the LIPH gene, in our in silico investigation, we employed a range of sequence- and architecture-based bioinformatics techniques. Three nsSNPs  were chosen as potentially harmful. The present findings will likely be helpful in future large population-based studies, as well as in drug discovery, particularly in the creation of personalized medicine, since this study provides an initial thorough investigation of the functional nsSNPs of LIPH. Originating from the ectoderm of the skin, hair is one of the crucial components of the human body. It is a protective projection which, along with sebaceous organs or glands, nails, and sweat glands, is considered to improve skin structure . Hair prThis reverse gene transcribes from its mRNA 4001 bp cDNA; this produces a member of the Lipase H family, a 451 amino acid protein (LIPH En-zyme). To create 2-acyl lyso-phosphatidic acid (LPA) and fatty acids outside of a cell’s membrane, lipase H hydrolyzes phosphatidic acid (PA) . Some phLIPH gene mutations result in the development of an irregular protein or a protein with no function whatsoever. When this enzyme is non-functional, certain cellular functions, such as the maturation and proliferation of hair follicle cells, result in the non-formation of LPA. Such hair follicles are structurally irregular, underdeveloped, and immature, resulting in fragile hair and modified hair growth and structure. In individuals that have autosomal recessive hypotrichosis, the lack of Lipase-H enzymes may also often contribute to skin deformities. In this study, the nsSNPs (non-synonymous single nucleotide polymorphisms) of the LIPH amino acid chain were examined. In addition to this, the effect of the sequence variant on the LIPH protein has been recognized. Studies have also been conducted to examine the impact of the mutation on the role and durability of the LIPH amino acid chain.The objective of the present study is to detect and predict deadly nsSNPs within the LIPH gene, along with their links to diseases and the ramifications of detrimental nsSNPs on the behavior and structure of the protein. Several bioinformatics tools, including SIFT , PolypheA variety of bioinformatics applications and datasets, such as the ensemble gene annotation tool and the dbSNP resource, were employed to identify effective SNPs, which can be situated at multiple locations on the gene, within the LIPH gene. This research examined the effects of nsSNPs on the structure and functionality of the Lipase-H amino acid chain encoded by the LIPH gene. Additional SNPs were found in other protein portions as well; while most of the identified SNPs were located within the intronic segment, our study centered on the exonic segment’s clinically significant SNPs, as depicted in The sorting intolerant from tolerant algorithm was utilized on 307 nsSNPs to ascertain the score for the tolerance index (TI) of the mutations. By aligning similar conserved amino acid sequences, SIFT determines the TI score, which ranges from 0 to 1. During ours initial examination, of 307 examples, SIFT detected 259 non synonymous SNPS, displaying TI scores between 0 and 0.3, with 199 nsSNPs exhibiting TI scores of 0, 22 showing TI scores of 0.1, 17 expressing TI scores of 0.2, and 21 revealing TI scores of 0.3, indicating the importance of these nsSNPs . Out of The large dataset of predicted deleterious SNPs was narrowed down based on the clinical significance of all the mutations. The extensive literature studies suggested that only three nsSNPs  be classified as clinically significant. These selected nsSNPs were analyzed using five resources—SNP&GO, Polyphen-2, PhD-SNP, SIFT, and PROVEAN—to check pathogenicity and to predict nsSNPs with a significant deleterious outcome affecting the structural character and the role of the LIPH amino acid chain. Each of the chosen nsSNPs were predicted to be adverse or pathogenic .The pathological implications of mutations on the LIPH protein were annotated using the PMUT service. The PMUT results reflected the PMUT scores of 0.93, 0.90, and 0.90 for mutations LIPHW108R, LIPHC246S, and LIPHH248N, respectively. These results show that there is around a 93% probability of LIPHW108R producing a pathological impact, and a 90% probability for LIPHC246S and LIPHH248N to convey an associated pathological impact. The prediction class was identified as “disease” for all three of the mutant sequences.The protein structure stability was predicted through an online I-Mutant server (version 2.0). To express the outcome of I-Mutant 2.0, the reliability index (RI) and the free energy change value (DDG) were employed. The subjected three mutations yielded a stability decrease of  kcal/mol. The I-Mutant results confirmed that selected nsSNPs cause a decrease in the protein stability because they have a DDG value (<−0.5), which is a sign of a larger effect on the protein. These steep declines in the stability of the LIPH protein may cause the loss of LIPH function, which triggers hypotrichosis.To determine the evolutionary conservation of the modified protein configurations, the ConSurf computational server was employed. Out of the three nsSNPs, two amino acids  were detected in the LIPH gene as functional, highly conserved, and exposed, while one nsSNP amino acid (LIPHH248N) was shown to be strongly conserved and prominently displayed . LIPHW10To determine whether the high-risk nsSNPs selected had a significant impact on the final proteins, predicted 3D modeling and comparisons of structure between mutant models and wild-type were used. SWISS-MODEL was used to predict the model for LIPH protein. SWISS-MODEL provided 53 templates, but we selected 2ppl.1, which is the highest query coverage value, and PyMol was used to construct the LIPHMT models. The predicted model, along with the mutation position, was visualized by PyMol. The results were then confirmed by the nsSNPs . To checRMSD, RMSF, and the percentage of amino acid secondary structures. The molecular dynamics simulation analysis was conducted to assess the The flexibility analysis of each residue was measured by root mean square fluctuation (RMSF) analysis. The average RMSF value for LIPHWT was observed to be 0.24 Å, whereas the average RMSF values for mutant LIPHW108R, LIPHH248D, and LIPHC246S were  Å, respectively. The norm RSMF range of LIPHWT and all LIPHMTs revealed that all were stable during the simulation period of 200 ns. The residue Pro234 exhibited higher fluctuations in LIPHW108R and LIPHH248D, whereas in LIPHWT, the residue Phe25 showed the highest fluctuation. Furthermore, the residue His305 was the most fluctuating residue in LIPHC246S, as shown in The conformational behavior of the protein was evaluated by analyzing the system’s radius of gyration values. A lower Rg value is indicative of a more compact amino acid architecture. The norm Rg value for LIPHWT was 27.10 Å, whereas for mutant LIPHW108R, LIPHH248D, and LIPHC246S, it was 27.08 Å, 26.92 Å, and 26.35 Å, respectively. The lowest Rg value was obtained for LIPHC246S, which reveals that LIPHC246S showed the most compactness C.In this study, hydrogen bond profiles of the proteins were also examined, as shown in 2, 2142.5 Å2, 2228.37 Å2, and 2097.09 Å2, respectively, throughout the simulation , which was calculated from the time-dependent data of 3D positional coordinates of multiple variant models during the 200 ns MD simulation. This analysis is commonly known as PCA. The results show that the LIPHWT system and its four variations  all exhibited varied arrangements and failed to converge into a single energy level, demonstrating that the mutant forms of the LIPH amino acid had an unstable arrangement of configurations  was conducted using motion mode analysis. The variables for the urations .Hair is included in those important parts of the human body originating from the ectoderm of human skin. Hair is a protective projection on the human body, and it is considered to be skin accessory, along with sebaceous organs or glands, nails, and sweat glands . Hair prNon-synonymous SNPs are created when an amino acid is mutated in a protein chain, impacting the protein’s composition and purpose. Many genetic abnormalities are caused by SNPs. The functionally relevant area is at significant risk of mutation due to amino acid degeneracy. Finding the amino acid that significantly influences disease development and differentiating between beneficial and harmful SNPs are both very challenging tasks . When anBioinformatics has been impactful in the field of genome-wide association studies (GWAS) for mutation detection ,19, annoc.2T > C; p.M1T and c.322T > C; p. W108R) have been identified in both families, causing autosomal recessive hypotrichosis. LIPH gene mutations result in the development of an irregular protein or a protein with no function. When this enzyme is non-functional, certain cellular functions, such as the maturation and proliferation of hair follicle cells, result in the non-formation of LPA. Such hair follicles are structurally irregular, underdeveloped, and immature, resulting in fragile hair and altered hair shaft growth and structure. These hairs are weak and quickly split. In individuals who have autosomal recessive hypotrichosis, a lack of Lipase-H enzymes can also often contribute to skin deformities (NIH). In this research, an attempt is designed to identify SNPs that modify the architecture and operation of the coded Lipase-H protein. The gene LIPH encodes the enzyme. Using various bioinformatics computational protein prediction methods, we tested the pathogenicity of mutation . SIFT, POLYPHEN-2, PROVEAN, SNP&GO, I-MUTANT, and PhD-SNP were used to describe the SNP causing the illness by classifying the mutations. Both  and  are deleterious and likely to be toxic, according to the evaluations using SIFT and the Polyphen2 tool [In the present research, we used in silico methods to perform various analyses of the nsSNPs, since a mutation in the LIPH gene is accountable for autosomal recessive hypotrichosis. Alopecia is a rare sub-type of hair loss that causes hair to become scarce (hypotrichosis) on the scalp skin. At position 27.22, The LIPH gene or amino acid is situated on chromosome 3 (eq27.2). The typical function of lipase is to hydrolyze PA outside the cell membrane to produce 2-acyl lysophosphatidic acid  and fatty acid. In this gene, two mutations (https://asia.ensembl.org/index.html) (accessed on 3 February 2023). We retrieved all the nsSNPs found in the dbSNP and Ensembl genome browser.The primary sequence of the LIPH protein, with a length of 451aa in the FASTA format, was retrieved from browsing the ensemble genome website (SIFT (sorting intolerant from tolerant—http://sift.jcvi.org) (accessed on 16 March 2023) [PROVEAN  [Polyphen-2 (polymorphism phenotypingv2) [SNP&GO (single nucleotide polymorphism and gene ontology), which are linked using PhD-SNP (predictor of human deleterious single nucleotide polymorphism—https://snps.biofold.org/snps-and-go/snps-and-go.html (accessed on 16 March 2023)) [The predictions of damaging nsSNPs affecting the function of LIPH protein were developed using different bioinformatics equipment: ch 2023) , PROVEANnalyzer) , Polypheypingv2) , and SNPh 2023)) . The nonhttp://mmb.irbbarcelona.org/PMut/ (accessed on 16 March 2023)) [nsSNPs of a score with values of 0.5 or less may be considered neutral, whereas those score with values of >0.5 are considered disease associated [PMut served as a means to confirm the pathogenicity of the identified suspected harmful nsSNPs (h 2023)) . For 12,sociated .https://folding.biofold.org/i-mutant/i-mutant2.0.html (accessed on 16 March 2023)). This method evaluates the corresponding values of free energy transform when determining the increase or decrease in durability transformation in the mutant proteins (DDG). I-Mutant version 2.0 employs an SVM machine learning algorithm and ProTherm-derived information, or a dataset, which is a more detailed collection of databanks that contain experimental thermodynamic data on mutant protein stability. This web server additionally generated a reliability index (RI) ranging from the lowest reliability (0) to the highest reliability (10), in addition to the other forecasts [I-Mutant V2.0 was employed to forecast the protein stability of the nsSNPs ).The determination of a 3D protein model by NMR or X-ray crystallography methods is very expensive; thus, the homology modeling technique, which is less time consuming and highly accurate, can be used for the prediction of a 3D protein model. For systematic comparative modeling of 3D amino acid structures based on models and accessible through an offline script-based tool, Modeler was used . PyMOL iMD simulations were carried out for 200 ns using Desmond, a Schrödinger LLC platform. The initial structures of the proteins were obtained from the predicted models. The amino acid architecture was preprocessed using Maestro’s Protein Preparation Wizard, which revealed protein refinement, as well as reduction. The Device Builder tool was used to prepare all structures. The orthorhombic box solvent model was employed, using TIP3PP. In the simulation, the OPLS-2005 force field was used . The sysij illustrated the time-correlated information between the (i) and (j) atomic particles of a protein, where Δri and Δrj were the displacements from the mean position of the ith and jth residues with respect to time. The angular brackets “〈〉” represented the time norm over the entire route. The Cij ranged from −1 to 1. The only alpha carbon atoms from the last 5000 snapshots were selected at 0.002 ns time intervals to create the matrix. The following displayed graph from DCCM is based upon two positive (+ve) and negative (−ve) values; the (+ve)-values explain the residue motion in a unique direction, while the (−ve) values indicate the residue displacement in the opposite direction.A DCCM plot was created to investigate the cross-correlation shift of the backbone atom (C) and to offer insight into how mutations affect the dynamics of LIPHWT and LIPHMTs. DCCM was created to analyze and determine the dominating correlated movements of each residue in distinct LIPH systems.Using the trajectories files produced by MD simulation, we examined the dynamic movements of every system, including bound GalN6SWT, bound GalN6SMTs, free GalN6SWT, and free GalN6SMTs, using principal component analysis (PCA) or conformational sampling . The rotIn this study, the LIPH gene was examined using a computational technique to determine the significance of harmful SNPs in the coding and untranslated zones. Based on clinical importance, 3 out of a total of 307 missense SNPs were projected to be the most harmful. These SNPs were anticipated to be highly conserved and to influence protein stability. The structural analysis found that all W108R, C346S, and H248N mutations exhibited significant RMSD values, indicating a loss of total hydrogen bonds. As a result, we determined that the three nsSNPs W108R, C346S, and H248N, might be key players in the development of hypotrichosis, a rare type of alopecia.


Level of Evidence III, Systematic Review/Actualization.The progressive evolution of post-traumatic vertebral necrosis and consequent loss of structural integrity of the vertebral body along with neurological risk, makes it one of the most feared and unpredictable pathologies in spine traumatology. Several studies have addressed the role of vertebroplasty, kyphoplasty, and corpectomy in its treatment; however, it remains a controversial concept without a defined therapeutic algorithm. The recent emergence of expandable intravertebral implants, which allow, by a percutaneous transpedicular application, the capacity for intrasomatic filling and maintenance of the height of the vertebral body, makes them a viable option, not only in the treatment of acute vertebral fractures, but also in non-union cases. In this study, we present a review of the current evidence on the application of expandable intravertebral implants in cases of post-traumatic vertebral necrosis. Based on the available scientific literature, including previous classifications of post-traumatic necrosis, and on the mechanical characteristics of the main expandable intravertebral implants currently available, we propose a simplified classification of this pathology, considering parameters that influence surgical therapeutic guidance, the morphology and the dynamics of the necrotic vertebra’s mobility. According to its stages and based on authors’ experience and on the scarce literature, we propose an initial therapeutic algorithm and suggest preventive strategies for this disease, considering its main risk factors, that is, fracture comminution and impairment of vertebral vascularity. Therefore, expandable intravertebral implants have a promising role in this condition; however, large prospective studies are needed to confirm their efficacy, to clarify the indications of each of these devices, and to validate the algorithm suggestion regarding treatment and prevention of post-traumatic vertebral necrosis.  Atrophic type pseudarthrosis in general fractures is usually treated with bone resection, repairing bony ends to restore blood and growth factors for the site; local application of bone graft, stimulating the process of bone healing; and fixation. However, in spine, cementoplasty techniques (vertebroplasty and kyphoplasty) have been used to treat this disease, immediately stabilizing the vertebral body without waiting for bone healing. 5-(9-(®) and SpineJack® systems. - who underwent vertebral augmentation with the SpineJack® were prospectively included. Patients were considered eligible for inclusion if they met the following criteria: OVCFs involving the lower thoracic and/or lumbar vertebrae, considered unstable (grade A3 according to Magerl’s classification), kyphosis of at least 20° at the vertebra’s level, fractures older than six weeks, intractable back pain, with a visual analogue scale (VAS) of at least four. Preoperative evaluation included clinical examination and an imaging workup, including a computed tomography (CT) and a spine magnetic resonance imaging (MRI). All patients had postoperative spine and chest control X-rays in the operating room followed by a spine CT scan focused on the treated site. A systematic clinical follow-up was performed at one and six months after intervention. This way, they identified significant improvements between the preoperative visual analogue pain scale (median 7) and after six months postoperatively (median 2). The improvement in the mean local kyphosis was significant in 94.7% of the cases, going from 24.4 ± 4.1 to 11.7˚ ± 6.7. The mean Beck index increased significantly, from 0.43 to 0.66. Additionally, the anterior (11.2 mm ± 3.1 to 16.3 mm ± 2.7) and middle (11.5 mm ± 3.3 to 17.2 mm ± 2.7) vertebral heights also had significant improvements, with a smaller increase in posterior height (23.4 mm ± 3.4 to 24.2 mm ± 3.5). There was no worsening of posterior wall protrusions. The mean of injected cement was 5.9 ± 1.4 mL. By using computerized tomography (CT), the authors identified that 36.8% of patients presented discal extravasations, 15.4% presented venous extravasations, and one (5.3%) presented pulmonary embolism with cement, all asymptomatic. There were 21.1% of adjacent vertebral fractures, with a significant higher prevalence in cases with more accentuated corrections of the local kyphosis, which leads to the recommendation of prophylactic vertebroplasties at the adjacent levels in cases of chronic fractures with severe kyphosis.We selected an article on SpineJack, technique, previously described by the same group, to treat 56 vertebrae with osteonecrotic intravertebral clefts. 18,, which allows for containing the application of expandable intravertebral implants, permitting a vertebral body interior reconstruction instead of its total replacement. Therefore, in these cases, we recommend armed kyphoplasty, in which empty spaces within the vertebral body are created by expandable intravertebral implants, which are surrounded by bone trabeculae impacted by the devices. Afterwards, the body is filled with bone cement or graft, which provides it with interior consistency and stability. In mobile vertebrae (pseudarthrosis), that is, with intravertebral clefts, regardless of their non-plana or plana morphology, it is possible to restore almost the entire height of the vertebral body by the positioning of the spine in hyperextension, which causes the separation of the upper and lower halves of the pseudarthrosis, increasing the cleft size and restoring the vertebral body height, which is filled internally. Thus, armed kyphoplasty is also indicated in these cases. The complete filling of the intrasomatic cleft is essential to stabilize the vertebral body, eliminating pathological intravertebral mobility. In turn, in vertebrae with immobile deformity, the goal is not to gain height, but only to fill the necrotic body, stabilizing it and preventing its progressive flattening by necrosis and bone resorption. 1-, vertebral expansion is not possible by positioning the spine in hyperextension; therefore, the creation of intrasomatic spaces is totally dependent on the action of intravertebral implants. Thus, in immobile vertebrae non-plana, we recommend SpineJack® implants, which, despite not being space-occupying implants, have a more powerful and mechanical expansion capacity, that is not directly dependent on pressure, managing to create intrasomatic spaces even in vertebrae with immobile deformity, which will be filled with bone cement or graft . We recommend the use of autologous cancellous graft extracted from the patient’s iliac bone for intrasomatic filling and, if the case demands more quantity, it is possible to mix the autograft with cancellous allograft from bone bank. In the same way of the treatment of general bone pseudarthrosis, in vertebral necrosis we sought to use a type of bone graft combining all the properties of osteoconduction, osteoinduction, osteointegration, and osteogenesis that are favorable to bone healing. 38-(,,,,-(In turn, situations concerning the morphology of immobile vertebra plana, defined as those with a vertebral body with a height that is less than one third of the original on, in which there is no intravertebral cleft and the vertebral body bone tissue was practically completly reabsorbed, it is impossible to apply expandable intravertebral implants, as there is not enough somatic bone cover to allow a stable implant containment within vertebral bone tissue  and 3. A37,(Considering this algorithm, it is easily understood that we should early intervene in situations of post-traumatic vertebral necrosis, ideally in vertebrae non-plana stages (stages 1i and 1m - -(® expandable intravertebral implant filled with bone cement in osteoporotic fractures or with bone graft in traumatic fractures in individuals with healthy bone and under 60 years old (® implants by multidirectional interior impaction of bone trabeculae, namely elevation of the central portion of the vertebral endplates, which guarantees anatomical reduction and its maintenance over time, as interior metallic supports (Although there is no clear scientific evidence, the most probable and accepted cause of evolution of a vertebral fracture to non-union is the injury of intraosseous blood vessels during the fracture, compromising the vertebral body bone tissue blood supply, which prevents bone healing and favor progression to necrosis and pseudoarthrosis. 1-(1ears old . In typesupports . As for supports .This article reviews the promising role of expandable intravertebral implants in the treatment of post-traumatic vertebral necrosis and in its prevention in acute fractures with a high risk of non-union since these devices allow interior replacement of the vertebral body and stable anterior support of the spine by a percutaneous transpedicular approach. The authors propose a simplified classification of post-traumatic vertebral necrosis and a therapeutic algorithm based on the role of expandable intravertebral implants, reserving corpectomy or multilevel pedicle fixation only for immobile vertebrae plana. Currently, scientific evidence on the treatment of post-traumatic vertebral necrosis is limited, despite more studies have been addressing vertebroplasty and kyphoplasty more frequently, only a few focus on the application of intravertebral expansive implants in this context. Moreover, there is little scientific literature regarding the ability to identify high risk acute vertebral fractures that will evolve into non-union, thus enabling early action to prevent this dangerous disease. Large prospective studies are needed to clarify the indications for each of the expandable intravertebral implants in the treatment and prevention of post-traumatic vertebral necrosis and to consolidate their effectiveness.


This study investigated changes in the interfacial properties of epoxy-coated concrete exposed to various conditions, regarding the epoxy type, coating equipment, and exposure environment and period. The measured coating thickness and pull-off bond strength exhibited diverse trends, depending on the exposure period and conditions. In the real sea (RS) environment, the average bond strengths for bisphenol A (BPA) (E1), BPA with zinc powder (E2), and BPA with cresyl glycidyl ether (E3) were 1.26, 1.93, and 1.92 MPa, respectively. The coating method did not significantly affect the measured coating thickness and strength values. The conventional roller (D1) exhibited the highest thickness variation, with a value of 214.45 μm. The RS condition significantly increased the coating thickness (34% to 158%) compared to the tap water (TW) condition. The exposure conditions had little impact on bond strength except for E3, which showed an increased strength (2.71 MPa) over 7–91 days, especially under RS conditions, while E2 remained constant at approximately 1.82 MPa. This study offers insights into factors influencing marine concrete coating performance and discusses limitations and future work. Hang et al. [Marine concrete structures face exposure to harsh and aggressive environments, such as chloride and sulfate attacks, which can significantly impact their service life. Underwater coatings are recognized as an economical and rapid repair method for preventing water and moisture infiltration into the concrete. Numerous studies have been conducted to develop effective repair strategies for concrete structures with surface protection, with some focusing on specific coating types ,9,10,11.g et al.  describeg et al.  reportedg et al. ,14,15,16g et al. . Furtherg et al. ,19.The coating method, encompassing coating tools, the coating procedure, and the type of pre-treatment, plays a significant role in shaping the interfacial bond properties between the coating and the substrate. Sadowski et al.  affirmedIn their respective studies, Al-Kheetan et al.  examinedThis study experimentally investigated the significant factors, including the epoxy resin type, coating equipment, exposure time, and exposure conditions, that must be considered when applying coatings to marine concrete structures. This study considered three different epoxy resins and coating equipment options, based on the results of previous studies. In addition, the effects of the exposure period and conditions on the measured pull-off bond were evaluated. The investigated test variables, materials, and experimental procedures are summarized in the following sections.The majority of the prior research on concrete surface repair has primarily concentrated on conventional, land-based structures, with less emphasis on marine structures. This discrepancy can be ascribed to the limited understanding of underwater coating materials, their suitability for real marine environments, and the reliability of experimental outcomes. Experimental studies that specifically addressed the bond performance of underwater coatings in real sea conditions are currently limited in the literature. Such research would hold significant value for individuals engaged in the repair and retrofitting of submerged concrete structures. In addition, studies on the development and performance evaluation of coating materials for underwater operations are limited, and the time-dependent interfacial adhesion between applied coatings and substrates has not been systematically investigated. Therefore, this study performed experiments to determine the bond strength between underwater coatings and concrete substrates. The results presented in this paper are part of an ongoing research project and are expected to greatly contribute to the maintenance of marine concrete structures located in actual marine environments.A 300 mm × 300 mm × 30 mm rectangular concrete substrate was prepared. A mixer truck and electric concrete vibrator were used to cast the concrete. The adopted water-to-cement ratio (w/c) was 0.24, and ordinary Portland cement (OPC) was used. The prepared specimens were water-cured for 28 d under controlled temperature and humidity conditions. Subsequently, the surface was water-jetted and relocated to the laboratory or onsite for surface coating. The compressive and splitting tensile strengths of the substrate concrete were measured according to the ASTM C39 and ASTM C496, respectively . At leas2). One-way analysis of variance (ANOVA) and Tukey’s honest significant difference (HSD) tests were used for the statistical analysis of the measured values to determine whether there were statistically significant differences in the means of the results. The null hypothesis for the ANOVA was that each group would have similar values and not exhibit significant differences. In contrast, the HSD test was used to detect differences between any pair of groups.After establishing the appropriate test duration for each exposure condition, the coated specimens were extracted. The specimens were then initially cut into small rectangular sizes of 20 mm × 20 mm × 20 mm to capture scanning electron microscopy (SEM) images and observe the changes at the interface between the coating and substrate. These images were captured using an EM-30AX device manufactured by COXEM, Daejeon, Republic of Korea, following the completion of the proper curing, grinding, and polishing processes. Images were captured at two exposure periods of 7 and 91 d, and two different magnifications (×100 and ×1000) were used at the same location. The presence of separations, residual voids, and cracks near the interface was visually inspected to investigate the interfacial bond behavior. The coating thickness was measured according to the ASTM D6132 . A commeThe coating thickness was measured according to the ASTM D6132 procedure; The measured strengths varied significantly, as shown in p-value of less than 0.0001 (p = 0.0001) and between E1 and E3 (p = 0.0001). However, no significant difference was observed in the mean coating thickness between E2 and E3 (p = 0.3222). The mean bond strengths of E1, E2, and E3 were 1.26, 1.93, and 1.92 MPa, respectively, as shown in p < 0.0001), as shown in The mean thickness values for E1, E2, and E3 were 117.54, 204.60, and 227.40 µm, respectively, as shown in n 0.0001 . TherefoSEM was used to investigate the internal porosity within each epoxy coating, and the results from SEM under the RS condition confirmed that E1 had larger internal pore sizes than E2 and E3, as shown in p-value of 0.787 further supported this conclusion. Notably, D1 exhibited the highest variation with an S.D. of 123 µm, which was unexpected considering that D1 was initially anticipated to have a stable thickness compared with other methods based on previous findings [findings ,21,22. Tfindings ,41,42. Tp-values for E1 and E2 were greater than 0.05, suggesting no significant changes in the strength values. These results also reaffirmed the insignificant correlation between strength and thickness. Furthermore, the bond strength values were found to be similar under all conditions at the 0.05 significance level, with the coating method having no significant effect. Overall, it can be inferred that the exposure condition can significantly influence the coating thickness, resulting in potentially thicker and more dispersed coatings compared with conventional conditions. Furthermore, within the range of this study, the exposure conditions had a limited impact on the measured bond strength, except for E3.Neither E1 nor E2 exhibited significant changes or trends in strength during the exposure period c,d. By cE3 exhibited a slight increase in bond strength with an increased exposure period, especially in the RS condition, while E1 and E2 showed constant values. The two additives, zinc powder and cresyl glycidyl ether (CGE), resulted in performance variations among the three coatings. As mentioned previously, while zinc powder tends to increase viscosity and lead to a thicker consistency, CGE may not directly increase viscosity like zinc powder. However, it can influence the curing process and the final properties of the epoxy, potentially affecting its flow characteristics. These results are consistent with those of Park et al. , who repOverall, this study confirmed that the exposure period and conditions had a combined effect on the early strength gain, suggesting that further long-term investigations are necessary.This study aimed to establish and conduct an experimental program to investigate the significant factors influencing the surface protection of marine concrete structures. The coating performance was assessed by measuring both the coating thickness and bond strength. It was observed that the exposure conditions and period significantly influenced the coating thickness and strength. The results also indicated a high degree of variability. However, it is imperative to emphasize the need for further research in underwater coatings for marine structures. These structures are constantly exposed to harsh underwater environments, which can result in material corrosion and degradation over time. Continuous research efforts can play a pivotal role in the development of and improvement in coatings that offer effective corrosion protection, thereby extending the lifespan of these structures and ultimately reducing maintenance costs ,51,52,53In this study, we noted significant variability in the test results, primarily stemming from uncontrolled conditions and human errors. To mitigate this variability in underwater coatings and ensure reliability, a multifaceted approach is essential. This encompasses factors such as meticulous material selection, precise application techniques, stringent quality control measures, and continuous maintenance. In particular, the proper surface preparation of target structures and thorough training for applicators play pivotal roles in achieving the desired performance. Regular monitoring and maintenance are equally vital to secure long-term effectiveness. The high variability in the results can be considered a limitation of this study, as it may hinder the proper selection of coating materials and methods, considering their appropriate application areas. Similarly, reducing the high variability in underwater coatings and achieving reliability involves factors such as proper material selection, application techniques, quality control measures, and ongoing maintenance. These limitations should be properly addressed through ongoing testing and future research.Within this research, it was further affirmed that the exposure conditions had the most substantial influence on both the thickness and strength, while the effect of the coating method was deemed negligible following a thorough statistical analysis. Specifically, the differences between the maximum and minimum mean thickness and strength values were 83% and 37% higher in the RS condition compared to the TW condition, while no significant difference in the coating method was observed at the 0.05 significance level. This contradicts the results obtained in previous laboratory testing. Hence, it is evident that conducting tests in authentic sea conditions is indispensable. This is because the performance of underwater coatings on concrete structures can exhibit substantial variations between controlled laboratory settings and the real sea environment. In addition, within the scope of this study, E3 can be recommended to ensure proper bonding performance for underwater structures, while the coating method could not be optimized.Additional research is required to gain a deeper understanding of the wear resistance and fatigue characteristics of underwater coatings through long-term investigations. Conducting extended studies is essential to enhance the performance assessment of underwater coatings. It is worth noting that short-term studies may not provide a precise reflection of the long-term performance of these coatings. Over time, various environmental factors, such as saltwater corrosion, biofouling, and other wear and tear, can significantly affect the effectiveness of these coatings. Long-term studies provide a more realistic simulation of the actual conditions these coatings will face in practice, while allowing for a comprehensive assessment of the durability and robustness of underwater coatings. This encompasses the evaluation of their resistance to deterioration, the preservation of their protective properties, and their ability to endure prolonged exposure to the demanding conditions underwater. Extended testing proves invaluable in uncovering any latent weaknesses or vulnerabilities in coatings that might escape notice in shorter-term investigations. This, in turn, leads to refinements and enhancements in the formulation and application of these coatings, ultimately bolstering their long-term performance. In summary, continuous research into underwater coating technologies is imperative, to tackle the distinct challenges presented by marine environments, extend the longevity and efficacy of marine structures, and adhere to evolving environmental and regulatory standards, ensuring that these coatings retain their effectiveness, safety, and environmental sustainability over time.BPA  had the lowest coating thickness and bond strength, whereas BPA with zinc powder (E2) and BPA with cresyl glycidyl ether (E3) demonstrated similar values.The impact of the chosen coating method on the measured thickness and strength values appeared to be minimal, and notably, the conventional roller (D1) had the highest thickness variation. This might be attributed to the possibility that the other factors had a more significant influence than the coating method.Under RS conditions, there was a noticeable increase in coating thickness compared to the controlled condition. As for bond strength, the exposure conditions had only a limited effect, except for E3.Thickness values remained relatively stable regardless of the exposure period, and E3 demonstrated an upward trend in bond strength with increasing exposure time, particularly under the RS conditions.The relationship between the measured thickness and bond strength appeared unclear, and this pattern aligns with findings from previous studies.This study conducted experimental investigations into the alterations in the interfacial bond properties of BPA epoxy resins when applied to underwater concrete. It specifically examined the impact of various epoxy types, coating techniques, and exposure conditions and durations on both the coating thickness and bond strength. The following conclusions have been derived from the test results and subsequent analyses:The measured thickness and strength values exhibited high variability, which could be attributed to environmental factors . This study offers valuable insights into the key factors that need to be considered when applying coatings to marine concrete structures, thereby contributing to the ongoing research and development of underwater coating technologies.


The use of tricalcium phosphate (TCP) as a bone substitute is gaining increasing interest to treat severe acetabular bone defects in revision total hip arthroplasty (rTHA). The aim of this study was to investigate the evidence regarding the efficacy of this material. A systematic review of the literature was performed according to the PRISMA and Cochrane guidelines. The study quality was assessed using the modified Coleman Methodology Score (mCMS) for all studies. A total of eight clinical studies (230 patients) were identified: six on TCP used as biphasic ceramics composed of TCP and hydroxyapatite (HA), and two as pure-phase ceramics consisting of TCP. The literature analysis showed eight retrospective case series, of which only two were comparative studies. The mCMS showed an overall poor methodology (mean score 39.5). While the number of studies and their methodology are still limited, the available evidence suggests safety and overall promising results. A total of 11 cases that underwent rTHA with a pure-phase ceramic presented satisfactory clinical and radiological outcomes at initial short-term follow-up. Further studies at long-term follow-up, involving a larger number of patients, are needed before drawing more definitive conclusions on the potential of TCP for the treatment of patients who undergo rTHA. The amount of revision procedures following total hip arthroplasty (THA) continues to grow worldwide, with a failure rate of 12% at a 10-year follow-up, mainly due to the increasing average age of first implants and the rising life expectancy of patients ,4,5,6, hSynthetic bone substitutes, such as bioactive ceramics, have recently received great focus due to their potential in stimulating cell proliferation, differentiation, and bone tissue regeneration . Among tThe aim of this systematic review was to investigate safety, clinical and radiological outcomes of TCP as a bone substitute to treat severe acetabular bone defects in hip revision surgery.A systematic review of the literature was performed on TCP use to reconstruct bone defects in hip revision surgery. This study was registered on the international prospective register of systematic reviews (PROSPERO registration CRD42022370721) .A comprehensive literature search was conducted on 29 October 2022 in three electronic databases , with no time limitation and without any filters, using the following string: ((ceramic bone graft) OR (synthetic bone graft) OR (bone graft substitute) OR (bone substitute)) AND ((revision hip replacement) OR  OR (revision hip arthroplasty) OR (acetabular revision) OR (acetabular defect) OR (acetabular loss)).According to the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) and Cochrane guidelines , the artFor the included studies, relevant data were extracted from article texts, tables, and figures, and then summarized and analyzed according to the purpose of the present work. In particular, the following data were collected: year of publication, study design, surgical technique, details of the bone substitute used, survival rate of the implant, number of evaluated patients, patient characteristics, acetabular defects, clinical and radiological follow-up length, clinical and radiological evaluation methods, main results, failures, and adverse events. The survival rate of the revision acetabular cup was summarized including clinical and radiological failures. The efficacy of TCP as a bone graft in THA was evaluated by summarizing data of the clinical scores and data of the radiological examinations, while the safety of the procedures was evaluated by identifying the reported complications.The quality of the included studies was assessed using the modified Coleman Methodology Score (mCMS) for all studies . The mCMThe electronic search yielded 643 studies. After duplications and non-English articles were removed, 419 studies remained. Of these, 408 were excluded after a review of the abstracts and full-text articles not concerning the use of TCP as bone substitute on the management of acetabular bone loss in revision THA (rTHA). One article was identified through the reference lists. Consequently, 12 articles were selected for eligibility according to the inclusion/exclusion criteria. Four studies were excluded after full-text evaluation: three articles were excluded because they reported the same patients of other included studies updated with a longer follow-up ,28,29 anAmong the included articles, the analysis by study type showed eight retrospective case series, of which two were comparatives. Different types of bioactive ceramics including TCP were investigated: six articles investigated biphasic ceramics composed of TCP and HA, and two pure-phase ceramics consisting of TCP.The evaluation with the mCMS showed an overall poor methodology of the included studies, with an average score of 39.5 points out of 100 (range 28–59).A total of 231 acetabular revisions were performed on 230 patients affected by THA failures. The surgical indication of rTHA was documented by 5/8 studies, including a total of 175 hips, where aseptic loosening was the diagnosis in all cases. The average age of the patients was 69.9 (65.6/74.3) years, where 65.2% were female and 34.8% were male. The follow-up duration varied from 7 months to 16 years, with an average of 7.7 years. Moreover, acetabular deficiencies were classified according to the system of Parry et al., to the American Academy of Orthopedic Surgeons (AAOS) classification, and to the Paprosky classification ,33. Fina®, Stryker, UK) [®, Arthrex, Germany) [®, Stryker, USA) [®, DOT GmbH, Germany); and one study used two biphasic ceramics composed of 45% TCP and 55% (HA) , and 35% TCP and 65% HA  [®, Kyeron, The Netherlands) with osteoconductive properties to the bone substitute [TCP was used in different types of bioactive ceramics, constituting of several molecules in different percentages. Four studies utilized a biphasic ceramic composed of 80% TCP and 20% HA  ,35,39,40Germany)   ; one a b France) ,35. Morebstitute . FurtherTo evaluate clinical outcomes, the Oxford Hip Score (OHS) (four studies) and the Harris Hip Score (HHS) (three studies) were the most commonly used scores. Other scores, like WOMAC, Short Form 36 (SF-36), Short Form (SF-12), Satisfaction Scale for Joint Replacement Arthroplasty (SAPS), Japanese Orthopaedic Association (JOA) score, University of California at Los Angeles (UCLA) activity scale and, Merle d’Aubigné Postel scale, were also used in some studies . To evalThe main finding of the included studies was an overall improvement in functional and radiographic outcomes of patients treated with TCP in the management of acetabular bone loss in rTHA. Radiolucency around revision cups was investigated, where six studies reported a total of 77 (49.3%) patients without any signs of radiolucent lines at the radiographic examination, while 21 (13.4%) patients had signs of radiolucent lines in at least one zone. Absorption, in general, was observed in constant growth throughout the follow-up periods; however, two migrations of the cup were reported. Finally, the survival rate of the implants was reported in five studies with an overall mean survival of 93.3% .The safety of TCP for the treatment of acetabular defects in rTHA was documented by 7/8 studies for a total of 200 rTHAs. No severe adverse events occurred during the surgical procedures. During the follow-up periods, 21 (10.5%) reoperations, not involving the acetabular cup, were performed. Further details of adverse events were reported in ® Ortho Foam , was used for acetabular bone stock reconstruction in 11 acetabular revisions performed between April 2018 and November 2021. The indication for using Cerasorb® was a massive bone defect of the acetabulum, that required grafting to fill the bone gap. Cerasorb® is a bone substitute composed of a mixture of 85% β-tricalcium phosphate (β-TCP) particles 150–2000 μm in diameter, and 15% porcine collagen consisting of 80% type I collagen, 15% elastin, and 5% type III collagen, with a porosity of 65% [In our institute, the bone graft substitute, Cerasorby of 65% . The stuThe diagnosis of periprosthetic joint infection (PJI) was ruled out both preoperatively and intraoperatively. Before surgery, C reactive protein and erythrocyte sedimentation rates were analyzed for every patient, to rule out the presence of active infection. Moreover, in patients suspected of PJI, leukocyte scintigraphy was obtained. During surgery, an analysis of fresh sections of periprosthetic tissue to verify leukocyte counts was carried out. If the pathologist prevented an active infection during the surgery, the prosthetic components were implanted. Meanwhile, during the surgical procedure, permanent histological sections and intraoperative cultures of periprosthetic tissue were collected and sent to microbiology.Clinical assessments evaluating HHS and radiological evaluation with standard anteroposterior X-rays were performed in all cases, and CT scans were carried out in five cases. The hip center of rotation in standard anteroposterior X-rays of the pelvis was individuated . The dis® and the bone allograft was defined radiologically by the presence of trabecular crossing of the graft–host interface. The graft resorption was graded as minor (<1/3 of graft resorbed), moderate (1/3 to 1/2 of graft resorbed), and severe (>1/2 of graft resorbed), and was analyzed using the three zones of the acetabulum defined by DeLee and Charnley [According to the criteria of Dorr et al. , the preCharnley .®); Delta Revision in two cases (LimaCorporate®); and in two cases, the acetabular defect (Paprosky 3B/pelvic discontinuity) proved to be so huge, that a custom-made acetabular implant was required . In those cases, the CT scan was performed for the development of a custom-made component, and preoperative planning was also carried out for the correct positioning of the prosthetic implant. Meanwhile, a cemented cup Muller (Zimmer®) on an acetabular cage (LimaCorporate®) was only implanted in one case. Moreover, acetabular screws to achieve further stability were utilized in 10 cases. Finally, in four patients, the femoral component was also revised (LimaCorporate®) at the time of index surgery, three due to deep infection and one for aseptic mobilization.During the surgical procedure, acetabular bone loss was evaluated and classified according to the Paprosky classification ,33. PatiAll surgeries were performed by the first author (M.R.), who is an experienced specialist hip surgeon. Two different approaches were used during revision surgeries: postero-lateral in 10 patients, and Smith-Petersen in only one patient. The presence of active infection during reimplantation was ruled out in four patients using bacteriologic analysis (cultivation), histologic samples, and an antibiogram. In every surgery, debriding of the granuloma tissue adhering to the acetabulum remaining bone was performed, thus the extent of the acetabular defect was evaluated with the Paprosky classification. In one patient (Paprosky IIIB), it was necessary to stabilize the pelvic discontinuity with the placement of a posterior plate. Subsequently, in nine patients the acetabulum was regularized with hemispheric reamers, and in two cases the acetabulum was prepared with guides for the custom-made implant.® was used for acetabular bone defect reconstruction  years and the mean radiological follow-up was 1.7 (4 m–3.6 y) years. Furthermore, one patient was lost at the first radiographic follow-up.The evaluation of clinical results revealed an increase in pre-operative HHS from an average of 33.5 (15.7–46.2) points to an average of 79.2 (64.7–91.8) points at the most recent follow-up. Moreover, the average preoperative limb length discrepancy was −3.0 (−6.8/+0.3), shrinking remarkably to −0.4 (−3.0/+1.0) after the surgical procedure and remaining constant over the follow-up periods .Radiologically, the HD and VD distances were calculated on the pelvis radiograph after surgery and at the last radiological follow-up. The HD was corrected from preoperative 30.5 mm (17.5–56.9) to postoperative 33.2 mm (21.4–44), the VD was corrected from preoperative 32.2 mm (22.0–90.0) to postoperative 26.7 mm (15.5–69.0). Furthermore, a migration  of one acetabular cup 12 months after surgery was observed, but has remained stable in subsequent radiographic controls . The patNo severe adverse events occurring during the surgical procedure and during the postoperative period were reported. One patient developed a pulmonary emboly after stopping enoxaparin, after six months. There were not any cases of deep infections or prosthetic dislocations of the operated hips. Although a crutch remained necessary in two of the cases, hip pain was nearly or totally alleviated.The current systematic review revealed the increasing attention on TCP as a bone substitute for the treatment of acetabular bone loss in rTHA. While the number of studies and their methodology is still limited, the available evidence suggests safety and overall satisfactory results of TCP bone grafts in acetabular revision, as confirmed by early case-series reported results.Particularly, TCP was described in literature since the 1970s ,49, gainAmong the different aspects of TCP, combination with other compositions or none is one of the most debated. Some preclinical evidence suggests that biphasic ceramics show higher osteogenesis, angiogenesis, and biocompatibility in comparison to the monophasic constitutes, where their bioresorbability could be optimized by varying the TCP/HA content . VariousThis systematic review showed an overall clinical improvement, even if only three studies reported preoperative values of clinical scores used ,39,40. TThe survival rate of the implants in the included studies was calculated using different endpoints. Two articles used the Kaplan–Mayer analysis with radiographic failure as the endpoint, revealing an average of 85.8% (74.2–97.5%) at a mean follow-up of 9.4 years; two studies applied the Kaplan–Mayer analysis with acetabular revision as the endpoint, disclosing an average of 96% (94–96%) at a mean follow-up of 11.12 years, and one article reported implant survivorship of 100% at a mean follow-up of 2.91 years, with acetabular revision as the endpoint. The mean survival rate of the prosthesis in the included studies (93.3%) and in the case-series (90.9%) was similar to those reported in huge registries that analyzed survival rates of rTHA with Kaplan–Mayer curves ,59, althAmong the included studies, acetabular bone loss was characterized by a high heterogeneity relative to the different classifications and types of defects. The literature suggests a common consensus regarding lower survivorship of rTHA performed on severe acetabular bone deficiencies compared to those with smaller bone defects ,60. In fThe limitations of this systematic review reflect the limitations of this field. The literature analysis showed that clinical studies on TCP as a bone substitute in the management of acetabular revisions are few and characterized by a low methodology quality and high heterogeneity. No RCTs were available, and only two comparative studies comparing TC to other bone grafts were conducted. Moreover, there are not enough stratified and homogeneous data based on the type of bioceramic used, making it difficult to merge and compare clinical results, thus impairing the possibility to perform a reliable meta-analysis to draw clear conclusions. Accordingly, it was not appropriate to proceed with the data analysis, and the systematic review offers a state-of-the-art picture of the field. Aligned with this aim, the methodology of the selected studies was evaluated with mCMS, which confirmed the limited quality of the literature. Similarly, the included studies did not always report the exact number and reason for failures, hindering the possibility to obtain a survival curve based on a unique endpoint. Finally, the relatively short follow-up in some of the included studies leaves concerns regarding the durability and effectiveness of TCP as a bone substitute for rTHA.TCP for the management of massive bone loss has been proven safe, effective, and associated with a low risk of failure. While the number of studies and their methodology is still limited, the available evidence suggests overall promising results. Consistent with these data, the case-series presented in the current study revealed satisfactory preliminary results. Further studies at long-term follow-up, involving a larger number of patients compared with a control group, are needed before drawing more definitive conclusions on the real potential of TCP for the treatment of patients who undergo rTHA.


Background and Objectives: The optimal assessment of cognitive function, including the impact of education, is crucial in managing Alzheimer’s disease (AD). This study aimed to evaluate the role of cognitive reserve (CR), represented by the metabolic status of regions of the cerebral cortex, to evaluate cognitive decline considering the educational attainment of patients with AD. Materials and Methods: We used data from the Alzheimer’s Disease Neuroimaging Initiative database, and selected 124 patients who underwent both baseline F-18 fluorodeoxyglucose (FDG) and F-18 florbetaben (FBB) positron emission tomography (PET) scans. Demographics, cognitive function variables , and the average standardized uptake value ratio (SUVR) of cerebral cortex regions to those of the cerebellum were obtained from the data. The participants’ education level was divided into low and high education subgroups using four cut-offs of 12, 14, 16, and 18 years of educational attainment . Demographic and cognitive function variables were compared between the two subgroups in each of the four groups, and their correlations with the SUVRs were evaluated. Results: There was no significant difference between the high and low education subgroups in each of the four groups, except for ADAS11/13 and MMSE in G14 and age in G16. The SUVRs of FDG PET (FDGSUVR) were significantly correlated with CDR, ADAS11/13, and MMSE scores. FDGSUVR showed different trajectories of neurodegeneration between the low and high education groups. Conclusions: FDGSUVR correlated moderately but significantly with neuropsychological test results, without being influenced by education level. Therefore, FDG PET may reflect CR independent of education level, and therefore could be a reliable tool to evaluate cognitive decline in AD. Alzheimer’s disease (AD) is a neurodegenerative disorder characterized by the mismatched production and clearance of β-amyloid (Aβ) and tau proteins. This is followed by adverse neuro-inflammation. Cognitive decline is the most common symptom of AD, and is a key factor in the diagnosis and evaluation of AD progression and treatment response. Conventional neuropsychological tools used to measure cognitive function include the Mini-Mental State Examination (MMSE), the Clinical Dementia Rating (CDR), and the AD Assessment Scale (ADAS) ,2,3.The discrepancy between the severity of cognitive decline and postmortem pathological findings among participants in the low and high education groups has been termed “cognitive reserve (CR)” ,5. The CF-18 fluorodeoxyglucose (FDG) positron emission tomography (PET) is used as an image biomarker to assess AD, and for the differential diagnosis of other dementia types. Amyloid PET depicts the accumulation of Aβ and plays a role in the diagnosis of AD [F-18 is of AD ,8,9. Theis of AD ,11,12. Tis of AD .Therefore, this study aimed to evaluate the correlation of FDG PET-based SUVR with neuropsychological test results according to education level and to assess whether the measurement of SUVR by FDG PET can be a surrogate for conventional cognitive measures and a proxy for education-independent CR in AD.SUVR and FBBSUVR of 124 participants were analyzed in this study. The FDGSUVR was defined as the average of the FDG PET-based SUVR values of the angular, temporal, and posterior cingulate regions. The FBBSUVR was defined as the average of the FBB PET-based SUVR values of the frontal cortex, anterior cingulate gyrus, precuneus cortex, and parietal cortex. The educational attainment in years (EDU), number of apolipoprotein E4 alleles (APOE), MMSE score, CDR, and ADAS11/13 data were also obtained from the baseline study of ADNI datasets. The APOE results were available for 99 of the 124 (79.8%) participants. Cerebrospinal fluid Aβ data were not available. The Institutional Ethics Committee of Ulsan University Hospital confirmed that ethical approval was not required for this observational study, and waived the requirement for informed consent (IRB file number: UUH2022-05-029).Several key variables from various clinical information reports and biomarker results from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) protocols are merged to create the “adnimerge” table. A total of 2159 participants in ADNI-3 datasets were screened and 124 participants who had both baseline FDG PET and florbetaben (FBB) PET amyloid imaging were finally enrolled. The FDGSUVR, and FBBSUVR were compared between mild cognitive impairment (MCI) and AD groups using an independent t-test and a Mann–Whitney U test for continuous and categorical variables, respectively. Four cut-offs of 12, 14, 16, and 18 years for EDU were used and participants were divided into low and high education subgroups . The association of each subgroup of G12, G14, G16, and G18 with neuropsychological results was evaluated using Pearson’s and Spearman’s correlation analyses. For the MCI and AD groups, univariable and multivariable analyses were performed to evaluate the association of age, sex, EDU, APOE, FDGSUVR, and FBBSUVR with neuropsychological tests to assess cognitive function. In multivariable regression analyses, dummy variables were used for categorical variables, including sex and APOE.All data are described as mean and standard deviation for continuous variables and as numbers (percentages) for categorical variables. Age, sex, EDU, APOE, CDR, ADAS11/13, MMSE, FDGSUVR and FBBSUVR, showed significant differences. One of the three healthy participants was 90 years old and had CDR, ADAS11, ADAS13, and MMSE scores of 7, 29.33, 41.33, and 20, respectively. The other two healthy participants exhibited normal neuropsychological results. Detailed demographics of all participants are presented in There were no statistically significant differences regarding age, sex, and EDU between the MCI and AD groups; however, APOE, CDR, ADAS11/13, and MMSE scores, as well as FDGp = 0.038 and 0.032, respectively) and the MMSE score (p = 0.017) in G14  in G12 and G14, and age and MMSE scores  in G16. In the AD group, only ADAS11 and FBBSUVR  in G16 exhibited statistically significant differences between the low and high education groups , except for the ADAS11 and 13 scores  in G14 . Howevern groups .SUVR, and FBBSUVR were correlated with CDR, ADAS11/13, and MMSE scores. Age correlated with ADAS11/13; however, the correlation was not statistically significant (SUVR, FBBSUVR, and age with CDR, ADAS11/13, and MMSE were observed. The AD group showed almost no correlations with the results of the neuropsychological tests (Correlation analyses for all participants revealed that APOE, FDGnificant . In the al tests .SUVR was a significant independent factor correlating with CDR, ADAS11/13, and MMSE in most groups, followed by FBBSUVR and age. Sex, EDU, and APOE were not significant variables (SUVR and FBBSUVR for CDR, ADAS11/13, and MMSE scores are shown in SUVR downward slopes for the participants with high education levels for the ADAS11/13 and MMSE scores in the G12, G14, and G16 groups were steeper than those for the participants with low education levels. The slopes for CDR in all EDU groups as well as the ADAS11/13 and MMSE scores in the G12, G14, and G16 groups were gentler for those with high than for those with low education levels (SUVR were not as regular as the downward sloping lines of FDGSUVR (Multivariable linear regression analyses revealed that FDGariables . The regn levels . The upw FDGSUVR .SUVR correlated with the results of various neuropsychological tests used to evaluate CR, and whether FDGSUVR could reflect CR in a manner that was independent of the influence of education. We observed that FDGSUVR was significantly and moderately correlated with CDR, ADAS11/13, and MMSE scores.With the global aging of society, AD is increasingly becoming a public health issue . CognitiIn our study, the age of high-education-level participants at baseline was expected to be older than that of the low-education-level participants, as their neuropsychological results did not differ according to the concept of CR. However, we found that the age at baseline did not differ between patients with low or high education levels. In contrast, the ADAS11/13 and MMSE differed for all participants in G14, and the MMSE scores for the MCI group differed in G12 and G14 between the low- and high-education groups. Only in the MCI group for G16 did age differ significantly according to different MMSE results. None of the other groups exhibited significant differences. These results suggest that CR may not affect the early detection of AD, regardless of the education level.SUVR and FBBSUVR revealed a moderate correlation with neuropsychological test results across all EDU-based subgroups in our study. Regression lines of FDGSUVR and FBBSUVR (SUVR and FBBSUVR between the low- and high-education level groups might indicate the existence of CR, although this was not based on an analysis with real data. In addition, longitudinal correlations between FDG or FBB PET/CT and ADAS11 have been presented in other studies [Therefore, the question might arise regarding whether the concept of CR is meaningful. Since CR could delay AD diagnosis in the higher education group, FDG and amyloid PET were evaluated as tools to assess CR, regardless of the level of education ,5,15. In FBBSUVR  data at  studies . Another studies . FDG and studies , therebySUVR and FBBSUVR were more reliable in representing CR with the current cognitive status demonstrated by neuropsychological test results, independent of educational levels. In multivariable analyses, FDGSUVR was the factor most significantly correlated with CDR, ADAS11/13, and MMSE scores, followed by FBBSUVR and age. Other studies also showed that FDGSUVR and FBBSUVR were significantly correlated with cognition [SUVR with cognitive status may be more significant than that of FBBSUVR, as our study also indicated [Neuropsychological tests remain the mainstay for evaluating treatment responses in patients with AD. Conducting neuropsychological tests in an AD population with profound cognitive decline is challenging. Questionnaire-based neuropsychological assessments may be difficult to obtain, particularly for individuals with intellectual disabilities. Indeed, the low sensitivity of questionnaire-type cognitive assessments has been previously reported . The evaognition . In addindicated ,23,24. Sndicated ,10. ThesSUVR and neuropsychological results, which were not evaluated in this study. However, neuropsychological assessments become more difficult as cognitive decline progresses. Nevertheless, our study indicated that even in advanced cases FDGSUVR could provide reliable information on CR, which showed different trajectories between low and high education level participants. Our study was further limited in that only the average FDGSUVR of the angular, temporal, and posterior cingulate regions in the brain were included. As regional changes in the brain glucose metabolism in AD have been well evaluated, more detailed correlations with each brain region based on time and neuropsychological results might provide a better understanding of CR. Further studies should be designed based on these considerations.Our study had some limitations. This was a cross-sectional study, in which chronological changes in cognitive decline were not monitored. The duration of subjective or objective cognitive impairment could vary and affect the time-based correlation between FDGSUVR showed significant correlations with the results of neuropsychological tests based on questionnaires. The FDGSUVR displayed different trajectories of neurodegeneration between participants with low and high education levels based on diminished cognitive function, supporting the concept of CR. Therefore, FDG PET could be a reliable and objective imaging tool to assess cognitive decline and might be a proxy of CR which is independent of educational influence in patients with AD.In conclusion, FDG


Pain, sedation, delirium, and iatrogenic withdrawal syndrome are conditions that often coexist, algorithms can be used to assist healthcare professionals in decision making. However, a comprehensive review is lacking. This systematic review aimed to assess the effectiveness, quality, and implementation of algorithms for the management of pain, sedation, delirium, and iatrogenic withdrawal syndrome in all pediatric intensive care settings.A literature search was conducted on November 29, 2022, in PubMed, Embase, CINAHL and Cochrane Library, ProQuest Dissertations & Theses, and Google Scholar to identify algorithms implemented in pediatric intensive care and published since 2005. Three reviewers independently screened the records for inclusion, verified and extracted data. Included studies were assessed for risk of bias using the JBI checklists, and algorithm quality was assessed using the PROFILE tool . Meta-analyses were performed to compare algorithms to usual care on various outcomes .From 6,779 records, 32 studies, including 28 algorithms, were included. The majority of algorithms (68%) focused on sedation in combination with other conditions. Risk of bias was low in 28 studies. The average overall quality score of the algorithm was 54%, with 11 (39%) scoring as high quality. Four algorithms used clinical practice guidelines during development. The use of algorithms was found to be effective in reducing length of stay , length of mechanical ventilation, duration of analgesic and sedative medications, cumulative dose of analgesics and sedatives, and incidence of withdrawal. Implementation strategies included education and distribution of materials (95%). Supportive determinants of algorithm implementation included leadership support and buy-in, staff training, and integration into electronic health records. The fidelity to algorithm varied from 8.2% to 100%.The review suggests that algorithm-based management of pain, sedation and withdrawal is more effective than usual care in pediatric intensive care settings. There is a need for more rigorous use of evidence in the development of algorithms and the provision of details on the implementation process.https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42021276053, PROSPERO [CRD42021276053]. However, prolonged intravenous administration of opioids and sedatives can lead to tolerance, delirium, and iatrogenic withdrawal syndrome (IWS) –3. MaintSeveral studies on algorithm implementation in PICUs has been published in the last decade, predominantly quasi-experimental and focused on sedation algorithms. In studies where patients were managed using a sedation algorithm, mixed results have emerged; positive outcomes included reduced PICU length of stay (LOS), decreased total duration of sedation, decreased doses of sedatives, and decreased prevalence of IWS , 25. HowWhile effectiveness is an important component of implementation , researc1)To evaluate the effectiveness of the algorithm for pediatric intensive care patient outcomes (outcome).2)To evaluate the quality of the content and the development of algorithm attributes (structure).3)To describe the implementation of the algorithms, including strategies of implementation, the determinants (barriers and facilitators), the fidelity to the algorithm and/or its components, and users' satisfaction (process).Effectiveness is not the sole indicator of quality of care. Donabedian's concepts of “structure-process-outcome” are universally accepted as a framework for quality assessment . Structu2.The Cochrane Guidelines for Systematic Reviews handbook guided this review . The Pre2.1.All studies with a before and after implementation design, including RCTs, quasi-experimental and cohort studies with prospective or retrospective controls. The PICO criteria: population (P) of interest: premature infants and children up to 18 years of age admitted to any pediatric intensive care setting . Intervention (I): studies using an algorithm for at least one of the four conditions with an embedded measurement instrument. Compared (C) to usual/baseline care. Each study had to contain at least one patient outcome (O) of interest: LOS in the ICU or hospital, length of mechanical ventilation (MV), duration of analgesics and sedatives, cumulative dose of analgesics and sedatives, incidence of IWS and delirium, adequate pain and sedation management, scores, length of medication weaning, and methadone use. Studies published after 2005, as this aligns with the publication year of the first CPG on analgesia and sedation in pediatric intensive care . Languag2.2.1)Database searches in PubMed, Embase.com, CINAHL with Full Text (EBSCO), and Cochrane Library , ProQuest Dissertations and Thesis Global (ProQuest)2)Complementary searches in Google Scholar. As recommended the first 300 entries (30 pages) were manually assessed .3)Manual citation searches were conducted for all included studies, using the reference list and Web of Science and Google Scholar to identify additional relevant studies on development, implementation, or adaptation of the original algorithm.A biomedical information specialist (AT) assisted in developing the search strategy. An advanced search strategy was developed for PubMed using Medical Subject Headings (MeSH) and free-terms describing: (1) pain, sedation, delirium or withdrawal, (2) pediatric intensive care, and (3) algorithm, clinical pathway, or protocol. The strategy was then adapted for each informational source, using the appropriate index terms and syntax. No published search filters or hedges were used. Contrary to what was stated in the protocol, no language limit was applied, and records published before 2005 were excluded. In Embase.com, conference abstracts and conference reviews published before 2016 were excluded. All search strategies were peer-reviewed by another librarian using the PRESS checklist , to remove duplicates (AT). The remaining records were uploaded to Rayyan  for the screening process .Three reviewers  independently screened titles and abstracts for inclusion. Full-text publications meeting inclusion criteria were assessed, and the reasons for exclusion were recorded. Disagreements were resolved through discussion and consensus. One reviewer (IMD) conducted the complementary search on Google Scholar and manual citation searches and identified full-texts, and two reviewers independently assessed inclusion criteria (IMD and MM).2.4.The review team designed, and pilot tested the data extraction tables; one change was made, the addition of one category to the Effective Practice and Organisation of Care (EPOC) implementation strategies  RCTs (13 items), (2) quasi-experimental studies (9 items), and (3) cohort studies (11 items) . Each it2.4.2.editorial independence as this is not applicable for locally developed algorithms; and c) adding eight items related to content and development based on a literature review of clinical pathway appraisal tools  stakeholder involvement; (3) rigor of development; (4) content and process; and (5) implementation. The domains are further categorized across three processes: (a) development (domains 1–3), (b) content (domain 4), and (c) implementation (domain 5). Each item was scored as either “1 = yes” or “0 = no”. No algorithm was excluded based on quality. The PROFILE has three types of scores: (1) an overall quality score that uses all items; (2) domain scores, five in total, one for each domain; and (3) process scores, three in total. It was pre-tested using one algorithm by all three reviewers , following which a consensus meeting was used to finalize the items and create a user manual with details for each item (as with the AGREE II instrument). An overview of the PROFILE is available in No tool exists for the appraisal of the methodological quality of algorithms. We modified the Appraisal of Guidelines for Research and Evaluation (AGREE) II instrument  to creatal tools –51. Thisal tools . The PRO2.5.The information extracted from each study and how it was analyzed to meet the three objectives are described below. Descriptive information on the study characteristics and details of each algorithm was extracted and summarized in two tables.2.5.1.Meta-analyses were conducted using STATA version 17 software . Random-When the median and interquartile range (IQR) were reported, they were transformed using Wan's method and Excel tool .I2 test was used to assess statistical heterogeneity, which was considered low if <40%, moderate 30%–60%, substantial 50%–90% and considerable 75%–100%  table was created using the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) approach . The GRAAll corresponding authors were sent a personalized email to clarify unclear risk of bias items or missing details of algorithm content, development, and implementation. Six authors provided additional information included in the analysis –66.2.5.2.The three PROFILE scores  of algorithm implementation, narrative descriptions were extracted. and categorized as intervention, professional or organizational using Lau's framework . Each deTo analyze algorithm fidelity, rates were extracted, reported as percentages and ranges, and presented in a table. Fidelity is defined as whether an intervention has been implemented as intended with two subcomponents: adherence and dose . AdherenStaff and family satisfaction was reported in a table.3.K = 0.92–0.97).The database search yielded 6779 records and the complementary search (Google Scholar and citation screening) added 20 records. After removing duplicates, 123 full-text studies were screened, and 91 were excluded . Thirty-3.1.3.1.1.The characteristics of the 32 included studies are summarized in n = 24) had a sample with a mean or median age of less than 4 years . Seventy-five percent of the studies   integrated the measurement instruments into the electronic health record , 92–95, The primary analgesic agent used by algorithms was morphine 77%) .Twenty-five of the 29 studies with data on ICU LOS were included, with Vipond et al. having two different medication groups , 87–95. Four studies were not included in the meta-analysis because of missing data, three of them showed no significant differences between the two groups , 83, 84,3.3.2.p = 0.001; I2 = 77%).All ten studies with outcome data on hospital LOS were included, and the algorithm group showed a small decrease in hospital LOS .Twenty-six studies included duration of MV , 94, 95,p = 0.58) (I2 = 81). Sensitivity analysis showed that Larson et al. .The four studies that reported MV in hours showed no difference in the length of MV between the algorithm and usual care groups  , 80, 85.One study with missing data and showed no significant difference between the algorithm and the usual care groups .3.3.4.p = 0.0001; I2 = 89).Nineteen studies included cumulative dose of analgesic medications , 92–95. Of the four studies not included in the meta-analysis, one study showed a statistically significant decrease in the cumulative morphine dose (mg/kg/visit) in the algorithm group , while t3.3.5.p = 0.0001; I2 = 73).Eighteen studies included the outcome of cumulative dose of sedative medications , 92–95. Three studies not included in the meta-analysis showed statistically significant decreases in the algorithm group: one in cumulative lorazepam dose (mg/kg/visit), another in total dose of midazolam (displayed as box plots) , and the3.3.6.p = 0.03; I2 = 79).Twelve studies evaluated the duration of use of analgesic medications , 92, 95.Three studies not included in the meta-analysis showed no statistically significant differences between the algorithm and the usual care groups , 76, 83.3.3.7.p = 0.01; I2 = 88).Fifteen studies included the duration of sedative medications , 92, 95.Three studies not included in the meta-analysis showed no statistically significant difference between the algorithm and usual care groups when measuring duration in hours instead of days , 76, 83.3.3.8.p < .0001; I2 = 47; Thirteen algorithms reported the percentage of patients with IWS symptoms , 82, 89.Two studies not included in the meta-analysis showed a decrease in the rates of IWS in the algorithm compared to the usual care group , 82, and3.3.9.p = 0.09) (One study reported on the treatment of delirium with antipsychotics and there was no significant difference between the two groups ( = 0.09) .3.3.10.p = 0.54; I2 = 82; Figure 6B)  , 62, 85.Sensitivity and subgroup analyses were not performed because there were only three studies.Two studies reported on over-sedation and were not statistically significant but had opposite directions of effect, one with more incidents of over-sedation in the algorithm group  and the 3.3.11.Three studies reported on inadequate pain management , 76, 95,3.3.12.p = 0.0001; Figure 6C) than the usual care group. Heterogeneity was moderate (I2 = 52).Six studies reported on the duration of weaning, and all were included in the analysis , 90, 92.p = 0.04; Figure 6D) than the usual care group. Heterogeneity was substantial (I2 = 84).Four studies reported the duration of methadone exposure and were all included in the analysis , 89, 91.3.3.13.p < .001); however, there was no difference between the two groups for modal pain scores of less than 4  and the usual care groups ; a decrease in the cumulative dose of analgesic medications    , 90, 92; = 0.09) , 90, 92.•“Pain-sedation” algorithms showed a decrease in length of MV  (I2 = 41) , 94, 95.•Pain-sedation-IWS” algorithms showed a decrease in the cumulative dose of analgesic medications   (“2 = 28%) , 78–80;  = 0.29) , 78, 79.There were some differences observed by algorithm subgroup types:3.3.15.The summary of findings table for the seven key outcomes, using GRADE, is presented in 3.3.16.No publication bias was observed for any of the outcomes with more than 10 studies .3.3.17.I2 decreased by 30% with the same small-sized effect . Secondly, for duration of analgesic medications, two studies were outliers . Lastly, for incidence of withdrawal where one study   .p = 0.34; I2 = 53%) but not for NICUs, and a decrease in the cumulative dose of analgesic medications for NICUs  but not for PICUs. The test of group difference was not significant for either analysis (results not shown).Sensitivity analysis by type of setting showed a decrease in LOS ICU for PICUs .3.4.The overall PROFILE and the three process scores of the 28 algorithms are displayed in The mean percentage of the overall score was 54%. Eleven algorithms scored as high (39%) , 86, 93,The mean percentage of the development process score was 46%. Eight algorithms scored as high (29%) , 83, 93,The mean percentage of the content process score was 76%. All but one algorithm scored as high , 88–95, The mean percentage of the implementation process score was 55%. Twelve algorithms scored as high (43%) , 94, 95,Among the five domains of the PROFILE, Domain 1 (scope and purpose) scored high for all algorithms, with at least two out of the three items being present. Domains 4 and 5 were discussed in the previous section and are related to two of the three process scores . The lowest represented domain was Domain 2 (stakeholders), with only one algorithm including the patient or family, during development . DetailsConcerning content and development, 15 algorithms were developed because of an identified clinical problem (54%) , 93–95. 3.5.3.5.1.n = 24, 92%)          –93, 95, 13, 50%) , 93, 95.12, 46%) , 93, 95.= 2, 8%) , 81, tai= 2, 8%) , 81, use= 1, 4%) , manager= 1, 4%) , and mon= 1, 4%) . The mea3.5.2.Fifty-five determinants (barriers or facilitators) were reported across ten studies , 90, 95 The major organizational barriers were lack of leadership support, lack of planning for training, and competing priorities. The organizational facilitators were team buy-in, support, and involvement.The major professional barriers relate to the complexity of applying algorithms to patients due to stability and age, and nurses' lack of knowledge of the algorithm. Professional facilitators included education and a positive attitude.The major intervention facilitators were the structure of the algorithm, automatic alerts for assessment, and support for decision-making, resulting in ease and efficiency. No intervention barriers were reported.3.5.3.Fidelity to the algorithm was reported in 19 studies (68%) , 93, 95.3.5.4.Six studies reported on staff satisfaction levels , 90, 95 4.To the best of our knowledge, this was the first systematic review that examined the effectiveness of 28 algorithms for the management of pain, sedation, delirium and IWS in pediatric and neonatal intensive care. There were four key findings; firstly, standardized algorithm-based management across the four conditions had a weak but positive effect on improving most outcomes of interest for critically ill children in pediatric intensive care settings. Secondly, the evidence base used to develop algorithms varied with inconsistent multidisciplinary and little patient and family involvement in development and implementation. Thirdly, implementation processes were poorly described. Fourthly, although, adherence rates varied, they showed improved assessment and documentation practices.Standardizing the management of pain, sedation, delirium and IWS using an algorithm is recommended as a strategy , 20; howIn this study, over a third of the algorithms were scored as high-quality, indicating their potential to improve the management of the four conditions. However, given the undisputed benefits of CPGs, the lack of their use in the development of algorithms was an important finding. Out of 28 algorithms, only four used CPGs during development, suggesting that CPGs are not fully utilized, possibly due to lack of awareness or trust among HCPs. This finding was consistent with two recent surveys of PICUs showing that PICU practices related to pain and sedations management varied widely across Europe , 97. OutIn this review, barriers to the implementation process of algorithms in pediatric intensive care settings were identified. However, the implementation processes were often poorly reported, highlighting the importance of robust implementation processes as a barrier to transferability. Implementation strategies for algorithms tended to focus on education and training strategies, but these are often considered insufficient for successful implementation . Other sThe review identified organizational barriers, such as planning and leadership support, as crucial facilitators, which is consistent with existing literature . It alsoIn terms of professional barriers, this review highlighted the importance of planning for training, leadership support, and team buy-in to supporting the implementation process. This is supported by a study that described knowledge translation strategies used across 16 pediatric units, including neonatal and pediatric ICUs . AlgoritThe levels of adherence to the algorithm, including the dose, components, and measurement instruments were mixed. However, given the varied use of measurement instruments, increased compliance with assessment recommendations, and limited change in scores, this suggests that embedding measurement instruments into algorithms increases their frequency of use without changing the scores. This demonstrates the adequacy of the management strategies outlined in the algorithm. The use of algorithms improved both assessment and documentation practices, which are often cited as areas of concern by HCPs .4.1.An important contribution and strength of this review is the comprehensive evaluation of the development (structure), implementation (process), and outcomes of algorithm use. To the best of our knowledge, this method of evaluation has not been performed in a systematic review. However, this is also a limitation, as many of the algorithms were developed prior to the recommendations for using implementation frameworks and their standardized reporting, such as the template for intervention description and replication . ReportiAnother strength of this review is the recognition of the importance of ensuring the quality of algorithms, which was the reason for developing and using the PROFILE tool. Given the potential variability in algorithm quality and the impact this can have on patient outcomes, the assessment of rigor and transparency of algorithm development is crucial. The PROFILE provides a comprehensive framework for performing evaluations of algorithms and serves to identify areas for improvement in development and reporting. This underscores the need for a standardized approach to algorithm development and evaluation to ensure they are sfe, effective, and reliable.Another limitation is the possible sources of heterogeneity, including the non-standardized reporting of outcomes, which affected the ability to include outcomes in meta-analyses. Some outcomes had considerable differences, such as the different dosages and forms of medication administration , and the definitions of the treatment point for the outcomes being examined. Other factors could also have affected the results, such as age, underlying disease and severity, and concomitant medications. Currently, standardized core outcome sets do not exist in the PICU, which likely leads to variability.The variability in research designs is another limitation. While RCTs are considered the gold standard, they are tightly controlled and conducted with homogenous populations. Therefore, although RCTs may show better treatment effects for outcomes of interest, their results cannot be readily used in the clinical setting where these algorithms are often applied to the entire unit or much broader populations. With unit-based algorithms , the best possible results are achieved for these children based on continuous assessment and individualized care. However, retrospectively acquired methods may decrease the treatment effects.4.2.This systematic review has established that algorithm-based management is potentially associated with reductions in most of the outcomes of interest and improved fidelity to algorithm components, including assessment and documentation across the four conditions. While many of the algorithms contained a mixture of these conditions, only one combined all four conditions . Likely This review provides an overview of the implementation strategies used and the common determinants to consider when developing implementation plans. Implementation teams should consider these determinants in their planning to hasten implementation efforts by focusing on the contextual assessment of missing factors. The review also demonstrates the need to include all outcomes related to the implementation process, such as fidelity, to interpret successful implementation efforts or ineffective interventions. The use of implementation frameworks to guide the process is essential for advancing algorithms into practice , 116, alThis review highlights the limited inclusion of patients and families in both algorithm development and implementation planning, and it is recommended that teams consider their inclusion throughout the process. Patient and family involvement has been recognized as integral in CPG development , and it Although the implementation of an algorithm for the management of pain, sedation, delirium, and IWS is an important first step for critically ill children, a cultural shift that includes the ABCDEF bundles is important , 118, alThis review highlights that many patient outcomes are not defined, and those that are vary in the depth of their definitions, making them difficult to pool. This study further supports the need for researchers to develop a PICU-specific core outcome set to examine effectiveness.As indicated in the review of clinical pathway effectiveness, this study confirms the need for future systematic reviews to group algorithms and clinical pathways by condition to reduce heterogeneity . Both re5.This comprehensive systematic review provides valuable insight and a much-needed evaluation of the use of algorithms for the management of pain, sedation, delirium, and IWS in children in pediatric intensive care settings. The study results demonstrate that the implementation of algorithms can lead to improved patient outcomes and increased adherence to EB practices and documentation. Algorithms not only improve outcomes but also ensure standardization, preventing important interventions from being missed and ensure timely and appropriate treatments are applied, leading to improved documentation and satisfaction of HCPs. However, this review has highlighted gaps in the processes and reporting of algorithm development and implementation. The implementation of algorithms can be challenging, and evidence suggests that barriers such as lack of staff buy-in, resistance to change, and difficulties with implementation can affect the effectiveness of algorithms. There is a need for rigorous use of EB recommendations in the development of algorithms and overcoming these challenges with the use of implementation frameworks to facilitate algorithm quality and successful implementation aligned with the clinical setting.