Anxiety–depressive disorders (ADD) are a risk factor of cardiovascular mortality in patients with coronary artery disease (CAD). Acute coronary syndrome (ACS) is the main clinical manifestation of a progressing CAD. Metabolic processes disorder in platelets can be one of the causes of cardiovascular complications in patients with ACS and concomitant ADD. We studied platelets metabolism and prognostic informativity of NAD(P)-dependent dehydrogenases of platelets in ACS patients with ADD in terms of forecasting cardiovascular complications development over a year of observation. The levels of NAD- and NADP-dependent dehydrogenases of platelets were determined by means of a bioluminescent method during the first 24 h after admission to hospital and in dynamics in 10 days. Among 315 examined patients, ADD was found in 161 (51.1%). ACS patients with concomitant ADD had both cytoplasmic and mitochondrial processes impairment in platelets that consisted in a decrease of energy metabolism intensity, inhibition of anaerobic glycolysis reactions and lipid catabolism. After 12 months of follow-up, 41 (25.5%) cardiovascular complications were detected in the group of ACS patients with ADD and 20 (13.0%) in the group of ACS patients without ADD. According to the results of the analysis of the neural network based on NAD(P)-dependent dehydrogenases of platelets activity in ACS patients with ADD, indicators were obtained that are informative for predicting the development of recurrent cardiovascular complications. According to data found in literature, the prevalence of anxiety–depressive disorders (ADD) in patients with cardiovascular diseases ranges from 20% to 45%, which is 3–4 times higher than among the general population ,2,3,4. IA possible mechanism of a negative interaction between ADD and CAD is a combination of a higher level of catecholamines, a low variability of a cardiac rhythm, an endothelium dysfunction and an activation of inflammation reactions ,6,7,8.ACS is the main clinical manifestation of atherosclerosis progression in coronary arteries. Platelets activity and aggregation are key components of an ACS ,10. DespWith a high probability a risk of recurrent cardiovascular complications in patients with ACS can be related to functional activity of platelets. A connection between depression and hyperreactivity of platelets has been established ,14. TakiGuided by the above stated, this research was fulfilled to study the platelets metabolism and to determine the most informative prognostic indices to forecast risks of the development of recurrent cardiovascular incidents in patients with ACS combined with ADD based on the activity of NAD(P)-dependent dehydrogenases of platelets.The study comprised 315 ACS patients . ADD was detected in 161 (51.1%) patients, and in 154 (48.9%) patients no affective spectrum disorders were observed. The patient characteristics are presented in The control group comprised 55 relatively healthy volunteers .After the 12-month follow-up there were detected 56 (17.8%) recurrent cardiovascular complications . Among ACS patients without ADD, cardiovascular complications were observed in 20 subjects (13.0%) whereas for ACS with ADD group—in 41 subjects (25.5%). The results of prospective observation are summarized in The study of activity of metabolic enzymes of platelets in ACS patients showed low NADPH–GluDH level on the first day in patients without affective disorders. By the time of discharge from hospital the levels of this enzyme increased to some extent, but still did not reach the control values a. In theIn ACS patients with ADD who developed over the follow-up period recurrent cardiovascular complications, there was observed a low NADP–MDH activity on the first day in comparison with both control group data and the results of ACS patients without ADD who had no complications b. By theNADP–GluDH activity in patients who had ACS without affective spectrum disorders on the 1st day of the disease was significantly lower than the control numbers regardless of the development of repeated cardiovascular events c. It shoIn patients with ACS without affective disorders, there was a decrease in the activity of Glu6PDH on the 1st day of the disease compared to the control group, regardless of the presence or absence of recurrent cardiovascular complications. In addition, regardless of the development of complications, by the time patients were discharged from the hospital, on the 10th day, there was an increase in the Glu6PDH levels in ACS patients without ADD d.NADP–ICDH activity in ACS patients without ADD, but with recurrent cardiovascular complications during the follow-up period on the 1st day of the disease was 2.7 times higher than the results of patients without recurrent cardiovascular events e. By theAssay of the activity of NAD-dependent platelet dehydrogenases in ACS patients without ADD revealed that on the 1st day of the disease, there was a decrease in NADH–LDH levels in patients with the recurrent cardiovascular events compared to the control results and ACS patients without ADD and cardiovascular complications during the one-year follow-up a.By the time patients were discharged from the hospital, on the 10th day, the activity of NADH–LDH increased significantly and did not significantly differ from the results of the control group. At the same time, in the group of ACS patients without affective disorders and recurrent cardiovascular events, on the 10th day of observation the level of NADH–LDH decreased by 1.9 times compared to the 1st day of the disease. On the 1st day of hospitalization in ACS patients without ADD, but with recurrent cardiovascular complications, there was a low activity of NADH–MDH in platelets. On the 10th day of follow-up, the levels of this enzyme increased, but still remained below the indicators of the control group b.Meanwhile, ACS patients without affective disorders and repeated cardiovascular events on the 10th day of treatment had low values of NADH–MDH comparing to the control group. On the 1st day of hospitalization, the activity of NAD–GluDH in ACS patients without ADD, but with recurrent cardiovascular complications, was increased comparing to the patients without such complications c.By the time of discharge, on the 10th day of treatment, the activity of NAD–GluDH in patients with ACS without affective spectrum disorders, but with recurrent cardiovascular events, decreased by 3.9 times compared to the results of the first day of hospitalization.In ACS patients without ADD and cardiovascular complications during the follow-up period, the activity of NAD–ICDH on the 1st day of the study was significantly increased comparing to the control group and remained at a high level till the discharge of patients on the 10th day of treatment d. On theIn analysis of the activity levels of NADP-dependent platelet dehydrogenases in ACS patients with ADD without recurrent cardiovascular events on the 1st and 10th days of the study, low levels of NADP–GluDH activity a, NAD–ICIn ACS patients without ADD and cardiovascular complications, the activity of NADPH–GluDH d and GluIn ACS patients with ADD without repeated cardiovascular events during the one-year follow-up, both on the first day of hospitalization and by the time of discharge from the hospital on the 10th day, low levels of NADH–GluDH activity a, NADH–MGly3PDH levels were reduced in comparison with control levels when ACS patients with ADD and recurrent cardiovascular events were discharged. In ACS patients with ADD, regardless of the presence or absence of cardiovascular complications, on the 1st day of the disease, low levels of LDH activity e and MDHThe most informative in the neural network model of classification of patients in predicting the development of repeated adverse cardiovascular events in ACS patients with ADD were the activity levels of NADPH–GluDH, GR and NADH–GluDH .Platelets play a key role in the hemostatic system ,19,20. DMaintaining the functional activity of platelets largely depends on the state of the processes of cell energy balance. A main source of stable and affordable energy in the blood platelets is mitochondria ,25,26. ASince platelets activation is an energy-dependent process, for example, secretion, adhesion and aggregation induced by thrombin, collagen or ADP, the study of the dehydrogenase activity will determine the intensity of bioenergetic cell metabolism ,28. TherAnalyzing the activity levels of NAD- and NADP-dependent platelets dehydrogenases obtained in our work, we found that only in patients with ACS without ADD with the development of cardiovascular complications in platelets on the 1st and 10 day of treatment, the activity of NADP–MDH was reduced, which allows us to make an assumption about the inhibition of bypass reaction of the Krebs cycle in mitochondria and the reactions of the xenobiotic catabolism .On the 1st day of hospitalization in patients with ACS without ADD and without cardiovascular complications, activity of terminal reactions of platelet glycolysis according to the level of activity of the anaerobic LDH reaction and the NADH-dependent reaction of MDH corresponds to the control range. On the 10th day of treatment, a decrease in the activity of the LDH anaerobic reaction and NADH-dependent reaction of malate dehydrogenase is revealed, which may indicate inhibition of anaerobic glycolysis .At the same time, in patients with ACS without ADD, but with the development of cardiovascular complications during the year of observation, on the 1st day of treatment, a decrease in the activity of the anaerobic LDH reaction and NADH-dependent reaction of malate dehydrogenase which reflects the inhibition of anaerobic glycolysis while on the 10th day of treatment, an increase in the activity of NADH-dependent reaction of lactate dehydrogenase and NADH-dependent reaction of malate dehydrogenase was found. NADH–MDH provides metabolic support of the respiratory chain in mitochondria, ensuring functioning of the malate aspartate shuttle .It can be assumed that the intensity of the substrate flow at terminal reactions of glycolysis will affect the entry of pyruvate into the tricarboxylic acid cycle and accordingly the state of mitochondria aerobic respiration. Indeed, on the 1st day of follow-up, inhibition of NADH-dependent reactions of lactate dehydrogenase and malate dehydrogenase in platelets of patients with ACS without ADD lead to an increased activity of NAD–ICDH and NADP–ICDH which was associated with an increase in the intensity of substrate flow at the initial stage of the citric acid cycle. However, on the 10th day of treatment in patients of this group, the activity of NAD–ICDH and NADP–ICDH decreased. However, NADP–ICDH is known to perform auxiliary dehydrogenase reactions of the mitochondrial compartment, the function of which is aimed at increasing intensity of the substrate flow in the Krebs cycle .Another mechanism for regulating intensity of the substrate flow in the Krebs cycle is the state of activity of NAD- and NADP-dependent glutamate dehydrogenases. On the 1st and 10th days of examination a marked decrease in the activity of NADPH–GluDH, an enzyme that ensures the entry of amino acid metabolism substrates into the Krebs cycle is revealed in ACS patients without concomitant disorders of the affective spectrum and without cardiovascular complications during the year of observation . In patiDepending on the development of complications, characteristic features were also found in the inflow of substrates onto the Krebs cycle through glutamate dehydrogenase. Thus, in ACS patients without ADD and cardiovascular complications, the activity of NADP–GluDH on the 1st day of follow-up was significantly reduced whereas on the 10th day of follow-up, by the time of discharge from the hospital, it was increased. In patients with cardiovascular complications, the activity of the enzyme was significantly reduced both on the 1st and on the 10th day of treatment.Meanwhile, on the 1st day of follow-up the activity of NAD–GluDH in patients with complications exceeded that of patients without complications. However, by the 10th day of treatment the activity of the enzyme decreased. Such a state of activity in ACS patients without ADD is characteristic for a low level of NADP-dependent inflow of substrates to the Krebs cycle, regardless of the development of future cardiovascular complications. In ACS patients without cardiovascular complications, as a result of the treatment, the inflow of substrates through NADP–GluDH was restored, while in patients with complications it remained at a low level. At the same time, the level of NAD-dependent inflow of substrates on the energy processes in platelet mitochondria during the development of subsequent cardiovascular complications was higher than in their absence.+, glutamine, α-ketoglutarate, acetyl- coenzyme A and glutathione are identified as the most important metabolites that affect the activity of enzymes that change the structure of chromatin and, consequently, gene expression and cell activity [There is also another mechanism of metabolic regulation of platelet functions. In recent years, the metabolic mechanisms of epigenetic regulation were actively discussed. It is established that various intracellular metabolites affect epigenetic processes, being substrates or coenzymes of epigenetically modifying enzymes ,35,36. Nactivity ,38,39.+ and glutathione in platelets and affect the epigenome of cells.Therefore, intracellular enzymes that affect the concentration of these metabolites determine the functional cell activity (both through metabolic regulation mechanisms and mechanisms of epigenetic regulation). These metabolic mechanisms characterize the prognostic significance of NADH–GluDH, NADPH–GluDH and GR, as enzymes that determine the concentration of glutamate, α-ketoglutarate, NADThe study comprised patients who received hospital treatment in the cardiologic department of Krasnoyarsk Interdistrict Clinical Hospital of Emergency Medical Care named after N.S. Karpovich, Krasnoyarsk, the Russian Federation from 2011 to 2014. The inclusion criteria were the following: ACS in patients of both sexes aged from 35 to 70 years over the first 24 h of admission to hospital from the onset of the disease as well as signed informed consent. Exclusion criteria: concomitant diabetes mellitus and other severe somatic pathology ; the age of patients younger than 35 years and older than 70 years; thrombolysis at the prehospital or stationary stage; heart failure stage III; cardiogenic shock upon admission to the hospital; lack of informed consent. All subjects gave their informed consent for inclusion before their participation in the study. The study was conducted in accordance with the Declaration of Helsinki, and the protocol was approved by the ethics committee of Professor V.F. Voino-Yasenetsky Krasnoyarsk State Medical University . The diagnosis of ACS and further on that of unstable angina or acute myocardial infarction (AMI) was given according to the recommendations of the European Society of Cardiology .The study of platelets enzymes activity was conducted in both groups of all patients during the first 24 h after their hospitalization to ICU and in dynamics on the 10th day before they were discharged from hospital. For the first 72 h after transfer from ICU, all the patients underwent a psychometric examination using the hospital anxiety and depression scale (HADS). All patients were divided into two groups: ACS patients with ADD formed the first group and ACS patients without ADD formed the second one. No differences in clinical-anamnestic characteristics between the groups were detected . In the All patients were examined again 12 months after being included into the study with the purpose to detect possible cardiovascular complications, such as acute myocardial infarction (AMI) relapse in hospital, repeated myocardial infarction, stroke development, thromboembolism, onset of unstable post-infarction angina, increase of cardiac deficiency functional class, formation of post-infarction aneurysm of the left ventricle and death from cardiovascular causes.Blood samples were collected from the antecubital vein in vacutainer tube with 3.8% tri-sodium citrate, the morning and on an empty stomach. Blood was centrifuged for 10 min at 140 g at room temperature to produce platelet-rich plasma. Further platelet isolation was carried out according to the method described in article of Chiang J.Y. et al. (2019) with modifications . EvaluatBioluminescent method was used to determine the levels of activity of NAD- and NADP-dependent dehydrogenases in platelets . The actThe activity of NAD- and NADP-dependent dehydrogenases was expressed in enzymatic units on 1 mg of protein (1 U = 1 µmol/min) .Protein concentration was determined using Pierce™ modified Lowry protein assay kit .25 and C75). To determine the pattern of variables distribution Kolmogorov–Smirnov criterion was used. When distributions were symmetrical the variables are represented as means and standard deviations. The validity of differences between parameters of independent sample collections was estimated by the Mann–Whitney U test. Statistical significance of differences between the parameters of dependent sample collections was estimated by the Wilcoxon matched-pairs test. The differences were considered significant at p < 0.05. The estimation of informativity of the studied parameters was performed by neuroclassification model data mining general classification. Statistical analysis was conducted using the Statistica 8.0 software package .Descriptive statistics for categorical variables are presented as frequencies and percentages. The description of the sample collection was performed by means of median (Me) and an interquartile range of 25 and 75 percentiles , NADH-dependent reaction of glutamate dehydrogenase (NADH–GluDH) and glutathione reductase (GR) were determined as the most informative indices in the prognosis of recurrent cardiovascular complications using neural network analysis and obtained data on the enzyme activity in platelets of ACS patients with ADD.


Introduction: The most important factor which is responsible for the positive course of implant treatment is the process of osseointegration between the implant structure and the host’s bone tissue. The aim of this study was to assess what effect the 25-hydroxycholecalciferol concentration and vitamin D deficiency treatment have on changes in the bone level at the implant site during the process of osseointegration in the mandible. Materials and Methods: The study was with 122 people qualified for implant surgery, who were assigned to three research groups . Laboratory, clinical, and radiological tests were performed on the day of surgery, and after 6 and 12 weeks. The bone level in the immediate proximity of the implant was determined by radiovisiography (RVG). Results: The bone level after 12 weeks in Groups B and C was significantly higher than after 6 weeks. The bone level in the study Group B was significantly higher than in Group A. The study showed that the higher the levels of 25-hydroxycholecalciferol were observed on the day of surgery, the higher was the level of bone surrounding the implant after 6 and 12 after surgery. Conclusion: The correct level of 25-hydroxycholecalciferol on the day of surgery and vitamin D deficiency treatment significantly increase the bone level at the implant site in the process of radiologically assessed osseointegration. The implant–bone bond and how it is used for embedding a dental prosthesis is of key importance to implant prosthetic treatment. The process of forming of a stable, structural, and functional bond between living bone and the implant surface is called osseointegration ,2.In the process of osseointegration, the priority is that the implant material is not rejected by the recipient tissue, and, consequently, mechanisms leading to the production of new tissue around the implant surface are activated . The sucIt is assumed that the mechanisms of intraosseous integration of the implant include osteoconduction, i.e., de novo bone formation as well as its reconstruction, the so-called remodeling . In the Because it participates in bone metabolic processes and controls the immune system, vitamin D is currently of particular interest to doctors who perform implant procedures . It is aVitamin D pleiotropism is also of interest to modern dentistry, mainly as a result of its influence on bone metabolism ,15,16,17During the postsurgical phase and also after loading the implant with a prosthetic restoration, the subsequent influence of vitamin D metabolites on the processes of homeostasis with bone tissue adjacent to the implant surface, which determines the correct induction of osteoclasts and osteoblasts, is particularly important . The funAccording to the best of our knowledge, the literature is deficient in unambiguous results and implant treatment plans in which the level of vitamin D3 is taken into account. This was the motivation for conducting this study.The aim of this study was to evaluate the impact of the 25-hydroxycholecalciferol concentration and vitamin D deficiency treatment on changes in the bone level at the implant site during the process of osseointegration in the mandible. The authors assume that vitamin D does increase the bone level at an implant site in the process of osseointegration assessed radiologically.The study was conducted after obtaining the consent of the Bioethics Committee (KB-001258/18 as of 23 April 2018).The study covered 122 people with missing teeth in the premolar or molar regions in the mandible for whom implant treatment had been suggested. The patients who qualified for the procedure were generally healthy adults, with no known no allergy to dental materials or drugs, did not take regular medications, and did not take any vitamin or mineral supplements. Recruitment of patients took place from September 2018 to February 2019.The exclusion criteria included inappropriate bone conditions (necessity to perform augmentation procedures), general diseases, being under the age of 18 years, smoking, gingivitis, and periodontitis. All available patients meeting the inclusion and exclusion criteria, who applied to the clinic from September 2018 to February 2019, by convenience sampling, were consider to be participants for the study.n = 43) with <30 ng/mL of 25-hydroxycholecalciferol in blood serum, without vitamin D supplementation;Study Group A (n = 48) with <30 ng/mL of 25-hydroxycholecalciferol in blood serum, with vitamin D supplementation;Study Group B (n = 31) with the normal level of 25-hydroxycholecalciferol in blood serum (≥30 ng/mL).Study Group C  using the Ortophos SL 3D apparatus . Those patients whose implantation site was characterized by an appropriate amount of horizontal and vertical bone tissue were qualified for surgery. After taking the implant diameter into account, a margin of at least 2 mm of the vestibular and lingual bone plate was kept. The position of the implant was determined using software designed for its precise site designation.All surgical procedures and control tests were performed by one operator. The implantation was performed under local, infiltrative anesthesia (2% lidocaine with 0.01 mg of epinephrine). Then, the bed was drilled according to the implant system drilling protocol using a low-speed contra-angle handpiece and an array of drill bits. The surgery area was cooled with sterile saline (0.9% NaCl).Conical implants , with surface made by combining sandblasting and acid etching, made of grade 23 titanium (Ti 6Al4-V ELI), with conical connection and an anti-rotation, six-position index with diameter of 3.3–4.2 mm and length of 8–11.5 mm, were inserted into the bed using a contra-angle handpiece with a maximum torque of 45 Ncm. The implant was secured with a locking screw and the wound was closed with single loop sutures.After surgery, a cold compress was applied for 30 min to the cheek skin adjacent to the region on which the operation was performed. Postsurgical recommendations included the use of an antiseptic rinse based on a 0.1% chlorhexidine solution.The first test was performed on the day of surgery and it included assessment of the implant stability and a laboratory analysis of the 25-hydroxycholecalciferol level in blood serum. Six weeks after implantation, a radiographic image was taken, and a control examination of the level of 25-hydroxycholecalciferol was performed. Twelve weeks after surgery, before the healing screw was inserted, the success of the osseointegration process was assessed by carrying out a comparative measurement of the implant stability. A radiographic image was taken and the third examination of the 25-hydroxycholecalciferol level in blood serum was commissioned. A laboratory analysis was performed three times, i.e., on the day of surgery, after six weeks, and after twelve weeks. The level of 25-hydroxycholecalciferol was monitored for a comparative analysis as well as exclusion of the possibility of achieving toxic levels in patients who took supplements. All samples were tested in the same accredited reference laboratory, according to standardized procedures, by ECLIA electrochemiluminescence on the Cobas 8000 (Roche) analyzer.After taking into account the recommendations adopted in the study, a decision was made to supplement the study Group B with vitamin D. The group’s level of 25-hydroxycholecalciferol in blood serum was below 30 ng/mL. In light of European guidelines, the recommended dose for the treatment of vitamin D deficiencies for people over 19 years of age is 7000–10,000 IU/24 h ,21. The All control tests were performed by the second operator (GT). The evaluation of bone loss/growth was performed on the basis of radiovisiography (RVG) images taken with the long cone paralleling technique using a positioner . The bonStatistical analysis was performed using R software version 3.5.3 .p = 0.05 was assumed in the analysis. All p values lower than 0.05 were interpreted as showing the existence of significant relationships.The significance level of t-test was used to compare the values of quantitative variables in two groups when normal distribution of a particular variable occurred. Otherwise, the Mann–Whitney test was used.The Student’s A comparison of the values of quantitative variables was performed using ANOVA in three or more groups in the case of normal distribution of the variable in the groups. Otherwise, the Kruskal–Wallis test was used. A post hoc analysis, after detecting statistically significant differences, was performed using the least significant differences (LSD) test if normal distribution occurred. Otherwise, the Dunn test was used.∘|r| ≥ 0.9, very strong relationship;∘0.7 ≤ |r| < 0.9, strong relationship;∘0.5 ≤|r|< 0.7, medium strong relationship;∘0.3 ≤ |r| < 0.5, weak relationship;∘|r|< 0.3, very weak relationship (omitted).When both quantitative variables were normally distributed, the correlations between them were analyzed using the Pearson correlation coefficient. Otherwise, the Spearman correlation coefficient was used. The strength of relationships was interpreted according to the following Hinkle’s scheme :∘|r| ≥ 0n = 43) with 25-hydroxycholecalciferol at a level below 30 ng/mL in blood serum, consisting of 20 women and 23 men; study Group B (n = 48) with 25-hydroxycholecalciferol at a level below 30 ng/mL in blood serum, consisting of 22 women and 26 men receiving postsurgical vitamin D supplementation, and Group C (n = 31) with 25-hydroxycholecalciferol at a level of 30 ng/mL or more in blood serum, consisting of 23 women and eight men. A total of 99 implantations were performed in the molar region and 23 implantations were performed in the premolar region in the mandible. The mean age of the patients was 43.8 (±12.15). From the CBCT examination, both the length and the diameter of the implants were determined. The length values were 8 mm (n = 31), 10 mm (n = 80), and 11.5 mm (n = 11). The diameter values were 3.3 mm (n = 14), 3.75 mm  and 4.2 mm (n = 49). The average torque was 36.92 ± 7.77 Ncm. The average ISQ value was 78.67 ± 6.51 ISQ. A total of 122 people who qualified for implant surgery were included in the study. The patients were divided into the following three groups: study Group A (p < 0.05). It was shown that the bone level after 12 weeks was significantly higher than after 6 weeks  for differences in the bone level at the implant site after 12 weeks. In Group B it was significantly higher than in Group A  and positively with the bone level at the implant site after 6 and 12 weeks. The higher the levels of 25-hydroxycholecalciferol were observed on the day of surgery, the higher the level of bone surrounding the implant, 6 weeks and after 12 weeks following surgery. It was shown that in Group A and B and ABC the concentration of 25-hydroxycholecalciferol on the day of surgery did not correlate significantly.  between changes of the level of 25-hydroxycholecalciferol between the day of surgery and the 6th and 12th week after surgery and bone loss/growth at the implant site 6 weeks after implant surgery.The analysis showed no statistically significant correlations (p < 0.05) and negatively with changes in the concentration of 25-hydroxycholecalciferol between the day of surgery and the sixth week. Higher bone levels after 6 weeks were observed in Group C in patients whose level of 25-hydroxycholecalciferol was changed to a lesser degree. This data is presented in The statistical analysis showed that, after 12 weeks following implant surgery in Group C, the bone level at the implant site correlated significantly (p < 0.05) and positively in study Group B with changes in the 25-hydroxycholecalciferol concentration between the day of surgery and the sixth week. The greater the change in the 25-hydroxycholecalciferol concentration between the day of surgery and the sixth week, the greater the change in the bone level at the implant site.It was shown that bone loss/growth at the implant site correlated significantly (p < 0.05) and negatively with the change in the 25-hydroxycholecalciferol concentration between the day of surgery and the 6th and 12th week. The greater the change was in the 25-hydroxycholecalciferol concentration in Group C, the lower was bone growth at the implant site. This data is presented in The change of the bone level at the implant site in Group C correlated significantly , which, by the way, have no vitamin D receptors, are formed as a result of the fusion of about 5 to 10 precursor cells influenced by vitamin D. Osteoblasts (osteogenic cells) have that receptor, and the bone modeling process occurs through osteoclasts contacting osteoblasts via RANK and RANKL receptors .In the context of the continuing success of implant treatment, maintaining the optimal condition of tissues at the implant site is as important as obtaining stabilization. The cause of implant disintegration after achieving osseointegration may be gradual loss of bone tissue around the implant, which results from the inflammation in the region . Hence, An analysis of the effects of 25-hydroxycholecalciferol on the bone tissue in the mandible was conducted by Kawakami et al. . The stuThe relationships demonstrated in the study are consistent with the results of the analysis by Hong et al. , carriedDvorak et al.  conducteAn international team led by Naito  obtainedOur own study on patients showed a significant correlation between changes of the bone level at the implant site and the level of 25-hydroxycholecalciferol in blood serum. The analysis showed a statistical significance for the difference in bone levels around the implant, 12 weeks following surgery. In the group which received deficiency treatment (Group B), it was significantly higher than in the group which took no vitamin D supplements (Group A).It should be taken into consideration that our research also has some limitations. We had to believe the patients that they were taking 8000 IU of Vitamin D daily (24 h) because they were taking the drug themselves at home. From the study Group A, five people were removed from the study because they did not show up for the control tests.Although the studies were carried out after the period of greatest exposure to sunlight, it cannot be ruled out that patients were exposed to sunlight to varying degrees.In view of the scientific reports and the analysis carried out in our own study, we suggest that 25-hydroxycholecalciferol is a potential factor that stimulates the growth of bone tissue at implant sites. It is worth paying attention to the benefits resulting from determining the concentration of vitamin D metabolite on the process of implant osseointegration and soft tissue repair. On the basis of the growth of bone tissue observed and assessed radiographically in the group which took vitamin D supplements, we conclude that monitoring the 25-hydroxycholecalciferol concentration along with radiological assessment of the bone level is a simple and minimally invasive method of assessing the process of osseointegration at the intraosseous implant site. Such an algorithm could be introduced into the record of the assessment of the results of implant treatment.The correct level of 25-hydroxycholecalciferol on the day of surgery and vitamin D deficiency treatment have a significant influence on the increase in the bone level at the implant site during the process of osseointegration assessed radiologically.


The results showed that (1) the strength of N-MBER obeyed a compound function relation with curing period and additive amount of NS. The relationship between strength and curing period obeyed an exponential function when the additive amount was constant. The strength and additive amount were a power function when the curing period was fixed. The compressive strength of N-MBER increased by more than 15% compared with MBER at day 28 of the curing period, and 50% compared with grade 32.5 cement. (2) The pozzolanic catalytic activity of NS significantly increased the amount of calcium silicate hydrate gel (C–S–H) in the N-MBER colloid. NS was also able to make the distribution of the network structure of colloidal space more uniform and improved the fractal dimension of particles by 0.05. The above results provide theoretical data for exploring the mechanism of soil stabilizer strength growth and for promoting the application of solid waste utilization.A new nano-soil stabilizer  material was developed in this research by using the high activity and ultrafine properties of nano-SiO With the continuous promotion of global environmental protection, the construction mode of sand mining by digging mountains and rivers to build concrete projects is not only expensive, but also harmful to the local environment. The waste soil and slag from engineering construction could also pollute the environment again, and is difficult to use. In addition, Portland cement and other traditional building materials have higher requirements of sand, stone, and water quality when mixing, which leads to the increase of engineering cost, poor effect of soil stabilization, and aggravation of environmental hazards in the loess plateau and other areas lacking rock and sand . Therefo2 on the mechanical properties and durability of concrete. Kong et al. [2 could effectively improve the unconfined compressive strength of loess and improve pore structure. The above explorations have enriched the research on the improvement of the properties of soil stabilizers, but generally speaking, compared with the broad application prospects showed by soil stabilizers as materials for efficient utilization of soil and water resources, the current research status still needs to be deepened. Using new ideas, materials, and technologies to improve the performance of soil stabilizers and further clarify the stabilization mechanism is urgently needed in further research.As a burgeoning kind of environmental protection building material, soil stabilizer has obtained a series of research achievements in water conservancy, road engineering, and other areas in recent years ,3,4,5,6.g et al.  found th2, such as high activity and ultrafine properties, this study explored the N-MBER strength enhancement mechanism and hydration process by designing typical tests and physicochemical analysis methods, so as to provide scientific support for the improvement of the engineering performance of soil stabilizers and for the application in the field of environmental protection constructions.Based on the characteristics of nano-SiO3 content in cement clinker are shown in The soil stabilizer used in this research was MBER, developed by Jianen Gao . MBER is2 used in this study, which is commercially available, was a nanomaterial with high purity and activity, and came from the manufacturing industry in Xi’an, China. The average size of the nano-SiO2 (NS) particles was about 30 nm, and the basic properties are shown in The nano-SiO2 selected was 1%, 1.5%, 2%, 2.5%, and 3% of the total weight of MBER. Untreated MBER and grade 32.5 cement were used as reference groups. At the beginning of the experiment, tap water was added to the stirring pot with a 0.5 water–cement ratio, and then hydrophilic nano-SiO2 was dissolved in water for dispersion and stirring; lastly, quantitative MBER and ISO  standard sand were added into the pot. The above nanosilica-MBER mortar (N-MBER) was mixed and prepared by a J-55 type planetary mortar mixer. A ZS-15 type cement sand vibrator was used to shape the mixed samples. The content of nano-SiOTo obtain the mechanical properties of N-MBER, the samples of each period were first tested on the TYE-6A cement mortars bending tester after the curing period, with a loading rate of 50 ± 10 N/s. The broken samples were immediately tested by a TYE-300 pressure testing machine for compressive strength after the breaking strength tests. The samples were uniformly loaded at a rate of 2400 ± 200 N/s until destroyed. To examine the quality of the samples and prevent possible errors, the breaking strength of the specific samples was repeatedly tested three times, and the compressive strength was repeatedly tested six times. The average value of the repeated samples was used in the data analysis. After the strength tests, the fractured samples were carefully collected and sealed. The microstructure and chemical composition of the samples at days 3 and 28 of the curing period were analyzed by S-4800 field emission scanning electron microscopy (SEM) and an energy spectrum analyzer (EDS). All of the tests were conducted in Yangling, ShaanXi Province in China.As shown in The correlation was established between the parameters and the NS content, respectively, and the results are shown in By substituting the correlation between parameters and P into Equations (1) and (2), respectively, it could be known:P = 0%, N-MBER can be considered as ordinary MBER. Under this condition, the relationship between the strength and the curing period was a kind of exponential function. This indicates that after adding NS, the function expression of the strength growth law was more complex and the reaction inside the material was more sufficient. As shown in Equations (3) and (4), the breaking strength and compressive strength of N-MBER followed composite function relationships with the NS content and curing period, respectively. When E1 and E2 were continuously differentiable, Equations (3) and (4) were used to obtain partial derivatives of T1 and T2.In order to quantitatively analyze the variation law of the strength with curing period under each NS content, assuming 1 and E2 had maximums of The first derivative curve increases monotonically and the second derivative curve decreases monotonically. The results show that the breaking and compressive strengths of N-MBER increased gradually with the growth of curing duration, and the increasing rate of strength tended to become stable gradually with the increase of curing period. EThis research compared the strength of N-MBER (2.5% NS content), MBER, and 32.5 grade cement. cE is the compressive strength of the material, measured in MPa; cT represents the curing period, measured in days, and CT ≥ 3; and m, and n are the model parameters.The visual fitting tool of Origin software was used to conduct a regression analysis on the changes of compressive strength of the three materials with curing period. As shown in 2 and residual sum of squares (RCS). The closer the R2 to 1 and the closer the RCS to 0, the better the fitting effect of the equation. It can be seen from C of three cement-based soil stabilizer materials with curing period CT.The degree of fitting analysis provided by Origin software was used to calculate the determination coefficient RThe samples obtained from the cement mortar test were analyzed by S-4800 field emission scanning electron microscopy (SEM) and energy spectrum (EDS) to explain the changes in the microstructure and chemical composition of the samples, and to explore the influence mechanism of NS on the hydration process of N-MBER.1,a2) and 1,c2), the early curing period SEM images of MBER and N-MBER reveal that NS addition produced an obvious filled effect in pores between particles, which caused a decrease in porosity and an increase in density of the network structure at the phase interface. At the same time, NS caused variations in the hydration reaction inside the samples and changed the type and amount of hydration products.1,a2) and 1,c2) show the SEM images of MBER and N-MBER during the hydration reaction in 3 days. It can be seen from 1,b2) and 1,d2), while in N-MBER hydration products, the crystal shapes and quantities of C–S–H were more abundant and evenly distributed. At the same time, the amount of CH was significantly reduced, and hexagonal prismatic ettringite (AFt) interlacing was visible. The energy spectrum analysis results of the hydration reaction are shown in 3S), dicalcium silicate (C2S), tricalcium aluminate (C3A), and tricalcium ferro aluminate (C4AF). Calcium silicate hydrate gel (C–S–H), ettringite (AFt), calcium hydroxide (CH), calcium carbonate (CaCO3), and other hydration products were generated by the above reactions, and a certain amount of heat was released. The reaction equations are shown in Equations (6) to (9).The reaction types of volcanic ash mainly included tricalcium silicate .Due to its high activity and ultra-fine properties, the added NS had the effect of inducing hydration and strong volcanic ash activity, which could have caused a secondary hydration reaction with the early hydration products, such as tricalcium silicate CThe microstructure complexity of N-MBER-stabilized loess was reflected by the irregularity, nonlinearity, and uncertainty of its macroscopic properties. Since nano-stabilized soil (N-SS) has typical self-similar characteristics in particle size, pore size, and interface structure, the fractal geometry created by Mandelbrot  was adopD of the box is shown in Equation (12).To extend the topological dimension to the fractional dimension, it needs to break through the limitation that d is an integer and take the limit of the above Equation (11). The fractal dimension Based on the above theories, the calculation model of fractal dimension by Tyler  and Yangby Tyler  was usedTaking the logarithm of both sides of Equation (13), it could be known that:It was assumed that the particle density of the stabilized soil was uniform, so the volume fraction was equal to the mass fraction. D value of stabilized soil particles.As is obvious from The average particle size of NS selected in this study was 30nm, and the effects of NS particles with other particle sizes on the stabilization effect of cement-based soil stabilizer is still unclear. Since the particle size of NS has certain influence on its properties, such as volcanic activity, fluidity, water adsorption ability, and pore filling properties, the effect of NS particle size on the stabilization effect will be an important research direction in the future.The following conclusions were obtained through this research: (1) A composite function model of N-MBER breaking strength and compressive strength under different NS contents and curing periods was proposed. (2) It was found that the strength of N-MBER increased by more than 15% when the content of NS was 2.5%, and the strength increased by 50% compared with that of grade 32.5 cement. (3) The stabilization mechanism of N-MBER was expounded based on microstructure analysis and fractal theory. The results could provide scientific support for further research and application of soil stabilizers.Soil stabilizers have been successfully applied in the Loess Plateau for more than 10 years, and have obtained a large amount of positive results ,33,34,35


The efficiency of this model has been confirmed in a reprotoxicological experiment with glyphosate as a toxic factor: the action of the toxic factor against the background of reduced availability of B vitamins and salts Fe3+ and Mg2+ led to significant changes in such indicators of reproductive function as mating efficiency, postimplantation loss, and the total number of alive pups, while the toxic effect of glyphosate was not so pronounced against the normal level of essential substances. The obtained results prove that this adaptation potential reduction model can be recommended for the research of the low-toxicity objects reproductive toxicity in rats and for the safety assessment of novel food, in particular.The modeling of adaptation potential decrease in rats due to modification of the diet's vitamin–mineral composition allows to increase animals' sensitivity to toxic load in reprotoxicological experiments. The threshold values of vitamins B1, B2, B3, and B6 and mineral substances Fe In the safety assessment of a novel food and genetically engineered organisms of plant origin, in particular, the central place is occupied by reprotoxicological studies to prove the absence of remote negative effects that may manifest themselves only in the next generation. The complex research of reproductive function, pre- and postnatal progeny development usually involves the study of a large number of parameters, with a wide range of physiological fluctuations in each, whereas the heterogeneous distribution of some indicators' values complicates the interpretation of the results, especially under conditions of toxic impact of low intensity –3.Indeed, the recognition of an organism's response in the range of physiological adaptation/pseudoadaptation   is a verin vivo model, which increases the susceptibility of the rats to the toxic factors action by reducing the supply of B vitamins  and minerals (Fe3+ and Mg2+) [Modeling of additional load that reduces the adaptation potential and, consequently, excludes the possibility of compensatory pseudoadaptation is a promising tool to improve the diagnostic reliability of the experiment results –4. SinceB1, B2, B, and B6 This work was aimed at proving the efficiency of adaptation potential reduction model of rats (against the background of the known toxic factor) for application in reprotoxicological experiments.Herbicide glyphosate was used as a toxic factor and now is one of the most widely used herbicides in the world, whose toxic effect is well studied . GlyphosGlyphosate is characterized by a low capacity for cumulation and can be excreted with feces and urine in a virtually unchanged form when enters the body . Approxi3+ and Mg2+: the 19% content group—“Control-19” and the 75% content group—“Control-75.”The experiment of total duration of 155 days was conducted on Wistar rats of generation F0  and F1 (684 pups and 265 fetuses). The animals of parental generation F0  were divided equally and randomly into four groups: two control and two test groups, 16 males and 44 females in each. Rats of the control groups received semisynthetic casein diets , 13 withModifications within the AIN-93 , 13 dietGlyphosate herbicide was chosen as a toxic factor, whose effect on reproductive function is described in detail –16. BaseReproductive function was estimated by the fertility of animals F0 and by the character of prenatal and postnatal development of F1 progenies. The work with animals and all procedures performed were done according to the American Veterinary Medical Association   and RuleThe euthanasia procedure was completed after the animals were deprived of food for 12 h via physical method (decapitation).Fertility was determined by (1) the mating efficiency as a ratio of fertilizing ability of males over the total number of cohoused males, or as a ratio of pregnant females over the total number of cohoused females, and (2) endocrine function of the ovaries .For prenatal development assessment, F0 females were euthanized on the 20th day of pregnancy (one day prior to the expected day of delivery). The uteruses were removed by cesarean section and the uteruses and the fetuses were examined. The females were examined macroscopically for any structural abnormalities or pathological changes. The number of ovarian corpora lutea, resorptions, implantation sites, the number of alive and dead fetuses, and the preimplantation loss  as well as the postimplantation loss  were determined. The fetuses were extracted, examined macroscopically; weight and craniocaudal size were determined and examined by Wilson's method and Dawson's method –20.Postnatal F1 progeny development was being assessed during the first month of life by counting the number of alive and dead pups, dynamics of body weight and length, and physical developmental landmarks . Pups' body weight and length were measured on postnatal days 2, 5, 10, 15, 20, and 25 , 22 and The rats had been kept in plastic cages with wood shavings, in ventilated and heated T ∼20–23°C) room with natural light. All animals were observed once daily for mortality, moribundity, and overt signs of toxicity. Individual body weights of F0 animals were obtained once weekly for 30–100 days of age [–23°C roop < 0.05 level [M ± SE and min-max, where M was the mean, SE was the standard error, and min-max were the minimal and maximal values, as well as percentage or absolute figures.Statistical analysis was executed with the use of SPSS 17.0 software package . Reliability assessment of the mean figures differences of data normally distributed was analyzed by one-way ANOVA. Statistical significance was assigned at the 05 level . The datp < 0.05), 12% in males (p < 0.05), and those of Control-19 and Test-19 groups stand at 12% in females and 17% in males (p < 0.05), respectively , but the body weights were slightly lower than in corresponding control groups . The differences in body weights of Control-75 and Test-75 groups stand at 7% in females  lower than in Control-75 group but did not exceed the norm, while the differences between Test-19 and Control-19 groups were 72% (p < 0.05). The decrease in the number of alive fetuses in Control-19 group reached 32% (p > 0.05) compared to Control-75 group.Analysis of F1 fetuses prenatal development found that the number of ovarian corpora lutea and implantation sites in the females of control and test groups did not demonstrate significant differences; the values of these indicators fell within the limits of physiological fluctuations . The avep > 0.05) higher against Control-75. Postimplantation loss in groups Control-75 and Test-75 reached the upper limit of the norm and had no significant differences; the average values of this indicator in Control-19 rats were 151% (p > 0.05) higher against Control-75 group and 155% (p < 0.05) higher in Test-19 rats against Control-19 group.Preimplantation loss in both test groups was similarly above the norm, but showed some differences between control groups: in Control-19, this indicator was slightly above the norm and 56% (p < 0.05), respectively.The fetuses' zoometric indices and the internal organs weights varied within the physiological norm; Test-75 fetuses expressed no reliable differences from Control-75. Test-19 fetuses on the whole did not differ from Control-19, but some distinctions were noted in craniocaudal size, an absolute and relative weight of kidneys: these indices in Test-19 group were slightly lower than in Control-19 group—by 5%, 21%, and 20%  did not differ from Control-75 group, while Test-19 indices were 95% and 35% lower against Control-19 group, respectively .The analysis of physical development of F1 pups did not reveal any deviations from the norm. The survival rate during the first month of life in Control-75 and Test-75 groups was 98% and 99%. According to the scientific data, the Wistar rats are characterized by the relative variability of certain reproductive function indicators; hence, 98-99% value corresponded to the highest level of survival rate for rats of this line.In the Control-19 group, the survival rate was 39%, which is much lower than the typical values for this line of animals. In Test-19 group, the survival rate stood at 100%, with all 9 pups survived, although such a limited sample cannot be considered representative, which does not allow us to assess the result.The effects observed could be brought about by a general decline of the adaptive potential, as well as the shortage of essential substances affecting reproductive function. Vitamins are crucial to maintain gametogenesis, participate in redox processes and many enzymatic reactions . ThiaminMany enzymes are characterized by the specificity of the active centers formed by their component metals including copper, zinc, manganese, selenium, and gem iron. Therefore, the intake shortage may result in a decrease of the corresponding enzymes activity. Deficiency of trace elements in mammalian diets leads to abnormalities of gametogenesis and endocrine function of gonads, reduced fertility, teratogenic effects, and changes in pregnancy duration. Deficiency of calcium, iron, manganese, and copper in diets appears to cause premature labor, anemia, skeleton ossification disorders, and central nervous system disorders –35.The iron content in the body is regulated mainly by its absorption level in the intestines. Considering that hemoglobin accounts for 60–70% of all iron content, the iron deficiency in the diet shall be primarily regarded as a threat of anemia . Iron de3+ and Mg2+ in the semisynthetic casein diet of laboratory animals provides a well-detectable and unambiguously interpreted response of the reproductive system to toxic factors due to the complex action of essential substances deficit on the reproductive function and adaptive potential of the body.Thus, the reduced content of B vitamins and salts Fe3+ and Mg2+ led to significant changes in such indicators of reproductive function as mating efficiency, postimplantation loss, and the total number of alive pups, while the toxic effect of glyphosate was not so pronounced against the normal level of essential substances. The obtained results prove that this adaptation potential reduction model can be recommended for the research of the low-toxicity objects reproductive toxicity in rats and for the safety assessment of novel food, in particular.The action of the toxic factor against the background of reduced availability of B vitamins and salts Fe


The complications after stroke inhibit functional recovery and worsen the prognosis of patients. The implementation of a critical pathway (CP) can facilitate functional recovery after stroke by enabling comprehensive and systematic structured rehabilitation.  To evaluate the effects of the implementation of CP in stroke patients for 10 years.  The data were collected from 960 patients who were diagnosed with a stroke at the university hospital emergency room, who were transferred to the rehabilitation center after the acute phase, and who were discharged after undergoing comprehensive rehabilitation. Based on data collected over a period of 10 years, changes in demographic and stroke characteristics, preexisting medical conditions, poststroke complications, and functional states, as well as length of stay (LOS), were evaluated before and after CP implementation. The modified Rankin Scale (mRS) and the Korean version of the Modified Barthel Index (K-MBI) were used to evaluate functional states.  There were no significant differences in demographic and stroke characteristics before and after CP implementation. For those with preexisting medical conditions, there was no significant difference between before and after CP implementation. The majority of the complications were significantly decreased after the implementation of CP. Except for hemorrhagic stroke patients, the Brunnstrom stage in the ischemic and total stroke patients after CP implementation was significantly increased in the upper and lower extremities. The total hospitalization LOS and rehabilitation center hospitalization times were significantly reduced in ischemic and total stroke patients. There was no statistically significant difference in the functional gain of K-MBI and the efficiency of rehabilitation between before and after CP implementation.  The implementation of CP allows for better application of evidence- and guideline-based key interventions and helps to provide early, comprehensive, organized, and more specialized care to stroke patients. Despite limited evidence, CP is still recommended as a means of promoting best practices in hospital care for stroke patients. Stroke has been a major cause of death and disability of people over 65 years old. In Korea, the fast migration toward aging society accompanies increasing cases of stroke and causes rising economic burden , 2. The Medical teams strive to provide the objective and accurate medical services for stroke patients, and the structured comprehensive treatment plans, the critical pathways (CP), are implemented to give patients proper treatment sequentially , 5. The The implementation of CP can raise the level of communication between medical teams and effect of rehabilitation, and it has been known that it can minimize treatment delay, reduce length of stay in the hospital and incidence of complications on patients, and decrease treatment cost –8. In adIn the studies that employed CP for the rehabilitation of patients suffering from stroke, Falconer et al. reported that they found no effect of the implementation of CP pertinent to stroke, whereas Sulch et al. reported an improvement in the functional state and quality of life from a randomized controlled trial, and Lim et al. reported the decreased length of stay in the hospital from their study based on the modified Rankin Scale (mRS) –12. Kim The present study is intended to find long-term effect of implementation of CP for inpatients suffering from stroke in the department of rehabilitation medicine in a university hospital. The data accumulated for 10 years were used for comparative analysis on varied complications, demographic and stroke characteristics, preexisting medical conditions, functional states, site of discharge, and length of stay of patients before and after implementation of CP.The 960 patients diagnosed with ischemic or hemorrhagic stroke through examinations of brain computed tomography or magnetic resonance imaging, and based on findings obtained from patients' history and physical examination, and transferred and discharged from the department of rehabilitation medicine upon completion of treatment of the acute phase followed by comprehensive rehabilitation treatment, were selected as subjects of the present study among patients who came to the emergency room of OO university hospital. A total of 100 patients who came to the hospital during the period from January 1, 2008, to December 31, 2009, and then transferred to the department of rehabilitation medicine, were classified as patients of the group before implementation of CP, whereas the 860 patients who came to the hospital during the period from January 1, 2010, to February 28, 2019, and were transferred and discharged from the department of rehabilitation medicine were classified as patients of the group after implementation of CP.For the treatment of patients in an acute phase of stroke through CP, the early rehabilitation program including prevention of complications was implemented upon assessment based on physical examination, degree of severity, functional state, and presence of complications through collaboration with the department of rehabilitation medicine within 3 days from the onset of stroke. In the early rehabilitation program, the patients, who manifested neurological stability, were supposed to transfer to the department of rehabilitation medicine for comprehensive treatment or discharged as outpatient upon the appraisal of transferability, and in cases of the progression of stroke in the course of treatment, the state of patients was reappraised for treatment pertinent to corresponding states of patients . The prePrior to CP implementation, a neurologist or neurosurgeon evaluated the patients' condition and referred them to the department of rehabilitation for rehabilitation treatment. After the implementation of CP, it is necessary that rehabilitation physicians assessed stroke patients early and conducted comprehensive rehabilitation through an evidence-based care protocol.Medical records of subjects were examined retrospectively. Features of stroke and demographics before and after implementation of CP including age, sex, types of causes of stroke (ischemic or hemorrhagic), sides of hemiplegia  due to stroke, and location of lesion  were examined. Underlying medical diseases of patients such as hypertension, abuse of alcohol, diabetes mellitus, smoking, cardiac arrhythmia, osteoarthritis, dyslipidemia, previous stroke, coronary artery disease, valvular heart disease, renal failure, chronic obstructive pulmonary disease or asthma, deep vein thrombosis, hydrocephalus, and history of seizure were examined.Following complications of stroke that occurred before discharge from the department of rehabilitation medicine were also examined: poststroke shoulder pain, dysphagia, poststroke depression, Foley catheter insertion, pneumonia, urinary tract infection, hydrocephalus, adverse effects of drugs, tracheostomy, progression of stoke, gastrointestinal symptoms , electrolyte imbalance, deep vein thrombosis, fall, poststroke seizure, nutrition supply through gastrostomy (percutaneous endoscopic gastrostomy), decubitus ulcer, and heterotopic ossification.All subjects were classified into patients of ischemic and hemorrhagic strokes to appraise the functional state of each patient, and the mRS and Brunnstrom stage on proximal and distal upper limbs and lower limbs, before and after transfer to the department of rehabilitation medicine, were examined. And the Korean version of the Modified Barthel Index (K-MBI) was examined upon transfer to and discharge from the department of rehabilitation medicine to calculate the functional gain (scores at discharge–scores on transfer to department of rehabilitation medicine) and efficiency of rehabilitation .To identify the effect of implementation of CP upon length of stay in the hospital of patients, the periods from the onset of stroke to initiation of early rehabilitation treatment, of length of stay before transfer to the department of rehabilitation medicine, of length of stay in the department of rehabilitation medicine, and of overall length of stay in the hospital were examined.Besides, the transfer of patients to home or other hospitals upon discharge from the department of rehabilitation medicine was also examined to appraise the return to society after rehabilitation. Other hospitals mentioned here include the short-term general hospital with rehabilitation department, specialized rehabilitation hospital, and nursing homes.t-test was performed to compare the mean values of variables between two independent groups (pre-CP and post-CP). Variables are mRS, Brunnstrom stage, K-MBI, and length of stay in the hospital. Levene's test was performed for homogeneity of the variance test. In the independent t-test, when the significance level was 5%, the significance probability values of all variables were greater than the significance level. The basic assumptions  for the population were satisfied, so the parametric statistic methods were used.An independent p < 0.05.The data on sex, cause of stroke, location of lesion, sides of hemiplegia due to stroke, past medical history of patients, complications occurring before discharge from the hospital, and types of discharge were comparatively analyzed by conducting a Chi-squared test. SPSS version 21.0 for Windows  was employed for all statistical analyses conducted in the present study with the level of statistical significance of Among all 960 subjects, the subjects belonging to the group before implementation of CP were 100 subjects wherein 53 male subjects (53.0%) and 47 female subjects (47.0%) were included; the average age of the 100 subjects was 62.0 ± 13.1 years. 860 subjects belonging to the group after implementation of CP comprised 433 male subjects (50.3%) and 427 female subjects (49.7%), and the average age of the group was 63.9 ± 12.9 years.Regarding the types of stroke of subjects, the stroke ascribable to ischemic causes comprised 48 subjects (48.0%) and the stroke ascribable to hemorrhagic causes comprised 52 subjects (52.0%) before implementation of CP. The stroke attributable to ischemic causes comprised 412 subjects (47.9%), and the stroke attributable to hemorrhagic causes comprised 448 subjects (52.1%) after implementation of CP. Sides of hemiplegia before implementation of CP consisted of 49 subjects of right side (49.0%), 36 subjects of left side (36.0%), and 15 subjects of both sides (15.0%), whereas 349 subjects of right side (40.6%), 379 subjects of left side (44.1%), and 132 subjects of both side (15.3%) were in the group after implementation of CP. Locations of lesions of stroke comprised 3 subjects of cortical lesion (3.0%), 10 subjects of infratentorial lesion (10.0%), and 87 subjects of subcortical lesion (87.0%) before implementation of CP, whereas 37 subjects of cortical lesion (4.3%), 140 subjects of infratentorial lesion (16.3%), and 683 subjects of subcortical lesion (79.4%) were in the group of subjects after implementation of CP. The proportion of the cortex lesion was very lower than that of the subcortical lesion. This is because cortical engagement was included only when the lesions were confined to the cortex. Subcortical engagement included both cortical and subcortical lesions as well as those limited to subcortical. There were no significant differences between the two groups .The underlying medical diseases of subjects before implementation of CP appeared in the following order of 70 subjects of hypertension (70.0%), 38 subjects of alcohol abuse (38.0%), 33 subjects of diabetes mellitus (33.0%), 31 subjects of smoking (31.0%), 28 subjects of cardiac arrhythmia (28.0%), 25 subjects of osteoarthritis (25.0%), 25 subjects of dyslipidemia (25.0%), and 20 subjects of previous stroke (20.0%), whereas that of subjects after implementation of CP appeared in the following order: 640 subjects of hypertension (74.4%), 365 subjects of alcohol abuse (42.4%), 236 subjects of diabetes mellitus (27.4%), 221 subjects of smoking (25.7%), 221 subjects of osteoarthritis (25.7%), 144 subjects of cardiac arrhythmia (16.7%), 145 subjects of past history of stroke (16.9%), and 104 subjects of dyslipidemia (12.1%). The two groups exhibited significant decreases of cardiac arrhythmia from 28.0% to 16.7% and dyslipidemia from 25.0% to 12.1%; no significant differences in the distribution of other underlying medical diseases between two groups were found .78 subjects of poststroke shoulder pain (78.0%) and 66 subjects of poststroke dysphagia (66.0%) appeared over half of the total population of the group of subjects before implementation of CP; these were followed by the appearance of the following complications: 46 subjects of depression (46.0%), 38 subjects of Foley catheter insertion (38.0%), 32 subjects of pneumonia (32.0%), and 23 subjects of urinary tract infection (23.0%). Upon implementation of CP, poststroke complications appeared in the following order: 461 subjects of dysphagia (53.6%), 389 subjects of shoulder pain (45.2%), 192 subjects of Foley catheter insertion (22.3%), 169 subjects of depression (19.7%), and 122 subjects of gastrointestinal symptoms (14.2%). Except for gastrointestinal symptoms, nutrition supply through gastrostomy (percutaneous endoscopic gastrostomy), decubitus ulcer, and heterotopic ossification, the appearance of poststroke complications decreased significantly with the implementation of CP .In the group of subjects of total stroke, the Brunnstrom stages in proximal and distal upper extremity and lower extremity were 3.4 ± 1.2, 3.4 ± 1.3, and 3.4 ± 1.1, respectively, before implementation of CP. The stages were significantly increased to 3.9 ± 1.2, 3.8 ± 1.3, and 4.0 ± 1.1, respectively, along with the implementation of CP. In the group of subjects of ischemic stroke, the Brunnstrom stages in proximal and distal upper extremity and lower extremity also manifested statistically significant increase upon implementation of CP; however, the increase was not statistically significant for the hemorrhagic stroke.The group of subjects of total stroke and the groups distinguished by ischemic and hemorrhagic strokes did not show statistically significant differences of functional gain and efficiency of rehabilitation reflected in terms of mRS, K-MBI at transfer, and K-MBI at discharge .Upon implementation of CP, the times of the period from the onset of stroke to initiate rehabilitation treatment and of the length of stay from the onset of stroke to transfer to the department of rehabilitation medicine decreased significantly for the groups of subjects of total, ischemic, and hemorrhagic strokes.The length of stay in the department of rehabilitation medicine and the total length of stay in the hospital for the groups of subjects of total and ischemic strokes commonly exhibited significant decreases; however, the group of subjects of hemorrhagic stroke did not show statistically significant differences in length of stay .The site of discharge of subjects was distinguished into discharge to home and discharge to transfer to other hospitals. The group of subjects of ischemic stroke showed 6 cases of discharge to home (12.5%) and 42 cases of discharge to other hospitals (87.5%) before implementation of CP, whereas the site of discharge to home increased significantly with the following figures: 175 cases of discharge to home (42.5%) and 237 cases of discharge to other hospitals (57.5%), upon implementation of CP. The groups of subjects of total and hemorrhagic strokes did not exhibit statistically significant differences in the site of discharge .The present study is intended to identify long-term effect of implementation of CP for rehabilitation prepared for inpatients of stroke in the university hospital. Although there are many previous studies on ischemic stroke, few studies have analyzed hemorrhagic stroke despite the high proportion of hemorrhagic stroke accounting for total stroke . TherefoThe medically underlying diseases such as hypertension, abuse of alcohol, diabetes mellitus, and smoking appeared high before and after implementation of CP. These were similar to results of previous study that presented hypertension, smoking, diabetes mellitus, and dyslipidemia as risk factors of stroke . The carIn the present study, the significant decrease in the rate of occurrence of most of the complications in the group of subjects suffering from stroke was found upon implementation of CP, wherein the complications of shoulder pain and dysphagia were found dominantly from both groups. The significant decrease in the rate of occurrence of aspiration pneumonia seems attributable to the early assessment and treatment for dysphagia upon implementation of CP. The results agree with those of previous studies that reported the decreases in the rate of onset of pneumonia, length of stay, and mortality by early diagnosis and treatment of dysphagia . The onsPoststroke depression also appeared significantly decreased in the group of patients after implementation of CP. Appropriate management through psychotherapy and drug medication upon diagnosis of patients' symptoms are recommended for cases of poststroke depression that could decrease functional rehabilitation and participation in rehabilitation treatment of patients; the early mobilization has been known to alleviate the depressive mood of patients of stroke , 20. UpoA Foley catheter is used in cases of urinary dysfunction due to brain damages from stroke or for operation and examination thereof, and it has been known that complications such as urinary tract infection due to the insertion of a Foley catheter together with urinary incontinence and neurogenic bladder dysfunction occur frequently , 21. TheFall and deep vein thrombosis were decreased significantly due to the increase in early mobilization and education on fall and postures in bed in the early rehabilitation besides the complications mentioned earlier. And the occurrence of complications of hydrocephalus, poststroke seizure, and electrolyte imbalance together with progression of stroke was decreased by identifying the presence of problems through examinations on blood and brain images and by the use of anticonvulsant pertinent to the reduction of risk of seizure upon early assessment of patients. These consequences correspond to findings of reduced occurrence of poststroke complications through an intervention of early treatment pertinent to rehabilitation , 21, 22.The mRS score tended to decrease in the groups of subjects of total, ischemic, and hemorrhagic strokes upon implementation of CP with the transfer to the department of rehabilitation medicine, whereas the Brunnstrom stage increased significantly in the groups of subjects of total and ischemic strokes. The results correspond to the result of previous study that reported that a comprehensive assessment and implementation of early rehabilitation plan would help functional rehabilitation and development of discharge plan of patients  as well On the contrary, the group of subjects of hemorrhagic stroke exhibited no statistically significant differences in terms of the Brunnstrom stage. This was estimated that it would be attributable to difficulties in making early active treatment of rehabilitation due to postoperative treatment in the intensive care unit (ICU) and delay in initiation of comprehensive rehabilitation for the group of patients of hemorrhagic stroke who are frequently in need of a surgical procedure.The score of K-MBI upon transfer to and discharge from the department of rehabilitation medicine tended to be increasing upon implementation of CP in the groups of subjects of total and ischemic strokes though it was not statistically significant, and the scores of functional gain and efficiency of rehabilitation also tended to be increasing though they were not statistically significant. The group of subjects of hemorrhagic stroke exhibited a decreasing score of K-MBI upon transfer to and discharge from the department of rehabilitation medicine though it was not statistically significant; this was estimated that it would be ascribable to a higher rate of occurrence of poststroke complications in the group of subjects of hemorrhagic stroke. The consequence corresponds to the result of study that reported increasing risk of onset of complications by the sustainment of invasive procedure in ICU of most of the patients suffering from hemorrhagic stroke . FunctioFrom the onset of stroke, the times to points of initiation of rehabilitation and of transfer to the department of rehabilitation medicine upon implementation of CP appeared significantly shortened compared to those before implementation of CP in the groups of subjects of total, ischemic, and hemorrhagic strokes. This was estimated to be a consequence that resulted from early assessment and rehabilitation upon implementation of CP. The length of stay in the hospital also manifested a significant decrease in groups of subjects of total and ischemic strokes upon implementation of CP; this was attributed to the decrease in the rate of occurrence of poststroke complications. In the previous study, the complications that occurred on inpatients during rehabilitation have been known as a strong prognostic factor of increasing length of stay . On the The cases of discharge to home upon implementation of CP increased significantly in the group of subjects of ischemic stroke compared to those of before implementation of CP. This was estimated that it would be ascribable to the decrease in incidence of complications and increase in the Brunnstrom stage, which is increased functional recovery.The limitations of this study included the following: first, the retrospective approach that relied on medical records might have influenced the result of the present study depending on integrity of medical records. Second, the deficiency in items of comparative analysis due to differences in systems of medical records before and after implementation of CP resulted in the limited 100 samples for the control group before implementation of CP which are smaller than 860 instances after implementation of CP. Thirdly, there were differences between hospitals regarding points of initiation of rehabilitation and transfer to the department of rehabilitation medicine and length of stay, and these might have resulted in different consequences in hospitals that implemented the CP. Thus, the development of a standardized critical pathway based on large-scaled multi-institutional research seems necessary.The academic significance of the present study resides in the long-term tracking and follow-up for more than 10 years of effect of implementation of CP upon poststroke complications, functional states, and length of stay of patients in the department of rehabilitation medicine for the first time. The results of the present study are expected to be exploited for the clinical application and as a foundation of implementation of CP intending for rehabilitation of patients suffering from stroke.Implementation of a critical pathway promotes the key intervention based on evidences and guidelines, as well as helps provide patients with comprehensive, systematic, and professional treatment in the early times. The implementation of a critical pathway is recommended as a means of promoting the best treatment for patients suffering from stroke despite limited evidences.