To evaluate the effect of different protocols of low-level intensity laser therapy (LLLT) irradiation on the osseointegration of implants placed in grafted areas. 84 rats were randomly allocated into six groups: DBB: defect filled with deproteinized bovine bone; HA/TCP: defect filled with biphasic ceramic of hydroxyapatite/β-tricalcium phosphate ; DBB-LI: defect filled with DBB and treated with LLLT after implant placement; HA/TCP-LI: defect filled with HA/TCP and treated with LLLT after implant placement; DBB-LIB: defect filled with DBB and treated with LLLT after graft procedure and implant placement; and HA/TCP-LIB: defect filled HA/TCP and treated with LLLT after graft procedure and implant placement. The bone defects were made in the tibia and they were grafted. After 60 days, the implants were placed. The rats were subsequently subjected to euthanasia 15 and 45 days after implant placement. The pattern of osseointegration and bone repair in the grafted area was evaluated by biomechanical, microtomographic, and histometric analyses. Furthermore, the expression of bone biomarker proteins was assessed. The LLLT groups presented higher removal torque, mineralized tissue volume, and a greater degree of osseointegration, especially when LLLT was performed only after implant placement, and these findings were associated with higher expression of BMP2 and alkaline phosphatase. LLLT performed on implants placed in grafted areas enhances the osseointegration process. Although the use of osteoconductive bone substitutes reduces bone formation in bone defects,3 muscles,4 cutaneous tissue,5 and nerve tissue6 lesions. It has been proposed that the activation of mitochondrial chromophores stimulates the action of the respiratory chain with subsequent increase in cellular metabolism, producing the beneficial actions of LLLT in the process of tissue regeneration.7 The benefits of LLLT use have also been demonstrated in bone tissue by the stimulation of the differentiation and activation of osteoblastic cells.8 Preclinical studies have shown that the use of LLLT accelerated the repair of long bone fracture models,9 stimulated the healing of critical-sized calvarial defects,11 and accelerated the osseointegration of implants placed in native15 and grafted bone.18Low-level laser therapy (LLLT) has been successfully used in several clinical conditions, such as those involving joints,21 A preclinical study demonstrated that the use of LLLT at an 808 nm wavelength increased bone tissue formation in grafted areas with deproteinized bovine bone (DBB) and biphasic ceramics based on hydroxyapatite and β-tricalcium phosphate (HA/TCP) and that this effect was related to the increased expression of biological mediators that stimulate the formation of bone tissue.22Previous studies using LLLT in infrared wavelength range have shown improvement in the healing of grafted areas with different types of osteoconductive biomaterials.18 However, LLLT protocols to accelerate the osseointegration of implants in areas of native bone use LLLT sessions after implant placement.24 Moreover, the association of the use of LLLT sessions at two different times (after grafting and after implant placement) was also not described. Thus, this study compares the effect of different LLLT protocols on osseointegration in areas grafted with DBB and HA/TCP.The use of LLLT aimed to accelerate osseointegration in grafted areas has not been previously explored. In an earlier study, our research group demonstrated that the use of LLLT to DBB and HA/TCP grafted areas in the tibia of rats improved the osseointegration process of implants.Rattus novergicus, Hotzman strain) aged three months old and weighing 250-300 g were used. The animals were kept in an environment with controlled temperature (21±1°C), humidity (65-70%), and light-dark cycles (12 hours) and they had access to appropriate food and water ad libitum.This study was submitted and approved by the Research Ethics Committee on Animal Use of our institution (08/2014) and it was conducted according to the international guiding principles for biomedical research involving animals and followed the ARRIVE guidelines. In total, 84 animals ; the HA/TCP group: defect filled with biphasic ceramic based on hydroxyapatite/β-tricalcium phosphate (HA/TCP) ; the DBB-LI group: defect filled with DBB and treated with LLLT after implant placement; the HA/TCP-LI group: defect filled with HA/TCP and treated with LLLT after implant placement; the DBB-LIB group: defect filled with DBB and treated with LLLT after the graft procedure and implant placement; the HA/TCP-LIB group: defect filled with HA/TCP and treated with LLLT after the graft procedure and implant placement. The bone defects and grafting procedures were performed 60 days before implant placement, and the animals were euthanized 15 and 45 days after implant placement. LLLT was performed after implant placement in the LI groups; in the LIB groups LLLT was performed after grafting procedures and implant placement.   was used to perform the irradiation. The grafted area was delimited after the sutures of the surgical site, aided by a tissue marker pen. Four equidistant 3-mm points were marked in order to encompass the whole area to be irradiated; these points also served as a guide for laser irradiation. The laser was irradiated with the laser tip in contact with the skin tissue for 10 seconds at each point (1 J), totaling 40 seconds of irradiation per session (4 J). Seven sessions were performed – which were repeated every 48 hours for two weeks after the grafting procedure or implant placement. The energy density at each point was approximately 354 J/cm18. The animals were anesthetized by a combination of 0.08 ml/100 g body weight of ketamine  and 0.04 ml/100 g body weight of xylazine . Subsequently, a trichotomy of the inner region of the right and left legs and disinfection with sterile gauze soaked in iodopovidone solution were performed.The surgical protocol was the same as that used in another preclinical studyA 10-mm incision was made in planes on the tuberosity of the tibial. After a delicate dissection, the bone tissue was subjected to osteotomy by a spherical drill mounted at a contra-angle with the aid of an electric motor adjusted to 1200 rpm under abundant irrigation of sterile saline solution. The defect formed had measurements of 4 mm in both length and width and 1.5 mm in depth. A periodontal probe was used to measure defects that were later filled with biomaterials. The tissue was sutured by planes internally with resorbable wire  and externally with silk thread . The animals received a single dose of multibiotic at a dose of 0.3 ml/kg of body weight  and ketoprofen at a dose of 0.3 ml/kg body weight .®, Curitiba, Brazil) to accommodate a titanium implant with 4 mm high and 2.2 mm in diameter . All perforations were performed using an electric motor  adjusted to 1200 rpm under abundant irrigation of sterile saline solution. The implant was installed with the help of a digital key. The tissue suture and the postoperative drug protocol were similar to those used in the first surgery.After 60 days, a second surgical intervention was performed in the previously grafted area to place the implants. An incision similar to the first surgical procedure was performed on the tuberosity of the tibia. The grafted region was prepared for implant placement by applying a progressive sequence of milling drills , and an anti-clockwise movement was performed to unscrew the implant. The maximum peak needed to move the implant was noted as the removal torque value.The tibiae that had the implants removed were fixed in 4% paraformaldehyde for 48 hours, washed in running water for 12 hours and placed in 7% EDTA solution for decalcification for a period 8 weeks with 3 changes of EDTA solution during the week at room temperature. Subsequently, the samples were washed and dehydrated in alcohol, diaphanized in xylol and embedded in paraffin. The sections were made parallel to the long axis of the site where the implants were placed. The 4-μm-thick slices were fixed in common (for haematoxylin-eosin staining) and silanized slides .The histological description focused on the appearance of the bone tissue with emphasis on the bone remodelling and maturation process. The evaluations were performed by a trained and blinded rater (GJO) for the experimental groups using an optical microscope  with a magnification of 100X and 200X.25 A trained rater blinded to the experimental groups performed this analysis (FEP).The right tibiae were scanned by a micro-CT scanner  with the following parameters: camera pixel: 12.45; X-ray tube power: 65 kVP, X-ray intensity: 385 μA, integration time: 300 ms, filter: Al-1 mm and voxel size: 18 μm. The images were reconstructed, spatially repositioned and analyzed by specific software . The region of interest (ROI) was defined as a 0.5-mm circular region around the entire diameter of the implant. This ROI was defined as the total volume (0.5 mm margin around implants - 4.5 mm x 3.2 mm). As the implants placed did not receive cover screws, in some cases, there was bone formation inside the prosthetic platform. A second ROI for the removal of the platform volume was defined in order to not interfere with the volume of mineralised tissue analysis in this osseous formation,. With the results obtained in the two ROIs, it was possible to define the volume of the mineralized tissues using the following equation: Total Volume − Platform Volume = Volume of mineralized tissues. The threshold used in the analysis was 25-90 shades of grey, and the values of the volume of mineralised tissues around the implants were obtained as a percentage.18 We also performed an analysis of the percentage of bone and biomaterial in the region of the six threads near to the implants. These analyses were performed by a blinded and trained rater (FEP).The tibiae that underwent microtomographic analysis were used for histomorphometric analysis. The samples were dehydrated in a growing series of ethanol (60-100%) and infiltrated and polymerised in light-curing resin . The blocks containing the implant and the bone tissue were cut at a central point using a wear-and-tear system . The final sections were approximately 45 μm thick, stained with Stevenel blue associated with acid fuchsin and analyzed under an optical microscope  at a magnification of 100X. Histomorphometric evaluations were performed with image analysis software . The percentages of bone-implant contact (% BIC) and bone area between the threads (% BBT) were separately evaluated at the first six threads of the implants manually without establishing thresholds in the software.26 (0) without labelling (0% of cells/matrix); (1) weak labeling (<25 % of cells/matrix); (2) moderate labelling (<50% of cells/matrix); (3) strong labeling (<75 % of cells/matrix). The analyses were performed by a blinded and trained rater (GJO).Immunohistochemistry evaluation was performed to identify and to localize the expression of bone remodelling-related proteins: osteocalcin (OCN), bone morphogenic protein 2 (BMP2), and alkaline phosphatase (ALP). The histological sections were mounted on silanized slides, followed by routine laboratory procedures for deparaffinization and rehydration. Subsequently, the sections were subjected to nonspecific epitope blockade with the application of hydrogen peroxide block for 10 minutes and protein block for 30 minutes . Then, the sections were incubated for 16 hours in primary antibodies against OCN (1:400), BMP2 (1:400), and ALP (1:800) . As negative control, the histological sections were treated with 1% PBS. Subsequently, the sections were treated with the conjugate and HRP conjugate and stained with DAB . The sections were counterstained with Carrazi haematoxylin solution for visualization of the cell nuclei. The images were obtained with a camera coupled to a light microscope  with a magnification of 200X. The analysis of the expression of proteins was performed in the area of the bone near to the first six threads of the implants with a protein-labeled extension index:The data generated by the histometric, tomographic, and biomechanical analyses are numerical data; thus, they were subjected to the Shapiro-Wilk Normality test to evaluate the normal distribution according to the central distribution theorem. Data from biomechanical and immunohistochemical analysis were not normally distributed, thus the non-parametric Kruskal-Wallis test complemented by the Dunn test were used for the comparison between groups, and the Mann-Whitney test was used to evaluate the data within each group after varying the bone substitute and the experimental period. The other data were normally distributed, thus a parametric two-way ANOVA complemented by Tukey’s test were used to evaluate the data between the groups considering the relation between bone substitute and LLLT protocol used, whereas the independent t-test was used to compare data within each group after varying the experimental period. GraphPad Prism 6 software  was used for the statistical tests. All statistical tests of this study were carried out with a 5% significance level.18 The minimum difference between the averages of groups – where significant differences were found – was 12.85 %, with a standard deviation of 4.83 %. Therefore, the sample size of seven animals per group was sufficient for the application of the statistical tests with error type α of 0.05 and power 1-β greater than 0.90. The descriptive data of biomechanical and immunochemistry analyses are presented as mean [median] ± standard deviation, whereas the descriptive data of the micro-CT and histometric analyses are presented as mean ± standard deviation. The micro-CT, histometry, and immunohistochemistry analyses were repeated by the raters in 10 rats, and the data correlation was higher than 0.90.All animals tolerated the surgical procedures and showed no suffering, weight loss or death during the experimental period. For the sample size estimation, the histological data of %BIC from a previous preclinical study evaluating the effect of LLLT applied to the grafted area of the osseointegration implant was used.It was observed that the DBB-LI group (6.00 [5.00] ± 2.70 Ncm at 15 days and 9.42 [9.00] ± 3.78 Ncm at 45 days) presented higher removal torque values than those of the DBB group at 15 days (2.28 [2.00] ± 0.48 Ncm) and the DBB-LIB group (2.71 [2.00] ± 1.25 Ncm at 15 days and 2.00 [2.00] ± 1.00 at 45 days) at both periods of evaluation (p<0.05). The HA/TCP-LIB group had a higher removal torque (4.14 [3.00] ± 2.79 Ncm) compared with the HA/TCP group (1.57 [2.00] ± 0.53 Ncm) at 15 days (p<0.05). Furthermore, the DBB-LI group (6.00 [5.00] ± 2.70 Ncm) presented higher removal torque values than the HA/TCP-LI group (3.14 [2.00] ± 1.86 Ncm) at 15 days (p<0.05) .The volume of mineralized tissues around the implants increased in the 45-day period compared with the 15-day period in all groups (p<0.05). The DBB-LI group (37.56 ± 4.64 % at 15 days and 44.53±5.07 % at 45 days) presented higher volumes of mineralized tissues than those of the DBB-LIB group (27.77±6.27 % at 15 days and 36.63±3.92 % at 45 days) at both periods of evaluation (p<0.05), whereas the HA/TCP-LI group (44.16±2.93%) had a higher volume of mineralized tissues than the HA/TCP group (38.11±3.41%) and HA/TCP-LIB group (38.86±3.86%) at 45 days (p<0.05). Furthermore, the DBB (32.95±5.15 %) and DBB-LI groups (37.56±4.64 %) presented higher volumes of mineralized tissues than the HA/TCP (23.46±3.51 %) and HA/TCP-LI groups at 15 days (28.99±5.00%), respectively .After 15 days, it was observed that the DBB, HA/TCP, DBB-LI, and HA/TCP-LI groups presented a large presence of immature bone associated with rounded osteocytes and active osteoblasts. Furthermore, the presence of Havers channels attested the formation of a large number of new blood vessels. The DBB-LIB and HA/TCP-LIB groups had bone tissue with more mature appearance, flattened osteocytes, well-formed Havers channels, and large presence of reversion lines and blood vessels. At 45 days, no differences were observed between the groups in relation to the histological aspect characterized by the presence of mature bone, with Havers channels associated with flattened osteocytes, and well-established lamellar bone. In all groups and evaluation periods, the presence of biomaterials in contact with the bone and connective tissue without the presence of significant inflammatory reactions were verified .Regarding the histometric analysis, a higher %BIC was observed in the DBB-LI group at 45 days (42.48±8.55%) and in the DBB-LIB group at 15 days (25.56±10.42%) compared with the DBB group (8.15±5.69% at 15 days and 20.32±7.69% at 45 days). The HA/TCP-LI group (18.79±7.90% at 15 days and 24.59±14.48% at 45 days) had a higher %BIC than the HA/TCP group (7.89±5.47 % at 15 days and 11.21±6.82 % at 45 days) and the HA/TCP-LIB group (7.27± .89% at 15 days and 10.86±5.50% at 45 days) at both periods of evaluation (p<0.05). Furthermore, the DBB-LIB group (25.56±10.42%) presented a higher %BIC than the HA/TCP-LIB group at 15 days (7.27±4.89%) (p<0.05), and the DBB (20.32±7.69%), DBB-LI (42.48 ± 8.55 %), and DBB-LIB (39.41±22.21%) groups presented a higher %BIC than the HA/TCP (11.21±6.82%), HA/TCP-LI (24.59±14.48%), and HA/TCP-LIB (10.86±5.50%) groups at 45 days (p<0.05), respectively .Regarding the %BBT, it was shown that the DBB-LI group (53.54±13.68%) and the DBB-LIB group (46.70±14.74%) had higher values for this parameter than the DBB group (25.64±11.70%) at 45 days. It was also shown that the HA/TCP-LI group (30.89±14.40% at 15 days and 31.00±13.75% at 45 days) had higher %BBT than the HA/TCP group (12.57±8.11% at 15 days and 11.37±7.09% at 45 days) at both experimental periods and a higher %BBT than the HA/TCP-LIB group (8.13±6.59%) at 15 days (p<0.05). Moreover, the DBB-LIB group (22.28±16.29%) presented higher %BBT than the HA/TCP-LIB at 15 days (8.13±6.59%) (p<0.05), and the DBB (25.64±11.70%), DBB-LI (53.54±13.68%), and DBB-LIB (46.70±14.74%) groups presented higher %BBT than the HA/TCP (11.37±7.09%), HA/TCP-LI (31.00±13.75%), and HA/TCP-LIB (25.33±12.56%) groups at 45 days (p<0.05), respectively .In relation to the amount of bone and biomaterial in the grafted areas near the implants, a greater amount of bone was verified in the HA/TCP group at 15 days (24.67±8.87%) and in the HA/TCP-LI group at 45 days (36.67±12.26%) compared to that of the HA/TCP-LIB group (12.06±4.15% at 15 days and 20.85±8.05% at 45 days) (p<0.05). The DBB-LIB group (25.70±11.05%) presented more bone than the HA/TCP-LIB group (12.06±4.15%) at 15 days (p<0.05) . The amoThe HA/TCP-LIB group (2.20 [2.00]±0.44) had higher expression of OCN than the HA/TCP group (0.80 [1.00]±0.83) at 45 days. Regarding the BMP2 expression, it was verified that the DBB-LIB group (1.60 [2.00]±0.54) expressed higher amounts of this protein than the DBB group (0.80 [1.00]±0.44) at 15 days. The HA/TCP-LI group (1.00 [1.00]±0.00) had higher BMP2 expression than the HA/TCP group (0.20 [0.00]±0.44) at 45 days. Furthermore, a greater expression of ALP was observed in the DBB-LIB (1.40 [1.00]±0.54) and HA/TCP-LIB groups (2.00 [2.00]±0.70) than in the DBB (0.40 [0.00]±0.54) and HA/TCP groups (0.60 [1.00]±0.54) at 15 days .25This study showed that LLLT improves osseointegration process in areas grafted with DBB and HA/TCP, but this effect was greater when the irradiation protocol was used only after implant placement, whereas the use of LLLT at two time points (after the graft procedures and after implant placement) demonstrated limited superiority in relation to non-irradiated groups. Notably, the histometric data presented significant differences that were slightly different than the biomechanical and micro-CT data since this model evaluated osseointegration in a 2D view, the biomechanical analysis evaluated osseointegration in an indirect way, and micro-CT was not able to evaluate the BIC because of the artefacts induced by the implants and bone substitutes.27 Furthermore, Altan, et al.3 (2015) demonstrated that increased LLLT dosage (198 J in five sessions) reduced bone tissue formation in a model of hard palate expansion in rats. The dosage used in our (28 J in seven sessions in the LI group) was effective in improve bone repair in areas grafted with different osteoconductive biomaterials in different preclinical models22 as well as improving osseointegration in areas of native28 and grafted bone, and this may be the reason for the better outcomes of this protocol compared with the LIB protocol (56 J in 14 sessions) used in this study. However, previous studies demonstrated an improvement in the osseointegration of implants placed in grafted areas, where the double LLLT protocol was applied (4-184 J).17 Most likely, the different animal models of these preclinical studies (rabbit tibiae17 and maxillary sinus of sheep16) may explain these contradictory outcomes since in the tibia of rats, the distance required for the laser energy induce some effects on the bone defects is smaller than in the models mentioned above, and probably the energy required to reach the bone defect could be higher in the model used in this study. Considering that the supposedly beneficial LLLT dosage for bone repair associated with the treatment of bone defects using biomaterials, positively influencing the osseointegration of implants is unknown, demonstrates that this topic requires more research.The use of LLLT after implant placement in areas grafted with DBB increased the removal torque and the volume of mineralized tissues around the implants compared to the double irradiation protocol (LIB). Moreover, there was an increased volume of mineralized tissues in implants placed in areas grafted with HA/TCP that were submitted to LLLT after implant placement compared with non-irradiated implants and the areas where the double irradiation protocol (LIB) was performed. These data demonstrate that the benefits of LLLT use are dose-dependent and that double irradiation reduces the beneficial effects of LLLT. This phenomenon was previously described in a study where increased irradiation dosage (16 J in two sessions) impaired the proliferation, migration, ATP activity, and viability of human skin fibroblast cells.29 A preclinical study that evaluated the effect of LLLT on a model of Teflon domes filled with HA/TCP and DBB that were fixed in the lateral surface of the mandibular ramus of rats demonstrated that the use of LLLT in grafted areas increases the bone formation,22 and this finding may be the explanation for the greater bone maturation found after LLLT on the grafted areas shown in our study.The histological analysis of the decalcified sections showed that the group in which the double irradiation was performed presented a more evident pattern of bone maturation in the 15-day period than the other groups, and this fact may have occurred because of the LLLT treatment in the grafted area, which promoted an acceleration of bone maturation in the grafted area compared with the other groups, a fact that corroborates the findings of other preclinical studies.14 and osteopenic animals,28 facilitating the osseointegration of implants placed in the maxillary sinus of sheep grafted with autogenous bone grafts16 and improving the osseointegration of implants placed in the tibiae of rabbits grafted with blocks of deproteinized bovine bone.17 The preclinical study by Oliveira, et al.18 (2020) – that evaluated the effect of LLLT applied on noncritical defects in the tibia of rats grafted with HA/TCP and DBB prior to implant placement – promoted an increase in the %BIC and %BBT. To our knowledge, this is the first study showing that LLLT improves the osseointegration of implants placed in grafted areas when irradiation was performed only after implant placement.Another significant finding of this study was that LLLT increased the osseointegration of implants in grafted areas and that this effect was higher, especially when LLLT was used only after implant installation. It has been previously shown that LLLT increases osseointegration of implants placed in native bone in healthy30 and some histological studies show that areas grafted with DBB and HA/TCP present no differences regarding bone formation.33 However, a clinical study showed that biopsies harvested from the maxillary sinus grafted with DBB presented higher levels of osteoconduction than biopsies from the maxillary sinus grafted with HA/TCP.32 It is likely that this better pattern of osteoconduction justifies the better pattern of osseointegration obtained in areas grafted with DBB that were treated with LLLT.The effects of LLLT were also dependent on the type of bone substitute used for the grafting procedures, and the implant placements in the defects grafted with DBB presented a better pattern of osseointegration than the implant placements in HA/TCP grafted areas. Both bone substitutes tested in this study have shown good clinical outcomes,34 increased angiogenesis,35 and an improvement in osteoblastic differentiation and activity.3637 Indeed, an increase in the expression of OCN, BMP2, and ALP, significant mediators in the formation and maturation of bone tissue, were observed in this study.40 Previous studies have demonstrated that LLLT irradiation at infrared wavelength increased the expression of ALP, OCN, BMP2, and Jagged 1 in HA/TCP- and DBB-grafted areas.22 Furthermore, Kim, et al.41 (2009) showed that LLLT increased the expression of RANK, RANKL, and OPG in critical-sized calvarial defects of rats grafted with DBB, and this finding was related to the increase in the stimulus of bone remodelling. These events may be associated with the increase in osseointegration observed in our study because of the LLLT use.The use of LLLT is associated with proliferative tissue effects in connective tissue,43 Clinical studies evaluating LLLT with infrared lasers on osseointegration are also required. Only one clinical study evaluated the effect of infrared laser LLLT on osseointegration, and no differences were found in achieving the secondary stability of implants. In the initial period of evaluation, the stability obtained by the implants installed in the control and laser groups reached high values of stability.23 However, in this study the implants were installed in the posterior region of the mandible, and this area is not considered an area with poor bone quality.The results presented in this study raise the possibility of using LLLT in areas with poor bone quality as a way to improve osseointegration. It is necessary to compare the effects of the infrared laser with the red laser to evaluate whether there are differences in the use of these two distinct wavelengths since the results presented in the literature to this date are conflicting.This study presents some drawbacks that need to be considered in the our data interpretation. The type of defect tested in this study was a noncritical size defect because of the limitations of space to perform a critical-sized defect in the tibia that enables implant placement, so the type of defect tested may be less challenging than the conditions normally present in humans. The absence of a control group in which the implants should be placed in native bone limits the comparison of our data with the ideal conditions for implant placement, since this condition may be a more conventional positive control. Furthermore, it is necessary to compare the LLLT performed only after the grafting procedures to understand if the LLLT performed at two different times (after the grafting procedure and implant placement) presents inferior outcomes compared with the LLLT applied just after the implant placement, and also to assess whether these outcomes were due to the high doses of irradiation or to previous impact of the LLLT in the grafted area, and this evaluation was not possible in this study. Finally, the method used in this study to evaluate protein expression (immunohistochemistry) is more susceptible to systematic errors than other techniques used to evaluate protein expression , and the evaluation of the mechanisms of LLLT on bone formation in grafted areas should be performed with these techniques in the future.Thus, it can be concluded that LLLT performed after implant placement in the grafted areas enhances osseointegration. However, the LLLT irradiation protocol after the grafting procedures associated with LLLT after implant placement showed limited improvement in osseointegration compared with the non-irradiated groups.


Some paediatric surgical diseases showed a declining incidence in recent years, among which hypertrophic pyloric stenosis has been particularly striking shortly in the years after the millennium. We aimed to assess whether this development continued over the following decade, as it might offer the chance to better understand the underlying reasons.We analysed data files obtained from the German federal statistics office for principal diagnosis of hypertrophic pyloric stenosis and pyloromyotomies from 2005 to 2017. Changes over time were assessed via linear regression for incidences per 1000 live births.P < 0.0001) in boys—from a maximum of 2.96 to a minimum of 1.63–and 0.03 pyloromyotomies annually  in girls—from a maximum of 0.64 to a minimum of 0.28. There was considerable regional variation in incidences between the German länder.In the respective time interval, there were a mean of 1009 pyloromyotomies (95% CI 906–1112) per year, of which a mean of 835 (95% CI 752–917) were performed in boys. The incidence of hypertrophic pyloric stenosis per 1000 live births almost halved between 2005 and 2017: it decreased by 0.12 pylorotomies annually (95% CI 0.09–0.14; The decreasing incidence of hypertrophic pyloric stenosis noted around the millenium continued into the following decades. The underlying reasons are unclear, which should prompt further research on the subject matter. In recent years, infantile hypertrophic pyloric stenosis is diagnosed earlier and thus metabolic derangements occur less often , althougHowever, this finding seems to be influenced by seasonal , regionaStatistisches Bundesamt  including principal diagnoses and procedures of the German Modification of the International Classification of Diseases—Version 10 for the years 2005 to 2017 were obtained. Cases with operation codes for infantile pyloromyotomy (OPS 5-432.0) and the principal diagnosis of hypertrophic pyloric stenosis (ICD-10-GM Q40.0) were analysed. Only cases occurring in the first year of life were included. These administrative datasets count cases, not patients. Consequently, a patient may be included twice in case of a referral from one hospital to another. To quantify these cases, we subtracted the number of pyloromyotomies from the number of diagnoses of a hypertrophic pyloric stenosis. The detailed properties and pitfalls of these administrative dataset have been described elsewhere  pyloromyotomies was performed per year, of which 835 (95% CI 752–917) were in boys and 175 (95% CI 152–197) were in girls  pyloromyotomies per 1000 male live births per year from the maximum of 2.96 in 2006 to a minimum of 1.62 in 2016  pyloromyotomies per 1000 female live births from a maximum of 0.64 in 2007 to a minimum of 0.28 in 2016 , P = 0.0861) in the study period.The relative difference between cases diagnosed with hypertrophic pyloric stenosis and cases that underwent pyloromyotomy was 12.9%  in boys and 14.8%  in girls, indicating that a little over a tenth of the patients were transferred from one hospital to the other. Both relative differences did not change over time (♂: Δ = 0.18% (95% CI − 0.05 to 0.4), ibid and a minimum of 1.05 per 1000 boys born alive 2016 in Berlin. Likewise, the highest incidence per 1000 live born girls was recorded in Bremen with a mean of 1.51 (95% CI 0.96–2.06), whereas the lowest mean incidence was found in Berlin with 0.5 (95% CI 0.38–0.61) per 1000 girls born alive  in Baden-Württemberg to 5.09 95% CI 3.94–6.23) in Bremen (Table .94–6.23 Studies from the twentieth century described an increasing incidence of hypertrophic pyloric stenosis , 4, wherIn a previous report from Germany, population-based data were assessed using only the number of coded ICD-10-GM diagnoses of infantile hypertrophic pyloric stenosis to describe the reduction in cases . As the A previous study showed that the incidence of hypertrophic pyloric stenosis declined of by more than a third around the millennium . Our stuThe ratio between male and female cases was calculated at 4.8:1 in our dataset—similar to preceding studies from Taiwan at 4.3:1 , 4.2:1 iSimilar to preceding reports , 13, we In conclusion, the previously described substantial decline in the incidence of hypertrophic pyloric stenosis in Germany continues, although the reasons remain cryptic. However, administrative data are not suitable to explore associations and potentially causative factors. Consequently, future studies should focus on a multivariate analysis of possible associated factors: which underlying parameters changed over time and which remained stable? Administrative data cannot answer these questions.


However, relatively few epidemiologic studies focus on the health impacts of wildfire smoke PM2.5 compared with the number of studies focusing on total PM2.5 exposure.Substantial increases in wildfire activity have been recorded in recent decades. Wildfires influence the chemical composition and concentration of particulate matter ≤2.5 μm in aerodynamic diameter ) and combined respiratory disease ). No significant relationships were evident for cardiovascular diseases and smoke PM2.5. Associations with non-smoke PM2.5 were null for all outcomes. Positive age-specific associations related to smoke PM2.5 were observed for asthma and combined respiratory disease in children, and for asthma, bronchitis, COPD, and combined respiratory disease in adults. No significant associations were found in older adults.Per 1 μg/m2.5 exposure due to wildfires. Our results allow for a more precise assessment of the population health impact of wildfire-related PM2.5 exposure in a changing climate.This is the first multi-year, high-resolution epidemiologic study to incorporate statistical and chemical transport modeling methods to estimate PM Despite2.5, airborne particles < 2.5 μm in aerodynamic diameter) is of particular concern due to its ability to travel deep into the human respiratory system and enter the blood stream  visits at all public and private hospitals for the fire seasons (May-August) of 2011–2014 from the Colorado Department of Public Health and Environment. Information included in the patient records are dates of admission, residential address, age, sex, payer information and International Classification of Diseases version 9 (ICD9) codes for primary and secondary diagnoses. Patients admitted to the hospital through the ED were only counted once, and those with elective hospitalizations were excluded from analysis.We analyzed multiple endpoints for primary cardiovascular and respiratory diagnoses. Respiratory outcomes include asthma (ICD9: 493), bronchitis (ICD9: 490), chronic obstructive pulmonary disease , upper respiratory infection (ICD9: 460–465 and 466.0), and combined respiratory disease . Cardiovascular outcomes include ischemic heart disease (ICD9: 410–414), acute myocardial infarction (ICD9: 410), congestive heart failure (ICD9: 428), dysrhythmia (ICD9: 427), peripheral/cerebrovascular disease , and combined cardiovascular disease . Due to inadequate numbers, events in children were not analyzed for COPD or any cardiovascular outcomes.2.2.2.5 from ambient sources. To accomplish this, daily mean PM2.5 concentrations were adopted and improved from our previous study by adding new data . Compared to 2.5 enhancement near wildfires, allowing for a better representation of high values found during fire events , 3daytemp is the 3-day moving average temperature, ns(doy) is a spline for day of year , 3daysmoke2.5PM represents the three-day moving average smoke PM2.5; and 3daynonsmoke2.5PM denotes three-day moving average PM2.5 not related to wildfires. Cardiovascular outcome models were conducted using the same models shown in model specifications 1 and 2, but with 2-day averaging windows. Exposure windows of 3-day average PM for respiratory outcomes and 2-day average PM for cardiovascular outcomes were decided a priori based on published studies and consensus information found in the latest Integrated Science Assessment from the USEPA . However, these parameters did not influence the results and were omitted in the final model. Analyses to examine the presence of potential effect modification were completed using sex and age-stratification. Age-stratified categories included children (0–18 years), adults (19–64 years), and older adult (65+ years). We conducted all analyses in R 3.4.3 (2017) and SAS© 9.4.3.3.1.2.5 concentrations is shown in 2.5 values ranged from close to 0 to 47.48 μg/m3, with an overall mean value of 4.67 μg/m3. The exposure model was also used to separate smoke PM2.5 from nonsmoke PM2.5. This separation is based on the CMAQ fraction, with total PM2.5 equal to the sum of non-smoke PM2.5 and smoke PM2.5. Ratios of smoke PM2.5 to total PM2.5  ranged from 0 to 99.56% (mean = 0.006%), with smoke PM2.5 levels ranging from 0 to 37.34 μg/m3. The statewide daily mean smoke vs. total PM2.5 ratio is also shown for the entire study period . The peaks of highest smoke PM2.5 ratios tended to correspond with active fire days. 2.5 and smoke PM2.5 ratio for June 22, 2013, a peak fire day during the West Fork Fire Complex. As depicted, when compared to satellite imaging, the modeled smoke PM2.5 appears to capture the apparent visible smoke plume adequately.A time series plot for modeled statewide daily mean PMriod See . As show3.2.After excluding duplicate events and events with non-geocoded addresses, 44,262 of 490,368 (9%) of cases were excluded from the analysis. A total of 446,106 ED visit and hospitalization events were analyzed from the Colorado Department of Public Health and Environment. Of those included, there were 204,823 male and 241,283 female cases. The lowest case count occurred in 2011 , with the highest number of cases in 2014 . While many reasons could exist, the large increase seen in 2014 could be explained by changes in health seeking behavior due to wider Medicaid coverage resulting from the implementation of the Affordable Care Act . Other s2.5 and individual health outcomes. As shown in 3 increases in 3-day moving average fire exposures and both asthma ) and combined respiratory disease ) in a model that adjusted for PM2.5 from other sources. There were no significant positive associations linked to cardiovascular outcomes and 2-day smoke PM2.5 exposures ) and upper respiratory infection in children , see 2.5 exposure , see 2.5 exposure , see 2.5 ) than in male cases ). Female bronchitis cases ) and female total respiratory cases ) were also positively associated with smoke PM2.5. Additional sex-stratified, 3-day average smoke PM2.5 results can be found in To investigate potential effect modification of the relationship between exposures and respiratory outcomes, we conducted stratified analyses based on sex and age. While most sex-stratified total PM see 2.5  and 11. 2.5 with any specific age group . The design of this study is centered on smoke PM2.5 contributions to health outcomes. This work builds on our previous work by improving exposure data metrics and expanding from a 1-month pilot study ). Additionally, we observed heterogeneity in the association estimates when stratifying by age group. Positive associations were observed for asthma events, where ED/hospitalizations increased significantly in children ) and in adults ) whereas the association estimate was lower in magnitude and was less precise for older adults ). Similarly, an increase was seen for combined respiratory diseases with increases in ED/hospitalizations and adults ). Specifically, in the adult group, increases were also shown for both bronchitis ) and COPD ). As opposed to other studies, there was no association shown for respiratory diseases when stratified for the older adult age group.As we hypothesized, many of the respiratory disease outcomes increased during periods of wildfire activity. For respiratory outcomes, we estimated an increase ) in ED/hospitalizations per 1 μg/m2.5 and cardiovascular outcomes. Results for combined cardiovascular disease yielded null results ). Similar results were shown for both the adult and older adult age groups. This is not wholly surprising given differing results in current literature regarding the links between cardiovascular outcomes and wildfire events. There are fewer examples of cardiovascular associations with wildfire smoke exposure compared to respiratory outcomes. Additionally, associations with cardiovascular outcomes tended to be substantially lower in magnitude than for the respiratory outcomes. These differences are consistent with published studies on both types of outcomes .2.5 exposure enhanced the exposure estimations, however, the PM2.5 concentrations were not separated into smoke and non-smoke concentrations (Our high-resolution epidemiological study furthers the current knowledge in the field by incorporating random forest modeling methods combining information from MAIAC AOD, CMAQ simulations, and ground measurements to elucidate the portion of PM2.5 present in the air due to wildfire smoke. Previous work has been done to enhance the spatial coverage and resolution of total PM2.5 estimates during wildfire events . While mtrations .Other work has utilized methods combining wildfire emissions and smoke plume modeling. For example, Hutchinson et al. examined similar epidemiological questions using exposure data derived from a model that combined the Wildland Fire Emissions Information System and the Hybrid Single-Particle Lagrangian Integrated Trajectories . Their sThe asthma association found in our study is substantially larger than those shown in previous publications. In addition to 2.5. Since different chemical compositions of PM2.5 may affect the body differently, it has been suggested that toxicological differences may play a role in how wildfire smoke PM affects the human anatomy and physiology. Multiple toxicological studies have shown differences in the composition and effects of wildfire smoke compared to ambient air (While we did not investigate physiological mechanisms, these results may be explained by the toxicity of smoke PMient air . It has ient air . Franzi ient air .2.5 measured by ground monitors and, thus give an accurate representation of overall trends. Additionally, several health events were left out of the analysis due to issues with address geocoding or non-Colorado residency. However, the exclusions were relatively small with only 9% of cases not used in the final analyses. Additionally, our analyses lacked the ability to differentiate chemical compositions of PM2.5. Thus, we cannot link toxicological effects to our exposure metrics. Finally, the selection of averaging window size, though based on current literature, may also introduce error into the analysis.Despite the strengths of our study, some limitations remain. While we sought to enhance the exposure estimates for individual cases, some exposure misclassification is still possible given the assumption that the location of a person’s address is a good representation of their short-term exposures to smoke PM. An additional limitation exists due to the use of modeled exposure data. However, as stated previously and despite this uncertainty, the model accurately captures the temporal and spatial trends of PM2.5 from background PM2.5. Unlike ground monitors that provide spatially sparse measurements, the exposure model used here provides daily concentrations for each 4 km × 4 km grid cell in our epidemiological study.Notwithstanding these limitations, our methods lend insight into important challenges that remain in the wildfire smoke exposure and health effects literature. The use of higher resolution enhanced exposure data provides a new approach to assigning exposure to individual events. Using multiple data products, our method aids in distinguishing wildfire smoke PM5.2.5 exposure estimates, we found significant associations between wildfire smoke and acute respiratory outcomes in Colorado, despite an absence of association with total PM2.5 concentrations. Our findings point to potential toxic differences between smoke and non-smoke PM2.5 exposure; suggesting that PM2.5 from wildfire smoke could pose a significant threat to public health. This is especially true given the expected climate change-related impacts on wildfire incidence. It is, therefore, important to derive more accurate concentration-response relationships specific to wildfire smoke in order to develop a better understanding of future potential health risks based on increased wildfire activity. Taken together, the current analysis can inform public health agencies and healthcare systems regarding the potential future burden of wildfire smoke PM2.5 exposure within the context of climate change. This information may be a key element in evaluating and enhancing current preparations aimed at wildfire-event response readiness.Supported by high-resolution PMSupplementary data


The study estimated service coverage for severe mental disorders , globally and regionally, using data collected from the Mental Health Atlas 2017.Service coverage was defined as the proportion of people with a disorder contacting a mental health service among those estimated to have the disorder during a 12-month period. We drew upon 12-month service utilisation data from the Mental Health Atlas 2017. Expected prevalent cases of individual disorders were estimated using the disorder-specific prevalence rate estimates of the Global Burden of Disease Study 2016 and total population sizes. Methods for assessing the validity of country-reported service utilisation data were developed and applied.From 177 countries, 50 countries provided reliable service coverage estimates for psychosis, along with 56 countries for bipolar disorder, and 65 countries for depression. The mean service coverage for psychosis was lowest in low- [10.9%  3.3–30.4)] and lower middle-income countries [21.5% (95% CI 11.9–35.7)] and highest in high-income countries [59.5% (95% CI 42.9–74.1)]. Service coverage for bipolar disorder ranged between 3.1% (95% CI 0.8–11.5) and 10.4% (95% CI 6.7–15.8). Mean service coverage for moderate-severe depression ranged between 2.9% (95% CI 1.3–6.3) for low-income countries and 31.1% (95% CI 18.3–47.6) for high-income countries.The reporting method utilised by the Mental Health Atlas appears to be reliable for psychosis but not for depression. This method of estimating service coverage provides progress in tracking an important indicator for mental health; however, it highlights that considerable work is needed to further develop global mental health information systems. This specific measurement has been termed ‘contact coverage’ by Tanahashi We drew upon 12-month service utilisation data from the Mental Health Atlas 2017; specifically, data from specialist (inpatient and outpatient) mental health facilities  for psychosis, bipolar disorder and depression. Data, including the number of people receiving care from inpatient and outpatient services, population representativeness and population size, were extracted from section 8 of the Mental Health Atlas Questionnaire 2017 into Microsoft Excel 2016 for analysis . Data were excluded if they did not report on service utilisation of both inpatient and outpatient facilities for a specific disorder, or if countries did not report representativeness of the population that the data were drawn from.Data from section 7 of the Mental Health Atlas Questionnaire 2017, relating to the number of inpatient and outpatient visits, were used as a validity check of the service utilisation data . If the number of visits (from section 7) per individual case (from section 8) was less than 1, data were excluded from further analysis.Total treated cases were calculated according to the following formulas:et al., et al., et al., Expected prevalent cases of individual disorders were estimated using the disorder-specific prevalence rate estimates of the Global Burden of Disease Study (GBD) 2016  as estimated by GBD 2016 were adjusted in two ways to ensure consistency with service utilisation data for each country that provided Mental Health Atlas 2017 data. Firstly, point prevalence rates of depression were adjusted to 12-month prevalence rates using the inverse of a covariate coefficient which adjusted studies reporting 12-month prevalence to point prevalence. Given the understanding that mild cases of depression are rarely treated in specialist services, we further adjusted depression prevalence estimates to reflect the proportion of cases which are moderate-severe by applying the GBD severity splits   population estimates, UN population estimates were used , schizophrenia  and bipolar disorder .The Atlas questionnaire requests that service coverage data are reported for non-affective psychosis (ICD-10: F20–29), bipolar disorder (ICD-10: F30–31) and depression (ICD-10: F32.1-3–F33.1-3). For this reason, we have avoided using the diagnostic term ‘major depression’ and instead used ‘depression’ with the understanding that some depression cases may not reach diagnostic thresholds. We also refer to the term ‘psychosis’ for the remainder of the manuscript as representing ‘non-affective psychosis’.To prevent double-counting of individuals who had used both inpatient and outpatient facilities, total service coverage rates were adjusted to appropriately reflect the total number of unique cases of individuals utilising mental health facilities. Countries were categorised into inpatient-prioritised countries (i.e. most of the population are treated in inpatient facilities) or outpatient-prioritised countries (i.e. most of the population are treated in outpatient facilities) based on reported data. In inpatient-prioritised countries, the data were not adjusted. In outpatient-prioritised countries, it was assumed that all individuals utilising inpatient facilities also utilised outpatient facilities.1.25% or less of discharged inpatients received a follow-up outpatient visit within one month2.26–50% of discharged inpatients received a follow-up outpatient visit within one month3.51–75% of discharged inpatients received a follow-up outpatient visit within one month4.More than 75% of discharged inpatients received a follow-up outpatient visit within one monthThe total unique cases adjustment was based on question 9.3 of the Mental Health Atlas 2017 questionnaire, which provides a follow-up rate ranging from 1 to 4, as follows:The adjusted outpatient estimate was calculated by averaging the follow-up range, multiplying this by the inpatient cases, and subtracting this product from the reported outpatient utilisation value (see formula below). For countries that did not report a follow-up rate, the median follow-up rate for the respective GBD world region was used  around each countries' service coverage estimates using the following steps:–s.e. of the treated prevalence Estimate the –s.e. of the GBD prevalence Estimate the –Estimate the proportion of cases that are treated –s.e. of the service coverage estimate Estimate the We calculated the standard error , the sample comprised 70 countries reporting on psychosis, 64 countries reporting on bipolar disorder, and 66 countries reporting on depression. After the WMHS service coverage thresholds were applied, the final numbers were 50, 56 and 65 countries for each disorder, respectively, reporting seemingly reliable service coverage estimates from the Atlas 2017 data. All six WHO regions and all four World Bank income regions were represented.Using our methods, seven low- and 14 lower-middle-income countries were found to have reported reliable service utilisation data; providing a mean service coverage of 10.9% (95% CI 3.3–30.4) and 21.5% (95% CI 11.9–35.7), respectively. There were 14 upper-middle-income countries with a mean service coverage of 29.2% (95% CI 19.9–40.7). Fifteen high-income countries reported a mean service coverage of 59.5% (95% CI 42.9–74.1) .Table 2Three world regions reported mean service coverage rates above 50% . The mean service coverage across all countries was 31.3% (95% CI 22.9–41.0).Seven low- and 15 lower-middle-income countries were found to have reported reliable service utilisation data, providing a mean service coverage for bipolar disorder of 3.1% (95% CI 0.8–11.5) and 3.5% (95% CI 1.8–6.8), respectively, per group . There wThe WHO South-East Asia region reported the highest service coverage for bipolar disorder at 21.7%, although this was based on only one country. This was followed by the GBD high-income region at 14.5% (95% CI 10.3–20.1). The mean service coverage for bipolar disorder across all countries was 4.4% (95% CI 3.1–6.2).The estimated mean service coverage for moderate-severe depression was extremely low overall at 10.7% (95% CI 7.4–15.2) and ranged between 2.9% (95% CI 1.3–6.3) for low-income countries and 31.1% (95% CI 18.3–47.6) for high-income countries .Table 4Service coverage for moderate-severe depression was lowest in the WHO African region at 3.4% (95% CI 2.2–5.3), the WHO Eastern Mediterranean region at 3.6% (95% CI 1.5–8.3), the GBD Sub-Saharan Africa region at 2.7% (95% CI 1.4–5.0) and the GBD South Asia region at 3.7% (95% CI 0.6–19.4). Service coverage for depression was highest in the WHO European region at 30.9% (95% CI 18.9–46.1) and the GBD High income region at 35.5% (95% CI 20.1–54.6).et al. using WHO-AIMS data . However, there were key differences between the studies. Firstly, this earlier analysis examined schizophrenia, not all psychosis. Additionally, the WHO-AIMS sample of countries included a smaller sample from upper-middle-income countries, and no high-income countries.Our estimates of service coverage for psychosis were similar overall compared to those produced from a previous study using WHO-AIMS data . Differing methodologies likely explain this: the WMHS asks individuals whether they have received treatment from any mental health provider, whereas the Mental Health Atlas relies on health information systems reporting on mental health specialist service utilisation. However, the low coverage reported for bipolar disorder may also be partially attributed to frequent misdiagnoses of this condition  , population-based surveys and data from non-specialist health facilities  may be more effective methods.The method of estimating service coverage outlined in this paper provides significant progress in tracking a critical mental health indicator. However, it has also highlighted that considerable work is still needed to develop global mental health information systems further. Several countries could not provide data for the service utilisation questions in the Mental Health Atlas 2017 questionnaire. For example, data availability on service coverage was remarkably low in the WHO regions of South East Asia and Africa. In these two regions, according to Atlas 2017, at least 20% of Member States reported that no data for mental health had been compiled during the last 2 years. The most common reason for non-reporting is that routine data collection is either absent or incomplete in these countries. For example, data may be only available at outpatient or inpatient facilities but not both; or data may be collected at the district or regional levels but not aggregated nationally.Even when data are routinely collected, other challenges are observed – such as the absence of a unique patient identifier system which makes the process of identifying visits of each case or follow-up of cases after discharge a challenge leading to a risk of overcounting cases. Issues of correct reporting on disorder-specific data lie in the fact that the Atlas questionnaire does not request countries to report on the diagnostic system used in medical records and variations in the system; criteria and clinical expertise may vary within and between countries.Some limitations in our approach to estimating global service coverage for mental disorders should be noted. The Mental Health Atlas 2017 data are restricted to service utilisation in specialist mental health services. Service utilisation data from primary care, private service providers, non-governmental organisations and other service providers are not captured. This is especially poignant for countries with few mental health services typically restricted to large cities. Data collection from sentinel primary care settings may be important to estimate service coverage for disorders such as depression.et al., Differences in case-definitions for psychosis were addressed through an adjustment of GBD 2016 prevalence estimates of schizophrenia (ICD-10: F20) to meet the Mental Health Atlas 2017 case-definition of psychosis (ICD-10: F20–29). We also adjusted GBD 2016 depression prevalence estimates to reflect the 12-month prevalence of moderate and severe cases only. The GBD 2016 definition of bipolar disorder includes cyclothymia , whilst the Mental Health Atlas 2017 does not include cyclothymia but does include mania (ICD-10: F30–31). However, these differences are unlikely to significantly impact because the prevalence of cyclothymia is extremely low, and mania will typically be classified as bipolar I disorder (Akiskal An additional difference in case-definitions exists within the derivation of service coverage thresholds described in the methods. While the WMHS reports service coverage estimates for psychosis, the Mental Health Atlas reports estimates for the narrower definition of non-affective psychosis. However, given our thresholds are very low, we do not anticipate a significant impact on our findings.For the commitments by countries made for mental health in WHO's Mental Health Action Plan and UN's SDGs to be satisfactorily implemented, a robust monitoring system is essential. Service coverage for severe mental disorders is an essential indicator for this system. There is an urgent need to develop better methods to obtain information on this indicator and increase the capacities of countries to generate reliable data using a routine health information system. Any delay in doing this will compromise the achievement of stated objectives and targets of commitments countries have made.It is important to note that the Mental Health Atlas, the tool used to measure coverage in this exercise, is an on-going activity of the WHO. As more accurate and comprehensive information on service coverage and other aspects of mental health systems become available, and the concepts and definitions of resources become more refined, it is expected that the database of the Mental Health Atlas will also become better organised and more reliable. While, in many cases, countries' information systems are weak, the Atlas exercise itself, including regular follow-up with countries every 2 years, may catalyse further development by demonstrating the utility of such systems.


Relevant studies focusing on epidemiological of profiles hypertensive disorders of pregnancy from global data that report the cause-specific prevalence and trends of hypertensive disorders of pregnancy at global, regional and national levels from 1990 to 2019 by age and sociodemographic index are still limited.For hypertensive disorders of pregnancy, point prevalence, annual incidence, and years lived with disability numbers and age standardized rates per 100,000 population were compared at regional and national levels by age and sociodemographic index using data from the global Burden of Disease 2019 Study, covering populations from 204 countries and territories. Estimates are reported with uncertainty intervals to exhibit the changing trends during a specific period.The incidence of hypertensive disorders of pregnancy increased from 16.30 million to 18.08 million globally, with a total increase of 10.92 % from 1990 to 2019. The age-standardized incidence rate decreased, with an estimated annual percent change of -0.68 . The number of deaths due to hypertensive disorders of pregnancy was approximately 27.83 thousand in 2019, representing a 30.05 % decrease from 1990. Based on the incidence and prevalence, the number of deaths and years lived with disability were highest in the group aged 25–29 years, followed by the groups aged 30–34 and 20–24 years, while the lowest estimated incidence rate was observed in the group aged 25–29 years and higher incidence rates were observed in the youngest and oldest groups. Positive associations between incidence rates and the sociodemographic index and human development index were found for all countries and regions in 2019. Age-standardized incidence rates were higher in countries/regions with lower sociodemographic indices and human development indices.Our study provides a comprehensive overview of the global burden of hypertensive disorders of pregnancy. The death and incidence rates are decreasing in most countries and all regions except for those with low sociodemographic and human development indexes. This difference is mainly due to the increasing attention to prenatal examinations and health education. Further investigations should focus on forecasting the global disease burden of specific hypertensive disorders of pregnancy and modifiable risk factors.The online version contains supplementary material available at 10.1186/s12884-021-03809-2. Hypertensive disorders of pregnancy (HDP) is one of the leading causes of maternal and fetal morbidity and mortality worldwide and potentially a critical threat to maternal and infant health . In 2013Recent evidence has indicated an increase in the incidence rate of HDP over the past few decades, , 8 suggeIn recent years, the burden of HDP has been presented in some review papers based on a few national studies, but no detailed information from all countries has been provided. The overall aim of this study was to determine the epidemiological characteristics of HDP in a population-based cohort. This study presents the modeled global-, regional- and national-level prevalence and incidence rates, mortality rates and years lived with disability (YLDs) of HDP as revealed in the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2019 and analyzes the associations between epidemiological data and socioeconomic factors, such as the sociodemographic index (SDI) and human development index (HDI), to provide comprehensive, comparable and up to date information on the HDP burden.http://ghdx.healthdata.org/). These data were segmented by country/region and SDI quintile, which reflects the degree of social development and correlates with total fertility, per capita income, and average years of education  to 18.08 million (95 % UI 15.26 to 21.11 million) globally, with a total increase of 10.92 % from 1990 to 2019. The number of deaths due to HDPs was approximately 27.83 thousand (95 % UI 24.30 to 27.83 thousand) in 2019, with a 30.05 % (95 % UI 28.92–32.71 %) decrease from 1990 to 2019 ], western sub-Saharan Africa [3.71 million (95 % UI 3.14 to 4.27 million)] and eastern sub-Saharan Africa [3.12 million (95 % UI 2.64 to 3.63 million)]. Conversely, Australasia [30.11 thousand (95 % UI 23.08 to 38.67 thousand)], Oceania [37.06 thousand (95 % UI 29.64 to 46.29 thousand)] and Central Europe [78.06 thousand (95 % UI 64.04 to 94.23 thousand)] had the lowest incidence estimates ], Niger [2256.95 (95 % UI 1883.97 to 2644.81)] and Somalia [2251.26 (95 % UI 1893.54 to 2597.09)] were the countries with the highest ASIR estimates in 2019. Korea [36.34 (95 % UI 29.61 to 45.73)], Canada [49.13 (95 % UI 41.84 to 57.00)] and Luxembourg [58.27 (95 % UI 45.34 to 74.77)] had the lowest estimates ], Qatar [-3.97 (95 % CI -4.19 to -3.75)] and Oman [-3.68 (95 % CI -3.86 to -3.50)] showed the greatest decreasing trends. Ecuador [2.09 (95 % CI 1.90 to 2.28)], Switzerland [1.55 (95 % CI 1.14 to 1.96)] and Denmark [1.52 (95 % CI 0.98 to 2.06)] showed the greatest increasing trends  to 0.15 (95 % UI 0.05 to 0.25) per 100,000 population between 1990 and 2019. Iron deficiency was recognized as a risk factor for HDP progression. Unfortunately, data on several factors were limited in the GBD study, such as body mass index, maternal age and preexisting diseases, which impeded the assessment of the HDP risk.As HDP is considered one of the major causes of maternal mortality worldwide, epidemiological surveillance of HDP is critical to gestational healthcare . To the Socioeconomic status is associated with several diseases, such as neurological and immunorelated diseases . Obstetrhttps://maternalhealthatlas.org/)   . Studiesk of HDP . AlthougOur study found a decreasing trend in HDP due to iron deficiency from 1990 to 2019, which may be related to an increasing number of obstetricians prescribing iron supplements during pregnancy. However, some controversy still exists regarding the relationship between iron supplementation during pregnancy and the occurrence of HDP. Maintaining optimal iron levels is a delicate balance, with high levels associated with toxicity. One study found that pregnant women who subsequently developed HDP had lower serum iron levels in the first trimester than those who did not develop HDP. However, other studies showed different trends . AnotherOur study provides a comprehensive overview of the global HDP burden. Although variations were observed between regions and countries in the prevalence of, incidence of and mortality due to HDP, the burden of HDP is decreasing in most countries and in all regions. This decrease is mainly because prenatal examinations and health education have received increasing attention. The prevalence of HDP was associated with the sociodemographic index and human development index. Further investigations should focus on forecasting the global disease burden of specific classifications of HDP and modifiable risk factors.Additional file 1:Supplementary Figure 1. The changes in ASRs of DALYs, YLDs and YLLs in different global regions from 1990 to 2019. ASR, age-standardized rate; DALYs, disability-adjusted life years; HDP, hypertensive disorders of pregnancy; YLDs, years lived with disability; YLLs, years of life lost.Additional file 2:Supplementary Figure 2. The incident number of HDP cases in the different SDI quintiles. HDP, hypertensive disorders of pregnancy; SDI, sociodemographic index.Additional file 3:Supplementary Table 1. The age-standardized death rate of HDP in 2019.Additional file 4:Supplementary Table 2. The ASRs of DALYs, YLDs and YLLs of HDP in 2019.Additional file 5:Supplementary Table 3. ASIR of HDP in different countries and regions in 2019.Additional file 6:Supplementary Table 4.The prevalence of HDP in different countries and regions in 2019.Additional file 7:Supplementary Table 5.The EACP of the ASIR of HDP in different countries and regions from 1990 to 2019.Additional file 8:Supplementary Table 6. The relationship between the ASIR and SDI.Additional file 9:Supplementary Table 7. The relationship between the ASIR and HDI.


The motivations that govern the adoption of digital contact tracing (DCT) tools are complex and not well understood. Hence, we assessed the factors influencing the acceptance and adoption of Singapore's national DCT tool – TraceTogether – during the COVID-19 pandemic. We surveyed 3943 visitors of Tan Tock Seng Hospital from July 2020 to February 2021 and stratified the analyses into three cohorts. Each cohort was stratified based on the time when significant policy interventions were introduced to increase the adoption of TraceTogether. Binary logistic regression was preceded by principal components analysis to reduce the Likert items. Respondents who ‘perceived TraceTogether as useful and necessary’ had higher likelihood of accepting it but those with ‘Concerns about personal data collected by TraceTogether’ had lower likelihood of accepting and adopting the tool. The injunctive and descriptive social norms were also positively associated with both the acceptance and adoption of the tool. Liberal individualism was mixed in the population and negatively associated with the acceptance and adoption of TraceTogether. Policy measures to increase the uptake of a national DCT bridged the digital divide and accelerated its adoption. However, good public communications are crucial to address the barriers of acceptance to improve voluntary uptake widespread adoption. Contact tracing is an essential strategy for mitigating the transmission of SARS-CoV-2 and reducing the morbidity and mortality associated with COVID-19  AOR (95% CI) [1] 1.62 (1.39–1.88); [2] 1.52 (1.24–1.87); [3] 1.68 (1.25–2.27)) and if ‘TraceTogether is used by many people’ ([cohort] AOR (95% CI) [1] 1.35 (1.17–1.56); [2] 1.71 (1.40–2.08); [3] 1.49 (1.09–2.04)).Respondents had increasing likelihood of accepting TraceTogether over time if they believe that the data collected by the TraceTogether are secure ([cohort] AOR (95% CI) [1] 1.26 (1.06–1.49); [2] 1.44 (1.13–1.84); [3] 1.67 (1.23–2.27)). Respondents in cohort 2 were less likely to accept TraceTogether if they felt that it only benefits themselves (AOR (95% CI) 0.80 (0.70–0.92)) and older adults (>50 years old) in cohort 1 are more likely to accept TraceTogether (AOR (95% CI) [cohort 1] 1.31 (1.03–1.68)).The final models for each of the three cohorts are shown in The likelihood of adopting TraceTogether is higher among respondents who think that the ‘people important to them would recommend the use of TraceTogether’ ([cohort] AOR (95% CI) [1] 1.31 (1.13–1.51); [2] 1.41 (1.18–1.68); [3] 1.37 (1.03–1.81)) and respondents who think that ‘TraceTogether is used by many people’ ([cohort] AOR (95% CI) [1] 1.67 (1.48–1.90); [2] 1.55 (1.33–1.81); [3] 1.70 (1.29–2.25)).Respondents in cohort 1 who were ‘not concerned about people who may fall ill or die from COVID-19 due to them’ were less likely to adopt TraceTogether (AOR [1] (95% CI) 0.87 (0.78–0.97)). Respondents in cohort 2 were also less likely to adopt TraceTogether if they ‘think that it only benefits themselves’ (AOR [2] (95% CI) 0.85 (0.76–0.94)) and likewise for respondents in cohort 3 if they ‘needed someone to teach them how to use TraceTogether’ (AOR [3] (95% CI) 0.56 (0.44–0.69)).Older adults (>50 years old) in cohorts 2 and 3 ([cohort] AOR (95% CI) [2] 1.98 (1.46–2.70); [3] 2.39 (1.49–3.85)), employed respondents in cohort 2 (AOR 1.37 (1.01–1.86)) and tertiary educated respondents in cohort 1 (AOR (95% CI) 1.41 (1.10–1.80)) were more likely to adopt TraceTogether.We assessed the determinants of the acceptance and adoption of Singapore's national DCT tool – TraceTogether – across the different periods when new policy measures were implemented to increase its adoption, in response to the evolving COVID-19 pandemic. The attitudes and perceptions of health technology adoption among TraceTogether's users are complex under the circumstances of the COVID-19 pandemic and policies that necessitate its adoption. Hence, the stratified analysis enabled us to assess the attitudes and perceptions of TraceTogether concomitantly with the various policy implementations that precipitated the uptake of TraceTogether.Respondents were more likely to accept and adopt TraceTogether if they perceived it as useful and necessary during the COVID-19 pandemic. Likewise, the perceived lack of benefit was found to be a barrier to DCT app uptake in a Swiss study . The perStudies have cited concerns on the privacy and security of DCT tools as the main barriers to its adoption , 25. AltAnother factor that could influence the acceptance and adoption of TraceTogether is the notion of the common good. As expected, respondents who valued liberal individualism were less likely to accept and adopt TraceTogether . Other sApart from the policy measures that require the use of TraceTogether, influence from family members and widespread popularity may nudge hesitant individuals to adopt the new technology . We founOne essential measure to increase the uptake of TraceTogether was to bridge the digital divide among people with and without access to or knowledge of use of smartphones and the Internet. The tertiary educated and employed were more likely to be early adopters of TraceTogether, while older adults had a higher likelihood of acceptance but low adoption rates at the earlier period of TraceTogether's implementation. Older adults were more likely to adopt TraceTogether only after Bluetooth tokens were distributed to the population, although the increase in adoption rates was likely a combination of other promotional and mandatory measures to accelerate the population uptake rates. Since the ease of use of TraceTogether was mainly associated with adoption, the increased likelihood of adoption over time due to this factor could have been a combination of the effect of adaptability to the tool under the conditions of mandatory adoption and its ease of use. Notably, the acceptance or adoption of TraceTogether was not different between gender.Limitations of the study include our inability to generalise the study over the entire population. Although respondents were limited to the patients and visitors of two hospital outpatient clinics, the study team purposively recruited a diverse profile of respondents to minimise biases that would substantially skew the population profile. We also could not assess the changes in perceptions of the same respondent longitudinally over time, as the study was cross-sectional in nature. Further work could explore the notions of the common good in other populations on the acceptance of health technology in response to large-scale infectious diseases outbreaks. Future qualitative studies could also provide more in-depth understanding of the motivations that influence the acceptance and adoption of new technologies under the circumstances of a pandemic.In conclusion, the perceived necessity, injunctive social norms and descriptive social norms were major determinants of the acceptance and adoption of a national DCT tool during the course of the COVID-19 pandemic. On the other hand, concerns about personal data collected by TraceTogether and liberal individualism were barriers to its adoption. Policy measures to increase the uptake of the tool bridged the digital divide and accelerated its adoption. However, good public communications are crucial to address the barriers to acceptance to improve voluntary uptake and widespread adoption.


Ultrahigh molecular weight polyethylene (UHMWPE) materials have been prevalent joint replacement materials for more than 45 years because of their excellent biocompatibility and wear resistance. In this study, functionalized activated nanocarbon (FANC) was prepared by grafting maleic anhydride polyethylene onto acid-treated activated nanocarbon. A novel porous UHMWPE composite was prepared by incorporating the appropriate amount of FANC and pore-forming agents during the hot-pressing process for medical UHMWPE powder. The experimental results showed that the best prepared porous UHMWPE/FANC exhibited appropriate tensile strength, porosity, and excellent hydrophilicity, with a contact angle of 65.9°. In vitro experiments showed that the porous UHMWPE/FANC had excellent biocompatibility, which is due to its porous structure and hydrophilicity caused by FANC. This study demonstrates the potential viability for our porous UHMWPE/FANC to be used as cartilage replacement material for biomedical applications. Artificial joints are used to replace the malfunctioning bones, enabling thousands of people to enjoy an active lifestyle ,2,3,4. TPorous UHMWPE simulating as closely as possible the porous articular cartilage is a promising composite polymer used for various implant materials, which can provide excellent bearing capacity for human joints. Various porous UHMWPE with appreciate porosity have been prepared by non-dense injection molding methods with higher efficiency, template-leaching methods, and non-foaming leaching techniques ,20,21,22Unfortunately, due to the appearance of holes, the integrity of UHMWPE is destroyed, which affects its hydrophilicity and mechanical properties. Therefore, some investigations found that hydroxyapatite ,24, grapThe main purpose of this study is to fabricate porous UHMWPE materials with excellent hydrophilicity and mechanical properties, NaCl is used as pore-forming agent to endow UHMWPE material with a porous structure, and FANC is used as the reinforcing agent to improve the hydrophilicity and mechanical properties of UHMWPE. Porous UHMWPE/FANC composites were prepared by incorporating the appropriate amount of FANC and pore-forming agents during the hot-pressing process of medical UHMWPE powder. The porosity, morphological, tensile properties, hydrophilicity, and biocompatibility of porous UHMWPE/FANC in vitro were evaluated.6 was purchased from the Shenzhen Teli New material Technology Co., Ltd. from Shenzhen, China. ANCs with a specific surface area of 500 m2/g were supplied by Jiangsu Enkai Equipment Co., Ltd. from Taizhou, China. PE-g-MAH with a grafting rate of 0.5 wt.% was purchased from the Coace Chmesitry Co., Ltd. from Fujian, China. Mouse embryonic fibroblast cells (3T3 cells), fetal bovine serum (FBS), Dulbecco’s modified Eagle’s medium , and 3--2, 5-diphenyl-2-H-tetrazolium bromide (MTT) purchased from Aladdin reagent website were produced by GIBCO, from New York, NY, USA.The medical UHMWPE powder with a molecular weight of 5.0 × 10x were reported in our previous investigations [x denotes the weight ratio of PE-g-MAH to ATANC used in the preparation processes of FANCx particles, and the values of x were 5, 10, 12.5, 15, and 20. It can be seen from the Fourier-transform infrared spectroscopy (FT-IR) and the morphology on the surfaces by transmission electron microscope (TEM)  results that the prepared FANCx exhibited excellent structure when x = 12.5. Therefore, only FANC12.5 was used in the preparation of UHMWPE/FANCx in subsequent studies.Detailed experimental procedures for preparation of FANCigations ,30,31. T12.5 and medical UHMWPE powder were dispersed and dissolved in decalin at 135 °C for 90 min, in which 0.1% BHT was added as an antioxidant. The gel was ground to particle sizes fine enough to pass through a 100-mesh shaker by ball-milling after cooling to room temperature. The powder was poured into n-hexane under stirring conditions. A top liquid layer and a solid bottom layer were obtained after filtration. The solid layer was washed with acetone 3 times, and then dried at 65 °C for 8 h to remove the remaining acetone solvent.Varying amounts of FANC12.5 specimens were successfully prepared after being cleaned 3 to 4 times, and dried in a constant temperature incubator at 37 °C.NaCl particles were ground fine enough to pass through a 100-mesh shaker. Varying amounts of NaCl particles together with modified UHMWPE were fully mixed and pressed in a model with a ZG-50 precision automatic tablet press . After being pressed for 10 min at 10 MPa and 25 °C, the temperature was gradually raised to 180 °C; then, the pressure and temperature were maintained for 20 min. The specimens were cooled in a drying box for 10 min after the pressure was removed, then fully immersed in distilled water for 96 h, with the water replaced by fresh distilled water every 12 h in order to dissolve and removed NaCl particles as much as possible. The porous UHMWPE/FANCx were reported in our previous investigations [Detailed experimental procedures for FT-IR spectroscopic measurements and the morphology on the surfaces by TEM of FANCigations ,30,31.12.5 specimens. Prior to analysis, all samples were degassed in ultrahigh purity nitrogen for 30 min at 90 °C, and then for 90 min at 200 °C. The porous texture of the UHMWPE/FANC12.5 specimens was determined with a 5-point Brunauer–Emmett–Teller (BET) measurement with ultrahigh purity nitrogen as the adsorbate and liquid nitrogen as the cryogen at −197 °C [12.5 sheet surface and tensile fractured surface, a TECNAI G20 scanning electron microscope  was used.A 3H-2000PM1 analyzer  was used to evaluate the porous texture of the UHMWPE/FANC −197 °C . In orde12.5 specimens, which were made into dog-bone splines of 8 mm × 4.4 mm × 1.4 mm, were measured using a tension testing machine . Five samples of each specimen were measured and averaged during the tensile strength measurements. Subsequently, the stress orientations of the fractured surface were analyzed.The tensile properties of the porous UHMWPE/FANCCA was measured at five different positions on the surface of the sample, and the average value was used as the reported result [Static water contact angles (CAs) on the sample surface were measured using an automatic contact angle measuring instrument . Samples of 8 μL of deionized water were used for measurements. The d result .12.5 specimens with areas of 1 cm2 were placed into each well of a 24-well plate. All specimens were washed 3 times with sterile PBS and were exposed to ultraviolet sterilization for 3–4 h, and then cultured in medium overnight. The 3T3 cells were widely used in the cell activity experiments of porous materials due to their strong contact inhibition and they can clearly identify transformed cells [5 cells per well for 1, 3 and 5 days in a 5% CO2 incubator at 37 °C. The culture media were replaced with fresh media every 2 days. After treatment, MTT solution (0.5 mL) was added to each well and cultured at 37 °C for 3–4 h. A sample of 1 mL of dimethyl sulfoxide was dropped into each well to dissolve intracellular formazan. Absorption was recorded using a micro plate reader at 570 nm [mOD and rOD is the optical density of the treated and untreated cells, respectively. Thin slices with 2 mm thickness of porous UHMWPE/FANC12.5 and porous UHMWPE were taken for cell viability test.Cell viability (CV) was tested by colorimetric assays using MTT. The porous UHMWPE/FANCed cells ,35,36. Tt 570 nm . Cell vi12.5 specimens, cells were washed with warm PBS to remove non-adherent cells and fixed with 4% paraformaldehyde. After the cells were fixed, live cells were stained with acridine orange and were observed under a fluorescent microscope .After 1, 3 and 5 days of culture on the porous UHMWPE/FANCx, and PE-g-MAH specimens. Excepting the similar characteristic peaks, three new peaks present at 1268, 2852, and 2923 cm−1, respectively, which indicates the successful graft of the ATANC and PE-g-MAH  was most likely due to the over-dosage of PE-g-MAH during the functionalization processes of FANCx specimens [-MAH see . The reapecimens ,31.x specimens. After being modified by PE-g-MAH, some translucent resins were found attached to the surfaces of ANC particles, wherein the content of attached translucent resins increased gradually as the values of x increased  values of porous UHMWPE/FANC12.5 specimens with varying weight contents of FANC12.5 as the addition of NaCl particles increased from 40% to 70% are depicted in The porosity , which may cause NaCl particles to be wrapped up; thus, more NaCl particles cannot be filtered out by distilled water, resulting in a decrease in porosity [vP of the porous UHMWPE/FANC12.5 specimens were all above 30% when the addition of NaCl particles exceeded 60% and could reach 38.4% as FANC12.5 and NaCl particles were added at 3% and 60%, respectively.The porosity ,38. The fδ) values of porous UHMWPE/FANC12.5 specimens with varying weight contents of FANC12.5 and NaCl particles. As expected, fδ values of the porous UHMWPE/FANC12.5 specimens decreased gradually with the same contents of FANC12.5 as the addition of NaCl particles increased from 40% to 70%. The decrease was attributed to the increase in porosity caused by the increased addition of NaCl particles [12.5 with 1% FANC12.5 and 40% NaCl were 21.02 MPa, 17.1 MPa and 15.2 MPa, respectively. It is shown that tensile strength of UHMWPE/FANC12.5 depends on the additional amount of FANC12.5 and the porosity of UHMWPE/FANC12.5 [12.5 was relatively low, e.g., 1%, the decrease in tensile strength of UMWPE/FANC12.5 was mainly due to the decrease in the orientation degree of the UHMWPE molecular chain caused by FANC12.5. At the same time, the increase in tensile strength of UHMWPE/FANC12.5 caused by the rigidity of FANC12.5 molecular chain can be ignored due to the small amount of FANC12.5. When the added amount of FANC12.5 increased from 2% to 4%, the tensile strength of UHMWPE/FANC12.5 increased from 16.3 MPa to 18.2 MPa. The reason for this is that the increase in tensile strength of UHMWPE/FANC12.5 caused by the rigidity of the molecular chain of FANC12.5 exceeded the decrease caused by the decrease in the orientation degree of the UHMWPE molecular chain. Therefore, at the same porosity, the tensile strength of UHMWPE/FANC12.5 decreased first and then increased with the gradual increase in the content of FANC12.5.articles ,40. TensFANC12.5 ,19,20,2112.5 specimens prepared with 3% FANC12.5 and 60% NaCl were determined to be more suitable for cartilaginous materials for subsequent research.Considering the important effect of porosity on properties, porous UHMWPE/FANC12.5 specimens with the 60% addition of NaCl particles and 0% and 3% weight contents of FANC12.5 are depicted in 12.5 and the 60% addition of NaCl particles  and photographs of water droplets on the different specimen surfaces are depicted in 12.5 prepared by incorporating 1% FANC12.5 and 40% NaCl, the contact angle decreased sharply to approximately 65.9°. Wenzel’s wetting equation is as follows:θw and θy are the apparent and intrinsic contact angle, respectively, and r is the ratio of the real surface area to the projected surface area and definitely greater than 1. Considering this information and the monotonous decrease in cosθ against θ from 0° to 180°, we can say that the rough surface structure makes the hydrophilic (θy < 90°) surface even more hydrophilic (θw < θy). Therefore, the hydrophilicity of porous UHMWPE/FANC12.5 was improved by hydrophilic groups on the surface of FANC12.5, such as -OH, C=O [Pure UHMWPE is hydrophobic due to its non-polar carbon chain, exhibiting a contact angle of 87.1°. For the porous UHMWPE/FANC-OH, C=O .12.5 specimens with appropriate mechanical strength are expected to be used as replacement cartilage material in biomedical applications. Therefore, cytotoxicity of the porous UHMWPE/FANC12.5 specimens is an essential criterion to assess before offering them as cartilage replacement materials. Using the proliferation of 3T3 cells on the surface of porous UHMWPE/FANC12.5 specimens, the cytotoxicity was studied by MTT assays. Viability values of the studied cells on porous UHMWPE/FANC12.5 specimens are shown in 12.5 specimens. Interestingly, viability of the cells on the porous UHMWPE/FANC12.5 was greater than that of porous UHMWPE without modification by FANC12.5, clearly indicating that porous UHMWPE/FANC12.5 is more naturally biocompatible than porous UHMWPE without modification by FANC12.5.Porous UHMWPE/FANC12.5 and porous UHMWPE specimens are shown in 12.5 and porous UHMWPE gradually became greater with prolonged incubation times . FANCx was prepared by grafting PE-g-MAH onto the ATANC surface. The optimal mass ratio  of PE-g-MAH to ATANC was determined to be 12.5:1 through FT-IR and SEM analysis. A novel, porous UHMWPE composition was successfully prepared by incorporating suitable contents of FANCx and pore-forming agent during the hot-pressing process of medical UHMWPE powder. The tensile properties of the porous UHMWPE were significantly improved due to the appropriate addition of FANC12.5. A large number of pores with different sizes were distributed irregularly on the surface and inside the porous UHMWPE/FANC12.5 specimens. The best tensile strength and porosity value for the porous UHMWPE/FANC12.5 specimens with a 3% content of FANC12.5 and the 60% addition of NaCl particles reached 14.3 MPa and 38.4%, respectively. The prepared porous UHMWPE/FANC12.5 exhibited excellent hydrophilicity, with a CA of 65.9°. The excellent biocompatibility of porous UHMWPE/FANC12.5 is due to its porous structure and hydrophilicity, caused by activated nanocarbon. Porous UHMWPE/FANC12.5 specimens with sufficient mechanical strength and hydrophilicity are promising materials to be used as cartilage replacement material for biomedical applications.ATANC was prepared using activated nanocarbons (ANCs) etched with H