Odontoid process fracture accounts for 5% to 15% of all cervical spine injuries, and the rate is higher among elderly people. The anterior cannulated screw fixation has been widely used in odontoid process fracture, but the fixation strength may still be limited under some circumstances. This study aims to investigate the biomechanical fixation strength of expansive double-threaded bi-directional compression screw (EDBCS) compared with cannulated lag screw (CLS) and improved Herbert screw (IHS) for fixation of type II odontoid process fracture.Thirty fresh cadaveric C2 vertebrae specimens were harvested and randomly divided into groups A, B, and C. A type II fracture model was simulated by osteotomy. Then the specimens of the 3 groups were stabilized with a single CLS, IHS, or EDBCS, respectively. Each specimen was tested in torsion from 0° to 1.25° for 75 s in each of 5 cycles clockwise and 5 cycles anticlockwise. Shear and tensile forces were applied at the anterior-to-posterior and proximal-to-distal directions, respectively, both to a maximum load of 45 N and at a speed of 1 mm/min.P < .05 and P < .05). The mean shear stiffness for the EDBCS was 238 N/mm, which was significantly greater than CLS (150 N/mm) and IHS (132 N/mm) (P < .05 and P < .05). All 3 screws only partly restored tensile stiffness, but not significantly.The mean torsional stiffness was 0.309 N m/deg for IHS and 0.389 N m/deg for EDBCS, which were significantly greater compared with CLS, respectively (0.169 N m/deg) (Fixation with the EDBCS can improve the biomechanical strength for odontoid process fracture compared with CLS and IHS, especially in terms of torsional and shear stiffness. Moreover, type II odontoid process fracture can hardly healing spontaneously, and its union rate is lower compared with types I and III fractures.–6 Nonoperative treatment with a rigid brace can facilitate fracture healing, but the mortality rate among elderly patients is 26% to 47%. Such high mortality rates are probably caused by respiratory-related complications due to long-term external immobilization. The union rates were 92.8% to 100% among patients undergoing traditional posterior C1–C2 arthrodesis.,9 A major untoward consequence of this technique is the decreased cervical motion: movement at C1–C2 accounts for more than 50% of all cervical spine rotatory motion and about 10% of all cervical spine flexion–extension.Odontoid process fracture accounts for 5% to 15% of all cervical spine injuries, and the rate is higher among elderly people. This technique provides immediate stabilization with minimal external support postoperatively,,6,12–15 and allows for good anatomical and functional restoration, with high union rates (90–100%).,14,16–22 Many types of screws have been used to treat type II odontoid process fracture, including Herbert screws,,23,24 Knoeringer double-threaded screws, cortical,20 or cancellous bone screws,,23 fully,,20 partially,20,22 threaded or lag screws,,20,21,23 cannulated screws,–16 and self-tapping,17,18 or nonself-tapping screws.,20,21 They are made of stainless steel or titanium,17,21 with diameter of 2.7, 3.0, 3.5,,18,20,23 4.0,,16 or 4.5 mm.,19,22–24 These screws may have different biomechanical properties, but fixation with a single cannulated lag screw (CLS) is accepted generally.,16,26–28 However, the usage of these screws is still limited by the weak fixation strength under some circumstances. The odontoid process also may rotate if the fixation screw is loose or cuts out of the C2 vertebrae body.Direct anterior screw fixation has been used to stabilize type II odontoid process fracture since early 1980s.–31 In addition, BMD is not uniformly distributed in the axis: the density is higher at the tip of the odontoid but lower in the neck of the axis, and the cortical bone density is high in the anteroinferior region of C2. Screw loosening, cut-out, displacement, and other incidents commonly occur in elderly patients because of the presence of osteoporosis and the weak holding ability of screws to the bone.Bone mineral density (BMD) as 1 major quantitative parameter of bone quality can affect the screw's stability.,24,28,34 The EDBCS combines the features of expansive pedicle screw, expansive cannulated screw, and CLS. The principal purpose of this study is to compare the mechanical torsional, shear and tensile stiffness of the EDBCS with those of the conventional screws including CLS and IHS, and to evaluate the mechanical properties for fixation of type II odontoid process fractures.To solve these problems, we designed an expansive double-threaded bi-directional compression screw (EDBCS) based on the IHS.22.1The double-threaded, cannulated, self-tapping, and self-drilling Herbert screw was made of Ti6Al4V. We improved its thread design by introducing varying diameters and pitches at different sections. The thread pitches at the proximal end are twice finer than at the distal end Fig. A. This tThe EDBCS consists of 2 titanium alloy components: a cannulated screw and a gauge screw. The gauge screw can be inserted into the cannulated screw to open the fins on both ends Fig. A. The pi2.2This study and the consent procedure were approved by the Institutional Review Broad of Fourth Military Medical University, Xi’an, Shaanxi Province, China. We did not conduct our research outside our country of residence and obtained written informed consent from all participants’ relatives involved in our study.,37Thirty fresh human cadaveric C2 specimens aged 48 to 78 (mean 67) years old were used in this study. They were all males and of Chinese origin. After dissection of all soft tissues and cartilage, anteroposterior and lateral view radiographs were obtained to rule out the possibility of abnormalities or fractures. Then the specimens were double-bagged, stored in a freezer at −20°C until 24 h before testing, and then thawed at room temperature.2.3BMD was scanned at 3 levels for each specimen: on the top, base of the odontoid, and on the anteroinferior part of the axis using a dual energy X-ray absorption meter . The mean BMD of the 3 levels was regarded as the BMD of the axis.2.4,37The C2 specimens were divided randomly into 3 groups . The mean ages of the donors and the BMD of the specimens were not different between the 3 groups. The specimens of groups A, B, and C were fixed with CLS, IHS, and EDBCS, respectively. The odontoid process was placed inside a metal ring with 4 threaded positioning rods and thereby rigidly affixed to the testing machine. Each rod had a sharp tip for securely fixation of the odontoid process. The C2 vertebrae were fixed using a similar but larger metal ring  858 . Each specimen was rotated from 0° to 1.25° in 75 s in each of 5 cycles clockwise and 5 cycles anticlockwise. There was a break of 1 min between every 2 cycles.,28,42,43 The shear stiffness was calculated from the slope of the “force versus displacement” curve, and then the values of all cycles were averaged . The results were expressed as mean ± standard deviation. The effects of BMD on stiffness were assessed using Pearson correlation. The results of stiffness among groups before fixation were compared using analysis of variance (ANOVA). The effects of fixation with screws on torsional stiffness, shear stiffness, and tensile stiffness within a group were evaluated using paired 3The diameters of the expandable parts of EDBCS in group C were measured by radiographs. The diameter ranged from 4.54 to 4.86 (mean 4.75) mm at the distal end and from 5.20 to 5.38 (mean 5.24) mm at the proximal end. The diameters of the distal and proximal ends of the EDBCS before expansion were 4.0 and 4.5 mm, respectively.The mean stiffness of the intact and instrumented specimens of each group was calculated from the slopes of the “torque/force versus angle/displacement” curves Fig. . Torsion2 and were not significantly different among groups  (Table P > .05) (Table P < .05). The results of shear stiffness were significantly different between groups A and C, and between groups B and C (P < .05). The results of tensile stiffness were not significantly different between groups (Table The BMDs of the specimens ranged from 0.533 to 0.792 (0.667 ± 0.084) g/cm4,38 As the primary control group, we used CLS with diameter of 4.0 mm, which is also used in our hospital. We also chose IHS as another control group because its fixation strength was well proven.,24,28 Herbert screw was also widely used for fixation of scaphoid bone fracture,,49 it was improved and had been applied to odontoid process fracture with high stability.,24,28,34 However, the fixation strength was weak,50 and the stiffness restoration ratio was <50% intact specimens.The use of anterior CLS in odontoid process fracture fixation has been well accepted. Morphologic studies suggest that the diametric dimensions of the odontoid in most patients are insufficient to accommodate only 1 but not 2 screws with diameter ≥3.5 mm.,30 Patients with pseudarthrosis experienced loss of fixation more frequently in the C2 body than in the odontoid.,16 Biomechanical studies confirmed these results.,52 This failure mode is consistent with the osseous structure of the C2 body, which has lower cortical thickness and lower bone density.–55 Thus, research focused on improving bony purchase within the C2 body.,52,54–56 A hybrid locking plate/variable pitch screw construct for anterior fixation of type II odontoid process fracture was used to strengthen the purchase within the C2 body. But this construct was much more complicated. In our study, IHS and EDBCS can improve the effective contact between the screw threads and the vertebra's cortical bone compared with CLS. We may infer that IHS and EDBCS can prevent the screw's proximal end from cutting out through the anteroinferior part of C2 body and decrease the pseudarthrosis rates.Despite the excellent results with CLS, pseudarthrosis rates were also up to 20%.–31 To account for possible variation in bone quality, we divided the specimens randomly into 3 groups with no difference in BMD. However, we found that BMD was not correlated with the odontoid stiffness either before or after screw fixation (P > .05).BMD could influence the screw's holding ability in the bone. and also the interaction between the screw threads and the axis’ cortical bone. The expandable ends of EDBCS may further contribute to higher torsional stiffness. In fact, the torsional stiffness of EDBCS was larger than IHS though not significantly. The shear stiffness was not significantly different between CLS and IHS, but the shear stiffness of EDBCS was greater than both CLS and IHS. Hence, our study demonstrates that the EDBCS provides higher fixation strength in terms of transverse shear compared with the widely used CLS and IHS.Fixation with IHS and EDBCS outperformed CLS in terms of torsional stiffness. The larger torsional stiffness may be attributed to the larger compressive force between the fracture fragments , Both measurement methods can be used to test the stability of type II odontoid facture. In our study, only tensile stiffness was measured. Load to failure was not used because the stiffness-provided initial stability was the major parameter before fracture healing. Furthermore, a nondestructive low load test allowed us to complete all mechanical tests on each specimen. The selected load was about half of the physiologic load and was enough to obtain the torque-angle and load-linear displacement curves.,28 All 3 types of fixation methods, CLS, IHS, and EDBCS, provided slightly greater tensile stiffness than the intact specimens, although the results were not significant (P > .05). Even the EDBCS did not provide greater compression force to the fracture fragments.The compression generated between the 2 fracture fragments after insertion of screws contributes to bone healing. The compression can be evaluated with tensile stiffness or load to failure.One limitation of the present study was that to establish a reproducible fracture model, an osteotomy with a thin oscillation saw at the junction of the odontoid process and the vertebra was performed to simulate a type II fracture pattern. However, such a smooth horizontal fracture line may not occur in patients.5In summary, we concluded that the use of an EDBCS can improve the biomechanical fixation strength for type II odontoid process fracture compared with CLS and IHS, especially in terms of torsional and shear stiffness. However, the experimental data may not be applicable to clinical outcomes and thus should be confirmed via prospective clinical studies in vivo.The authors thank the State Key Laboratory for Strength and Vibration of Mechanical Structures, School of Mechanical Engineering, Xi’an Jiao Tong University for research and institutional support.


The Brazilian Journal of Cardiovascular Surgery (BJCVS) is grateful for the reviewers,listed below, which collaborated in this edition. Without their work would be impossibleto keep the high scientific standard of our journal.Carla TanamatiClaudio GelapeDiego GaiaEdmo GabrielJoão de Deus e BritoLeonardo MianaLuís DallanLuiz Felipe MoreiraMelchior LimaMichel Pompeu B. de O. SáPaulo Roberto EvoraRobison PoffoValquíria Campagnucci


The current issue of the International Journal of Telerehabilitation (IJT) contains original research, policy, and a country report (India). A letter to the editor cogently describes the challenges faced by occupational audiologists in the United States, due to the current absence of interstate professional license portability. There is no doubt that the lead article, “UserAuthentication in Mobile Phones and Its Application to Healthcare,” is highly relevant given the current security challenged environment.What do these articles have in common? They collectively describe the current status of telerehabilitation: successes, challenges, and future needs., Electronic Publications Associates at the University of Pittsburgh.In this season of giving thanks, we recognize that the IJT could not be produced without the generous efforts of others. We are grateful to new and returning reviewers; Sections Editor, William E. Janes, OTD, MSCI, OTR/L; colleagues at the Rehabilitation Engineering Research Center on Information and Communication Technology Access at the University of Pittsburgh; and, our publishers, Timothy S. Deliyannides, Director, Office of Scholarly Communication and Publishing, and Head, Information Technology, University Library System, and Vanessa Gabler and Michelle BradburyDid you know recent evidence suggests that expressing gratitude on a daily basis , can benefit physical and psychological health? Yet another reason to give a huge “tele-thanks” to all those who are advancing the status of telerehabilitation.The next volume of the International Journal of Telerehabilitation will be published in Spring, 2018. We cordially invite your 2018 submissions by mid-January 2018, and accept original research, case studies, viewpoints, technology reviews, book reviews, and country reports that detail the current status of telerehabilitation.Sincerely,Ellen R. Cohn, PhD, CCC-SLP, ASHA-FIJT EditorJana Cason, DHS, OTR/L, FAOTASenior Associate Editor


Age and number of recipients in need of kidney re-transplantation are increasing. Re-transplantation practices and outcomes in elderly recipients are not previously explored. We aimed to retrospectively evaluate the outcomes of recipients 65 years and older receiving their second deceased donor allograft.The study was designed as a retrospective registry based study. All recipients 65 years or older who received a deceased donor kidney transplant at Oslo University Hospital between 2000 and 2014 were included in the study. Survival outcomes were compared between recipients of first (TX1) and second (TX2) allograft. Survival analyses were performed using the Kaplan–Meier method and Cox proportional hazard models with patient survival, uncensored graft survival and death-censored graft survival as outcomes in the analyses.n = 687) or second (n = 46) deceased donor kidney transplant. Five years uncensored graft survival rates were 64% in TX 2 and 67% in TX 1 (P= 0.789). Estimated five years graft survival rates censored for death with functioning graft were 88% in TX2 and 90% in TX1 (P=0.475). Adjusted hazard ratio for uncensored graft loss (TX2 vs. TX1) was 1.24 (95% CI 0.77 – 2.00). Adjusted hazard ratio for graft loss censored for death with functioning graft (TX2 vs. TX1) was 1.70 (0.72-4.02).Seven hundred and thirty-tree recipients > 65 years received a first (Older recipients of second transplants have outcomes that are comparable to the outcomes of age-matched first transplant recipients, and far better than previously documented for older transplant candidates remaining on dialysis treatment. Advanced age by itself should not be a contraindication for re-transplantation. Best results are achieved with short time on dialysis before re-transplantation. Currently the majority of patients developing end-stage renal disease (ESRD) whom are eligible for kidney transplantation are between 45 and 65 years of age , 2. A kiDue to the relative scarcity of available deceased-donor kidneys, the waiting time is prolonged for most patients  and dataTo the best of our knowledge there is no evidence available to support or contradict the routine of offering a second renal allograft to elderly patients with graft-failure. We believe it is important to explore this issue both for clinical and policy reasons and consequently we designed this study to evaluate the survival outcomes of kidney re-transplantation in patients older than 65 years and compare them with age- and time-matched first kidney transplant recipients.st 2015.Data from all patients, older than 65 years at time of transplantation, who received their first or second deceased donor kidney transplant at our center between 2000 and 2014 were included in the study. Outcomes were compared between first (TX1) and second (TX2) transplants. Patient and transplant characteristics were reported prospectively to the Norwegian Renal Registry and these data were retrieved from the registry together with survival data. All patients who were included had previously given consent for the use of their clinical data in research. Last update of survival data was performed at September 1Patients accepted for TX1 or TX2 at our center have been screened using the same age-independent algorithm. The patient´s local nephrologist performs the screening and we have no need for mandatory dialysis treatment before the patient can be accepted for the transplantation wait list. Neither age at first transplant nor graft survival of first transplant influence the decision of listing patients for second transplantation. When allocating a deceased donor kidney, we strive to achieve some degree of age matching between the donor and the recipient. As a rule of thumb, we accept a maximal age difference of 20–30 years. We do not routinely perform graft nephrectomy prior to re-transplantation.Between 2000 and 2007, kidney transplant recipients at our center received a standard triple immunosuppressive regimen consisting of corticosteroids, Calcineurin inhibitor (CNI) with Cyclosprin A (CSA) as first choice, and either an IL2 receptor antagonist (IL2Rab) for induction therapy (2000) or mycophenolate mofetil (MMF) (2001–2007). From 2007 our standard protocol was changed to a quadruple regimen with IL2Rab induction, corticosteroids, CNI (tacrolimus or CSA) and MMF.P-value of less than 0.05 was considered as significant in all analyses. In the patient survival model, TX1 patients were censored from the analysis at time of second transplantation. Available variables with suspected association with the outcome were first tested in univariable Cox models. Variables with possible associations, defined as a P-value ≤ 0.2 in the univariable model, were then included in the final multivariable model. Recipient age and gender were implemented in all multivariable models regardless of the results in the univariable model. Except for three recipients with missing values for cold ischemic time (CIT), there were no missing values in the dataset for any of the variables included in the multivariable Cox models. CIT was excluded from the final model due to very low statistical significance in the preliminary univariable models. Accordingly, no patient was excluded from the final multivariable models because of missing values. All statistical analyses were performed using the statistical software package IBM SPSS 23®.Continuous data were analysed using an independent sample Mann–Whitney test to compare the groups. A two-sided Fisher’s exact test was used in analyses of binary data. Survival analyses were performed using the Kaplan–Meier method and Cox proportional hazard models with patient survival, uncensored graft survival and death-censored graft survival as outcomes in the analyses. A A total of 3812 kidney transplantations were performed from 2000 to 2014. Eight hundred and sixty-eight (23%) recipients were 65 years or older at time of first or second kidney transplant. Among these, 733 patients received a deceased donor kidney and were included in the final analyses. Median age was 70.9 years (range 65.0 - 82.9 years). One hundred and twenty-two patients (16.6%) received a pre-emptive transplantation, whereas 480 (65.5%) were on hemodialysis (HD) and 131 (17.9%) were on peritoneal dialysis (PD) at time of engraftment.Forty-six patients received their second and 687 patients received their first deceased donor kidney transplant. Eight patients included in the TX2 group received their first graft between 2000 and 2014 and were at that time older than 65. They were consequently included in both groups but censored from the patient survival model at time of second transplant. Median time between first and second transplantation was 7.7 years (range 0.0 – 41.4 years). One patient was re-transplanted because of primary non-function. If this patient is excluded, median time between first and second transplantation was 8.2 years (2.5-41.4 years). Patient and transplant characteristics in TX1 and TX2 are presented in Table P = 0.129). Among those with an ARE, only one out of five recipients in TX2 experienced the ARE within the first 90 days compared to 86 (61.4%) in TX1. Median time from transplantation to first ARE was 163 days (21–349) in TX2 compared to 58.5 days (3–1951) in TX1, but the difference was not statistically significant (P = 0.190).Only five recipients (11%) in the TX2 group experienced a biopsy verified acute rejection episode (ARE) compared to 140 (20.4%) in the TX1 group. The difference was however not statistically significant (During follow-up there were 20 (43%) graft losses in TX2 and 327 (48%) in TX1. Death with functioning graft was the predominant cause of graft loss in both groups being responsible for 14 (70%) graft losses in TX2 and 257 (79%) in TX1. Rejection was the cause of graft loss in two patients (10%) in TX2 and 31 patients (9.5%) in TX 1. All other causes were accounted for and because of low numbers comparisons between groups are of limited value and were not performed.P = 0.815). Estimated five-year patient survival was 68% and 69% in TX2 and TX1 respectively . Estimated five year uncensored graft survival rates were 64% in TX2 and 67% in TX1 . Estimated five years graft survival rates censored for death with functioning graft were 88% in TX2 and 90% in TX1  years in TX2, and 7.6 7.1-8.1) years in TX1 (Log Rank -8.1 year years inN = 46) by the following variables: age, time on dialysis, donor age > 60 years and reported prevalence of coronary heart disease, cerebrovascular disease, peripheral vascular disease and diabetes. Matching was performed using the “case control matching” syntax in the SPSS software. We managed to find only 42 case control pairs due to the matching variables we selected. The remaining four TX2 patients were however included in the analysis as they were all having more comorbidities than the rest and consequently did not contribute to any further selection bias in favor of the TX2 group. These analyses are presented in Table In order to adjust for selection bias caused by differences between TX1 and TX2 in age, donor age, time on dialysis and comorbidities, a case control dataset consisting of 42 TX1 patients matched with the whole TX2 group N = 4 by the fHazard ratio (HR) for uncensored graft loss (TX2 vs. TX1) adjusted for recipient age, recipient gender, cause of ESRD, donor age, donor source, time on dialysis, dialysis modality, prevalence of diabetes mellitus, peripheral vascular disease and HLA matching was 1.24  0.77-2.00). The unadjusted and adjusted Cox models for uncensored graft survival are presented in Table P = 0.012) and time on dialysis  were significantly associated with inferior uncensored graft survival. For induction treatment there was a trend towards an association with improved uncensored graft survival .In a separate uncensored graft loss Cox model analyzing only TX2; age, gender, time on dialysis, donor age and induction treatment were included in the multivariable model based on the results of the univariable analyses. In this model, only recipient age . In spite of this, in the multivariable Cox models we did not find any statistically significant increased risk of graft loss in recipients of second grafts. The number of recipients in the TX 2 group was however small, and consequently the results must be interpreted with caution. This is especially true for the death censored graft loss model in which we found a statistical non-significant increased risk for graft loss of 70% in TX2 compared with TX1. This increased risk is definitely of clinical significance, and it is likely that with a larger sample size, it would reach statistical significance as well. It is therefore very likely that the lower graft survival of second grafts previously described in adult recipients , 12 and Kidney re-transplantation has historically, regardless of recipient age, been associated with a poor prognosis but still provides the best chance for long-term survival and quality of life in patients facing allograft loss, as compared to maintenance dialysis therapy , 17–19. P = 0.062), protective variable. In concordance with this, our results show that with appropriate immunosuppression, graft and patient survival is good even in patients older than 65 years who receive their second transplant.Both DGF and acute rejection episodes are known to be independent predictors of graft survival –24. An iThe main reason for graft loss in both groups was death with functioning graft. Graft loss due to rejection was not different between TX2 and TX1, but it must be noted that the numbers are very low in the TX2 group making it difficult to draw any firm conclusions. We were not able to detect any statistically significant differences in ARE between the groups. The study was however clearly underpowered to investigate ARE and additional studies are needed.As always in observational studies there are several limitations. The main limitations are the small sample size, the retrospective design and the use of single centre data. Single-centre studies often end up including small numbers giving a low statistical power. Our centre has had a liberal policy regarding transplantation of the elderly . ConsequIt is quite obvious that patients enlisted for re-transplantation at age above 65 belong to a selected population. We do however use the same age-independent screening and acceptance criteria for both first and second transplants. Consequently, those patients who are accepted for listing are accepted because they are medically fit for transplantation. In spite of this, TX2 patients had significantly lower prevalence of coronary heart disease and diabetes mellitus, indicating that TX2 patients probably were “more selected” than TX1 patients. It is difficult to select a proper group for comparison analyses. One could argue that we should have compared our second transplant recipients with age-matched recipients with failing first grafts who were on dialysis. The analyses of the matched dataset in which TX1 and TX2 patients had comparable comorbidities, age and time on dialysis did however not reveal any increased survival difference between the groups.In a previous publication we found that 81% of dialysis patients older than 70 years who were accepted for their first kidney transplantation, eventually received a graft . ConsequOlder recipients of second transplants have outcomes that are comparable to the outcomes of age-matched first transplant recipients, and far better than previously documented for older transplant candidates remaining on dialysis treatment. Best results are achieved with short time on dialysis and consequently, the transplant work-up should be initiated as soon as possible, preferably before the patient becomes in need of dialysis.


Prescription opioid (PO) misuse is a major health concern across North America, and it is the primary cause of preventable death for the 18–35 year old demographic. Medication assisted therapy including methadone and buprenorphine, is the standard of care for patients with opioid-dependence. Moreover, both of these medications are recognized as essential medicines by World Health Organization. In Ontario Canada, the availability of medication assisted therapy has expanded substantially, with almost a ten-fold increase number of patients accessing methadone in Ontario in the past decade. In their manuscript, Fischer et. al. (2016), present a view that expansion of opioid maintenance therapy (OMT) has outpaced true patient need and alternate strategies should be considered as first-line treatments. Here, we present a countering perspective-that medication assisted therapy, along with other harm reduction strategies, should be widely available to all opioid-dependent people as first-line treatments. Prescription opioid (PO) misuse is a major health concern across North America. Fueled by liberal PO prescribing during the late 1990’s and 2000’s, Ontario is often cited as a region suffering from a public health crisis due to PO-dependence , 11, 14.The evidence to support the efficacy of medication assisted treatment  is well established for heroin-using patients , and dueRecently, the question has been raised, when is there too much medication assisted therapy? Fischer et. al., (2016) present a view that expansion of opioid maintenance therapy (OMT) has outpaced true patient need for treatment in the province of Ontario, Canada. Further, the authors imply that economic incentives surrounding delivery of methadone have ‘unduly influenced the expansion of OMT in Ontario’. Finally, the authors argue towards a continuum-of-care which focuses on alternatives to maintenance therapy citing taper, detox and abstinence-based approaches as alternatives for a subset of prescription-opioid dependent patients. Here, we argue against the position that OMT capacity has expanded beyond need; and we believe that significant need still exists, especially in Northern and rural regions of the province , 13.For the majority of opioid-dependent patients, the evidence overwhelmingly supports OMT , 6, 16, As suggested by Fisher et al., 2016), alternate approaches including tapering, counselling and psychosocial interventions may also have benefit; but again the evidence suggest that on their own, these treatment strategies are not as effective as OMT 6, altern, 21. OthQuantifying the absolute need of OMT is challenging. However, reliable surrogates such as overdose-related deaths, overdose-related hospitalizations, and generalized opioid prescribing are all reasonable markers which support the burden and need for opioid-dependence treatment. Across North America there is an acknowledged need to expand methadone (and/or buprenorphine) programming . Fisher In an earlier paper calling for expansion of MMT in Ontario, Fischer and colleagues used European countries and Australia, rather than the US, as a standard that would set the target for treatment availability in Ontario; a goal which is at least two-fold higher than the US comparison in the current paper . Fisher Several factors limit our collective ability to expand methadone programming due to the resource intensive nature of observed dosing treatment. Perhaps the largest barrier to expansion is the availability of methadone trained addiction specialists. Recent advances in telemedicine have disrupted the most cumbersome barrier to expansion by allowing a given physician to service a number of specialized clinics in a broad geographic area both urban and rural via telemedicine; and Ontario is at the forefront of telemedicine-delivered OMT. We believe this a trend that will be adopted by other provinces and countries in the near future.In the face of continued increases in opioid overdose deaths and other negative consequences of untreated opioid-dependence, OMT is still expanding in Ontario (and Canada); yet, there are still long wait lists and patients having to travel over 100 km to the nearest clinic in rural regions of the province . Like moWe support the Fisher et. al., (2016) recommendation that there is a need for more high quality epidemiological surveillance data to quantify and inform resource allocation towards treatment of opioid-dependence. However, we strongly oppose the implication that OMT programming is sufficiently serviced in the province of Ontario, especially in northern and rural regions. Moreover, the absence of robust data, which Fisher et. al., (2016) assert is lacking for other treatment options, is not a reason to reduce the availability of our most effective treatment at a time when people are dying from a public health crisis. It is our opinion that more resources should be allocated towards understanding and developing comprehensive care models which improve the overall health outcomes of this complex patient population - including expanded opioid maintenance treatment programming, especially in rural and remote regions of the country.


However, 1-year graft  and patient  survival and overall patient  survival were favorable. There is evidence of recipient and donor obesity disadvantage early, but survival curves demonstrate improved long-term outcomes. It is important to consider obesity in the donor-recipient match.There is a paucity of literature examining recipient-donor obesity matching on liver transplantation outcomes. The United Network for Organ Sharing database was queried for first-time recipients of liver transplant whose age was ≥18 between January 2003 and September 2013. Outcomes including patient and graft survival at 30 days, 1 year, and 5 years and overall, liver retransplantation, and length of stay were compared between nonobese recipients receiving a graft from nonobese donors and obese recipient-obese donor, obese recipient-nonobese donor, and nonobese recipient-obese donor pairs. 51,556 LT recipients were identified, including 34,217 (66%) nonobese and 17,339 (34%) obese recipients. The proportions of patients receiving an allograft from an obese donor were 24% and 29%, respectively, among nonobese and obese recipients. Graft loss (HR: 1.27; 95% CI: 1.09–1.46;  Currently, the two most common indications for liver transplant (LT) are alcohol and hepatitis C virus (HCV) related cirrhosis . NonalcoResearch investigating the influence of recipient obesity on LT outcomes is controversial with conflicting results. Some studies report increased mortality –8 and deAn important variable that has not been well studied in LT is the impact of donor obesity on posttransplant clinical outcomes. In pediatric LT recipients Perito et al. reported that children receiving adult donor livers with BMI > 35 had increased risk of graft loss and death. Pediatric recipients receiving a liver from an overweight or obese pediatric donor did not have an increase in graft loss or mortality . Yoo et The study was approved by the Institutional Review Board at Nationwide Children's Hospital with a waiver of individual consent (IRB14-00716). The United Network for Organ Sharing (UNOS) database was queried for first-time LT recipients who were ≥18 years of age transplanted between January 2003 and September 2013. Transplants from donation after cardiac death, split-livers, living donors, and combined transplants of liver with other organs were excluded. Transplants for acute liver failure were also excluded. We categorized the BMI of donors and recipients into nonobese (BMI < 30) and obese (BMI ≥ 30). Recipient BMI was collected at the time of transplantation. Outcomes of nonobese and obese recipients who received LTs from nonobese and obese donors were compared. Recipient-donor combinations included nonobese recipients (NOR) receiving grafts from nonobese donors (NOD), obese recipient-obese donor (OR-OD), obese recipient-nonobese donor (OR-NOD), and nonobese recipient-obese donor (NOR-OD). Nonobese recipients (NOR) receiving grafts from nonobese donors (NOD) were the reference group.There were 51,556 patients eligible to be included in the study with data on both recipient and donor BMI. The primary outcome was overall patient survival. Secondary outcomes were 30-day, 1-year, and 5-year patient and graft survival and re-LT and length of hospital stay during index admission for LT. Arbitrarily short survival duration was assigned to patients or grafts surviving < 1 day. We also included donor macrovesicular steatosis, as a covariate previously described  in a supplemental model . Based oUnivariate survival analysis excluded 99 patients with unknown survival duration and multivariable analysis excluded 10,979 patients missing data on recipient, donor, or LT procedure characteristics. Multivariable subanalyses of conditional patient survival  excluded 1,251 and 4,458 additional cases, respectively; multivariable subanalyses of conditional graft survival to 1 and 5 years excluded 1,922 and 5,682 additional cases, respectively; and multivariable analyses of length of hospital stay after LT and re-LT excluded 647 and 1,077 additional cases missing data on these respective outcomes.Statistical analysis was performed using Stata/IC, version 13.0 . Descriptive statistics were presented as means and standard deviations for continuous variables; and descriptive statistics for categorical variables were presented as counts and percentages. Cochran-Armitage tests for trends were used to describe the changing proportions of recipient-donor BMI combinations in LT performed over the study period. Comparisons among groups classified by recipient and donor obesity were performed using Chi-square tests for categorical variables and ANOVA for continuous variables. Kaplan-Meier curves and log-rank tests of survival functions were used to compare post-LT mortality and graft survival at 30 days, 1 year, and 5 years across four groups of patients defined by recipient and donor obesity. Recipient-donor obesity match was entered into a multivariable Cox proportional hazards model of overall patient survival adjusted for recipient, donor, and transplant characteristics to further examine differences in survival across recipient and donor obesity status. Due to a very high proportion of missing data, donor macrovesicular steatosis was added as a covariate in a supplemental model but was not included in the main analysis . The mulp < 0.001) or NOR and OD (p < 0.001) and a significant decrease in the proportion of LT involving NOR and NOD (p < 0.001) over the study period. The trend in the proportion of LT involving OR and NOD was not statistically significant (p = 0.25)  .p < 0.001)  status, portal vein thrombosis (PVT) at transplantation, and Model for End-Stage Liver Disease (MELD) score at the time of LT among the four categories of recipient-donor obesity matching. Similarly, donor age, gender, race, BMI, DM status, cold ischemia time (CIT), serum creatinine, and bilirubin were also significantly different among the four pairs. Obese recipients (OR) were more likely than nonobese recipients (NOR) to be white, to be male, to have a plausible diagnosis of NASH, and to have a history of DM. Obese donors (OD) were more likely to have a history of DM and hypertension and were older compared to NOD. Notably, the pair OR-NOD had the highest mean MELD score at LT  .p = 0.04). Neither recipient nor donor obesity was associated with the likelihood of re-LT (p = 0.18) (Obese recipients (OR) had a higher mortality at 30 days (4%) compared to NOR (3%). However, 1-year (8% versus 9%), 5-year (10% versus 11%), and overall mortality (23% versus 25%) after LT was slightly less common among OR than in the modal group of NOR-NOD. Recipients with NOD tended to have longer length of hospital stay after LT ( = 0.18) .p = 0.05). Kaplan-Meier 30-day, 1-year, and 5-year patient survival curves stratified by the combination of recipient and donor obesity are shown in p < 0.001). The survival functions of OR and NOR cross over at the 3-month mark, with no statistically significant differences in survival between 30 days and 1 year after LT (log-rank test: p = 0.08). Long-term (5-year) survival, conditional on survival to 1 year, demonstrated an emerging survival advantage of the OR groups, particularly OR-NOD (p = 0.004). A similar pattern was observed in Kaplan-Meier 30-day, 1-year, and 5-year graft survival curves stratified by recipient and donor obesity, as shown in p < 0.001), whereas 5-year graft survival favored the OR-NOD group (p = 0.01).A log-rank test indicated no statistically significant differences in overall patient survival among the four groups stratified by the combination of recipient and donor obesity status (p = 0.001) and 5 years  (p < 0.001) relative to NOR-NOD (p < 0.001). Including donor steatosis in this model of overall survival indicated that there were no statistically significant differences by donor-recipient obesity match, but donor steatosis in the 20–30% range  and in the >30% range  was associated with increased mortality relative to <15% donor macrovesicular steatosis. Further modification of this model found no statistically significant interaction of steatosis with either donor age or cold ischemia time, suggesting that the latter factors did not modify the influence of donor liver steatosis on recipient survival (data not shown).A multivariable Cox proportional hazards model of overall survival including recipient-donor obesity matching and potential confounding variables is presented in = 0.039)  and over NOR-NOD . Pairwisp < 0.001). Among the covariates described above, factors associated with increased risk of early mortality included PVT, older age, greater MELD score, and longer CIT. However, survival of the OR-OD group at 1 year  and overall survival  were favorable compared to NOR-NOD (p = 0.002), yet this difference was inverted by 1 year after LT, with OR-OD and OR-NOD having the lowest hazards of graft loss . At 5 years, conditional on 1 year of graft survival, no statistically significant differences remained in graft survival among groups defined by recipient and donor obesity . Repeating the survival analysis with an obesity threshold of 40 kg/m2 did not show any significant differences from the analysis reported here with obesity threshold of 30 kg/m2 (data not shown). Considering underweight recipients, there were 732 underweight patients (BMI < 18) of whom 130 (18%) had an obese donor. Multivariable Cox analysis of 556 underweight respondents with complete covariate data  (data not shown but available on request).Secondary outcomes of length of hospital stay and re-LT were analyzed using multivariable regression models . PredictIn this study we demonstrated the impact of matching pairs of recipient-donor obesity on clinical outcomes of liver transplantation. We noted an important trend in LT with an increase in NOR-OD and OR-OD pairs and decrease in NOR-NOD. This is consistent with other literatures suggesting that an increasing proportion of LT donors and recipients are obese . InteresResearch investigating the influence of recipient obesity on LT outcomes presents conflicting results with some demonstrating increased mortality and decreased graft survival in obese recipients and others demonstrating no difference in overall survival between obese and nonobese recipients –12. The Our study found evidence of obesity disadvantage very early after LT. This survival disadvantage later reverts to reduced risk of mortality around 3 months after LT with obese recipients emerging as having improved 1-year and overall survival. Similarly, there is an obesity disadvantage in terms of early graft loss among OR-OD in the 30 days following LT. This difference in graft loss reverts in OR-OD and OR-NOD by 1 year. Due to study design we cannot directly assess the cause of early obesity disadvantage, but we speculate that early disadvantage in patients receiving livers from OD could be due to the increased fat content in OD grafts resulting in primary graft nonfunction. Other investigators have demonstrated that there is increased fat content in grafts obtained from obese donors , 17. TheOur analysis demonstrates the lowest 1-year, 5-year, and overall mortality in the OR-NOD pair, relative to NOR-NOD. Several studies published this year reported equivalent survival among OR and NOR, without accounting for the obesity status of the donor. Using UNOS registry data from 2002 to 2013, Wong et al. reported that recipient obesity was not independently associated with worse outcomes for LT; however, presence of diabetes resulted in significantly lower survival . In a meObesity has been shown to be protective in patients in various clinical settings, including patients admitted to the intensive care unit (ICU) , 20, patp < 0.0001) [Our study found evidence of shorter length of stay in the OR-OD pair and OR-NOD pair. Predicted lengths of hospital stay were marginally shorter among OR-NOD or OD compared to the reference group of NOR-NOD. Singhal et al. report that patients with BMI > 40 have increased post-LT length of stay in comparison to patients with BMI < 40  . In a si 0.0001) . These aOur analysis found a reduced adjusted hazard of re-LT in the NOR-OD pair as compared to the reference pair. This was consistent with Yoo et al. who investigated LT outcomes related to donor obesity and donor liver steatosis and identified no differences in early re-LT outcomes associated with donor obesity and donor liver steatosis. However, their analysis did not include donor obesity as a covariate. Yoo et al. suggest, and we agree, that larger donor liver size may compensate in some respects for increased fatty infiltration in donor livers from OD , which iOur analysis has several limitations related to the nature of collection and reporting of data in the UNOS database, which could include data entry errors, missing data, and omission of important data. A substantial number of patients were excluded because of missing recipient/donor BMI and other variables. Due to the impact of ascites on weight, the reliability of recipient BMI measurement in liver transplant recipients may not be very accurate . ReportiIn conclusion, there is increasing trend of LT among NOR-OD and OR-OD pairs and decrease in NOR-NOD. We identified increased 30-day mortality and graft loss among OR-OD pairs; however, this relationship improved rather quickly and resulted in reduced mortality hazard at subsequent follow-up intervals of 1 year and 5 years and reduced graft loss at 1 year and equivalent graft loss at 5 years. Information on BMI based on outcomes may be helpful in selecting a donor for a specific recipient at the time of an organ offer. Holding consistent with obesity being protective, the match pair with the least hazard mortality was OR-NOD. Although we cannot determine causality of our findings due to study design, we have found intriguing donor-recipient interactions that may assist clinicians in important decisions with the need for further research to investigate the protective pathways associated with obesity in LT.


The aim of this study was to compare the expression of host-derived markers in peri-implant/gingival crevicular fluid (PCF/GCF) and clinical conditions at ceramic implants and contralateral natural teeth. As a secondary objective, we compared zirconia implants with titanium implants.n = 9).One zirconia implant (ZERAMEX® Implant System) and one contralateral natural tooth were examined in 36 systemically healthy subjects . The levels of Il-1β, Il-1RA, Il-6, Il-8, Il-17, b-FGF, G-CSF, GM-CSF, IFNɣ, MIP-1β, TNF-α, and VEGF were assessed in PCF/GCF using the Bio-Plex 200 Suspension Array System. The plaque index (PI), gingival index (GI), probing depth (PD), and bleeding on probing (BOP) were assessed at six sites around each implant or tooth. Titanium implants were also assessed when present (p = 0.003), while the mean GI, PD, and BOP were significantly higher (p < 0.001). A correlation was found in the expression of Il-1RA, Il-8, G-CSF, MIP-1β, and TNF-α at zirconia implants and teeth. The levels of IL-1β and TNF-α were significantly higher at zirconia implants than at teeth. No significant differences were found between zirconia and titanium implants. A correlation was found between the levels of IL-1RA, IL-8, GM-CSF, and MIP-1β at zirconia and titanium implants.The zirconia implants were examined after a loading period of at least 1.2 years (average 2.2 years). The mean PI was significantly lower at zirconia implants compared to teeth (The correlation in the expression of five biomarkers at zirconia implants and teeth, and of four biomarkers at zirconia and titanium implants, is compatible with the existence of a patient-specific inflammatory response pattern. Higher mean GI, PD, and BOP around implants suggests that the peri-implant mucosa may be mechanically more fragile than the gingiva.Similar expression of selected biomarkers at zirconia implants and teeth and at zirconia and titanium implants reflects existence of patient-specific inflammatory response patterns. So far, the available evidence for specific benefits of dental zirconia implants is however incomplete. The number of clinical studies is limited and their results are rather inhomogeneous [The prevalence of peri-implantitis at titanium implants is estimated in the order of 10 % implants and 20 % patients during 5 to 10 years after implant placement . To whatogeneous .Analysis of gingival crevice fluid (GCF) has been suggested as a way of evaluating host response in the periodontal tissues . It offeSince November 2009, we have treated a series of partially edentulous patients with a total of 76 two-piece zirconia implants supporting all-ceramic crowns. Treatment outcomes including 2-year cumulative survival rates were presented recently . In a liThis was a cross-sectional investigation of 36 participants taking part in a single-center, open-labeled, longitudinal case series. The Ethical Committee of the University Hospitals of Geneva, Geneva, Switzerland, approved the protocol. Research was conducted according to the principles outlined in the Declaration of Helsinki on human medical experimentation. Each participant signed a written informed consent.The patients included in this study were partially edentulous adults with at least one zirconia implant carrying a full-ceramic crown. They had been recruited between November 2009 and June 2012 among systemically healthy individuals, aged 20 or over, seeking treatment for replacement of missing teeth at the University of Geneva School of Dental Medicine, Geneva, Switzerland. Persons with an increased risk for complications, i.e., those with current major systemic or oral pathologies, or subjects needing extensive preparatory treatments of hard or soft tissues in order to make implant placement possible, had not been included. The following conditions were explicit exclusion criteria: smoking more than ten cigarettes per day, addicted to alcohol or other substances, heavily overweight, severely compromised general health, and extensive bone loss in the area of prospective implantation.2-ATZ-Bio-HIP, Metoxit AG, Thayngen, Switzerland). Thirteen patients were treated with the ZERAMEX 1st generation presenting with a sand-blasted surface, 23 with the ZERAMEX T implant presenting with a sand-blasted and acid-etched surface. The abutments were bonded into the implants with an adhesive resin-cement . Full-ceramic crowns were made from lithium disilicate glass-ceramic . In 9 of the 36 individuals available for the present analysis, previously placed titanium implants could also be examined. They were all from the same manufacturer , had a sand-blasted and acid-etched surface (SLA), and had been placed at various time points before 2009. The study population, the treatment protocol, and results from longitudinal monitoring up to 588 ± 174 days after loading have been previously presented [All participants had been treated with a two-piece implant system , consisting of an implant body and an abutment, both made from highly dense zirconium dioxide  performed all clinical procedures. She recorded the dental and medical history, including antibiotics taken within 3 months of the examination date, and took standardized photographs and peri-apical radiographs. The clinical examination included an assessment of the plaque index (PI) and gingival index (GI) , probingSamples of PCF and GCF were taken from the mid-buccal and mid-lingual/palatal crevice area at the selected implants and teeth as previously described : Study sBiomarkers were assessed in PCF and GCF using a multiplex fluorescent bead-based immunoassay and the Bio-Plex 200 suspension array system . The human cytokine 12-plex kit  included the following 12 cytokines: Il-1β, Il-1RA, Il-6, Il-8, Il-17, basic FGF, G-CSF, GM-CSF, IFN-γ, MIP-1β VEGF, and TNF-α. The assays were performed in 96-well filter plates according to the instructions of the manufacturer. In brief, the specimens were eluted in the assay buffer provided in the system’s kit. Microsphere beads coated with monoclonal antibodies against the 12 analytes were added. P/GCF samples, controls, and standards were incubated for 30 min in separate wells. Using vacuum filter, the wells were washed, and a mixture of biotinylated secondary antibodies was added. After another 30 min of incubation, the plates were washed again, and streptavidin conjugated to the fluorescent protein phycoerythrin was added. After 10 min, the plates were washed once more to remove the unbound reagents, and the assay buffer was added. The beads  were analyzed in the suspension array system. The lowest detection limit varied between 1 and 2.24 pg/ml, except for IL-1RA and TNF-α, where the limits were 5.63 and 6.63 pg/ml, respectively.For all measurements recorded at six sites of implants and teeth , an average  was calculated for the zirconia implant and the tooth of each patient, if available also for the titanium implant. The emergence profiles of the crowns were assessed on radiographs Fig.  as scorep values <0.05 were accepted for statistical significance.The biochemical read-outs were analyzed using Bio-Plex Manager 3.0 . A constant (0.1) was added to remove zero values. Because not all data were normally distributed, differences between zirconia implants and teeth, and differences between zirconia and titanium implants, were analyzed using Wilcoxon matched-pair signed-rank test, a non-parametric test. A Spearman’s correlation was used to test the relationship between measurements at implants and teeth. The Wilcoxon-Mann-Whitney test was used to analyze differences between independent groups. Table Table p = 0.001), the marker with the highest degree of correlation (r = 0.567). Zirconia implants with crowns with an emergence profile score of 0  had significantly higher levels of IL-1RA (p = 0.032) and significantly lower levels of IL-6 (p = 0.041) than implants with an imperfect emergence profile. An additional subgroup analysis suggested ZERAMEX 1st generation implants had higher levels of IL-1β, IL-8, and TNF-α than ZERAMEX T implants.Table Table This is the first report comparing clinical and biological findings around two-piece zirconia implant-supported crowns and natural teeth. We found significant differences of several clinical parameters and two biomarkers, and we noted significant correlations between two clinical and five biological parameters. PI scores at zirconia implants were generally low and correlated to those at contralateral teeth, indicating that the participants had a good overall level of oral hygiene. Nevertheless, PI scores at zirconia implant-supported crowns were significantly lower than at natural teeth and titanium implants, corroborating reports of low affinity of zirconia to plaque . PerhapsThe study’s split-mouth design permitted an intra-individual comparison of cytokine levels in GCF and PCF around the teeth and implants, respectively. The correlation in the expression of five biomarkers at zirconia implants and teeth, and of four biomarkers at zirconia and titanium implants, is compatible with the existence of a patient-specific inflammatory response pattern. The levels of two biomarkers (IL-1β and TNF-α) were significantly higher at zirconia implants than at teeth. Our results agree with findings of a recent study comparing levels of biomarkers in PCF at titanium implants and GCF, showing higher levels of TNF-α at implants and significant positive correlations between levels in PCF and GCF of several cytokines . An overIn the present study, except for PI, no significant differences in clinical or biological parameters at titanium or zirconium implants were found. Inflammatory profiles have been evaluated at peri-implant soft tissues adjacent to either titanium or zirconia healing abutments after 6 months of healing . These aThe biomarker levels obtained in this study were a result of a pooled 1-minute sample from the vestibular and lingual/palatal aspects of each tooth or implant. Differences in sampling protocols hinder direct comparisons of average values among studies. In addition, the cytokine threshold levels in healthy conditions are not defined. However, MMP-8 and IL-1beta levels were analyzed around teeth and implants during the course of experimental peri-implant mucositis and gingivitis . NonetheAlthough clinical parameters assessed at peri-implant tissues of zirconia implants and periodontal tissues of contralateral natural teeth showed significant differences, by and large, a similar expression of pro-inflammatory cytokines was observed. Correlations in the expression of several biomarkers at zirconia implants and teeth, and at zirconia and titanium implants, may reflect patient-specific inflammatory response patterns that are not modified locally by the implant material. The diagnostic value of such markers to determine differential benefits of zirconia or titanium implants remains to be determined in longitudinal studies.


It is still unclear whether the time interval from transplant to DSA occurrence influences graft damage. Utilizing sera collected longitudinally, we evaluated 114 consecutive primary pediatric kidney recipients grafted between 2002 and 2013 for dnDSA occurrence by Luminex platform. dnDSAs occurred in 39 patients at a median time of 24.6 months. In 15 patients, dnDSAs developed within 1 year (early-onset group), while the other 24 seroconverted after the first posttransplant year (late-onset group). The two groups were comparable when considering patient- and transplant-related factors, as well as DSA biological properties, including C1q and C3d complement-binding ability. Only recipient age at transplant significantly differed in the two cohorts, with younger patients showing earlier dnDSA development. Late AMR was diagnosed in 47% of the early group and in 58% of the late group. Graft loss occurred in 3/15 (20%) and 4/24 (17%) patients in early- and late-onset groups, respectively (p = ns). In our pediatric kidney recipients, dnDSAs predict AMR and graft loss irrespective of the time elapsed between transplantation and antibody occurrence. De novo posttransplant donor-specific HLA-antibody ( This observation has prompted recommendations on posttransplant HLA-antibody monitoring as a tool to identify patients at risk for antibody-mediated rejection and graft loss [Humoral alloimmunity leading to chronic antibody-mediated rejection (AMR) has been recognized as a major obstacle to long-term kidney graft (KTx) survival –5. In adaft loss –16. early-onset DSAs being associated with lower graft survival [It has also been shown that DSA development continues as an active process even many years after transplantation , 14–17, survival , 17. dnDSA appearance could influence AMR development and graft outcome.We conducted a longitudinal analysis on a pediatric cohort of pretransplant HLA-antibody-negative, first kidney recipients sequentially monitored for posttransplant DSA onset and alloantibody biological properties, in order to evaluate whether the timing ofBetween July 2002 and March 2013, 125 consecutive patients were referred to the Genoa Pediatric Kidney Transplant Program for first allografting. Pretransplant patient sera were screened periodically for the presence of panel reactive anti-HLA antibodies by complement dependent cytotoxicity technique and by a bead-based assay  or MDRD Graft biopsies were performed for clinical indication (graft function decline and/or proteinuria); since 2010, DSA positivity was also included among indications. Rejections were histologically graded following the Banff 97 criteria with updates. Banff 2009 and Banff 2013 criteria were employed for classifying C4d positive and negative AMR . All bioThis study was approved by the Institutional Review Board of the Fondazione Ca' Granda, Ospedale Maggiore Policlinico, Milano (867/2014).n = 11) were not included, resulting in a total of 114 nonsensitized first kidney allograft pediatric recipients monitored for dnDSA . p values < 0.05 were considered statistically significant. Event-free survival was estimated with the Kaplan-Meier method and was compared between risk groups with the log-rank test. For graft failure, censoring event was death with functioning graft. For AMR, censoring event was graft failure. Patients who did not experience graft failure or AMR were censored at the end of the follow-up. Stata 13  or the NCSS System  was used for computation.Data were described as the mean and standard deviation (SD) or median and range if continuous and as count and percent if categorical. To determine differences among patient groups, categorical variables were compared by chi-squared analysis, continuous variables with  dnDSAs at a median time of 24.6 months (range 3–115 months). The mean number of DSA specificities found per patient was 1.97 (±1.29).The cohort median follow-up was 6.7 years (range 2.0–12.6). Antibody identification was based on longitudinal analysis of collected sera in both retrospective and prospective sample series. Among the 114 patients analyzed, 39 patients (34%) developeddnDSA-positive KTx recipients were stratified in two groups, based on time to DSA appearance. We considered patients with antibody occurrence within the first 12 months (the period of greater immunosuppression reduction) as those more prone to mount an immune response to the graft  and patients with antibody occurrence beyond the first posttransplant year as the late-onset group (n = 24) ( dnDSA development ((n = 24) . The medelopment . dnDSA-positive patients recognized a total of 78 HLA antigen specificities. In the two patient groups, HLA class I and class II specificities were equally distributed, and a similar pattern was observed when the analysis was carried out for each HLA antigen locus  in the early-onset group, compared to 1.1 years  in the late-onset group. AMR-free survival did not differ between early- and late-onset groups  and in functional clusters . No significant differences were observed between the two groups  in the early-onset group, compared to 5.5 years (range 3.6–6.5) in the late-onset group (p = ns)  . As the t groups .The problem of clarifying whether HLA antibodies developing at different posttransplant intervals could have different cytotoxic capabilities and graft tissue damage potential has relevance in view of the need to establish the optimal terms of posttransplant DSA surveillance strategy, particularly concerning monitoring length. dnDSA appearance, does not differ in the early- and late-onset HLA-antibody groups. In previous studies, it had been shown that DSAs developing within the first year after transplantation resulted in early graft failure, whereas late-onset DSAs, although also detrimental, seemed to require a longer time to finally cause graft damage and loss [ dnDSAs emerging in the late posttransplant period. Through this longitudinal detection approach, we demonstrated that DSAs in the two patient groups displayed equivalent damaging capabilities. Indeed, early- and late-onset dnDSAs did not differ in the biological properties, such as high MFI values and complement-binding ability, recently demonstrated to be the main determinants of antibody-mediated graft damage and loss [ dnDSAs were comparably represented in both early- and late-onset groups. This apparent discrepancy could be in part explained by the fact that our study exclusively analyzed nonsensitized recipients. Indeed, in a first set alloresponse condition, the ubiquitous cellular expression of class I HLA antigens within the kidney graft tissue may be balanced by the greater stimulating capability of the highly polymorphic class II molecules, in particular HLA DQ antigens [ dnDSAs, we demonstrated in both patient groups that C3d binding was almost exclusively a property of class II, whereas C1q binding was expressed in a similar percentage by both classes. This finding gives additional strength to previous data demonstrating that, in nonsensitized low-risk kidney recipients, class II specific and, in particular, anti-DQ de novo antibodies are the principal effectors of graft loss in all posttransplant phases [ early and late dnDSA damaging capacity was further supported by the observation that the two study groups displayed a similar histological pattern of tissue graft damage. In this regard, it is worth underlining that, in our cohort represented by recipients of grafts from young donors, the susceptibility to HLA-antibody mediated insult is only marginally influenced by organ ageing [Our study, carried out in a homogeneous patient population not including sensitized recipients, demonstrates that the time interval to AMR development and graft loss, evaluated from the firstand loss , 9. Thesand loss , 29 and and loss . In our and loss , 30–32. and loss . The sizand loss , we founantigens –15, 22. t phases , 30. Then ageing . dnDSA production in some patients and not in others, as well as the biological factors influencing their development at different times after transplant, in the presence of the same degree of HLA mismatching and the same immunosuppressive regimen, are not completely understood. In this study, younger recipient age appeared to favor an earlier dnDSA production, likely reflecting a propensity to display a stronger alloreactivity, that suggests a note of caution in immunosuppressive therapy minimization in the pediatric setting.At present, the reasons for dnDSAs at late phases of posttransplant follow-up should not differ from that applied in the early-onset dnDSA patient group.Based on our findings, management of patients found positive forThus, monitoring of HLA antibodies throughout the entire posttransplant course is recommended, despite high costs and organization difficulties, in order to identify patients at risk for AMR and graft loss.


Background. Fracture load of implant-supported restorations is an important factor in clinical success. This study evaluated the effect of two techniques for screw access hole preparation on the fracture load of cement-screw-retained implant-supported zirconia-based crowns.Methods. Thirty similar cement-screw-retained implant-supported zirconia-based maxillary central incisor crowns were evaluated in three groups of 10. Group NH: with no screw access holes for the control; Group HBS: with screw access holes prepared with a machine before zirconia sintering; Group HAS: with screw access holes prepared manually after zirconia sintering. In group HBS, the access holes were virtually designed and prepared by a computer-assisted design/computer-assisted manufacturing system. In group HAS, the access holes were manually prepared after zirconia sintering using a diamond bur. The dimensions of the screw access holes were equal in both groups. The crowns were cemented onto same-size abutments and were then subjected to thermocycling. The fracture load values of the crowns were measured using a universal testing machine. Data were analyzed with ANOVA and Tukey test (P < 0.05).Results. The mean fracture load value for the group NH was 888.37 ± 228.92 N, which was the highest among the groups, with a significant difference (P < 0.0001). The fracture load values were 610.48 ± 125.02 N and 496.74 ± 104.10 Nin the HBS and HAS groups, respectively, with no significant differences (P = 0.44).Conclusion. Both techniques used for preparation of screw access holes in implant-supported zirconia-based crowns decreased the fracture load. However, they have some limitations, including early loosening, difficult or impossible retrieval, and impossible cleaning of excess cement in deeply placed implants.3Implant-supported restorations are considered a choice for replacing missing teeth. Selection of the type of attachment among different implant prostheses and implants plays a pivotal role in the clinical service and long-term success of an implant-supported restoration. Retention of implant-supported crowns may be provided by the use of a screw or cement. Screw-retained and cement-retained restorations have benefits as well as shortcomings. For instance, crown retrieval is easier in screw-retained restorations, but the crown may not be passively placed over the abutment, and the screw may become loose or broken.4 However, because of the increased patient demand for implant treatment, the prevalence of screw loosening and its associated biological and technical complications is on the rise.5According to a systematic review conducted by Jung et al,6 problems of the implant/abutment joint, such as screw loosening and fracture, are among the most common complications compromising the survival of implant-supported, screw-retained fixed partial dentures.6Currently, due to the improved design and a better understanding of the mechanics of screw, screw loosening or fractures are rare in dental implants.7 introduced a technique using a screw locked in the implant restoration to retrieve the cemented restoration. Okamoto et al8 suggested preparing cylindrical holes in the lingual surface for this purpose. McGlumphy et al9 suggested providing retention by both cement and screw, to facilitate accessing the screw hole of restorations and to enable cleaning of the subgingival cement. This technique was referred to as the “combination implant crown”.10This method has been recommended for use in implant-supported metal ceramic restorations; it also allows for permanent cementation of crowns instead of using a temporary cement.10Baige et al11 reported a technique to retrieve implant-supported cemented restorations that benefits from the advantages of both cement-retained and screw-retained fixations. A case report by Rojas-Vizcaya12 described restoration of a maxillary lateral incisor via a cement-screw-retained implant-supported zirconia-based crown. In this method, a screw-retained metallic substructure was designed and a cement-retained crown was fabricated over it. It seems that cement-screw-retained implant-supported restorations have been well developed in prosthodontics.Several methods have been proposed for the retrieval of cement-retained implant-supported crowns. Chee et al13 showed that treatment with implant-supported zirconia-based fixed prostheses yielded favorable outcomes and that screw retention was feasible at the implant level. However, these prostheses have to be screwed and suffer from the same limitations as metal-ceramic cemented crowns.3 Use of cement-screw-retained implant-supported zirconia-based restorations can be a solution to this problem. In this approach, a zirconia-base restoration with a screw access hole is fabricated, cemented on a titanium abutment in the lab, and finally screwed onto a dental implant in the oral cavity.On the other hand, implant-supported zirconia-based crowns, fabricated by computer-assisted design/computer-assisted manufacturing (CAD/CAM) systems, have acceptable esthetics, optimal biocompatibility, high fracture strength, resistance against crack propagation and high adaptation, which explains their popularity. Worni et al14the effect of screw hole preparation on the crown fracture load has yet to be clearly understood. Some previous studies on the fracture load of cement-retained and screw-retained implant-supported metal-ceramic restorations with and without screw access holes have shown that crowns with screw access holes had lower fracture load.16 In a clinical setting, the mechanical resistance of implant-supported restorations plays a pivotal role in the clinical service and long-term success of dental implants.17 The fracture load is defined as the maximum force that a material can tolerate before fracture. Several factors influence the fracture load of zirconia ceramics, including loading conditions, type of cement, and restoration design, the density of pre-sintered zirconia blocks, zirconia sinterability, mechanically created cracks, residual compressive stresses during preparation, yttria contents of zirconia, external stresses due to sandblasting, wear, cyclic loading and thermal or chemical aging .18Considering the structure of zirconia-based crowns and the mechanism of crack propagation and its control,24 the effect of screw access hole preparation on the fracture load of zirconia-based crowns has yet to be fully evaluated. Hence, the aim of this study was to assess the effect of two techniques for screw access hole preparation on the fracture load of implant-supported zirconia-based crowns. The null hypothesis was that screw access hole preparation would not affect the fracture load of implant-supported zirconia-based crowns.Despite some previous studies related to the fracture load of zirconia ceramics,This was an in vitro study which did not involve the use of any animals or human data or tissues, and thus an ethics approval was not required.22 Since all the abutments had equal dimensions, a wax pattern of an anterior crown without a screw access hole was made on the abutment for laser scanning using the Sirona inEos machine .The wax pattern was scanned and the scanned image was transferred to the Sirona inEos CAD/CAM machine .Then a screw access hole with predetermined dimensions  was created on the same wax pattern and scanning process was performed again. The scanned images were used to fabricate 30 zirconia cores with the thickness of 0.6 mm from zirconia blanks  (20 cores without screw access hole and 10 cores with screw access hole) , measuring 4.3mm in diameter and 15mm in height, were used in this experimental study. Three 15° esthetic abutments , measuring 0.5 in mm collar height and 7.5 mm in height, were selected. The abutments were fixed in the implant analogs by applying a torque of 35 N.cm based on the manufacturer’s instructions. A two-piece custom metal block was fabricated and the implant analogs were then embedded in the metal block at a 35° angle relative to the vertical axis. Taking into account the 15° angulation of the abutment relative to the longitudinal axis of implant analog, the final angulation of abutment relative to the vertical axis was 50°.ss hole) . The zirss hole) with a siss hole)  and diviGroup NH: This group included 10 zirconia-based crowns with no screw access holes.Group HBS: This group included 10 zirconia-based crowns with screw access holes which were prepared before zirconia core sintering. The holes were designed by the CAD/CAM system according to the scanned image, with predetermined dimensions. The zirconia cores were sintered and veneered.Group HAS: This group included 10 zirconia-based crowns with screw access holes which were prepared after zirconia core sintering. The holes were manually prepared in the palatal surface of zirconia cores using the mentioned bur, and matched dimensionally to group HBS.23The excess cement was removed. For specimens in groups HBS and HAS, after cementation, the screw access holes were completely filled with the same composite resin and the composite resin was light-polymerized. All the specimens were subjected to 500 thermal cycles in a thermocycler between 5 and 55°C, with a dwell time of 60 seconds for each specimen and 12 seconds of intermediate pause.The abutments were cleaned with pumice powder and water. Cotton pellets were placed over the abutment screws. For specimens in group NH, the abutment screw holes were filled with composite resin . Next, the composite resin was light-polymerized prior to cementation. All the thirty crowns were cemented over the abutments using resin cement  according to manufacturer’s instructions and pressed with finger pressure for 2 minutes.24 The load was applied 3 mm below the incisal edge23 out of the hole area. The load applicator of the universal testing machine was similar to the incisal edge of a mandibular incisor (dimension of 5.5×1 mm), to simulate clinical settings.25 The magnitude of the load, which was applied by the universal testing machine, increased until the zirconia core fractured. The fracture load was recorded. In case of ceramic veneer fracture without core fracture, the specimen was eliminated from the study. After fracture occurred, the specimens were heated to decrease the retention of cement on the abutment, and the crown was removed. After removal of the crown, the cement remaining on the abutment was thoroughly removed by an explorer. The abutment surface was cleaned with an acetone solution and water. Then the abutment was dried, tightened using a torque of 35 N.cm, and prepared to cement the next crown. This process was repeated for all the specimens. The fracture load was measured for each specimen in Newton (N). Data were analyzed with ANOVA and Tukey test using SPSS 20 . P < 0.05 was considered statistically significant.To determine the fracture load, the specimens were subjected to compressive load testing in a universal testing machine . Compressive loads were applied vertically and at a 50° angulation relative to the abutments at a crosshead speed of 2 mm/min .22,24 ThThe means and standard deviations for the fracture load values of the specimens in the three groups were 888.3 ± 228.9, 610.4 ± 125, and 496.7 ± 104.1 Nin the NH, HBS and HAS groups, respectively . After eBased on the results of the current study, preparation of screw access holes in cement-screw-retained implant-supported zirconia-based crowns before and after sintering  resulted in a significant reduction in the fracture load values. Moreover, considering the technique of the preparation, the manual and machine techniques gave rise to no differences in this respect. Thus, the null hypothesis of the study was refuted.26Therefore modifications on the substructures may affect the fracture of restorations. One of these modifications is to prepare screw access holes. Most relevant previous studies have evaluated the effect of access hole preparation on the fracture load of posterior metal-ceramic restorations and to the best of authors’ knowledge, no similar study has been conducted on cement-screw-retained implant-supported zirconia-base crowns.Cement systems, bonding procedures, occlusion and metal copings all play a role in the success of fixed prostheses and all these factors must be taken into account in order to be able to make a comparison among novel ceramic and metal substructures.27 Some researchers believe that the preparation of screw access holes in screw-retained restorations can undermine the ceramic around the hole and also the ceramic at the cusp tip, leading to ceramic fracture; however, this problem does not exist in cement-retained restorations.28Evidence has shown that cement-retained restorations with intact occlusal surfaces have higher porcelain fracture load than screw-retained restorations.30 Similar results were obtained in the current study since the preparation of screw access holes before and after sintering significantly decreased the fracture load of zirconia crowns. Wood et al31evaluated the effect of access cavity preparation for root canal therapy on the fracture load of zirconia and alumina restorations. All the specimens showed porcelain chipping around the access cavity and the decrease in the fracture load of the zirconia restorations was greater than that of the alumina restorations.31 However, it should be noted that in the study by Wood et al,31the access cavity prepared for root canal therapy was much larger than the screw access hole prepared in implant-supported restorations. This difference may have been responsible for the inconsistent comparisons. Screw access hole preparation in screw-retained restorations disrupts the structural integrity of the zirconia ceramic and results in subsequent displacement of the center of ceramic mass towards ceramic gaps during the sintering process. Such a displacement changes the behavior of ceramic in these restorations compared with cement-retained restorations.30 Nonetheless, it should be noted that due to the variability in the use of different methods, implant systems, loading conditions, cement materials, restoration design, type of abutment and type of alloy, a direct comparison of the results across different studies may not be feasible.Several studies have demonstrated that preparation of screw access holes in screw-retained metal-ceramic restorations decreased the fracture load of porcelain.19The strength of zirconia directly relates to the size, number, location and distribution of defects, cracks and superficial gaps/porosities.32 However, mass cracks possess a covering protection and are supported by the surrounding material. Superficial cracks directly serve as stress accumulation areas and intensify the applied stresses, depending on their extent.32This is due to the size of superficial cracks in all-ceramic restorations. Sharp, deep defects result in an increased concentration of stress at the tip of the cracks and likely serve as sites of crack initiation.33 Although the superficial defects created in the process of CAD/CAM preparation may have insignificant effects on the strength of specimens, they may have a significant impact on the fatigue behavior of zirconia restorations.34 Small defects propagate due to cyclic loading of mastication and eventually cause sudden fractures in ceramic.34 Consequently, despite their small size, superficial defects can serve as stress concentration sites and can lead to restoration fracture.34Fully sintered zirconia is very tough, making its preparation extremely difficult. Moreover, the preparation of zirconia ceramic has adverse effects on its mechanical properties.35 reported that many factors can affect the mechanical properties of zirconia ceramics such as hardness and strength. These factors include the density of pre-sintered zirconia blocks , sinterability of the powder (due to its correlation with the size of primary particles), mechanically created cracks, residual compressive stresses during preparation of specimens and high yttrium content .36Consequently, the screw access hole preparation may mechanically create cracks. This may be the reason for a decrease in fracture load following screw access hole preparation in the present study.Roebben et al36 Denry et al37suggestedthat the minimum thickness of zirconia core should be 0.5 mm to avoid fractures; accordingly, a durable zirconia core thickness was employed in the present investigation. Haraldson et al38reported a mean load of 206 N applied to the anterior region of dental arch during masticatory function. Maximum bite forces in the anterior incisor region correspond to approximately 150 Nin adults.39 Gay et al40 estimated human incisal bite forces ranging from a minimum of 25 N to a maximum of 400 N. Although the results of the present study cannot be directly generalized to a clinical setting, all the study groups showed higher fracture loads than the anterior biting force. Based on the results of this study and also the range of occlusal loads applied to the anterior teeth, the fracture load values of the study groups were within an optimal range of functional loads. Similarly, Worni et al13 demonstrated that screw-retained implant-supported zirconia crowns had optimal survival rates in the oral environments.In the current study, the thickness of the zirconia core was adjusted at 0.6mm according to a study by Potiket et al.41 Obviously, application of a single, compressive load cannot simulate all the clinical loads that a restoration is exposed to.42 In fact, one may not be able to exactly relate a fracture load test, performed with the application of single compressive load until fracture in a dry environment, to the dynamics of numerous fractures that occur in the wet oral environment due to cyclic loading.43 Therefore, generalization of the results would have been possible if the specimens had been tested under fatigue loading. Moreover, quick load application to a single point is different from normal mastication in the oral environment because the clinical pattern of loading decreases the loads applied to the restorations.44 Furthermore, a clinical pattern of load application can cause fatigue fractures in small amounts compared to in vitro loading conditions. Therefore, further studies are necessary under the conditions noted above. If the results of the current study can be supported by further successful clinical researches, screw access hole preparation will be deemed a useful method to fabricate cement-screw-retained implant-supported zirconia-based restorations.The current study had some limitations; the crowns studied were only subjected to one cycle of compressive load until fracture; whereas, in a clinical setting, the crowns may undergo fracture following fatigue processes and the formation of small cracks.Based on the results of the present study in relation to a decreased fracture load in cement-screw-retained implant-supported zirconia-based crowns, reinforcement of the zirconia core is recommended in these cases. Also screw access hole preparation techniques need innovations and more investigations.Within the limitation of the study it was concluded that:The preparation of screw access hole in cement-screw-retained implant-supported zirconia-based crowns before sintering (machined technique) and after sintering  decreased the fracture load.In this respect, there was no significant difference between the two techniques of access hole preparation .The authors do not have any individual or organization to acknowledge with regards to this paper.HM, REA, and MM contributed to the concept and design of the work. The acquisition, analysis, and interpretation of data were accomplished by MM and FT. HM, MM, FT, and MA drafted and revised it critically for intellectual content. All the authors read and approved the final manuscript.This project was supported and funded by the authors.The authors declare no competing interests with regards to the authorship and/or publication of this article.Not applicable.