Aims

Giant cell tumour of bone (GCTB) is a locally aggressive lesion that is difficult to treat as salvaging the joint can be associated with a high rate of local recurrence (LR). We evaluated the risk factors for tumour relapse after treatment of a GCTB of the limbs.

In recent literature, the fragility index (FI) has been used to evaluate the robustness of statistically significant findings of dichotomous outcomes. This metric is defined as the minimum number of outcome events to flip study conclusions from significant to nonsignificant. Orthopaedics literature is frequently found to be fragile with a median FI of 2 in 150 RCTs across spine, hand, sports medicine, trauma and orthopaedic oncology studies. While many papers discuss limitations of FI, we aimed to further characterize it by introducing the Fragility Likelihood (FL), a new metric that allows us to consider the probability of the event to occur and to calculate the likelihood of this fragility to be reached.

We systematically reviewed all randomized controlled trials in the Journal of Bone and Joint Surgery (Am) over 10 years. The FL was calculated with the following formula: A x B x C x 100% (A= FI; B = probability of the event in the group with the smallest number of events; C= probability of the non-event in the group with the highest number of events). A smaller FL demonstrates more robust results and conversely, a larger FL illustrates a higher likelihood of fragility being reached and more fragile the findings.

The median FI for the statistically significant outcomes was 2 (Mean: 3.8; Range 0-23). The median FL for the statistically significant outcomes was 11% (Mean: 22%, Range: 2%-73%). This means that the probability of reaching non-significance is only 11% when considering the probability of the event to occur. When comparing studies with the same FI we found the FL to range from 3% to 43%. This illustrates the large differences in robustness between trials with equal FI when the likelihood of the event was taken into consideration.

As orthopaedic studies are frequently reported as fragile, we found that by calculating the FL, studies may be more robust than previously assumed based off FI alone. By using the FL in conjunction with FI and p-values will provide additional insight into the robustness of the reported outcomes. Our results indicate that by calculating the FL, study conclusions are stronger than what the FI alone predicts. Although conducting RCTs in surgery can be challenging, we must endeavor to critically evaluate our results so we can answer important orthopaedic questions with certainty.

Resection of the proximal femur raises several challenges to the orthopedic oncology surgeon. Among these is the re-establishment of the abductor mechanism that might impacts on hip function. Extent of tumor resection and surgeons’ preferences dictate the reconstruction method of the abductors. While some surgeons advocate the necessity of greater trochanter (GT) preservation whenever possible, others attempt direct soft tissues reattachment to the prosthesis. Sparse data in the literature evaluated the outcomes of greater trochanter fixation to the proximal femur megaprosthesis.

This is a retrospective monocentric study. All patients who received a proximal femoral replacement after tumor resection between 2005 and 2021 with a minimum follow-up of three months were included. Patients were divided into two groups: (1) those with preserved GT reattached to the megaprosthesis and (2) those with direct or indirect (tenodesis to fascia lata) abductor muscles reattachment. Both groups were compared for surgical outcomes (dislocation and revision rates) and functional outcomes (Trendelenburg gait, use of walking-assistive device and abductor muscle strength). Additionally patients in group 1 were subdivided into patients who received GT reinsertion using a grip and cables and those who got direct GT reinsertion using suture materials and studied for GT displacement at three, six and 12 months. Time to cable rupture was recorded and analyzed through a survival analysis.

Fifty-six patients were included in this study with a mean follow-up of 45 months (3-180). There were 23 patients with reinserted GT (group 1) and 33 patients with soft tissue repair (group 2). Revision rate was comparable between both groups(p=0.23); however, there were more dislocations in group 2 (0/23 vs 6/33; p=0.037). Functional outcomes were comparable, with 78% of patients in group 1 (18/23) and 73% of patients in group 2 (24/33) that displayed a Trendelenburg gait (p=0.76). In group 1, 70% (16/23) used walking aids compared to 79% of group 2 (27/33) (p=0.34). Mean abductor strength reached 2.7 in group 1 compared to 2.3 in group 2 (p=0.06). In group 1, 16 of the 23 patients had GT reinsertion with grip and cables. Median survival of cables for these 16 patients reached 13 months in our series. GT displacement reached a mean of two mm, three mm, and 11 mm respectively at three, six and 12 months of follow-up in patients with grip and cables compared to 12 mm, 24 mm and 26 mm respectively at the same follow-up intervals in patients with GT stand-alone suture reinsertion(p<0.05).

Although GT preservation and reinsertion did not improve functional outcomes after proximal femur resection and reconstruction with a megaprosthesis, it was significantly associated with lower dislocation rate despite frequent cable failure and secondary GT migration. No cable or grip revision or removal was recorded. Significantly less displacement was observed in patients for whom GT reattachment used plate and cables rather than sutures only. Therefore we suggest that GT should be preserved and reattached whenever possible and that GT reinsertion benefits from strong materials such as grip and cables.

Benign aggressive tumors are common and can be debilitating for patients especially if they are in peri-articular regions or cause pathological fracture as is common for giant cell tumor of bone (GCT). Although GCT rarely metastasize, the literature reports many series with high rates of local recurrence, and evidence about which risk factors influence recurrence is lacking. This study aims to evaluate the recurrence rate and identify local recurrence risk factors by reviewing patient data from a single high-volume orthopedic oncology center.

A retrospective analysis of all patients treated for GCT at a tertiary orthopedic oncology center was conducted. In total 413 patients were treated for GCT between 1989 and 2017. Multiple patient and tumour characteristics were analysed to determine if they influenced local recurrence including: age, gender, anatomical site, Campanacci stage, soft tissue extension, presence of metastasis, pathologic fractures, and prior local recurrence. Additional variables that were analysed included type of treatment (en bloc resection or aggressive intralesional curettage) and use of local adjuvants. The main outcome parameters were local recurrence- free survival, metastasis-free survival and complications. Patients treated with Denosumab were excluded from analysis given its recently documented association with high rates of local recurrence.

“There were 63/413 local recurrences (15.3%) at a mean follow-up of 30.5 months. The metastatic rate was 2.2% at a mean 50.6 months follow-up and did not vary based on type of treatment. Overall complication rate of 14.3% was not related to treatment modality. Local recurrence was higher (p=0.019) following curettage (55/310; 17.7%) compared to resection (8/103; 7.8%) however, joint salvage was possible in 87% of patients (270/310) in the curettage group. Use of adjuvant therapy including liquid nitrogen, peroxide, phenol, water versus none did not show any effect on local recurrence rates (p= 0.104). Pathological fracture did not affect local recurrence rates regardless of treatment modality (p= 0.260). Local recurrence at presentation was present in 16.3% (58/356) patients and did not show any significance for further local recurrence (p= 0.396). Gender was not associated with local recurrence (p=0.508) but younger patient age, below 20 years (p = 0.047) or below 30 years (p = 0.015) was associated with higher local recurrence rates. GCT in distal radius demonstrated the highest rate of local recurrence at 31.6% compared to other sites, although this was not significant (p=0.098). In addition, Campanacci stage and soft tissue extension were not risk factors for recurrence.

The overall GCT local recurrence rate was 15.3%, but varied based on the type of resection: 17.7% following joint sparing curettage compared to 7.8% following resection. Local recurrence was also higher with younger patient age (30 years or less) and in distal radius lesions. In addition, neither Campanacci stage, soft tissue extension or presence of a pathologic fracture affected local recurrence. Most patients with GCT can undergo successful curettage and joint sparing, while only a minority require resection +/− prosthetic reconstruction. Even in the presence of soft tissue extension or a pathologic fracture, most joints can be salvaged with curettage.

Myxofibrosarcoma (MFS) is the second most common subtype of soft tissue sarcoma (STS) and is associated with a high rate of local recurrence after resection. These tumours frequently present with peri-lesional edema, termed “tumour tails” on staging MRI scans [1]. Tumour tails(TT) may contain satellite neoplastic cells or can represent benign reactive edema. There are no clear radiological features to distinguish malignant from reactive peri-lesional edema which limits accurate surgical planning, resulting in either high rates of inadvertently positive resection margins and local recurrences or overly-aggressive resections which negatively impact function and increase morbidity [2]. The objective of this pilot study was to prospectively study a cohort of MFS patients with TTs in an attempt to identify radiological features that predict which type of edema is malignant and requires resection together with the main tumour mass.

Patients diagnosed with MFS on biopsy at an orthopaedic oncology referral centre between January 1-December 31 2018 who also had TTs on staging MRI scans were prospectively recruited for the study. Tumours were treated with wide surgical excision, including the TTs, and (neo)adjuvant radiotherapy as per institutional protocol. Staging MRI scans were reviewed in a blinded fashion by two musculoskeletal radiologists to distinguish malignant from reactive TTs. The main tumour mass underwent standard histological evaluation while the regions encompassing the TTs were photographed and sectioned into grids. Each tissue section was examined histologically for the presence of satellite neoplastic cells based on morphological criteria. Radiological and histological findings were compared.

Six patients met the inclusion criteria and underwent analysis. All tumours were located in the extremities and were deep to fascia. Mean age at presentation was 67 years (range 51 – 85), with a male:female ratio of 4:2. All patients received radiotherapy (50 Gy), either pre- (n=4) or post-operatively (n=2) based on multidisciplinary tumor board discussion or enrolment in a prospective clinical trial. Radiologically, TTs were labelled as malignant in four patients (66.7%) and as benign TTs in two others. The tails were recognised to be malignant due to the differing signal characteristics to reactive edema on mixed MRI sequences. The radiological evaluation correlated exactly with histological analysis, as satellite neoplastic cells were identified microscopically in the same four cases in which the TTs were designated to be malignant by MRI (specificity&sensitivity=100%). Surgical resection margins were microscopically positive in 50% of cases in the TTs themselves, and 75% of cases in which TTs were designated as malignant on staging MRI.

“The malignant nature of peri-lesional edema in MFS, also known as the TT, was accurately predicted in this small pilot study based on specific radiological features which correlated exactly with histologic identification of isolated tumor cells. These findings validate development of a larger prospective study to recruit additional patients with tumor tails beyond just MFS, in order to more robustly study the correlation between the MRI appearance and histological distribution of satellite sarcoma cells in peri-lesional edema in STS. We are already recruiting to this expanded radiological-histological investigation including evaluation of additional novel MRI sequences.

Myxoid or Myxoid Round Cell liposarcoma (MLS) is a mesenchymal malignancy with adipocyte differentiation accounting for 15–20% of liposarcomas and 5% of all adult soft tissue sarcomas (STS). Like other STS, treatment of MLS is generally by wide surgical resection in conjunction with radiotherapy and this approach is associated with low rates of local recurrence [1]. However, most MLS are located between muscles so wide local excision(WLE) can be quite morbid with adverse functional results. MLS are known to be extremely sensitive to radiotherapy which has led to development of treatment protocols utilizing neoadjuvant radiation. Given the radiosensitivity of MLS, we hypothesize that resection with marginal margins (1mm) does not result in higher rates of local recurrence or disease-free survival if performed following pre-operative radiotherapy.

We identified all patients with localized MLS who underwent preoperative radiation and surgical resection between January 2000 and January 2018 from a prospectively collected sarcoma database. We calculated the ellipsoid tumour volume(ETV=h x w x d x ()) at diagnosis and after radiation, and documented the necrosis percentage of the tumour and margin status following resection based on histological analysis [2]. Marginal resection was identified by the operative report describing no or only very minimal resection of muscle surrounding the tumour, and a negative surgical margin 0.1cm/1mm as defined histologically. In comparison, WLE was defined if the operative note described an attempt to remove the tumour with a cuff of surrounding muscle, and the final histology reported a negative margin 0.1cm/1mm which included skeletal muscle. The third group for analysis included patients with positive resection margins.

There were 91 patients with MLS of mean age 48 years (range 18–88) with 69% male and 31% female. The mean pre-radiotherapy ETV was 507cm³(16.1cm³ to 6961cm³) and decreased to 361cm³(8.7cm³ to 5695cm³) following radiation, with an average percentage reduction in ETV of −45%(+129%to-99%). Mean patient follow-up was 7.3 years (0.2–18) with no differences between margin groups(p=0.284). Only 10(11%) patients had positive margins, of which 43(47%) underwent marginal resection and 38(42%) WLE. Overall the mean necrosis as measured histologically following preoperative radiation was 69% (range 0–100%) with no differences between the 3 resection groups(p-0.151). Similarly, there was no significant difference in reduction in mean ETV between the three resection groups(p=0.311), there was no significant difference between the three treatment groups in 5-year LR-free survival (p=0.469), metastasis-free survival (p=0.841) or overall survival (p=0.873).

Most patients with MLS experienced significant reduction in tumour size and necrosis following preoperative radiation. We found no differences in the risk of local recurrence or survival based on the type of surgical approach for patients with MLS. Based on these results, we conclude that MLS can be safely removed by marginal resection following preoperative radiotherapy with high rates of local tumour control. Even following a positive margin resection, local recurrence remains uncommon after preoperative radiation. A marginal surgical approach for patients with MLS reduces the need for major muscle resection and is associated with improved functional outcomes with less complications.

Ewing Sarcoma is the second most common primary bone sarcoma in young patients, however, there remains geographical variation in the treatment of these tumours. All patients receive neoadjuvant chemotherapy and, in most cases, the soft tissue mass diminishes significantly in volume. Controversy surrounds whether to then treat the pre- or post-chemotherapy tumour volume. Many centres advocate either (1) resection of the pre-chemotherapy volume or (2) treatment of the pre-chemotherapy volume with radiation followed by resection of the post-chemotherapy volume. These approaches increase both the short and long-term morbidity for this young patient population. In this study, we retrospectively reviewed our experience resecting only the post-chemotherapy volume without the use of (neo)adjuvant radiotherapy.

A retrospective analysis of all patients with Ewing Sarcoma treated at a tertiary orthopaedic oncology centre was conducted. All patients were treated as per the consensus opinion of the multidisciplinary tumour board. Demographic and oncological variables were collected from our institutional database. Presentation and re-staging MRI scans were reviewed to evaluate pre- and post-chemotherapy tumour volumes. Operative and pathology reports were utilized to determine the extent of the surgical resection. Outcome variables included local recurrence free-, metastasis free- and overall survival.

Sixty-five patients were identified in our institutional database of which 56 did not receive (neo)adjuvant radiotherapy. Median age at diagnosis was 24 years (range 13–64), 60% of patients were male and 67.6% of tumours were located in the appendicular skeleton. All 56 patients not treated with radiotherapy had resection of the post-chemotherapy tumour volume. There were 3 local recurrences in this group with a mean follow-up of 70.8 months (range 2 to 328). The median overall survival was 47 months and the mean of 70.8months.

The rate of local recurrence is comparable to reports in the literature in which patients had their entire pre-chemotherapy tumour volume treated by radiation and/or surgery. Similarly, two-year overall survival for our patient cohort is not significantly different from previous studies in which more aggressive local control measures were employed. Resecting the post-chemotherapy tumour volume in Ewing Sarcoma without the use of (neo)adjuvant radiotherapy does not appear to increase the risk of local recurrence or negatively impact overall survival. This approach should be studied further as it reduces the risk of short and long-term complications for this patient population.”

Recent innovations in total ankle replacement (TAR) have led to improvements in implant survivorship, accuracy of component positioning and sizing, and patient outcomes. CT-generated pre-operative plans and cutting guides show promising results in terms of placement enhancement and reproducibility in clinical studies. The purpose of this study was to determine the accuracy of 1) implant sizes used and 2) alignment corrections obtained intraoperatively using the cutting guides provided, compared to what was predicted in the CT generated pre-operative plans.

This is a retrospective study looking at 36 patients who underwent total ankle arthroplasty using a CT generated pre-operative planning system between July 2015 and December 2017. Personalized pre-operative planning data was obtained from the implant company. Two evaluators took measurements of the angle corrected using pre- and post-operative weight bearing ankle AP X-rays. All patients had a minimum three-month follow-up with weightbearing postoperative radiographs. The actual correction calculated from the radiographic assessment was compared with the predicted angles obtained from pre-operative plans. The predicted and predicted alternative component sizes and actual sizes used were also compared. If either a predicted or predicted alternative size was implanted, we considered it to be accurate.

Average age for all patients was 64 years (range 40–83), with a body mass index of 28.2 ± 5.6. All surgeries were performed by two foot and ankle surgeons. The average total surgical time was 110 ± 23 minutes. Pre-operative alignment ranged from 36.7 degrees valgus to 20 degrees varus. Average predicted coronal alignment correction was 0.8 degrees varus ± 9.3 degrees (range, 18.2 degrees valgus to 29 degrees varus) and average correction obtained was 2.1 degrees valgus ± 11.1 degrees. Average post-op alignment was consistently within 5 degrees of neutral. There were no significant differences between the predicted alignments and the postoperative weightbearing alignments. The predicted tibia implant size was accurate in all cases. The predicted sizes were less accurate for talar implants and predicted the actual talar implant size used in 66% of cases. In all cases of predicted talar size mismatch, surgical plans predicted 1 implant size larger than used.

Preliminary analyses of our data is comparable to previous studies looking at similar outcomes. However, our study had higher pre-operative deformities. Despite that, post-op alignments were consistently within 5 degress of neutral with no significant difference between the predicted and actual corrections. Tibial implant sizes are highly accurate while talar implant sizes had a trend of being one size smaller than predicted. Moreover, this effect seems to be more pronounced in the earlier cases likely reflective of increasing surgeon comfort with the implant with each subsequent case. These results confirm that pre-operative cutting guides are indeed helpful in intra-operative implant selection and positioning, however, there is still some room for innovation.

The objective of this paper is to demonstrate the difference in post-operative complication rates between Computer-assisted surgery (CAS) and conventional techniques in spine surgery. Several studies have shown that the accuracy of pedicle screw placement significantly improves with use of CAS. Yet, few studies have compared the incidence of post-operative complications between CAS and conventional techniques.

The American College of Surgeons National Surgical Quality Improvement Program (ACS-NSQIP) database was used to identify patients that underwent posterior lumbar fusion from 2011 to 2013. Multivariate analysis was conducted to demonstrate the difference in post-operative complication rates between CAS and conventional techniques in spine surgery.

Out of 15,222 patients, 14,382 (95.1%) were operated with conventional techniques and 740 (4.90%) were operated with CAS. Multivariate analysis showed that patients in the CAS group had less odds to experience adverse events post-operatively (OR 0.57, P <0.001).

This paper examined the complications in lumbar spinal surgery with or without the use of CAS. These results suggest that CAS may provide a safer technique for implant placement in lumbar fusion surgeries.

Cervical spine fusion have gained interest in the literature since these procedures are now ever more frequently being performed in an outpatient setting with few complications and acceptable results. The purpose of this study was to assess the rate of blood transfusion after cervical fusion surgery, and its effect, if any on complication rates.

The American College of Surgeons National Surgical Quality Improvement Program (ACS-NSQIP) database was used to identify patients that underwent cervical fusion surgery from 2010 to 2013. Univariate and multivariate regression analysis was used to determine post-operative complications associated with transfusion and cervical fusion.

We identified 11,588 patients who had cervical spine fusion between 2010 and 2013. The overall rate of transfusion was found to be 1.47%. All transfused patients were found to have increased risk of: venous thromboembolism (TBE) (OR 3.19, CI: 1.16–8.77), myocardial infarction (MI) (OR 9.12, CI: 2.53–32.8), increased length of stay (LOS) (OR 28.03, CI: 14.28–55.01) and mortality (OR 4.14, CI: 1.44–11.93). Single level fusion had increased risk of: TBE (OR 3.37, CI: 1.01–11.33), MI (OR 10.5, CI: 1.88–59.89), and LOS (OR 14.79, CI: 8.2–26.67). Multilevel fusion had increased risk of: TBE (OR 5.64, CI: 1.15–27.6), surgical site infection (OR 16.29, CI: 3.34–79.49), MI (OR 10.84, CI: 2.01–58.55), LOS (OR 26.56, CI: 11.8–59.78) and mortality (OR 10.24, CI: 2.45–42.71). ACDF surgery had an increased risk of: TBE (OR 4.87, CI: 1.04–22.82), surgical site infection (OR 9.73, CI: 2.14–44.1), MI (OR 9.88, CI: 1.87–52.2), LOS (OR 28.34, CI: 13.79–58.21) and mortality (OR 6.3, CI: 1.76–22.48). Posterior fusion surgery had increased risk of: MI (OR 10.45, CI: 1.42–77.12) and LOS (OR 4.42, CI: 2.68–7.29).

Our results demonstrate that although cervical fusions can be done as outpatient procedures special precautions and investigations should be done for patients who receive transfusion after cervical fusion surgery. These patients are demonstrated to have higher rate of MI, DVT, wound infection and mortality when compared to those who do not receive transfusion.

Hemorrhage and transfusion requirements in spine surgery are common. This is especially true for thoracic and lumbar fusion surgeries. The purpose of this papersi to determine predictive factors for transfusion and their effect on short-term post-operative outcomes for thoracic and lumbar fusions.

The American College of Surgeons National Surgical Quality Improvement Program (ACS-NSQIP) database was used to identify patients that underwent lumbar or thoracic fusion surgery from 2010 to 2013. Univariate and multivariate regression analysis was used to determine predictive factors and post-operative complications associated with transfusion.

A total of 14,249 patients were included in this study; 13,586 had lumbar fusion and 663 had thoracic fusion surgery. The prevalence of transfusion was 35% for thoracic fusion and 17.5% for lumbar fusion. The multivariate analysis showed that age between 50–60 (OR 1.38, CI: 1.23–1.54), age between 61–70 (OR 1.65, CI: 1.40–1.95), dyspnea (OR 1.11, CI: 1.02–1.23), hypertension (OR 1.14, CI: 1.02–1.27), ASA class (OR 1.73, 1.18–1.45), pre-operative blood transfusion (OR 1.91, CI: 1.04–3.49), and extended surgical time (OR 4.51, CI: 4.09–4.98) were predictors of blood transfusion requirements for lumbar fusion. While only pre-operative BUN (OR 1.04, CI: 1.01–1.06) and extended surgical time (OR 4.70, CI: 3.12–6.96) were predictors of transfusion for thoracic fusion. In contrast, higher pre-operative hematocrit was protective against transfusion. Patients transfused who underwent lumbar fusion had an increased risk to develop superficial wound infection, deep wound infection, venous thromboembolism, myocardial infarction and had longer length of hospital stay. Patients transfused who underwent thoracic fusion were more likely to have venous thromboembolism and extended length of hospital stay. However, mortality was not associated with blood transfusion.

This study used a large database to characterise the incidence, predictors and post-operative complications associated with blood transfusion in thoracic and lumbar fusion surgeries. Pre- and post-operative planning for patients deemed to be at high-risk of requiring blood transfusion should be considered to reduce post-operative complication in this population.

Computer assisted surgery (CAS) has gained popularity in orthopaedics for both total knee (TKA) and total hip arthroplasty (THA) in the past decades as a stereotactic device that provides the surgeon with real-time feedback on implant position based on electromagnetic or infrared based instruments. The purpose of this study was to assess the effect of CAS on 30-day complication rates following THA and TKA.

The American College of Surgeons National Surgical Quality Improvement Program (ACS-NSQIP) database was used to identify all patients that underwent THA and TKA from 2011 to 2013, as well as any complication they had within 30-days of their surgery. Univariate and multivariate regression analysis was used to compare the post-operative complications in patients whose surgery involved the use of CAS with those by conventional surgical techniques.

We identified 104,550 patients who had THA (42,275 patients) and TKA (62,275 patients) procedures in the database between 2011 and 2013. Computer Assisted Surgery was used in 1,120 THA and 2,173 TKA procedures. There were higher overall adverse events (OR 1.40, CI: 1.22–1.59) in the Conventional group when compared to CAS for TKA. The rate of overall minor events (OR 1.38, CI: 1.21–1.58) and requirements for blood transfusion (OR 1.44, CI: 1.25–1.67) were higher in the Conventional group compared to the CAS group for TKA. However, rate of re-operation was significantly higher in the CAS group for TKA (OR 1.60, CI: 1.15–2.25). The results also showed higher overall adverse events (OR 2.61, CI: 2.09–3.26) in the Conventional group when compared to CAS for THA. The rate of overall minor events (OR 2.72, CI: 2.16–3.42) and requirements for blood transfusion (OR 3.27, CI: 2.52–4.25) was higher in the Conventional group whereas superficial wound infections (OR 0.46, CI: 0.46–0.81) were shown to be higher in the CAS group. The result also showed slightly longer operative times in CAS for both THA and TKA.

This study analysed a large patient database involving multiple institutions and surgeons and found that, overall, the use off CAS in primary total hip and total knee arthroplasty reduced the number of adverse events in the first 30-days postoperatively, compared to conventional surgical techniques. However, CAS was associated with an increased number of reoperations, superficial infections and operating time. The clinical benefits and disadvantages of CAS should be considered by arthroplasty surgeons when determining the potential benefit-cost ratio of this technology.