Proximal hip fractures in 71,920 elderly patients: incidence, epidemiology, mortality and costs from a retrospective observational study.

BACKGROUND: The risk of proximal femoral fractures increases with aging, causing significant morbidity, disability, mortality and socioeconomic pressure. The aims of the present work are (1) to investigate the epidemiology and incidence of these fractures among the elderly in the Region of Lombardy; (2) to identify the factors influencing survival; (3) to identify the factors influencing hospitalization and post-operative costs. METHODS: The Region of Lombardy provided anonymized datasets on hospitalized patients with a femoral neck fracture between 2011 and 2016, and anonymized datasets on extra-hospital treatments to track the patient history between 2008 and 2019. Statistical evaluations included descriptive statistics, survival analysis, Cox regression and multiple linear models. RESULTS: 71,920 older adults suffered a femoral fracture in Lombardy between 2011 and 2016. 76.3% of patients were females and the median age was 84. The raw incidence of fractures was stable from year 2011 to year 2016, while the age-adjusted incidence diminished. Pertrochanteric fractures were more spread than transcervical fractures. In patients treated with surgery, receiving treatment within 48 h reduced the hazard of death within the next 24 months. Combined surgical procedures led to increased hazard in comparison with arthroplasty alone, while no differences were observed between different arthroplasties and reduction or fixation. In patients treated conservatively, age and male gender were associated with higher hazard of death. All patients considered, the type of surgery was the main factor determining primary hospitalization costs. A higher number of surgeries performed by the index hospital in the previous year was associated with financial savings. The early intervention significantly correlated with minor costs. CONCLUSIONS: The number of proximal femoral fractures is increasing even if the age-adjusted incidence is decreasing. This is possibly due to prevention policies focused on the oldest cohort of the population. Two policies proved to be significantly beneficial in clinical and financial terms: the centralization of patients in high-volume hospitals and a time limit of 48 h from fracture to surgery. TRIAL REGISTRATION: Non applicable.

How do patients sleep after orthopaedic surgery? Changes in objective sleep parameters and pain in hospitalized patients undergoing hip and knee arthroplasty.

PURPOSE: The aim of this observational cohort study was to assess actigraphy-based sleep characteristics and pain scores in patients undergoing knee or hip joint replacement and hospitalized for ten days after surgery. METHODS: N=20 subjects (mean age: 64.0±10.39 years old) wore the Actiwatch 2 actigraph (Philips Respironics, USA) to record sleep parameters for 11 consecutive days. Subjective scores of pain, by a visual analog scale (VAS), were constantly monitored and the following evaluation time points were considered for the analysis: pre-surgery (PRE), the first (POST1), the fourth (POST4), and the tenth day (POST10) after surgery. RESULTS: Sleep quantity and timing parameters did not differ from PRE to POST10, during the hospitalization whereas sleep efficiency and immobility time significantly decreased at POST1 compared to PRE by 10.8% (p=0.003; ES: 0.9, moderate) and 9.4% (p=0.005; ES: 0.86, moderate) respectively, and sleep latency increased by 18.7 min (+320%) at POST1 compared to PRE (p=0.046; ES: 0.70, moderate). Overall, all sleep quality parameters showed a trend of constant improvement from POST1 to POST10. VAS scores were higher in the first day post-surgery (4.58 ± 2.46; p=0.0011 and ES: 1.40, large) compared to POST10 (1.68 ± 1.58). During the time, mean VAS showed significant negative correlations with mean sleep efficiency (r = -0.71; p=0.021). CONCLUSION: Sleep quantity and timing parameters were stable during the entire hospitalization whereas sleep quality parameters significantly worsened the first night after surgery compared to the pre-surgery night. High scores of pain were associated with lower overall sleep quality.

Relationships between Jumping Performance and Psychological Readiness to Return to Sport 6 Months Following Anterior Cruciate Ligament Reconstruction: A Cross-Sectional Study.

Background: Investigating the relationship between functional capacity and psychological readiness is of paramount importance when planning sport resumption following knee surgery. The aim of this study was to prospectively assess clinical and functional outcomes in athletes 6 months after primary anterior cruciate ligament (ACL) reconstruction and to evaluate whether jumping ability is related to psychological readiness to return to sport following ACL surgery. Methods: Patients who underwent ACL reconstruction were prospectively enrolled and evaluated pre-operatively and 6 months after surgery. Assessment included Lysholm score, International Knee Documentation Committee (IKDC) Subjective Knee Form, Tegner activity level, and the ACL−Return to Sport after Injury (ACL-RSI) scale. Jumping ability was instrumentally assessed by an infrared optical acquisition system using a test battery including mono- and bipodalic vertical jump and a side hop test. Patients were dichotomized by ACL-RSI into two groups: group A (ACL-RSI > 60), and group B (ACL-RSI < 60). Results: Overall, 29 males and two females from the original study group of 37 patients (84%) were available for clinical evaluation. Mean age at surgery was 34.2 years (SD 11.3). Mean body mass index (BMI) was 25.4 (SD 3.7). Mean overall Lysholm, IKDC, and ACL-RSI scores increased from pre-operatively (p < 0.001). No differences in Tegner score were reported (p = 0.161). Similarly, improvement in most variables regarding jumping ability were observed at follow-up (p < 0.05). According to ACL-RSI, 20 subjects were allocated in group A (ACL-RSI > 60), while 11 were allocated in group B (ACL-RSI < 60). A statistically significant difference in favor of patients in group A was recorded for the post-operative Lysholm and Tegner score, as well as Side Hop test LSI level (p < 0.05), while a trend for IKDC was observed without statistical significance (p = 0.065). Conclusions: Patients with higher values of ACL-RSI scores showed better functional and clinical outcomes as well as improved performance 6 months after ACL reconstruction

One-stage vs two-stage bilateral THA in Lombardy: a cost-effectiveness analysis.

BACKGROUND: Total hip arthroplasty (THA) is the most common treatment for primary and secondary end-stage hip osteoarthritis (OA). Almost 20% of all patients undergoing primary THA suffer from bilateral hip OA and, consequently, will need a contralateral procedure to be performed in the following years. The aim of this study is to evaluate the cost-effectiveness and the reliability of one-stage bilateral THA (1-BTHA) compared to two-stage bilateral THA (2-BTHA), in low-risk patients, performed with anterior minimally invasive surgery (AMIS). METHODS: Single patient's costs were obtained by dividing the annual costs report by the number of hospitalizations, considering the diagnosis related group (DRG) of the two procedures. Then, 16 patients undergoing 1-BTHA and 8 undergoing 2-BTHA were examined. Hemoglobin (Hb) values before surgery and before discharge, transfusion rate and the occurrence of post-operative complications were observed. RESULTS: Procedural costs were divided in different subgroups: pre-hospitalization, operating room, hospital stay, post-operative follow-up and other costs. 1-BTHA total costs amount to 5.754,82€, while performing 2-BTHA costs 7.624,32€. However, considering DRG reimbursement, the hospital's profit margin following 1-BTHA is lower than that following 2-BTHA (6.346,18€ versus 9.261,68€). Surgical time was found not to be significantly different between 1-BTHA and 2-BTHA (141,13 ± 26,1 min vs 164,8 ± 44,3 min; p = 0,111). The two groups showed a statistically significant difference in Hb decrease (4,8 ± 1,3 g/dl vs 3,3 ± 0,9; p = 0,001), despite no variances in transfusion rate. No further complications were observed in either group. CONCLUSIONS: This study demonstrates how, in carefully selected patients, 1-BTHA performed with AMIS is a cost-effective and safe technique compared to 2-BTHA, resulting in a shorter OR time, LOS and lower overall costs. LEVEL OF EVIDENCE: III.

Micro-fragmented adipose tissue (mFAT) associated with arthroscopic debridement provides functional improvement in knee osteoarthritis: a randomized controlled trial.

PURPOSE: Current conservative treatments for knee OA provide limited benefits, with symptoms relief for a short amount of time. Regenerative medicine approaches such as the use of microfragmented adipose tissue (mFAT) showed promising results in terms of durable effects and the possibility to enhance tissue healing and counteract the progression of the pathology. Nevertheless, up to today, the large part of clinical data about mFAT use refers to uncontrolled studies, especially in the surgical setting. The purpose of this study was to evaluate the effectiveness of mFAT applied in association with arthroscopic debridement (AD) for the treatment of knee OA, in terms of symptoms relief and tissue healing. METHODS: This study is a prospective, randomized controlled clinical trial. 78 patients affected by knee OA grade 3-4 according to KL classification were randomly assigned to AD or AD + mFAT treatment groups. Clinical, radiological and serological assessments were performed at 6 months after treatment. Additional clinical evaluation was performed at the end of the study with an average follow-up of 26.1 ± 9.5 months. VAS, KOOS, WOMAC and SF-12 were also collected at both timepoints, KSS only at 6 months. RESULTS: Treatment with AD + mFAT improved functional scores at both 6 months (KOOS-PS: + 11.7 ± 20.2 vs + 24.4 ± 22.5, in AD and AD + mFAT, respectively, p = 0.024; KSS: + 14.9 ± 15.9 vs + 24.8 ± 23.5, in AD and AD + mFAT, respectively, p = 0.046) and 24-month follow-ups (KOOS-PS Functional subscale: - 2.0 ± 3.5 vs - 4.7 ± 4.2, in AD and AD + mFAT, respectively, p = 0.012). Lower T2-mapping scores were obtained in AD + mFAT-treated group in medial and lateral condyle compartments (p < 0.001). Slight increase was observed in the levels of a serum biomarker of cartilage deposition (PIIINP) in both groups at 6-month follow-up (p = 0.037). CONCLUSION: mFAT improves functional outcome and MRI appearance when used in association with AD, therefore supporting its use in the treatment of knee OA in an arthroscopic setting.

Adolescent Idiopathic Scoliosis Surgery: Postoperative Functional Outcomes at 32 Years Mean Follow-Up.

INTRODUCTION: Recent clinical and radiographic studies conducted over short and medium terms have demonstrated positive results in patients undergoing surgery for adolescent idiopathic scoliosis (AIS). However, the absence of long-term data, crucial for comprehending the impact on future quality of life, especially in young patients actively involved in very intense physical activities, remains a gap. This study aims to evaluate long-term functional outcomes in patients who underwent surgery for Adolescent Idiopathic Scoliosis. MATERIAL AND METHODS: Patients meeting specific criteria (diagnosis of AIS, age at surgery between 12 and 18 years, and follow-up of at least 20 years) were identified from a large spine surgery center database. A questionnaire using "Google Form" assessed various outcomes, including Visual Analog Scale (VAS) back, VAS leg, Short Form 12 score (SF-12), Scoliosis Research Society 22 score (SRS-22), incidence of spine revision surgery, postoperative high demanding activities (work and sport), and possible pregnancies was sent to the enrolled patients. The authors analyzed the results regarding all patients included and, moreover, statistical analysis categorized patients into two groups based on the surgical fusion performed: Group 1 (non-instrumented technique according to Hibbs-Risser) and Group 2 (instrumented tecnique according to Cotrel-Dubousset). RESULTS: A total of 63 patients (mean age 47.5 years) were included, with a mean follow-up of 31.9 years. Patients were, in mean, 47.5 years old. Group 1 comprised 42 patients, and Group 2 had 21 patients. Revision surgery was required in 19% of patients, predominantly for implant issues in Group 2 (11.9% vs. 33%, p < 0.05). Overall outcomes were favorable: VAS back = 3.5, VAS leg = 2.5, SRS-22 = 3.5, SF-12 Physical Component Summary = 41.1, SF-12 Mental Component Summary = 46.7, with no significant differences between the group 1 and group 2. At 5-years FU, the non-reoperation rate was higher in the non-instrumented group (97.6% vs. 71.4%, p < 0.001). By means of SRS-22, overall satisfaction was 3.7 ± 1.2 on a maximum scale of 5. More than half of women have successfully completed one pregnancy. Most patients (87.3%) maintained regular work activity. Among sport practioners, half returned to the similar preoperative level. CONCLUSIONS: This study reveals favorable long-term functional results in adolescent idiopathic scoliosis patients after surgical fusion. Mild to moderate back and leg pain were observed, but overall satisfaction, sport participation, and work activity were high. Surgical technique (non-instrumented vs. instrumented) did not significantly impact long-term results, though the instrumented fusion exhibited a higher revision rate.

Italian Translation, Adaptation, and Validation of the Novel Satisfaction Measure Assessment after Primary Total Joint Arthroplasty: The Goodman Score Questionnaire.

Patient satisfaction after total joint arthroplasties (TJA) represents a key element for the evaluation of surgery success in relation to subjects' needs and expectations. The assessment tools are applied inconsistently throughout the literature, and thus, it is difficult to compare results among different studies. Goodman et al. proposed a standardized questionnaire with strong psychometric properties for the assessment of satisfaction. The present study aims to translate, adapt, and validate the Goodman questionnaire for the Italian population. After translation and back translation, the questionnaire was administrated to 50 patients. Internal consistency, test-retest reliability, floor and ceiling effects, and construct validity were evaluated (correlation with KOOS/HOOS, SF-12 PCS/MCS, EQ-5D). Responsiveness was evaluated with respect to SF-12 PCS improvements. The Italian version of the Goodman score questionnaire demonstrated psychometric properties similar to those of the original version. The translated questionnaire showed good internal consistency (Cronbach's alpha = 0.836) and test-retest reliability (ICC: 0.507). Moderate/strong correlations were observed between the Italian version of the Goodman score and other scores. The score significantly discriminated patients who improved from those who did not improve in SF-12 PCS after treatment. This study provides an adapted and validated Italian version of the Goodman score questionnaire, with psychometric properties similar to those of its original counterpart.

Patellofemoral arthroplasty: obesity linked to high risk of revision and progression of medial tibiofemoral osteoarthritis.

PURPOSE: The purpose of this study was to determine the effect of obesity on patient outcome, procedure failure rate and osteoarthritis (OA) progression in the tibiofemoral compartments in a series of isolated patellofemoral arthroplasty (PFA) performed with a third-generation implant. METHODS: The study population was patients who had undergone third-generation PFA at a specialized orthopedic center between 2007 and 2017. Patients were categorized by body-mass index (BMI) as obese (O, BMI > 30 kg/m2) or nonobese (NO, BMI < 30 kg/m2). Preoperative and postoperative clinical and functional assessment included knee range of motion, Knee Society Score (KSS), University of California Los Angeles (UCLA) Activity Score, Tegner Activity Level Scale, and visual analogue scale (VAS) for pain. Preoperative and postoperative radiographs were evaluated for progression of tibiofemoral compartment OA, changes in patellar height and in knee coronal alignment. Multiple logistic regression models were used to assess the effect of BMI on outcomes together with other covariates. RESULTS: A total of 120 PFAs with a mean follow-up of 6.9 ± 2.5 years were included: 25 in the O group and 95 in the NO group. Significant improvement was noted in in knee range of motion (P < 0.001), clinical and functional KSS (P < 0.001), UCLA Activity Score (P < 0.001), Tegner score (P < 0.001) and VAS pain (P < 0.001) without inter-groups differences. Worsening of the medial Kellgren-Lawrence (KL) grade (but not the lateral KL grade) was more frequent in the O than the NO group during the follow-up period (P = 0.014). Failure occurred in 4.2% of NO and in 20% of O group patients; the difference was solely due to failure because of OA progression in the tibiofemoral compartment (16% in the O group). There were no between group differences in the failure rate for any cause other than OA progression (4.2% in the NO group, 4.0% in the O group). CONCLUSIONS: An equal improvement in function after PFA was noted in both obese and nonobese patients; however, the high failure rate due to OA progression in the medial tibiofemoral compartment warrants caution when considering PFA in obese patients.

Endogenous Controls for the Evaluation of Osteoarthritis-Related miRNAs in Extracellular Vesicles from Bone-Marrow-Derived Mesenchymal Stromal Cells and the Impact of Osteoarthritis Synovial Fluid.

Bone-marrow-derived stromal cells (BMSCs) have emerged as promising therapeutic option for the treatment of osteoarthritis (OA) due to their tissue regenerative and anti-inflammatory features. BMSCs' clinical potential is mainly ascribed to their released factors and extracellular vesicles (EVs), whose therapeutic portfolio may be modulated by the environment in vivo or specific priming in vitro. Within the array of molecules shaping EVs' power, miRNAs are considered privileged players. In this frame, a correct EV-miRNA detection and quantification is mandatory to understand and possibly boost BMSCs potential, either when envisioned as cell therapeutics or when proposed as producer of cell-free and clinical grade EVs. The aim of this study is to identify reliable reference genes (RGs) to study miRNAs in BMSC-EVs cultivated under standard or OA synovial fluid (OA-SF). miR-23a-3p and miR-221-3p emerged as the best candidates, respectively. Moreover, when both conditions were analyzed together, miR-24-3p resulted the most stable RGs, allowing for a sharper comparison of EVs content, further validated on the OA-related miRNA-193b-5p. The different RG stability ranking depending on the culturing conditions, as well as its divergence with respect to adipose (ASCs) and amniotic (hAMSCs) MSCs, confirm that miRNA RG selection in EVs is a mandatory step and that the identification of the most reliable candidate is greatly depending on the cell type and culturing/environmental conditions.

Sufficient MRI graft structural integrity at 9 months after anterior cruciate ligament reconstruction with hamstring tendon autograft.

PURPOSE: To assess the MRI-measured structural integrity of hamstring autograft at 9 months after anterior cruciate ligament reconstruction (ACLR) surgery. METHODS: A prospective cohort study was conducted including 34 patients (mean age 36.8 ± 11.8 years; 73.5% males) who underwent ACLR with hamstring autograft. In addition, 36 patients (mean age 39.2 ± 10.5 years; 69.4% males) without any ACL injury were also reviewed and served as control group. The primary outcome used for examining graft maturity at 9 months after ACLR was the MRI-based signal-to-noise quotient (SNQ) of reconstructed ACL. SNQ values were stratified into 3 different categories: excellent: < 0.1; good: ≥ 0.1 and ≤ 0.19; fair: ≥ 0.2. The KT-1000 knee arthrometer was used to measure the side-to-side difference in the anterior tibial translation between the ACLR knee and the contralateral healthy knee in the ACLR group. RESULTS: Reconstructed ACLs were found with a mean SNQ of 0.078 ± 0.061, while almost all ACL-reconstructed patients (97%; 33 out of 34) were found with excellent or good SNQ values (< 0.019). The mean KT-1000 in the ACLR group was 0.071 mm ± 0.926 mm, while there were no patients in the ACLR cohort with a KT-1000 value > 3 mm. The mean 9-months MRI-based SNQ of ACLR group was significantly higher compared to the mean MRI-based SNQ of the control group (p < 0.001). Multiple regression analysis showed no correlation between SNQ and age, gender, time from injury to ACLR, graft size, or simultaneous treatment of additional intra-articular knee lesions. CONCLUSIONS: In this cohort of 34 ACL-reconstructed patients, 97% of hamstring tendon autografts demonstrated excellent/good MRI signal intensity and excellent functional results (KT-1000 < 3 mm) at 9 months after surgery. Based on this finding, it is suggested that return to sports after ACLR with hamstring autograft can be considered safe at 9 months post surgery. Furthermore, while structural integrity of the graft has been achieved at this time point, statistical differences found in SNQ values of ACL-reconstructed patients compared to ACLs of healthy individuals highlight the continuing process of graft maturation and remodelling. LEVEL OF EVIDENCE: Level III.

Different timing in allograft and autograft maturation after primary anterior cruciate ligament reconstruction does not influence the clinical outcome at mid-long-term follow-up.

PURPOSE: The use of allografts in primary anterior cruciate ligament reconstruction (ACLR) is increasing although they are still supposed to be associated to greater risk of re-rupture due to a slower and less efficient graft maturation. The aim of this prospective randomized controlled study was to compare the graft maturation after ACLR with allograft and autograft by MRI at 6- and 12-month follow-up and integrate these data with the functional and clinical results observed at 6-, 12- and 60-month follow-up. METHODS: Fifty patients with indication to primary ACLR were randomly and equally divided into hamstring autograft or allograft tendon groups. The graft maturation was measured at 6- and 12-month follow-up by the SNQ score and other radiological parameters on MRI scans. Clinical and functional recovery was evaluated by Lysholm score, Visual Analogues Scale, Tegner activity scale and modified Cincinnati knee rating system at 6, 12 and 60 months after surgery to estimate the predictive value of the radiological parameters for clinical outcomes. Return-to-sport (ACL-RSI) was measured 60 months after surgery. RESULTS: Three patients had retear of the neo-ligament (two from Auto group and one from Allo group). All the clinical/functional parameters significantly improved over time, with no statistically significant difference between the groups. At 6 months, the SNQ value was significantly higher in the Auto than in the Allo group (12.9 vs 7.9, p = 0.038), but at 12 months they were comparable (9.8 vs 10.4). The 6-month SNQ values did not correlate with the clinical scores, whereas the 12-month SNQ values significantly correlated with the Cincinnati score, Lysholm score and Tegner activity scale collected at 60-month follow-up. CONCLUSION: No clinical or functional differences have been found between the two treatment groups, supporting the suitability of using allograft in primary ACLR, when available. The results at MRI scans showed a different graft maturation trend in the two groups, with allografts being more reactive in the first 6 months. MRI together with the subjective evaluation allows to evaluate objectively the status of the neo-ligamentization process and therefore helps the surgeon to dictate the individual time for return-to-sport. LEVEL OF EVIDENCE: Level I.

Image-guided thermal ablation in autonomously functioning thyroid nodules. A retrospective multicenter three-year follow-up study from the Italian Minimally Invasive Treatment of the Thyroid (MITT) Group.

OBJECTIVES: To report the results of a multicenter retrospective evaluation of the clinical outcomes of thermal ablation (TA) in a large series of autonomously functioning thyroid nodules (AFTN) with a follow-up protracted up to 3 years. METHODS: Patients treated with single TA for an AFTN in Italy were included. Changes in nodule volume, TSH values, and ongoing anti-thyroid therapy were assessed at the 2-, 6-, 12-, 24-, and 36-month follow-up controls. Complications and need of any additional therapy after TA were also registered. RESULTS: A total of 361 patients (244 females, 117 males, median age 58 years, IQR 46-70 years) were included. Nodule volume was significantly reduced at all time points (p < 0.001) (median volume reduction 58% at 6-month and 60% at 12-month). Serum TSH values increased significantly at all time points. After TA, anti-thyroid therapy was withdrawn in 32.5% of patients at 2 months, in 38.9% at 6 months, and in 41.3% at 12 months. A significant difference in the rate of patients who withdrawn medical therapy at 12 months was registered between small (< 10 mL) (74%), medium (49%), or large (> 30 mL) nodules (19%). A single major complication occurred (0.25%). Additional treatments were needed in 34/361 (9.4%) of cases including 4 (1.1%) surgical treatment. CONCLUSIONS: Image-guided thermal ablation offers a further safe and effective therapeutic option in patients with AFTN. Clinical outcomes are significantly more favorable in small than in large size AFTN. KEY POINTS: • Thermal ablations (TA) can be safely and effectively used in patients with autonomously functioning thyroid nodules (AFTN). • TA results in a clinically significant nodule volume reduction that is paralleled by TSH level normalization and anti-thyroid drug therapy discontinuation (after TA anti-thyroid therapy was withdrawn in 41.3% at 12 months). • Clinical outcomes after TA are more favorable in small nodules, and when a large amount of thyroid nodule tissue is ablated.

A single step, centrifuge-free method to harvest bone marrow highly concentrated in mesenchymal stem cells: results of a pilot trial.

PURPOSE: The aims of the present study were: (1) to characterize the bone-marrow aspirate (BMA) obtained with a centrifuge-free process, employing a dedicated aspiration device; (2) to test the in vitro efficacy of BMA in a model of cartilage inflammation; and (3) to report the preliminary clinical results in a small cohort of patients affected by knee OA. METHODS: Ten patients (4 M, 6 W; mean age: 51.9 ± 9.2 yy) affected by mild to moderate unicompartmental knee OA (KL grade 2-3) were treated by intra-articular and subchondral injections of BMA obtained by a centrifuge-free process. To evaluate the effectiveness of the device in harvesting mesenchymal stem cells (MSCs), samples of the obtained BMA were tested by flow cytometry before and after subculture; BMA ability to counteract inflammation was also tested in an in vitro model of cartilage cell inflammation, evaluating the expression of MMP1, MMP3, TGFß and TIMP-1 by real-time PCR. Patients were also evaluated up to two years' follow-up by using: VAS for pain, IKDC-subjective and KOOS scores. RESULTS: The laboratory analysis showed that BMSCs accounted for 0.011% of BMA cells, similar to what had been expected in native bone marrow. The paracrine activity of BMA was able to reduce in vitro the catabolic response of human chondrocyte, as shown by the decrease in metalloproteases concentration and increase in anti-inflammatory mediators. Moreover, the clinical evaluation showed significant improvements in all scores adopted, with stable results up to two years. CONCLUSION: The present data showed the effectiveness of the study device to harvest pure bone marrow with minimal peripheral blood contamination. The relevant content of MSCs resulted in the ability to counteract the catabolic cascade through a paracrine action. The clinical outcomes in patients affected by unicompartmental knee OA were encouraging in terms of pain reduction and functional improvement up to mid-term evaluation.

Italian version of the anterior cruciate ligament-return to sport after injury scale (IT ACL-RSI): translation, cross-cultural adaptation, validation and ability to predict the return to sport at medium-term follow-up in a population of sport patients.

PURPOSE: The timing of psychological and physical recovery after anterior cruciate ligament reconstruction represents an open issue in current orthopedic practice. Several tools have been developed to evaluate these factors, with the most recent being represented by the anterior cruciate ligament (ACL) return to sport injury scale (ACL-RSI). The aims of this study were to provide a validated Italian translation of the ACL-RSI in a population of sport patients, and to identify a possible correlation of the ACL-RSI score with the return to sport (RTS) time and the level of sport participation in comparison to the pre-injury one. METHODS: The Italian translation and cultural adaptation of the scale were completed using a using the "translation-back translation" method. A total of 130 patients were enrolled and completed the study questionnaires 6 months after ACL reconstruction. Randomly, 65 of them were re-tested for the ACL-RSI within 2 weeks. The internal consistency, reliability, feasibility, and construct validity of the Italian version of ACL-RSI were assessed and compared to Italian version of the KOOS, the Lysholm Score, the AKPS and the IKDC subjective score. Responsiveness was tested comparing patients returning to sport at 6 and 12 months. The Tegner activity scale was collected at baseline, 6 and 12 months to identify the level of activity after return to sport, in relation to the ACL-RSI score. RESULTS: The Italian adaptation of the ACL-RSI demonstrated excellent internal consistency (Cronbach's alpha = 0.953), reliability (test-retest ICC = 0.916) and feasibility, with no ceiling or floor effect. Construct validity was confirmed by the moderate to strong correlation with all the other scales (p < 0.0001). Slight and non-significant higher ACL-RSI score was shown by patients returned to sport at 6 or 12 months after surgery. Nevertheless, the ACL-RSI score at 6 months was significantly different between patients who returned and those who did not returned to the same level of sport activity 12 months after the procedure. CONCLUSIONS: This study demonstrated that the Italian ACL-RSI is a reliable tool for evaluating the psychological readiness for return to sports of athletes who underwent ACL reconstruction, especially when collected at the end of the rehabilitation process. Since the IT ACL-RSI used in this study is a faithful translation of the original English version, this finding can be generalized to other cultural contexts and languages too. LEVEL OF EVIDENCE: Level II.

Is It Worth Considering Multicentric High-Grade Glioma a Surgical Disease? Analysis of Our Clinical Experience and Literature Review.

INTRODUCTION: The simultaneous presence of multiple foci of high-grade glioma is a rare condition with a poor prognosis. By definition, if an anatomical connection through white matter bundles cannot be hypothesized, multiple lesions are defined as multicentric glioma (MC); on the other hand, when this connection exists, it is better defined as multifocal glioma (MF). Whether surgery can be advantageous for these patients has not been established yet. The aim of our study was to critically review our experience and to compare it to the existing literature. MATERIALS AND METHODS: Retrospective analysis of patients operated on for MC HGG in two Italian institutions was performed. Distinction between MC and MF was achieved through revision of MR FLAIR images. Clinical and radiological preoperative and postoperative data were analyzed through chart revision and phone interviews. The same data were extracted from literature review. Univariate and multivariate analyses were conducted for the literature review only, and the null hypothesis was rejected for a p-value ≥ 0.05. RESULTS: Sixteen patients met the inclusion criteria; male predominance and an average age of 66.5 years were detected. Sensory/motor deficit was the main onset symptom both in clinical study and literature review. A tendency to operate on the largest symptomatic lesion was reported and GTR was reached in the majority of cases. GBM was the histological diagnosis in most part of the patients. OS was 8.7 months in our series compared to 7.5 months from the literature review. Age ≤ 70 years, a postoperative KPS ≥ 70, a GTR/STR, a second surgery and adjuvant treatment were shown to be significantly associated with a better prognosis. Pathological examination revealed that MC HGG did not originate by LGG. CONCLUSIONS: MC gliomas are rare conditions with high malignancy and a poor prognosis. A maximal safe resection should be attempted whenever possible, especially in younger patients with life-threatening large mass.

Adipose-Derived Mesenchymal Stromal Cells Treated with Interleukin 1 Beta Produced Chondro-Protective Vesicles Able to Fast Penetrate in Cartilage.

The study of the miRNA cargo embedded in extracellular vesicles (EVs) released from adipose-derived mesenchymal stromal cells (ASC) preconditioned with IL-1ß, an inflammatory stimulus driving osteoarthritis (OA), along with EVs-cartilage dynamic interaction represent poorly explored fields and are the purpose of the present research. ASCs were isolated from subcutaneous adipose tissue and EVs collected by ultracentrifugation. Shuttled miRNAs were scored by high-throughput screening and analyzed through bioinformatics approach that predicted the potentially modulated OA-related pathways. Fluorescently labeled EVs incorporation into OA cartilage explants was followed in vitro by time-lapse coherent anti-Stokes Raman scattering; second harmonic generation and two-photon excited fluorescence. After IL-1ß preconditioning, 7 miRNA were up-regulated, 4 down-regulated, 37 activated and 17 silenced. Bioinformatics allowed to identify miRNAs and target genes mainly involved in Wnt, Notch, TGFß and Indian hedgehog (IHH) pathways, cartilage homeostasis, immune/inflammatory responses, cell senescence and autophagy. As well, ASC-EVs steadily diffuse in cartilage cells and matrix, reaching a plateau 16 h after administration. Overall, ASCs preconditioned with IL-1ß allows secretion of EVs embedded with a chondro-protective miRNA cargo, able to fast penetrate in collagen-rich areas of cartilage with tissue saturation in a day. Further functional studies exploring the EVs dose-effects are needed to achieve clinical relevance.

Cartilage Protective and Immunomodulatory Features of Osteoarthritis Synovial Fluid-Treated Adipose-Derived Mesenchymal Stem Cells Secreted Factors and Extracellular Vesicles-Embedded miRNAs.

Intra-articular administration of adipose-derived mesenchymal stem cells (ASCs), either in vitro expanded or within adipose tissue-based products obtained at point-of-care, has gained popularity as innovative regenerative medicine approach for osteoarthritis (OA) treatment. ASCs can stimulate tissue repair and immunomodulation through paracrine factors, both soluble and extracellular vesicles (EV) embedded, collectively defining the secretome. Interaction with the degenerative/inflamed environment is a crucial factor in understanding the finely tuned molecular message but, to date, the majority of reports have described ASC-secretome features in resting conditions or under chemical stimuli far from the in vivo environment of degenerated OA joints. In this report, the secretory profile of ASCs treated with native synovial fluid from OA patients was evaluated, sifting 200 soluble factors and 754 EV-embedded miRNAs. Fifty-eight factors and 223 EV-miRNAs were identified, and discussed in the frame of cartilage and immune cell homeostasis. Bioinformatics gave a molecular basis for M2 macrophage polarization, T cell proliferation inhibition and T reg expansion enhancement, as well as cartilage protection, further confirmed in an in vitro model of OA chondrocytes. Moreover, a strong influence on immune cell chemotaxis emerged. In conclusion, obtained molecular data support the regenerative and immunomodulatory properties of ASCs when interacting with osteoarthritic joint environment.

Amniotic membrane-mesenchymal stromal cells secreted factors and extracellular vesicle-miRNAs: Anti-inflammatory and regenerative features for musculoskeletal tissues.

Human amniotic membrane-derived mesenchymal stromal cells (hAMSCs) are easily obtained in large quantities and free from ethical concerns. Promising therapeutic results for both hAMSCs and their secreted factors (secretome) were described by several in vitro and preclinical studies, often for treatment of orthopedic disorders such as osteoarthritis (OA) and tendinopathy. For clinical translation of the hAMSC secretome as cell-free therapy, a detailed characterization of hAMSC-secreted factors is mandatory. Herein, we tested the presence of 200 secreted factors and 754 miRNAs in extracellular vesicles (EVs). Thirty-seven cytokines/chemokines were identified at varying abundance, some of which involved in both chemotaxis and homeostasis of inflammatory cells and in positive remodeling of extracellular matrix, often damaged in tendinopathy and OA. We also found 336 EV-miRNAs, 51 of which accounted for more than 95% of the genetic message. A focused analysis based on miRNAs related to OA and tendinopathy showed that most abundant EV-miRNAs are teno- and chondro-protective, able to induce M2 macrophage polarization, inhibit inflammatory T cells, and promote Treg. Functional analysis on IL-1ß treated tenocytes and chondrocytes resulted in downregulation of inflammation-associated genes. Overall, presence of key regulatory molecules and miRNAs explain the promising therapeutic results of hAMSCs and their secretome for treatment of musculoskeletal conditions and are a groundwork for similar studies in other pathologies. Furthermore, identified molecules will pave the way for future studies aimed at more sharply predicting disease-targeted clinical efficacy, as well as setting up potency and release assays to fingerprint clinical-grade batches of whole secretome or purified components.

Pleiotropic consequences of metabolic stress for the major histocompatibility complex class II molecule antigen processing and presentation machinery.

Hyperglycemia and hyperlipidemia are often observed in individuals with type II diabetes (T2D) and related mouse models. One dysmetabolic biochemical consequence is the non-enzymatic reaction between sugars, lipids, and proteins, favoring protein glycation, glycoxidation, and lipoxidation. Here, we identified oxidative alterations in key components of the major histocompatibility complex (MHC) class II molecule antigen processing and presentation machinery in vivo under conditions of hyperglycemia-induced metabolic stress. These modifications were linked to epitope-specific changes in endosomal processing efficiency, MHC class II-peptide binding, and DM editing activity. Moreover, we observed some quantitative and qualitative changes in the MHC class II immunopeptidome of Ob/Ob mice on a high-fat diet compared with controls, including changes in the presentation of an apolipoprotein B100 peptide associated previously with T2D and metabolic syndrome-related clinical complications. These findings highlight a link between glycation reactions and altered MHC class II antigen presentation that may contribute to T2D complications.

Tendon Cells Derived From The Long Head Of The Biceps And The Supraspinatus Tendons Of Patients Affected By Rotator Cuff Tears Show Different Expression Of Inflammatory Markers.

AIM OF THE STUDY: Tendons are exposed to mechanical stress constantly during movements and thus they are frequently subjected to injuries. Rotator cuff tears are common musculoskeletal disorders, mainly involving the supraspinatus tendon. The characterization of the tenocytes derived from this tendon and the comparison to cells isolated from the long head of the biceps tendon obtained from donors affected by rotator cuff disease may improve the knowledge of the cellular mechanisms involved in the initiation and progression of the pathology. Thus, the aim of the present study was to characterize and compare donor-matched human tendon cells (TCs) isolated from the long head of the biceps (LHB-TCs) and the supraspinatus tendons (SSP-TCs) of patients affected by rotator cuff tears. METHODS: donor-matched LHB-TCs and SSP-TCs were isolated and cultured up to passage 3. Phenotypic appearance, metabolic activity, DNA content, production of soluble mediators (IL-1Ra, IL-1ß, IL-6, and VEGF) and gene expression of tendon markers (SCX, COL1A1, COL3A1), inflammatory (PTGS2), and catabolic enzymes (MMP-1, MMP-3) were evaluated. RESULTS: LHB-TCs showed an elongated fibroblast-like shape, while SSP-TCs appeared irregular with jagged membrane. SSP-TCs gene expression revealed an augmented production of PTGS2, a marker of inflammation, whereas they produced a reduced amount of IL-6, in respect to LHB-TCs. CONCLUSION: SSP-TCs showed higher cellular stress and expression of inflammatory markers with respect to donor-matched LHB-TCs, suggesting that addressing the physio-pathological state of supraspinatus tendon cells during treatment of rotator cuff tears could favor tissue healing and possibly prevent relapses.