How to assess, detect, and manage joint involvement in the era of transformational therapies: Role of point-of-care ultrasound.

BACKGROUND: Patients with haemophilia experience recurring hemarthroses, mainly involving knees, elbows and ankles, which lead to haemophilic arthropathy, the major chronic complication of haemophilia. With new approaches to haemophilia treatment leading to fewer joint bleeds and, in some cases, no bleeding events, assessing whether current outcome assessment tools provide adequate sensitivity and specificity for management and care of patients with haemophilia is needed. METHODS: An overview of current imaging tools for monitoring joint health, novel osteochondral damage and synovial proliferation biomarkers, and the relationship between assessments for functionality and imaging modalities is provided. Usefulness and sensitivity of point-of-care ultrasound (POCUS) to complement other assessments and use of ultrasound to monitor haemophilic arthropathy are also examined. RESULTS: This review provides rationale for haemophilia teams to move beyond traditional outcomes in joint imaging, as well as guidance and evidence on assessment of joint health for potential new treatment modalities, such as gene therapy. The role of POCUS in the existing paradigm for haemophilia care and management along with the use of ultrasound as a complement to other outcome assessment tools are also discussed. Finally, the clinical effects of subclinical bleeding on joint function are described, to motivate screening for synovial proliferation. CONCLUSION: POCUS can facilitate the early detection of joint damage and can monitor disease progression while providing insights into the efficacy of treatment regimens, and should be considered as an essential assessment tool for managing the care of patients with haemophilia.

The Role of Low-Level Laser Therapy in Bone Healing: Systematic Review.

Low-level laser therapy (LLLT) is a treatment that is increasingly used in orthopedics practices. In vivo and in vitro studies have shown that low-level laser therapy (LLLT) promotes angiogenesis, fracture healing and osteogenic differentiation of stem cells. However, the underlying mechanisms during bone formation remain largely unknown. Factors such as wavelength, energy density, irradiation and frequency of LLLT can influence the cellular mechanisms. Moreover, the effects of LLLT are different according to cell types treated. This review aims to summarize the current knowledge of the molecular pathways activated by LLLT and its effects on the bone healing process. A better understanding of the cellular mechanisms activated by LLLT can improve its clinical application.

Diagnosis and treatment of chronic synovitis in patients with haemophilia: consensus statements from the Italian Association of Haemophilia Centres.

Although synovitis is recognized as a marker of joint disease activity, its periodic assessment is not included in routine clinical surveillance of patients with haemophilia (PwH). In order to evaluate the current knowledge and to identify controversial issues, a preliminary literature search by the Musculoskeletal Committee of the Italian Association of Haemophilia Centres (AICE) has been conducted. Statements have been established and sent to the Italian AICE members to collect their level of agreement or disagreement by a Delphi process. Thirty-seven consensus recommendations have been drafted. We found a general agreement on the indication to consider the presence of synovitis as a marker of joint disease activity in PwH. Accordingly, there was agreement on the indication to search for synovitis both in patients reporting joint pain and in asymptomatic ones, recognizing ultrasound as the most practical imaging technique to perform periodic joint screening. Interestingly, after detection of synovitis, there was agreement on the indication to modify the therapeutic approach, suggesting prophylaxis in patients treated on demand and tailoring treatment in patients already under prophylaxis. Whereas the need of an early consultation with a physiotherapist is recommended for PwH affected by chronic synovitis, the exact timing for an orthopaedic surgeon consultation is currently unknown.

The Role of PEMFs on Bone Healing: An In Vitro Study.

Bone responses to pulsed electromagnetic fields (PEMFs) have been extensively studied by using devices that expose bone cells to PEMFs to stimulate extracellular matrix (ECM) synthesis for bone and cartilage repair. The aim of this work was to highlight in which bone healing phase PEMFs exert their action. Specifically, we evaluated the effects of PEMFs both on human adipose mesenchymal stem cells (hASCs) and on primary human osteoblasts (hOBs) by testing gene and protein expression of early bone markers (on hASCs) and the synthesis of late bone-specific proteins (on hOBs) as markers of bone remodeling. Our results indicate that PEMFs seem to exert their action on bone formation, acting on osteogenic precursors (hASCs) and inducing the commitment towards the differentiation pathways, unlike mature and terminally differentiated cells (hOBs), which are known to resist homeostasis perturbation more and seem to be much less responsive than mesenchymal stem cells. Understanding the role of PEMFs on bone regenerative processes provides important details for their clinical application.

Biomarkers for Ehlers-Danlos Syndromes: There Is a Role?

Ehlers-Danlos syndromes (EDS) are an inherited heterogeneous group of connective tissue disorders characterized by an abnormal collagen synthesis affecting skin, ligaments, joints, blood vessels, and other organs. It is one of the oldest known causes of bruising and bleeding, and it was described first by Hippocrates in 400 BC. In the last years, multiple gene variants involved in the pathogenesis of specific EDS subtypes have been identified; moreover, new clinical diagnostic criteria have been established. New classification models have also been studied in order to differentiate overlapping conditions. Moreover, EDS shares many characteristics with other similar disorders. Although distinguishing between these seemingly identical conditions is difficult, it is essential in ensuring proper patient care. Currently, there are many genetic and molecular studies underway to clarify the etiology of some variants of EDS. However, the genetic basis of the hypermobile type of EDS (hEDS) is still unknown. In this review, we focused on the study of two of the most common forms of EDS-classic and hypermobile-by trying to identify possible biomarkers that could be of great help to confirm patients' diagnosis and their follow up.

Pulsed Electromagnetic Fields in Bone Healing: Molecular Pathways and Clinical Applications.

In this article, we provide an extensive review of the recent literature of the signaling pathways modulated by Pulsed Electromagnetic Fields (PEMFs) and PEMFs clinical application. A review of the literature was performed on two medical electronic databases (PubMed and Embase) from 3 to 5 March 2021. Three authors performed the evaluation of the studies and the data extraction. All studies for this review were selected following these inclusion criteria: studies written in English, studies available in full text and studies published in peer-reviewed journal. Molecular biology, identifying cell membrane receptors and pathways involved in bone healing, and studying PEMFs target of action are giving a solid basis for clinical applications of PEMFs. However, further biology studies and clinical trials with clear and standardized parameters (intensity, frequency, dose, duration, type of coil) are required to clarify the precise dose-response relationship and to understand the real applications in clinical practice of PEMFs.

The Progression of Hemophilic Arthropathy: The Role of Biomarkers.

BACKGROUND: Hemophilia A and B are X-linked congenital bleeding disorders characterized by recurrent hemarthroses leading to specific changes in the synovium and cartilage, which finally result in the destruction of the joint: this process is called hemophilic arthropathy (HA). This review highlights the most prominent molecular biomarkers found in the literature to discuss their potential use in the clinical practice to monitor bleeding, to assess the progression of the HA and the effectiveness of treatments. METHODS: A review of the literature was performed on PubMed and Embase, from 3 to 7 August 2020. Study selection and data extraction were achieved independently by two authors and the following inclusion criteria were determined a priori: English language, available full text and articles published in peer-reviewed journal. In addition, further articles were identified by checking the bibliography of relevant articles and searching for the studies cited in all the articles examined. RESULTS: Eligible studies obtained at the end of the search and screen process were seventy-three (73). CONCLUSIONS: Despite the surge of interest in the clinical use of biomarkers, current literature underlines the lack of their standardization and their potential use in the clinical practice preserving the role of physical examination and imaging in early diagnosis.

Usefulness of bone microarchitectural and geometric DXA-derived parameters in haemophilic patients.

INTRODUCTION: Haemophilia is a recessive X-linked inherited bleeding disorder, whose typical symptom is spontaneous intra-articular haemorrhage leading to joint damage, which can be quantified by the Haemophilia Joint Health Score (HJHS). Arthropathy and other characteristics of haemophilic patients may reduce bone mineral density (BMD), increasing the risk for fragility fractures, which also may occur due to bone quality impairment. AIM: To evaluate bone quantity by BMD and bone quality by Trabecular Bone Score (TBS), bone strain (BS) and hip structural analysis (HSA) in a haemophilic population, and to relate these parameters to general and specific risk factors for osteoporosis and to HJHS. METHODS: Seventy haemophilic patients ≥18 years were enrolled. Densitometric derived lumbar spine and femoral BMD with TBS, BS and HSA were performed. Data regarding risk factors for osteoporosis, presence of arthroprosthesis or arthrodesis were collected, and HJHS was calculated. A Z-score ≤-2.0 defined a low bone mass. RESULTS: Overall, a reduced bone mass was present in 52 patients at the femur and in 38 at the lumbar spine. Lumbar spine BMD, TBS and BS did not correlate with HJHS. HSA bone geometric parameters correlated negatively with HJHS. BMD and HSA correlated with some risk factors for osteoporosis, namely HIV and its therapy, hepatitis C and smoking. CONCLUSIONS: Haemophilic patients showed a reduced BMD at lumbar spine and/or femur. Femoral bone density and geometry correlated with HJHS. The microarchitecture of the trabecular vertebral bone seemed to be not influenced by the haemophilic joint damage.

Total Knee Arthroplasty in People with Hemophilia: Higher Incidence of Periprosthetic Joint Infection and 1-Year Revision/Re-Operation than the General Population and Lower Prosthetic Survival When Early Postoperative Bleeding Complications Occurred: Current Literature Review.

The purpose of this narrative review of the recent literature is to analyze the outcomes, complications, and implant survival of total knee arthroplasty (TKA) carried out on people with hemophilia (PWH). It has been shown that TKA substantially alleviates preoperative pain and improves knee function and the patient's quality of life. However, the complication rates of TKA range between 8.5% and 28.7, with postoperative hemarthrosis being the most frequent (7.6%). Besides, when comparing if the TKA was implanted before or after the year 2000, a reduction was found in the rates of periprosthetic joint infection-PJI (6.2% to 3.9%) and aseptic loosening (3.8% to 2.1%). Comparing prosthesis survival between PWH who had suffered early postoperative bleeding complications (EPBC) and patients who did not suffer EBPC, the mean survival duration was 17 years for the EPBC group and 22.1 years for the non-EPBC group. Survival rates were 80% for the EPBC group and 96.4% for the non-EPBC group. Compared to patients without hemophilia, PWH had a substantially higher incidence of PJI (Odds Ratio-OR 1.6) and 1-year revision/re-operation (OR 1.4). In short, although TKA substantially improves the quality of life of PWH, it is an intervention that has a non-negligible percentage of complications. TKA in PWH should preferably be performed only in highly specialized centers for the orthopedic treatment of hemophilia.

Treatment of Periprosthetic Hip Fractures Vancouver B1 and C: The Significance of Bicortical Fixation. A Bicentric Study Comparing Two Osteosynthesis Systems.

INTRODUCTION The incidence of periprosthetic fractures (PFFs) is estimated to range from 0.1% to 4.1%1, due to the increasing prevalence of joint arthroplasties, coupled with an aging population. Numerous risk factors, including advanced age (>80 years), female gender, implant type, prior diagnoses of osteonecrosis and rheumatoid arthritis, revision surgery, aseptic stem mobilization, and the use of non-cemented stems, have been identified. Survivors of periprosthetic fractures often experience functional deterioration, facing a fourfold higher risk of hospitalization for postoperative complications compared to patients undergoing primary implantation, especially in the first postoperative year. MATERIALS AND METHODS Between 2018 and 2022, at the Maggiore Hospitals in Bologna and the San Matteo Policlinic in Pavia, we performed osteosynthesis on 84 patients with periprosthetic fractures of Vancouver type B1 or C. In 38 patients, we employed angular stable plates with the Zimmer Biomet NCB-PP® system. In 46 patients, we utilized INTRAUMA plates: DF distal femur and PFF proximal. Relevant postoperative follow-up outcomes considered included reintervention, infectious complications, radiographic healing, and functional recovery, with reference to changes in the Glasgow Outcome Scale (GOS) and the Harris Hip Score (HHS). All patients underwent clinical and radiographic evaluations during the follow-up period, averaging 28 months (range: 12-48 months), with a minimum follow-up duration of 12 months. RESULTS At the 4-month postoperative assessment, 71% of patients maintained their preoperative functional level, 19% experienced a 1-point GOS scale drop, and 10% died (GOS 5). The average HHS at 4 months was 80.2 points (range: 65-90). At the 6-month follow-up, 98.2% of patients achieved complete healing on radiographic examination. Only 1 patient (1.2%) developed a pseudoarthrosis site with synthesis device rupture. Only 1 patient (1.2%) required additional surgical treatment 2 years later due to the development of un aseptic perisynthetic fluid collection, while the remaining 5 patients (6%) who developed complications benefited from conservative treatment: 4 patients (3.6%) with infectious complications were treated with intravenous antibiotics. In the 2 patients (2.3%) with mobilization or rupture of synthesis devices, clinical and radiographic monitoring was opted for. 8 patients (10.7%) died: one 48 hours after the surgery, and the other 7 more than one month after the surgery. CONCLUSION Our clinical findings align with to existing scientific literature on periprosthetic fractures (B1 and C according to Vancouver classification). Moreover, good stability has been guaranteed at the radiological follow up by Zimmer Biomet NCB-PP® and INTRAUMA DF distal femur and PFF proximal plates. The locking construct allows for improved stability especially in osteoporotic bone.

Pain Care Management in Rare Diseases.

In this Special Issue on "Musculoskeletal Pain Care and Management in Rare Disease", it is essential to make it clear that, while specialists in rare diseases (RDs) are often very knowledgeable about the management of the specific diseases in which they are experts, primary care physicians and other physicians who are not experts in a given disease often have very little contact with the patients who experience it [...].

Pain in Ehlers-Danlos Syndrome: A Non-Diagnostic Disabling Symptom?

BACKGROUND: Ehlers-Danlos syndrome (EDS) is a phenotypically and genetically heterogeneous group of connective tissue disorders. Currently, diagnosis of EDS is based on a series of clinical and genetic tools. On the other hand, the hypermobile form has not yet been characterized from a genetic point of view: it is considered a part of a continuous spectrum of phenotypes, ranging from isolated non syndromic joint hypermobility, through to the recently defined hypermobility spectrum disorders (HSD). The aim of this study is to characterize the pain symptom that is not considered among the diagnostic criteria but is relevant to what concerns the quality of life of patients with EDS. (2) Methods: A review of the literature was performed on two medical electronic databases (PubMed and Embase) on 20 December 2022. Study selection and data extraction were achieved independently by two authors and the following inclusion criteria were determined a priori: published in the English language and published between 2000 and 2022. (3) Results: There were fifty eligible studies obtained at the end of the search and screen process. Pain is one of the most common symptoms found in Ehlers-Danlos (ED) patients. Different causes seem to be recognized in different phases of the syndrome. (4) Conclusions: Pain is a nonspecific symptom and cannot be considered among the diagnostic criteria, but it is a negative predictive factor in the quality of life of patients with EDS. Therefore, proper evaluation and treatment is mandatory.

Subtrochanteric femoral fractures: A case series of 194 patients treated with long and short intramedullary nails.

Background: IM nails are the gold standard of subtrochanteric fractures management. Indications to use a short rather than a long nail remain unclear. Operative complications of subtrochanteric fractures reach up to 25%. Objective: Retrospectively compare clinical and radiographic outcome of subtrochanteric fractures treated by long and short intramedullary nailing, analysing rates of complications. Methods: 390 patients were chosen from the archives. 194 patients were available: 70 treated with a short intramedullary nail (Group A), while 124 with long one (Group B). Radiographic evaluation at 6 and 12 months assess failure of the osteosynthesis. Clinical outcomes were the return to normal activities prior trauma and VAS scale. Group A mean age was 81.37 years, group B mean age was 78.9 years (29-99, SD: 15.38). Results: Radiografic Healing was found in 66 patients (94.28%) in group A, while in 116 patients (94.54%) in group B. Pseudarthrosis was found in 4 cases (5.71%) in group A, while in 8 cases (6.45%) in group B. Implant failure occurred in 5 cases: one required revision of fixation, while 4 require hip replacement. 59 patients of group A (84.29%) returned to social life, while 102 patients (81.94%) in group B. Group A mean VAS was 1.55, Group B mean VAS was 1.49. Conclusion: Comparison of the two group showed no differences. Complication percentages are in line with literature. Optimal reduction and fixation allow high percentage of healing and return to social life.

Fast Functional Rehabilitation Protocol versus Plaster Cast Immobilization Protocol after Achilles Tendon Tenorrhaphy: Is It Different? Clinical, Ultrasonographic, and Elastographic Comparison.

BACKGROUND: the incidence of Achilles tendon (AT) rupture is rising; however, there is no clear consensus regarding the optimal treatment. The aim of this retrospective study was to compare instrumental and patient-reported outcome scores after fast functional rehabilitation (group A) versus plaster cast immobilization (group B) programs in patients who underwent AT tenorrhaphy. METHODS: 33 patients, with similar clinical and demographic features, underwent open AT tenorrhaphy between January and July 2018. Of these, 15 patients were treated with fast functional rehabilitation program (group A), and 18 patients were treated with plaster cast immobilization protocol (group B). Sural triceps hypotrophy and functional scores (American Orthopaedic Foot and Ankle Society (AOFAS) Ankle-Hindfoot Score, and Achilles tendon Total Rupture Score (ATRS)) were recorded at a 12-month follow-up. Ultrasonography (US) and elastosonography (ES) were used to compare the characteristics of the tendons after surgery. RESULTS: At 12 months, no significant differences in any of the patient-reported outcomes or the instrumental measurement tests were seen between the two groups. CONCLUSIONS: fast functional rehabilitation after AT surgical repair is safe, effective, and may be the first choice of treatment, especially in young, collaborative, and active patients.

Patients with Musculoskeletal Disorders Presenting to the Emergency Department: The COVID-19 Lesson.

BACKGROUND: Musculoskeletal disorders (MSKDs) are the most common class of complaints among patients presenting for care in the Emergency Department (ED). There is a non-urgent patient population with musculoskeletal complaints attending ED services that creates a burgeoning waiting list and contributes to overcrowding in Emergency Departments (EDs), which is a major concern worldwide. The recent (Coronavirus disease-19) COVID-19 pandemic is an unprecedented challenge that is revealing the structural and situational strengths and weaknesses of healthcare systems. METHODS: This study retrospectively and prospectively assessed patients presenting to the Emergency Department before and after the COVID-19 outbreak (from 21 February 2019 to 3 May 2019 and from 21 February 2020 to 3 May 2020) with non-traumatic or low-severity musculoskeletal conditions to test the hypothesis that these patients should have access to care outside the ED and that the COVID-19 outbreak has changed patients' care and health perception. RESULTS: A total of 613 patients were identified, and 542 of them (87.56%) participated in a personalized survey. From this number, 81.73% of the total accesses took place in 2019, and only 18.27% of the accesses took place during the first outbreak and lockdown. More than 90% of patients admitted to the ED accessed care during the day shift in both periods. A total of 87.30% of patients presenting to the ED with a MSKD followed their general practitioner's (GP) advice/referral in 2019, and 73.87% did so in 2020. The differences in the means of transport to the ED was statistically significant (p-value 0.002). CONCLUSIONS: The outbreak and lockdown period confirmed that there is an inappropriate use of the ED related to patients with MSKD. However, the ED appears to be the only available solution for these patients. New services and pathways are therefore needed to enhance MSKD management and reduce ED crowding. Additional observational studies shall be developed to confirm and compare our findings with those of various EDs. The main limit of the inferential part of the study is probably due to the small sample of patients in 2020.

Promoting physical activity in people with haemophilia: the MEMO (Movement for persons with haEMOphilia) expert consensus project.

Regular physical activity can increase joint stability and function, reduce the risk of injury, and improve quality of life of people with haemophilia (PwH). However, a recent review of the literature shows that appropriate physical activity and sport are not always promoted enough in the overall management of PwH. A group of Italian experts in haemophilia care undertook a consensus procedure to provide practical guidance on when and how to recommend physical exercise programmes to PwH in clinical practice. Three main topics were identified -haemophilia and its impact on movement, physical activity recommendations for PwH, and choice and management of sports activity in PwH- and ten statements were formulated. A modified Delphi approach was used to reach a consensus. The group also created practical tools proposing different physical activities and frequencies for different age groups, the Movement Pyramids, to be shared and discussed with patients and caregivers. In conclusion, in the opinion of the working group, physical activity can be considered as a low-price intervention that can prevent/reduce the occurrence of chronic diseases and should be further encouraged in PwH to obtain multiple physical and psychological benefits. Future research should include prospective studies focusing on participation in sports, specific risk exposure and clinical outcomes.

Detection of SARS-CoV-2 in Cancellous Bone of Patients with COVID-19 Disease Undergoing Orthopedic Surgery: Laboratory Findings and Clinical Applications.

An emerging issue for orthopedic surgeons is how to manage patients with active or previous COVID-19 disease, avoiding any major risks for the surgeons and the O.R. personnel. This monocentric prospective observational study aims to assess the prevalence of SARS-CoV-2 viral RT-PCR RNA in cancellous bone samples in patients with active or previous COVID-19 disease. We collected data about 30 consecutive patients from our institution from January 2021 to March 2021 with active or previous COVID-19 disease. The presence of SARS-CoV-2 in the samples was determined using two different PCR-based assays. Eighteen of the thirty patients included in the study had a positive nasopharyngeal swab at the time of surgery. Twelve patients had a negative nasopharyngeal swab with a mean days since negativization of 138 ± 104 days, ranging from 23 to 331 days. Mean days of positivity to the nasal swab were 17 ± 17. Twenty-nine out of thirty (96.7%) samples were negative for the presence of SARS-CoV-2 RNA. In one sample, low SARS-CoV-2 load (Cycle threshold (Ct) 36.6.) was detected but not confirmed using an additional confirmatory assay. The conducted study demonstrates the absence of the viral genome within the analyzed cancellous bone. We think that the use of personal protection equipment (PPE) to only protect from aerosol produced during surgery, both in active and recovered patients, is not strictly necessary. We think that the use of PPE should not be employed by surgeons and the O.R. personnel to protect themselves from aerosols produced from the respiratory tract. Moreover, we think that our results could represent a valid basis for further studies related to the possibility of bone donation in patients that suffered and recovered from COVID-19.