Showing papers by "Nicola Maffulli published in 2020"

Musculoskeletal symptoms in SARS-CoV-2 (COVID-19) patients.

Abstract: The novel SARS-CoV-2 (COVID-19) became a pandemic on 11 March 2020. The epidemiological picture is constantly evolving, and on 13 May, 4,170,424 cases and 287,399 confirmed deaths have been reported (WHO Report). People with COVID-19 infection may show several symptoms, including fever, cough, nausea, vomiting, dyspnea, myalgia, fatigue, arthralgia, headache, diarrhea, and rarely arthritis [1]. COVID-19 clinical features range from asymptomatic patients to acute respiratory distress syndrome (ARDS) and multiple organ dysfunction [2, 3]. Influenza symptoms are associated with a cascade of inflammatory mediators. Interleukin-6 (IL-6) and tumor necrosis factor-α (TNFα) levels in plasma and upper respiratory secretions directly correlate with the magnitude of viral replication, fever, and respiratory and systemic symptoms, including musculoskeletal clinical manifestations [4, 5] Musculoskeletal symptoms such as fatigue, myalgia and arthralgia are common COVID-19 symptoms, but their prevalence has not yet been systematically investigated [6, 7]. We collected the published clinical data of the past 5 months to ascertain the prevalence of musculoskeletal symptoms and epidemiological characteristics published worldwide in COVID-19 patients. Data were tabulated using Microsoft Excel 2020 V.16.34. The value was showed as mean ± SD. Student t test was used to reveal musculoskeletal symptoms between the total sample. To assess the incidence for each clinical variable, frequency analysis was performed. Regression analysis (R) was used to examine correlations between the total sample and musculoskeletal symptoms extracted. The level of significant was set at p < 0.05. The relevant reference and the data collected from the included articles are indicated in Tables 1 and 2. Data on 12,046 patients (54% male and 46% females) were available. The number of patients in the selected studies ranged from 5 to 1590 patients (223 ± 312 patients). The sex ratio (male to female) was 1:15, and the overall average of patients was 52.13 years. The majority of the studies arose from China, mainly from Wuhan; one was from Singapore [57], two from Europe [46, 59], one from the USA [36], and one from Bolivia [58]. Musculoskeletal symptoms were present from the earliest stage of the viral illness and were reported in patients necessitating intensive care in the end stage of the condition. The total prevalence of fatigue symptom was 25.6% (R =0.56; p value = 0.004), while the prevalence of arthralgia and/or myalgia was 15.5% (R = 0.66; p value = 0.001; Fig. 1). Eight studies reported a prevalence higher than 50% of patients with fatigue [8, 9, 24, 25, 28, 37, 46, 47], while three studies reported higher values for arthralgia/myalgia symptoms [50, 53, 59]. The prevalence of musculoskeletal symptoms in studies from Europe reached high values [46, 59]; Lechien et al., for example, reported on 417 COVID-19 patients from 12 European hospitals and found myalgia in 246 (59%) and arthralgia in 129 (31%) of these patients [59]. Clinical presentation of COVID-19 ranges from absence of symptoms to severe pneumonia. Fever, dry cough and fatigue are common symptoms, as indeed are myalgia and arthralgia [6, 53]. Most of the articles are retrospective single center studies: data were collected in a non-homogeneous way, especially regarding comorbidities, lifestyle habits, and severity of the illness. Based on our work, we cannot state, for example, whether children and younger patients less commonly present musculoskeletal symptoms at onset [63]. Most studies originate from China, which is not surprising, and it is not clear whether the prevalence of musculoskeletal

ICON 2019: International Scientific Tendinopathy Symposium Consensus: Clinical Terminology

Abstract: Persistent tendon pain that impairs function has inconsistent medical terms that can influence choice of treatment.1 When a person is told they have tendinopathy by clinician A or tendinitis by clinician B, they might feel confused or be alarmed at receiving what they might perceive as two different diagnoses. This may lead to loss of confidence in their health professional and likely adds to uncertainty if they were to search for information about their condition. Clear and uniform terminology also assists inter-professional communication. Inconsistency in terminology for painful tendon disorders is a problem at numerous anatomical sites. Historically, the term ‘tendinitis’ was first used to describe tendon pain, thickening and impaired function (online supplementary figure S1). The term ‘tendinosis’ has also been used in a small number of publications, some of which were very influential.2 3 Subsequently, ‘tendinopathy’ emerged as the most common term for persistent tendon pain.4 5 To our knowledge, experts (clinicians and researchers) or patients have never engaged in a formal process to discuss the terminology we use. We believe that health professionals have not yet agreed on the appropriate terminology for painful tendon conditions. ### Supplementary data [bjsports-2019-100885supp001.pdf] The authors of this paper, a group of international clinical and research experts from different disciplines, aimed to achieve a consensus in terminology for persistent tendon disorders. We ran a Delphi and consensus process that culminated in a face-to-face meeting at the fifth International Scientific Tendinopathy Symposium (ISTS) in Groningen, the Netherlands, on 26 September 2018 (placeholder for sentence about the other two papers and accompanying editorial if they get accepted). Here, we present the resulting consensus statements on terminology for persistent tendon pain. Our two-stage Delphi design, consensus process consisted of an online survey followed by a face-to-face meeting. One of us (AS) drafted 11 statements about terminology …

Therapeutic potential of microRNA in tendon injuries

Abstract: Introduction The regulatory role of microRNA (miRNA) in several conditions has been studied, but their function in tendon healing remains elusive. This review summarizes how miRNAs are related to the pathogenesis of tendon injuries and highlights their clinical potential, focusing on the issues related to their delivery for clinical purposes. Sources of data We searched multiple databases to perform a systematic review on miRNA in relation to tendon injuries. We included in the present work a total of 15 articles. Areas of agreement The mechanism of repair of tendon injuries is probably mediated by resident tenocytes. These maintain a fine equilibrium between anabolic and catabolic events of the extracellular matrix. Specific miRNAs regulate cytokine expression and orchestrate proliferation and differentiation of stromal cell lines involved in the composition of the extracellular matrix. Areas of controversy The lack of effective delivery systems poses serious obstacles to the clinical translation of these basic science findings. Growing point In vivo studies should be planned to better explore the relationship between miRNA and tendon injuries and evaluate the most suitable delivery system for these molecules. Areas timely for developing research Investigations ex vivo suggest therapeutic opportunities of miRNA for the management of tendon injuries. Given the poor pharmacokinetic properties of miRNAs, these must be delivered by an adequate adjuvant transport system.

ICON 2019—International Scientific Tendinopathy Symposium Consensus: There are nine core health-related domains for tendinopathy (CORE DOMAINS): Delphi study of healthcare professionals and patients

Abstract: BackgroundThe absence of any agreed-upon tendon health-related domains hampers advances in clinical tendinopathy research. This void means that researchers report a very wide range of outcome measu ...

Italy and COVID-19: the changing patient flow in an orthopedic trauma center emergency department.

Abstract: On 12 March 2020, the World Health Organization declared a pandemic by Coronavirus disease (COVID-19) [1]. Despite the lockdown measures adopted to stop the spread of SARS-CoV-2, we are dangerously close to 400, 000 deaths worldwide [2]. In Northern Italy, the overwhelming number of COVID-19 patients required a complete reorganization of the healthcare system [3, 4]: wards were converted into COVID-19 care units, and deferrable surgeries and outpatient consultations were suspended. Some hospitals were designated hubs for specific urgent conditions [5], with the need to maximize resources and reduce patient crowding, reducing potential nosocomial COVID-19 spread. Major changes in the patient flow at the emergency department (ED) of Galeazzi Orthopaedic Institute in Milan, a major trauma center, were evident. The analysis of this aspect during the first month of the pandemic (12 March to 12 April 2020) compared to the same period in 2019 demonstrated marked differences in length of emergency department stay, request for chest radiographs, discharge diagnosis, triage color-code at admission and discharge (white code: non-urgent patients; green code: urgent but non-critical patients; yellow code: fairly critical patients; red code: patients at danger of death), and emergency department arrival and discharge modalities. The number of patients in this 1-month period was 2558 in 2019 and 670 in 2020, an overall patient flow reduction of 73.8%. Patients’ demographics and diagnoses at discharge are summarized in Table 1. Average patients’ age was significantly higher in 2020 than in 2019 (t(3226) = 14.75, p < 0.0001), with a marked reduction in the number of pediatric emergencies (age ≤ 18 years old) during lockdown (OR 0.31, 95% CI 0.23–0.42, p < 0.0001). The mean emergency department length of stay significantly decreased in 2020 (t(3226) = 10.85, p < 0.0001). Furthermore, during the pandemic, more chest plain radiographs were requested (OR 6.11, 95% CI 4.81–7.77, p < 0.0001). The number of patients discharged with a diagnosis other than “fracture” (therefore including sprains, contusions, back pain) was markedly reduced (OR 0.24, 95% CI 0.20–0.28, p < 0.0001) in 2020. On the other hand, both proximal femoral fractures showed a remarkable increase (OR 13.6, 95% CI 9.31–19.85, p < 0.0001) during the pandemic, as did the overall rate of fragility fractures in the elderly (OR 7.57, 95% CI 5.87–9.76, p < 0.0001). Table 2 reports the triage codes at admission and discharge. A reduction of 8.9% and 14.1% for white and green codes, respectively, was found in the pandemic month. As expected, comparing the walking wounded (green and white codes) and urgent patient (yellow and red codes) rates in 2019 and 2020, an odds ratio of 0.12 (95% CI 0.09–0.15, p < 0.0001) was found. Similarly, triage at discharge presented a reduction of the white codes and a relative increase of all the other triage categories (OR 0.56, 95% CI 0.44–0.70, p < 0.0001). The rate of patients brought to emergency department by ambulance increased in 2020 (Table 2) (OR 5.56, 95% CI 4.52–6.84, p < 0.0001). Finally, in 2020 more patients

Umbilical cord-derived Wharton's jelly for regenerative medicine applications.

Abstract: The last decade has seen an explosion in the interest in using biologics for regenerative medicine applications, including umbilical cord-derived Wharton’s Jelly. There is insufficient literature assessing the amount of growth factors, cytokines, hyaluronic acid, and extracellular vesicles including exosomes in these products. The present study reports the development of a novel Wharton’s jelly formulation and evaluates the presence of growth factors, cytokines, hyaluronic acid, and extracellular vesicles including exosomes. Human umbilical cords were obtained from consenting caesarian section donors. The Wharton’s jelly was then isolated from the procured umbilical cord and formulated into an injectable form. Randomly selected samples from different batches were analyzed for sterility testing and to quantify the presence of growth factors, cytokines, hyaluronic acid, and extracellular vesicles. All samples passed the sterility test. Growth factors including IGFBP 1, 2, 3, 4, and 6, TGF-α, and PDGF-AA were detected. Several immunomodulatory cytokines, such as RANTES, IL-6R, and IL-16, were also detected. Pro-inflammatory cytokines MCSFR, MIP-1a; anti-inflammatory cytokines TNF-RI, TNF-RII, and IL-1RA; and homeostatic cytokines TIMP-1 and TIMP-2 were observed. Cytokines associated with wound healing, ICAM-1, G-CSF, GDF-15, and regenerative properties, GH, were also expressed. High concentrations of hyaluronic acid were observed. Particles in the extracellular vesicle size range were also detected and were enclosed by the membrane, indicative of true extracellular vesicles. There are numerous growth factors, cytokines, hyaluronic acid, and extracellular vesicles present in the Wharton’s jelly formulation analyzed. The amount of these factors in Wharton’s jelly is higher compared with other biologics and may play a role in reducing inflammation and pain and augment healing of musculoskeletal injuries.

ICON PART-T 2019–International Scientific Tendinopathy Symposium Consensus: recommended standards for reporting participant characteristics in tendinopathy research (PART-T)

Abstract: We aimed to establish consensus for reporting recommendations relating to participant characteristics in tendon research. A scoping literature review of tendinopathy studies (Achilles, patellar, hamstring, gluteal and elbow) was followed by an online survey and face-to-face consensus meeting with expert healthcare professionals (HCPs) at the International Scientific Tendon Symposium, Groningen 2018. We reviewed 263 papers to form statements for consensus and invited 30 HCPs from different disciplines and geographical locations; 28 completed the survey and 15 attended the meeting. There was consensus that the following data should be reported for cases and controls: sex, age, standing height, body mass, history of tendinopathy, whether imaging was used to confirm pathology, loading tests, pain location, symptom duration and severity, level of disability, comorbidities, physical activity level, recruitment source and strategies, and medication use history. Standardised reporting of participant characteristics aims to benefit patients and clinicians by guiding researchers in the conduct of their studies. We provide free resources to facilitate researchers adopting our recommendations.

Tendon and Cytokine Marker Expression by Human Bone Marrow Mesenchymal Stem Cells in a Hyaluronate/Poly-Lactic-Co-Glycolic Acid (PLGA)/Fibrin Three-Dimensional (3D) Scaffold.

Abstract: We developed a (three-dimensional) 3D scaffold, we named HY-FIB, incorporating a force-transmission band of braided hyaluronate embedded in a cell localizing fibrin hydrogel and poly-lactic-co-glycolic acid (PLGA) nanocarriers as transient components for growth factor controlled delivery. The tenogenic supporting capacity of HY-FIB on human-Bone Marrow Mesenchymal Stem Cells (hBM-MSCs) was explored under static conditions and under bioreactor-induced cyclic strain conditions. HY-FIB elasticity enabled to deliver a mean shear stress of 0.09 Pa for 4 h/day. Tendon and cytokine marker expression by hBM-MSCs were studied. Results: hBM-MSCs embedded in HY-FIB and subjected to mechanical stimulation, resulted in a typical tenogenic phenotype, as indicated by type 1 Collagen fiber immunofluorescence. RT-qPCR showed an increase of type 1 Collagen, scleraxis, and decorin gene expression (3-fold, 1600-fold, and 3-fold, respectively, at day 11) in dynamic conditions. Cells also showed pro-inflammatory (IL-6, TNF, IL-12A, IL-1β) and anti-inflammatory (IL-10, TGF-β1) cytokine gene expressions, with a significant increase of anti-inflammatory cytokines in dynamic conditions (IL-10 and TGF-β1 300-fold and 4-fold, respectively, at day 11). Mechanical signaling, conveyed by HY-FIB to hBM-MSCs, promoted tenogenic gene markers expression and a pro-repair cytokine balance. The results provide strong evidence in support of the HY-FIB system and its interaction with cells and its potential for use as a predictive in vitro model.

Safety and efficacy of treating symptomatic, partial-thickness rotator cuff tears with fresh, uncultured, unmodified, autologous adipose-derived regenerative cells (UA-ADRCs) isolated at the point of care: a prospective, randomized, controlled first-in-human pilot study

Abstract: This study tested the hypothesis that treatment of symptomatic, partial-thickness rotator cuff tears (sPTRCT) with fresh, uncultured, unmodified, autologous adipose-derived regenerative cells (UA-ADRCs) isolated from lipoaspirate at the point of care is safe and more effective than corticosteroid injection. Subjects aged between 30 and 75 years with sPTRCT who did not respond to physical therapy treatments for at least 6 weeks were randomly assigned to receive a single injection of an average 11.4 × 106 UA-ADRCs (in 5 mL liquid; mean cell viability: 88%) (n = 11; modified intention-to-treat (mITT) population) or a single injection of 80 mg of methylprednisolone (40 mg/mL; 2 mL) plus 3 mL of 0.25% bupivacaine (n = 5; mITT population), respectively. Safety and efficacy were assessed using the American Shoulder and Elbow Surgeons Standardized Shoulder Assessment Form (ASES), RAND Short Form-36 Health Survey, and pain visual analogue scale (VAS) at baseline (BL) as well as 3 weeks (W3), W6, W9, W12, W24, W32, W40, and W52 post treatment. Fat-saturated T2-weighted magnetic resonance imaging of the shoulder was performed at BL as well as at W24 and W52 post treatment. No severe adverse events related to the injection of UA-ADRCs were observed in the 12 months post treatment. The risks connected with treatment of sPTRCT with UA-ADRCs were not greater than those connected with treatment of sPTRCT with corticosteroid injection. However, one subject in the corticosteroid group developed a full rotator cuff tear during the course of this pilot study. Despite the small number of subjects in this pilot study, those in the UA-ADRCs group showed statistically significantly higher mean ASES total scores at W24 and W52 post treatment than those in the corticosteroid group (p < 0.05). This pilot study suggests that the use of UA-ADRCs in subjects with sPTRCT is safe and leads to improved shoulder function without adverse effects. To verify the results of this initial safety and feasibility pilot study in a larger patient population, a randomized controlled trial on 246 patients suffering from sPTRCT is currently ongoing. Clinicaltrials.gov ID NCT02918136. Registered September 28, 2016, https://clinicaltrials.gov/ct2/show/NCT02918136. Level I; prospective, randomized, controlled trial.

COVID-19: not a contraindication for surgery in patients with proximal femur fragility fractures.

Abstract: During the SARS-CoV-2 outbreak, Italy was the leading country for the number of new positive cases from March 8 2020, to March 21, and the first for the total number of deaths from March 19, to April 12 2020 [1– 4]. The Italian National Healthcare System required the conversion of many wards into COVID-19 care units, and the suspension of deferrable treatments, surgical procedures and outpatient visits, to dedicate human and material resources to free Intensive Care Unit (ICU) beds. In the most struck regions, some hospitals were designated as hubs for non-delayable treatments [5, 6]. Our institution (IRCCS Orthopaedic Institute Galeazzi) was chosen amongst the Trauma Hubs. Orthopaedic trauma surgery focused mainly on femoral fragility fractures in the elderly, since the “lockdown” began on March 10, 2020. Proximal femur fractures carry a high mortality rate [7], and the standard of care involves surgery within 48 h from the trauma [8]. These elderly patients are also the most susceptible to the nefarious consequences of COVID-19 [9]. Thus, orthopaedic surgeons face the daily dilemma of performing life-saving surgery on patients who, given their severe respiratory compromise, have a higher risk of peri-operative death. Preliminary reports from Wuhan, Bergamo (the Italian province with the highest number of cases) and Spain drew different conclusions on the possible benefit effects of surgery on COVID-19 patients with proximal femur fractures [10– 12]. In the first case series, six patients reported proximal femur fractures, but only three were considered eligible for surgery because of no signs of pneumonia at CT scan or non-severe respiratory symptoms [10]. Three of them died, two after conservative management. Of the three surviving patients, two underwent surgery: the authors concluded that patients with proximal femoral fractures and COVID-19 have a higher risk of death. In a series of 16 such patients in Bergamo (Lombardy), Italy [11], three patients died before surgeries for respiratory failure. The other 13 patients (temperature < 38 °C, pO2 > 90% and no signs of multiorgan dysfunction) underwent surgery, with four dying in the first postoperative week. Oxygen saturation improved after surgery in the survivors. Finally, a multicentre observational study on 136 proximal femoral fractures reported an overall 30.4% mortality in COVID19 patients. The mortality rate was 67% in COVID-19 patients treated non-operatively, and only 4% in patients who underwent surgery [12]. The early outcomes (March 17–April 17, 2020) from our Trauma hub endorse the “to fix” faction. Ten swabconfirmed COVID-19 patients (8 women and 2 men) with a mean age of 83.9 ± 7.4 years (range 72-98) underwent surgical treatment for their proximal femoral fractures within 48 h from admission at our facility: 8 patients received intramedullary nailing for AO 31A fractures, and 2 received hemiarthroplasty for AO 31B fractures [13]. The

Extracellular vesicles from rat-bone-marrow mesenchymal stromal/stem cells improve tendon repair in rat Achilles tendon injury model in dose-dependent manner: A pilot study

Abstract: Mesenchymal stromal/stem cells (MSCs) are increasingly employed for tissue regeneration, largely mediated through paracrine actions. Currently, extracellular vesicles (EVs) released by MSCs are major mediators of these paracrine effects. We evaluated whether rat-bone-marrow-MSC-derived EVs (rBMSCs-EVs) can ameliorate tendon injury in an in vivo rat model. Pro-collagen1A2 and MMP14 protein are expressed in rBMSC-EVs, and are important factors for extracellular-matrix tendon-remodeling. In addition, we found pro-collagen1A2 in rBMSC-EV surface-membranes by dot blot. In vitro on cells isolated from Achilles tendons, utilized as rBMSC -EVs recipient cells, EVs at both low and high doses induce migration of tenocytes; at higher concentration, they induce proliferation and increase expression of Collagen type I in tenocytes. Pretreatment with trypsin abrogate the effect of EVs on cell proliferation and migration, and the expression of collagen I. When either low- or high-dose rBMSCs-EVs were injected into a rat-Achilles tendon injury-model (immediately after damage), at 30 days, rBMSC-EVs were found to have accelerated the remodeling stage of tendon repair in a dose-dependent manner. At histology and histomorphology evaluation, high doses of rBMSCs-EVs produced better restoration of tendon architecture, with optimal tendon-fiber alignment and lower vascularity. Higher EV-concentrations demonstrated greater expression of collagen type I and lower expression of collagen type III. BMSC-EVs hold promise as a novel cell-free modality for the management of tendon injuries.

In Vitro Innovation of Tendon Tissue Engineering Strategies.

Abstract: Tendinopathy is the term used to refer to tendon disorders. Spontaneous adult tendon healing results in scar tissue formation and fibrosis with suboptimal biomechanical properties, often resulting in poor and painful mobility. The biomechanical properties of the tissue are negatively affected. Adult tendons have a limited natural healing capacity, and often respond poorly to current treatments that frequently are focused on exercise, drug delivery, and surgical procedures. Therefore, it is of great importance to identify key molecular and cellular processes involved in the progression of tendinopathies to develop effective therapeutic strategies and drive the tissue toward regeneration. To treat tendon diseases and support tendon regeneration, cell-based therapy as well as tissue engineering approaches are considered options, though none can yet be considered conclusive in their reproduction of a safe and successful long-term solution for full microarchitecture and biomechanical tissue recovery. In vitro differentiation techniques are not yet fully validated. This review aims to compare different available tendon in vitro differentiation strategies to clarify the state of art regarding the differentiation process.

Chronic Lateral Ankle Instability: Topical Review.

Abstract: Chronic ankle instability can result from untreated or badly managed acute lateral ankle ligament injuries. Conservative management is the modality of choice for acute lateral ankle ligament injuries, and operative treatment is reserved for special cases. Failure after strict rehabilitation may be an indication for surgery. Several operative options are available, including anatomic repair, anatomic reconstruction, and tenodesis procedures. Anatomic repair can be performed when the quality of the damaged ligaments permits. Anatomic reconstruction with an autograft or allograft should be considered when the torn ligaments are not adequate. Ankle arthroscopy is a useful adjunct to ligamentous procedures, performed at the time of repair to identify and treat intra-articular conditions that may be associated with chronic ankle instability. Tenodesis techniques are not recommended because of their suboptimal long-term results related to the modification of ankle and hindfoot biomechanics.Level of Evidence: Level V, expert opinion.

Artificial intelligence and machine learning in orthopedic surgery: a systematic review protocol.

Abstract: Artificial intelligence (AI) and machine learning (ML) are interwoven into our everyday lives and have grown enormously in some major fields in medicine including cardiology and radiology. While these specialties have quickly embraced AI and ML, orthopedic surgery has been slower to do so. Fortunately, there has been a recent surge in new research emphasizing the need for a systematic review. The primary objective of this systematic review will be to provide an update on the advances of AI and ML in the field of orthopedic surgery. The secondary objectives will be to evaluate the applications of AI and ML in providing a clinical diagnosis and predicting post-operative outcomes and complications in orthopedic surgery. A systematic search will be conducted in PubMed, ScienceDirect, and Google Scholar databases for articles written in English, Italian, French, Spanish, and Portuguese language articles published up to September 2020. References will be screened and assessed for eligibility by at least two independent reviewers as per PRISMA guidelines. Studies must apply to orthopedic interventions and acute and chronic orthopedic musculoskeletal injuries to be considered eligible. Studies will be excluded if they are animal studies and do not relate to orthopedic interventions or if no clinical data were produced. Gold standard processes and practices to obtain a clinical diagnosis and predict post-operative outcomes shall be compared with and without the use of ML algorithms. Any case reports and other primary studies assessing the prediction rate of post-operative outcomes or the ability to identify a diagnosis in orthopedic surgery will be included. Systematic reviews or literature reviews will be examined to identify further studies for inclusion, and the results of meta-analyses will not be included in the analysis. Our findings will evaluate the advances of AI and ML in the field of orthopedic surgery. We expect to find a large quantity of uncontrolled studies and a smaller subset of articles describing actual applications and outcomes for clinical care. Cohort studies and large randomized control trial will likely be needed. The protocol will be registered on PROSPERO international prospective register of systematic reviews prior to commencement.

Covid-19-The real role of NSAIDs in Italy.

Abstract: On behalf of the scientists and surgeons of one of the biggest orthopedic institutes in Italy, located in Milan, we feel the urge to share our position about the recent warnings on the use of anti-inflammatory drugs (NSAIDs) in this coronavirus “era.” Similarly to the antihypertensive drugs angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), and beta blockers, and the oral antidiabetic drugs thiazolidinediones, some author have suggested that NSAIDs, particularly Ibuprofen, may induce increased sensitivity to more severe clinical features in coronavirus (Covid-19) infection. NSAIDs are widely used worldwide. In musculoskeletal medicine, they keep under control osteoarthritis, tendinopathies, bursitis, muscle soreness, radicular pain, and others. In Italy, about 12 millions of adults have osteoarthritis or rheumatoid arthritis, a number estimated to grow substantially in the next years [1]. Moreover, an extensive increase of orthopedic surgeries in both developed and developing countries, the low cost of drugs, and the progressive rise of the geriatric population have contributed to the growth of global NSAIDs use. According to the Italian Medicines Agency (AIFA), in 2018 the defined daily doses (DDDs) per 1000 inhabitants per day was 18.6 [2]. The warning about the possible role of NSAIDs in worsening the severity of Covid-19 infection was very powerful because it was spread by a representative of the national medical authority of one of the European countries strongly interested by this pandemic. The warning also suggested to the population already under anti-inflammatory drugs to ask their general practitioners for advice, unleashing a wave of panic among the population, especially through social media. Other official communications by the national health systems and emergency management agency (EMA) [3] attempted to bring back calm and rationality, with poor results. The effects of this warning has been very deleterious on our patients, especially on those who need to use these drugs for long periods for their medical conditions: NSAIDs allow these patients to lead a good quality of life, although we acknowledge that the prolonged use of these drugs may cause side effects, including kidney failure, liver failure, gastric ulcers, asthma attacks, heart and circulatory problems, and a partial immune depression [4]. Being based in Milan, we, more than others, are directly experiencing the devastating effects of this pandemic. We have been ready, and we still are now, to take any useful measures to reduce its impact on our population, without underestimating any possible new scientific information. Nevertheless, albeit in the midst of a general intellectual and emotional confusion, we try to maintain our scientific judgment, and would like to underline the danger of unproven and unfounded information, especially when spread out through mass and social media, which directly reach the general population without any filter. The current body of scientific literature reports just a few articles analyzing the relationship between exposure to NSAIDs and possible complications in patients with pneumonia. A recent article investigated whether exposure to NSAIDs prior to hospital admission among patients suffering from community-acquired pneumonia (CAP) was associated with the development of pleural complications or a lung abscess. NSAIDs intake was independently associated with the development of pleuroparenchymal complications (odds ratio = 2.57 [1.02–6.64], p = 0.049). Nevertheless, given the lack of consistent results about the direct effect of NSAIDs on the immunological response and the lack of controlled randomized studies in human, the authors could not conclude a direct effect of NSAIDs in the development of the complications of CAP [5]. Surely, in addition to the supposed interfering effect of

Current pharmacological approaches to the treatment of tendinopathy.

Abstract: Tendinopathies are common in elite and recreational athletes: traditionally considered overuse injuries, they involve excessive tensile loading and subsequent breakdown of the loaded tendon. Many p...

Artificial intelligence: A tool for sports trauma prediction.

Abstract: Injuries exert an enormous impact on athletes and teams. This is seen especially in professional soccer, with a marked negative impact on team performance and considerable costs of rehabilitation for players. Existing studies provide some preliminary understanding of which factors are mostly associated with injury risk, but scientific systematic evaluation of the potential of statistical models in forecasting injuries is still missing. Some factors raise the risk of a sport injury, but there are also elements that predispose athletes to sports injuries. The biological mechanisms involved in non-contact musculoskeletal soft tissue injuries are poorly understood. Genetic risk factors may be associated with susceptibility to injuries, and may exert marked influence on recovery times. Athletes are complex systems, and depend on internal and external factors to attain and maintain stability of their health and their performance. Organisms, participants or traits within a dynamic system adapt and change when factors within that system change. Scientists routinely predict risk in a variety of dynamic systems, including weather, political forecasting and projecting traffic fatalities and the last years have started the use of predictive models in the human health industry. We propose that the use of artificial intelligence may well help in assessing risk and help to predict the occurrence of sport injuries.

Progress with stem cell therapies for tendon tissue regeneration.

Abstract: Chronic musculoskeletal pain is very prevalent, and accounts for major health-care expenses Many of the present therapeutic modalities are only partially effective, and great interest is now posed

Freeze-Drying of Platelet-Rich Plasma: The Quest for Standardization

Abstract: The complex biology of platelets and their involvement in tissue repair and inflammation have inspired the development of platelet-rich plasma (PRP) therapies for a broad array of medical needs. However, clinical advances are hampered by the fact that PRP products, doses and treatment protocols are far from being standardized. Freeze-drying PRP (FD-PRP) preserves platelet function, cytokine concentration and functionality, and has been proposed as a consistent method for product standardization and fabrication of an off-the-shelf product with improved stability and readiness for future uses. Here, we present the current state of experimental and clinical FD-PRP research in the different medical areas in which PRP has potential to meet prevailing medical needs. A systematic search, according to PRISMA (Preferred Reported Items for Systematic Reviews and Meta-Analyses) guidelines, showed that research is mostly focused on wound healing, i.e., developing combination products for ulcer management. Injectable hydrogels are investigated for lumbar fusion and knee conditions. In dentistry, combination products permit slow kinetics of growth factor release and functionalized membranes for guided bone regeneration.

The role of the immune system in tendon healing: a systematic review

Abstract: Introduction The role of the immune system in tendon healing relies on polymorphonucleocytes, mast cells, macrophages and lymphocytes, the 'immune cells' and their cytokine production. This systematic review reports how the immune system affects tendon healing. Sources of data We registered our protocol (registration number: CRD42019141838). After searching PubMed, Embase and Cochrane Library databases, we included studies of any level of evidence published in peer-reviewed journals reporting clinical or preclinical results. The PRISMA guidelines were applied, and risk of bias and the methodological quality of the included studies were assessed. We excluded all the articles with high risk of bias and/or low quality after the assessment. We included 62 articles assessed as medium or high quality. Areas of agreement Macrophages are major actors in the promotion of proper wound healing as well as the resolution of inflammation in response to pathogenic challenge or tissue damage. The immune cells secrete cytokines involving both pro-inflammatory and anti-inflammatory factors which could affect both healing and macrophage polarization. Areas of controversy The role of lymphocytes, mast cells and polymorphonucleocytes is still inconclusive. Growing points The immune system is a major actor in the complex mechanism behind the healing response occurring in tendons after an injury. A dysregulation of the immune response can ultimately lead to a failed healing response. Areas timely for developing research Further studies are needed to shed light on therapeutic targets to improve tendon healing and in managing new way to balance immune response.

Bone metastases: a comprehensive review of the literature

Abstract: The last report of the World Health Organization (WHO) stated that approximately four million people experience bone pain due to malignant diseases. Among them, metastatic bone pain is one of the most important sources of complaint. The estimated median survival in the presence of bone metastases ranks from 10 to 12 weeks. Bone represents a potential target of distant metastases for the majority of malignant tumours. However, the exact incidence of bone metastases is unknown. Bone metastases have an important socio-economic impact, and due to the enhancement of the overall survivorship, their incidence is increasing. Malignant neoplasms such as lung, thyroid, renal cancer, multiple myeloma, and melanoma often metastasize to the bone. Bone metastases commonly localize to the spinal column, pelvis, shoulder, and distal femur. The proper treatment for painful skeletal metastases is still unknown. Hence, the purpose of this review of the literature was to update current evidence concerning the aetiogenesis, biological behaviour, and treatment algorithms for painful skeletal metastases.

Impact of an orthogeriatrician on length of stay of elderly patient with hip fracture

Abstract: Hip fracture patients are complex, and orthopaedic management is limited to the surgery phase To provide better evaluation pre-operatively and an optimal level of post-operative care, an orthogeriatrician was introduced in the orthopaedic team This ensured that time to surgery from admission consistently was below 48 h, decreasing hospitalization time after surgery and total length of stay Hip fractures are a major health issue in elderly and frail patient The integration of orthogeriatric care within the orthopaedic team could be useful to optimize the clinical conditions of these patients in perioperative phases and stabilize them after surgery, reducing hospital length of stay The present study evaluates the role of an orthogeriatrician in the management of patients with a hip fracture Data about patients admitted and operated from February to September 2018 and from February to September 2019 were collected from the San Giovanni di Dio e Ruggi d’Aragona Hospital of Salerno database A total of 352 patients were identified and divided in two groups according to the year in which the orthogeriatrician was working in Orthopaedic Department Records regarding age, sex, side and type of fracture, time of admission, day of surgery and discharge were collected and length of stay, days from the admission to surgery and days from surgery to discharge were calculated There were no statistically significant differences in the pre-surgery phases of both groups, and all patients were operated at a mean of 21 days ± 18 SD from admission (p > 005) No statistically significant difference between demographic data in both groups (p > 001) was observed There was, however, statistically significant reduction of hospitalization time after surgery and total LOS from 2018 to 2019 (p < 001) An Orthogeriatric doctor in an Orthopaedic and Traumatology Department may lead a multidisciplinary approach to manage elderly patients with hip fractures, ensuring that the time to surgery from admission is less than 48 h, and reducing hospitalization time after surgery and total length of stay

Management of Achilles and patellar tendinopathy: what we know, what we can do

Abstract: Tendinopathies are challenging conditions frequent in athletes and in middle-aged overweight patients with no history of increased physical activity. The term “tendinopathy” refers to a clinical condition characterised by pain, swelling, and functional limitations of tendons and nearby structures, the effect of chronic failure of healing response. Tendinopathies give rise to significant morbidity, and, at present, only limited scientifically proven management modalities exist. Achilles and patellar tendons are among the most vulnerable tendons, and among the most frequent lower extremity overuse injuries. Achilles and patellar tendinopathies can be managed primarily conservatively, obtaining good results and clinical outcomes, but, when this approach fails, surgery should be considered. Several surgical procedures have been described for both conditions, and, if performed well, they lead to a relatively high rate of success with few complications. The purpose of this narrative review is to critically examine the recent available scientific literature to provide evidence-based opinions on these two common and troublesome conditions.

Home-based motor imagery intervention improves functional performance following total knee arthroplasty in the short term: a randomized controlled trial

Abstract: Motor imagery (MI) is effective in improving motor performance in the healthy asymptomatic adult population. However, its possible effects among older orthopaedic patients are still poorly investigated. Therefore, this study explored whether the addition of motor imagery to routine physical therapy reduces the deterioration of quadriceps muscle strength and voluntary activation (VA) as well as other variables related to motor performance in patients after total knee arthroplasty (TKA). Twenty-six patients scheduled for TKA were randomized to either MI practice combined with routine physical therapy group (MIp) or to a control group receiving physical therapy alone (CON). MIp consisted of maximal voluntary isometric contraction (MViC) task: 15 min/day in the hospital, then 5 times/week in their homes for 4 weeks. MViC and VA of quadriceps muscle, knee flexion and extension range of motion, pain level, along with a Timed Up-and-Go Test (TUG) and self-reported measure of physical function (assessed using the Oxford Knee Score questionnaire [OKS]) were evaluated before (PRE) and 1 month after surgery (POST). Significantly better rehabilitation outcomes were evident on the operated leg for the MIp group compared to CON: at POST, the MIp showed lower strength decrease (p = 0.012, η2 = 0.237) and unaltered VA, significantly greater than CON (p = 0.014, η2 = 0.227). There were no significant differences in knee flexion and extension range of motion and pain level (p > 0.05). Further, MIp patients performed better in TUG (p 0.05). In addition, multiple linear regression analysis showed that failure of voluntary activation explained 47% of the quadriceps muscle strength loss, with no significant difference in perceived level of pain. MI practice, when added to physical therapy, improves both objective and subjective measures of patients’ physical function after TKA, and facilitates transfer of MI strength task on functional mobility. Retrospectively registered on ClinicalTrials.gov NCT03684148

Dose-Response Tendon-Specific Markers Induction by Growth Differentiation Factor-5 in Human Bone Marrow and Umbilical Cord Mesenchymal Stem Cells.

Abstract: Mesenchymal stem cells derived from human bone marrow (hBM-MSCs) are utilized in tendon tissue-engineering protocols while extra-embryonic cord-derived, including from Wharton's Jelly (hWJ-MSCs), are emerging as useful alternatives. To explore the tenogenic responsiveness of hBM-MSCs and hWJ-MSCs to human Growth Differentiation Factor 5 (hGDF-5) we supplemented each at doses of 1, 10, and 100 ng/mL of hGDF-5 and determined proliferation, morphology and time-dependent expression of tenogenic markers. We evaluated the expression of collagen types 1 (COL1A1) and 3 (COL3A1), Decorin (DCN), Scleraxis-A (SCX-A), Tenascin-C (TNC) and Tenomodulin (TNMD) noting the earliest and largest increase with 100 ng/mL. With 100 ng/mL, hBM-MSCs showed up-regulation of SCX-A (1.7-fold) at Day 1, TNC (1.3-fold) and TNMD (12-fold) at Day 8. hWJ-MSCs, at the same dose, showed up-regulation of COL1A1 (3-fold), DCN (2.7-fold), SCX-A (3.8-fold) and TNC (2.3-fold) after three days of culture. hWJ-MSCs also showed larger proliferation rate and marked aggregation into a tubular-shaped system at Day 7 (with 100 ng/mL of hGDF-5). Simultaneous to this, we explored the expression of pro-inflammatory (IL-6, TNF, IL-12A, IL-1β) and anti-inflammatory (IL-10, TGF-β1) cytokines across for both cell types. hBM-MSCs exhibited a better balance of pro-inflammatory and anti-inflammatory cytokines up-regulating IL-1β (11-fold) and IL-10 (10-fold) at Day 8; hWJ-MSCs, had a slight expression of IL-12A (1.5-fold), but a greater up-regulation of IL-10 (2.5-fold). Type 1 collagen and tenomodulin proteins, detected by immunofluorescence, confirming the greater protein expression when 100 ng/mL were supplemented. In the same conditions, both cell types showed specific alignment and shape modification with a length/width ratio increase, suggesting their response in activating tenogenic commitment events, and they both potential use in 3D in vitro tissue-engineering protocols.

Preliminary Experience With a Minimally Invasive Technique for Hallux Valgus Correction With No Fixation.

Abstract: Background:Percutaneous operative techniques for hallux valgus (HV) correction are less damaging to soft tissues and the first metatarsophalangeal joint, and they carry a lower risk of wound compli...

Delayed (14-30 Days) Percutaneous Repair of Achilles Tendon Ruptures Offers Equally Good Results As Compared With Acute Repair.

Abstract: Background:Minimally invasive repair of acute Achilles tendon ruptures has been performed for several years, resulting in reduced morbidity as compared with open repair.Hypothesis:A minimally invas...

Cell-free Stem Cell-Derived Extract Formulation for Regenerative Medicine Applications.

Abstract: Stem cells for regenerative medicine purposes offer therapeutic benefits, but disadvantages are still ill defined. The benefit of stem cells may be attributed to their secretion of growth factors (GFs), cytokines (CKs), and extracellular vesicles (EVs), including exosomes. We present a novel cell-free stem cell-derived extract (CCM), formulated from human progenitor endothelial stem cells (hPESCs), characterized for biologically active factors using ELISA, nanoparticle tracking analysis and single particle interferometric reflectance imaging sensing. The effect on fibroblast proliferation and ability to induce stem cell migration was analyzed using Alamar Blue proliferation and Transwell migration assays, respectively. GFs including IGFBP 1, 2, 3, and 6, insulin, growth hormone, PDGF-AA, TGF-α, TGF-β1, VEGF, and the anti-inflammatory cytokine, IL-1RA were detected. Membrane enclosed particles within exosome size range and expressing exosome tetraspanins CD81 and CD9 were identified. CCM significantly increased cell proliferation and induced stem cell migration. Analysis of CCM revealed presence of GFs, CKs, and EVs, including exosomes. The presence of multiple factors including exosomes within one formulation, the ability to promote cell proliferation and induce stem cell migration may reduce inflammation and pain, and augment tissue repair.

Dorsally Based Closing Wedge Osteotomy of the Calcaneus for Insertional Achilles Tendinopathy

Abstract: Background:Surgical management may be indicated for patients with insertional Achilles tendinopathy (IAT) after failure of nonoperative management, and various surgical techniques have been describ...