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In the female athletic community, there are several endogenous and exogenous variables that influence the status of the hypothalamus-pituitary-ovarian axis and serum sex steroid hormones concentrations (e. g., 17β-estradiol, progesterone, androgens) and their effects. Moreover, female athletes with different sex chromosome abnormalities exist (e. g., 46XX, 46XY, and mosaicism). Due to the high variability of sex steroid hormones serum concentrations and responsiveness, female athletes may have different intra- and inter-individual biological and functional characteristics, health conditions, and sports-related health risks that can influence sports performance and eligibility. Consequently, biological, functional, and/or sex steroid differences may exist in the same and in between 46XX female athletes (e. g., ovarian rhythms, treated or untreated hypogonadism and hyperandrogenism), between 46XX and 46XY female athletes (e. g., treated or untreated hyperandrogenism/disorders of sexual differentiation), and between transgender women and eugonadal cisgender athletes. From a healthcare perspective, dedicated physicians need awareness, knowledge, and an understanding of sex steroid hormones' variability and related health concerns in female athletes to support physiologically healthy, safe, fair, and inclusive sports participation. In this narrative overview, we focus on the main clinical relationships between hypothalamus-pituitary-ovarian axis function, endogenous sex steroids and health status, health risks, and sports performance in the heterogeneous female athletic community., Competing Interests: The authors declare that they have no conflict of interest., (Thieme. All rights reserved.)

Background: Oxidative stress and impaired autophagy are directly and indirectly implicated in exercise-mediated muscle injury. Trehalose, spermidine, nicotinamide, and polyphenols possess pro-autophagic and antioxidant properties, and could therefore reduce exercise-induced damage to skeletal muscle. The aim of this study was to investigate whether a mixture of these compounds was able to improve muscle injury biomarkers in endurance athletes through the modulation of oxidative stress and autophagic machinery., Methods and Results: sNOX2-dp; H 2 O 2 production; H 2 O 2 breakdown activity (HBA); ATG5 and p62 levels, both markers of autophagic process; and muscle injury biomarkers were evaluated in five endurance athletes who were allocated in a crossover design study to daily administration of 10.5 g of an experimental mixture or no treatment, with evaluations conducted at baseline and after 30 days of mixture consumption. Compared to baseline, the mixture intake led to a remarkable reduction of oxidative stress and positively modulated autophagy. Finally, after the 30-day supplementation period, a significant decrease in muscle injury biomarkers was found., Conclusion: Supplementation with this mixture positively affected redox state and autophagy and improved muscle injury biomarkers in athletes, allowing for better muscle recovery. Moreover, it is speculated that this mixture could also benefit patients suffering from muscle injuries, such as cancer or cardiovascular patients, or elderly subjects.

Williams-Beuren syndrome is considered to be at increased risk for celiac disease, as for recent literature data and celiac disease guidelines, despite pathogenic mechanisms are still unclear. Our study analyzed the prevalence of autoimmune disorders, HLA DQ2 and/or DQ8 haplotypes, of transglutaminase antibodies and of diagnosis of celiac disease in a cohort of 93 Williams-Beuren syndrome's patients (mean age 21.26 years). Our study showed an increased prevalence of celiac disease equal to 10.8% (10/93 patients). We did not find a significant different frequency of predisposing HLA in subjects with Williams-Beuren syndrome compared to literature data in the general population (49.5% vs. 42.9%, with p > .1), nor a susceptibility to autoimmunity. This suggests that the increased prevalence of celiac disease in Williams-Beuren syndrome cannot be ascribed to HLA haplotype and may be related to other factors that still need to be identified in these patients., (© 2022 Wiley Periodicals LLC.)

Background: The COVID-19 pandemic with the stay-at-home orders and lockdown has dramatically forced athletes to stop team training and competitions, causing deep changes in habits and lifestyle. Aim of this study was to evaluate in a retrospective single center study the cardiovascular (CV) health and fitness of elite football player after COVID-19 lockdown in Italy and to compare such findings with the 2019 off-season period, in order to identify potential differences in the CV features and outcomes., Methods: All 29 professional football players of the first male team were enrolled before resuming training and competition after COVID-19 lockdown and underwent several exams including physical examination, resting and stress electrocardiography (ECG), echocardiography, spirometry and blood tests., Results: Median age was 27 years (23; 31), with no athlete being COVID-19 positive at the time of the evaluation. In comparison with the usual off-season 2-month detraining, significant differences were found for left ventricular (LV) mass (189 g [172; 212] vs. 181 g [167; 206], P=0.024) and LV Mass Index for body surface area (94 g/m 2 [85; 104] vs. 88 g/m 2 [79.5; 101.5], P=0.017), while LV mass/fat free mass remained unchanged (2.8 g/kg [2.6; 2.9] vs. 2.9 g/kg [2.6; 3.2], P=0.222). Respiratory function and metabolic profile were improved, while no significant changes were found in ECG findings, at rest and during exercise., Conclusions: Prolonged abstinence from training and competitions induced by lockdown elicited significant changes in comparison with off-season in parameters ascribable to detraining, as the changes in LV mass, in respiratory function and in metabolic profile.

The aim of this systematic review is to determine the effectiveness on functional and pain outcomes of different exercise protocols as a conservative treatment for massive, irreparable rotator cuff tears in elderly patients. A literature search was carried out consulting Pubmed -Medline, Cochrane central and Scopus to select randomized clinical trials, prospective and retrospective cohort studies or case series, that evaluated functional and pain outcomes after physical therapy in patients aged 65 or over, affected by massive rotator cuff tears. The present systematic review followed the Cochrane methodology for systematic reviews and the reporting was implemented using through the PRISMA guidelines. The Cochrane risk of bias tool and MINOR score were used for methodologic assessment. Nine articles were included. Data concerning physical activity, functional outcomes and pain assessment were obtained from the included studies. The exercise protocols assessed within the included studies were extremely wide with equally different methods of evaluation of the outcomes. However, most of the studies demonstrated a trend of improvement after the treatment, in terms of functional scores, pain, ROM and quality of life. An intermediate methodological quality of the included papers was assessed through the risk of bias evaluation. Our results showed a positive trend in patients who underwent physical exercise therapy. Our conclusion is that further studies of a high level of evidence are needed to achieve consistent evidence to improve clinical practice in the future.

Purpose: The purpose of this systematic review and pooled analysis was to evaluate incidence and risk factors for glenohumeral osteoarthritis (OA) in patients who underwent Latarjet procedure with a minimum of 5-year follow-up., Methods: The PRISMA guidelines were followed to perform this systematic review. PubMed and EMBASE were searched up to February 29, 2020 for English, human in vivo studies that evaluated glenohumeral OA in patients undergoing Latarjet procedure at least 5 years after surgery. A pooled analysis on the included databases sent by authors was performed to evaluate the risk factors influencing the development or progression of dislocation arthropathy after the Latarjet procedure., Results: Four studies, including a total of 280 patients (213 males and 67 females), were analysed. In our study population, the median age at surgery was 25.0 years (range 20.8-32.6 years). and 92.1% were athletes. In 90% of the cases, the number of dislocations before surgery were fewer than 5. The recurrence of instability after Latarjet procedure was observed only in seven patients (2.5%). The position of the bone graft resulted flush to the anterior glenoid rim in 238 cases (85.3%), medial in 8 (2.9%) and overhanging in 33 (11.8%). Radiological signs of development or progression of shoulder OA were observed in 25.8% of the patients, of which 88.6% presented a grade 1 of OA according to Samilson and Prieto classification. The overhanging position of the bone graft resulted statistically significant for onset or worsening of OA. The age at surgery, the number of dislocations before surgery and the Hill-Sachs lesion were not significantly associated with joint degeneration. Instead, hyperlaxity showed a prevention role in the development of OA after open Latarjet procedure., Conclusion: The Latarjet procedure is a valid and safe surgical treatment in recurrent anterior shoulder instability with a low risk of developing moderate or severe OA also at long-term follow-up. The overhanging position of the bone graft represents the principal risk factor of joint degeneration, whereas the hyperlaxity seems to be protective. Finally, age, gender, time between first dislocation and surgery, and number of dislocations do not seem to affect the onset of OA after Latarjet procedure. Therefore, an accurate execution of the Latarjet procedure can be considered a valid treatment even in young and athletes thanks to the low recurrence rates and the low development of major long-term complications., Level of Evidence: IV., (© 2021. The Author(s).)

This systematic review of the literature aimed to highlight which criteria are described in the literature to define when a patient, after rotator cuff repair (RCR), is ready for return-to-play (RTP), which includes return to unrestricted activities, return to work, leisure, and sport activities. An online systematic search on the US National Library of Medicine (PubMed/MEDLINE), SCOPUS, Web of Science (WOS), and the Cochrane Database of Systematic Reviews, was performed with no data limit until December 2021. A total of 24 studies that reported at least one criterion after RCR were included. Nine criteria were identified and among these, the most reported criterion was the time from surgery, which was used by 78% of the studies; time from surgery was used as the only criterion by 54% of the studies, and in combination with other criteria, in 24% of the studies. Strength and ROM were the most reported criteria after time (25%). These results are in line with a previous systematic review that aimed to identify RTP criteria after surgical shoulder stabilization and with a recent scoping review that investigated RTP criteria among athletes after RCR and anterior shoulder stabilization. Compared to this latest scoping review, our study adds the methodological strength of being conducted according to the Prisma guidelines; furthermore, our study included both athletes and non-athletes to provide a comprehensive view of the criteria used after RCR; moreover, ten additional recent manuscripts were examined with respect to the scoping review.

Mechanisms of exercise-induced muscle injury with etiopathogenesis and its consequences have been described; however, the impact of different intensities of exercise on the mechanisms of muscular injury development is not well understood. The aim of this study was to exploit the relationship between platelet activation, oxidative stress and muscular injuries induced by physical exercise in elite football players compared to amateur athletes. Oxidant/antioxidant status, platelet activation and markers of muscle damage were evaluated in 23 elite football players and 23 amateur athletes. Compared to amateurs, elite football players showed lower antioxidant capacity and higher oxidative stress paralleled by increased platelet activation and muscle damage markers. Simple linear regression analysis showed that sNOX2-dp and H 2 O 2 , sCD40L and PDGF-bb were associated with a significant increase in muscle damage biomarkers. In vitro studies also showed that plasma obtained from elite athletes increased oxidative stress and muscle damage in human skeletal muscle myoblasts cell line compared to amateurs' plasma, an effect blunted by the NOX2 inhibitor or by the cell treatment with cocoa-derived polyphenols. These results indicate that platelet activation increased muscular injuries induced by oxidative stress. Moreover, NOX2 inhibition and polyphenol extracts treatment positively modulates redox status and reduce exercise-induced muscular injury.

Background: Autologous microfragmented lipoaspirate tissue has been recently introduced in orthopaedics as an easily available source of nonexpanded adipose-derived mesenchymal stem cells. Autologous microfragmented lipoaspirate tissue is expected to create a suitable microenvironment for tendon repair and regeneration. Rotator cuff tears show a high incidence of rerupture and represent an ideal target for nonexpanded mesenchymal stem cells., Purpose: To evaluate the safety and efficacy of autologous lipoaspirate tissue in arthroscopic rotator cuff repair., Study Design: Randomized controlled trial; Level of evidence, 2., Methods: Consecutive patients referring to the investigation center for surgical treatment of magnetic resonance imaging-confirmed degenerative posterosuperior rotator cuff tears were assessed for eligibility. Those who were included were randomized to receive a single-row arthroscopic rotator cuff repair, followed by intraoperative injection of autologous microfragmented adipose tissue processed with an enzyme-free technology (treatment group) or not (control group). Clinical follow-up was conducted at 3, 6, 12, 18, and 24 months; at 18 months after surgery, magnetic resonance imaging of the operated shoulder was obtained to assess tendon integrity and rerupture rate., Results: An overall 177 patients were screened, and 44 (22 per group) completed the 24-month follow-up. A statistically significant difference in favor of the treatment group in terms of Constant-Murley score emerged at the primary endpoint at 6-month follow-up (mean ± SD; control group, 76.66 ± 10.77 points; treatment group, 82.78 ± 7.00 points; P = .0050). No significant differences in clinical outcome measures were encountered at any of the other follow-up points. No significant differences emerged between the groups in terms of rerupture rate, complication rate, and number of adverse events., Conclusion: This prospective randomized controlled trial demonstrated that the intraoperative injection of autologous microfragmented adipose tissue is safe and effective in improving short-term clinical and functional results after single-row arthroscopic rotator cuff repair., Registration: NCT02783352 (ClinicalTrials.gov identifier).

Background: SARS-CoV-2 can lead to several systemic complications, including myocardial injuries; these might be worsened by heavy physical activity. The optimal approach to cardiac risk stratification following SARS-CoV-2 infection in athletes for a safe return to play (RTP) still needs defining. The aim of this study was to assess the prevalence of abnormal RTP test results, according to the protocol of Italian Federation of Sport Medicine (FMSI), which was endorsed by the Italian Ministry of Health, potentially representing COVID-19-associated cardiac injuries., Methods: This was a prospective, multicenter, observational study. All consecutive competitive athletes who underwent COVID-19 RTP testing protocol from 1 May to 31 July 2021, across 60 Italian Centers of Sports Medicine, were enrolled in the study. Athletes were tested at least 30 days after negativization of the nasopharyngeal swab (or immediately after negativization in professional athletes or Probable Olympians). A 12-lead electrocardiography at rest and during maximal incremental exercise test with continuous O 2 saturation monitoring and an echocardiographic examination were part of the protocol. In athletes with "moderate" disease (NHI classification), 24 h ECG monitoring (to be performed on a training day) and Magnetic Resonance Imaging (MRI) were also performed., Results: A total of 4143 athletes (67.8% males and 32.2% females) (53% > 18 years, 20% 18-35 years and 16% > 35 years), from more than 40 different sport disciplines, were included in the study. The mean age was 22.5 ± 13.3 years, with ages ranging from 8 to 80 years. Of these athletes, 52.3% were asymptomatic, 46.4% manifested mild symptoms, 1.1% and 0.14% had moderate or severe symptoms, respectively, while critical illness was evident in one athlete. Abnormal echocardiographic findings were detected in 80 cases (1.9%), and pericarditis in 7 cases (0.2%); all were from mildly symptomatic athletes. Arrhythmic events were recorded in 239 athletes, with 224 (5.4%) in the exercise test and 15 (0.4%) during 24 h ECG monitoring. Ventricular arrhythmias were observed in 101 (2.4%) athletes from the total population (mostly isolated or couples of premature ventricular beats): 91 in the exercise test and 10 during 24 h ECG monitoring. Cardiac magnetic resonance was performed in 34 athletes; the presence of myocarditis was confirmed in 5 athletes (0.12% of the total population, 14.7% of athletes in which MRI was performed)., Conclusions: According to our results, cardiac complications from SARS-CoV-2 in asymptomatic or mildly symptomatic competitive athletes are rare, and an RTP assessment based on symptoms and ECG-monitored exercise test would ensure a safe RTP in these athletes.

Introduction: Very limited data exist on normal age-related ECG variations in adolescents and no data have been published regarding the ECG anomalies induced by intensive training, which are relevant in pre-participation screening for sudden cardiac death prevention in the adolescent athletic population. The purpose of this study was to establish normal age-related electrocardiographic measurements (P wave duration, PR interval, QRS duration, QT, and QTc interval) grouped according to 2-year age intervals., Methods: A total of 2,151 consecutive healthy adolescent Soccer athletes (trained for a mean of 7.2 ± 1.1 h per week, 100% male Caucasians, mean age 12.4 ± 1.4 years, range 7-18) underwent pre-participation screening, which included ECG and transthoracic echocardiography in a single referral center., Results: Their heart rate progressively slowed as age increased ( p < 0.001, ranging from 80.8 ± 13.2 to 59.5 ± 10.2 bpm), as expected. The P wave, PR interval, and QRS duration significantly increased in older age classes ( p = 0.019, p = 0.001, and p < 0.001, respectively), and after Bonferroni's correction, the difference remained significant in all age classes for QRS duration. The QTc interval diminished progressively with increasing age ( p = 0.003) while the QT interval increased progressively ( p < 0.001)., Conclusions: Significant variations in the normal ECG characteristics of young athletes exist between different age groups related to increasing age and training burden, thus, age-specific reference values could be adopted, as already done for echocardiographic measurements, and may help to further discriminate potentially pathologic conditions., Competing Interests: Author GB-Z has consulted for Cardionovum, Bonn, Germany; Innovheart, Milan, Italy; Meditrial, Rome, Italy; Replycare, Rome, Italy. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Cavarretta, Sciarra, Biondi-Zoccai, Maffessanti, Nigro, Sperandii, Guerra, Quaranta, Fossati, Peruzzi, Pingitore, Stasinopoulos, Rigby, Adorisio, Saglietto, Calò, Frati and Pigozzi.)

The IOC recently published its framework on fairness, inclusion and non-discrimination based on gender identity and sex variations. This framework is drafted mainly from a human rights perspective, with less consideration for medical/scientific issues. The framework places the onus for gender eligibility and classification entirely on the International Federations (IFs), even though most will not have the capacity to implement the framework. The position of no presumption of advantage is contrary to the 2015 IOC consensus. Implementation of the 2021 framework will be a major challenge for IFs that have already recognised the inclusion of trans and women athletes with differences of sexual development (DSD) using a scientific/medical solution. The potential consequences for sports that need to prioritise fairness or safety could be one of two extremes (1) exclusion of all transgender or DSD athletes on the grounds of advantage or (2) self-identification that essentially equates to no eligibility rules. Exclusion of all transgender or DSD athletes is contrary to the Olympic charter and unlawful in many countries. While having no gender eligibility rules, sport loses its meaning and near-universal support. Athletes should not be under pressure to undergo medical procedures or treatment to meet eligibility criteria. However, if an athlete is fully informed and consents, then it is their free choice to undergo carefully considered or necessary interventions for gender classification for sport to compete fairly and safely in their chosen gender. Free choice is a fundamental human right, but so is the right to fair and safe competition., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Sport participation and exercise practice are considered to be beneficial for mental status, yielding an improved mood and better quality of life. On the other hand, good mental fitness is thought to lead to better physical status and sport performance. The key aim of this narrative review is to provide an unstructured overview on the topic with special considerations on the role of mental and physical health to summarize the evidence on their reciprocal influence. While very few papers describe the role of mental health measures in affecting physical performance, more evidence is available concerning the effect of exercise and sport in improving mental health outcomes. Furthermore, there is a consistent role of depressive and anxiety symptoms in influencing the risk of sport injury in either recreational or elite athletes. Moreover, the importance of investigating mental health issues in elite and retired athletes is highlighted. On the basis of the available literature, several biases were found to affect the provided evidence mainly because of the complexity of a proper study design in this field.

Millions of consumer sport and fitness wearables (CSFWs) are used worldwide, and millions of datapoints are generated by each device. Moreover, these numbers are rapidly growing, and they contain a heterogeneity of devices, data types, and contexts for data collection. Companies and consumers would benefit from guiding standards on device quality and data formats. To address this growing need, we convened a virtual panel of industry and academic stakeholders, and this manuscript summarizes the outcomes of the discussion. Our objectives were to identify (1) key facilitators of and barriers to participation by CSFW manufacturers in guiding standards and (2) stakeholder priorities. The venues were the Yale Center for Biomedical Data Science Digital Health Monthly Seminar Series (62 participants) and the New England Chapter of the American College of Sports Medicine Annual Meeting (59 participants). In the discussion, stakeholders outlined both facilitators of (e.g., commercial return on investment in device quality, lucrative research partnerships, and transparent and multilevel evaluation of device quality) and barriers (e.g., competitive advantage conflict, lack of flexibility in previously developed devices) to participation in guiding standards. There was general agreement to adopt Keadle et al.'s standard pathway for testing devices (i.e., benchtop, laboratory, field-based, implementation) without consensus on the prioritization of these steps. Overall, there was enthusiasm not to add prescriptive or regulatory steps, but instead create a networking hub that connects companies to consumers and researchers for flexible guidance navigating the heterogeneity, multi-tiered development, dynamicity, and nebulousness of the CSFW field., (© 2021. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Phosphoinositides are lipids that play a critical role in processes such as cellular signalling, ion channel activity and membrane trafficking. When mutated, several genes that encode proteins that participate in the metabolism of these lipids give rise to neurological or developmental phenotypes. PI4KA is a phosphoinositide kinase that is highly expressed in the brain and is essential for life. Here we used whole exome or genome sequencing to identify 10 unrelated patients harbouring biallelic variants in PI4KA that caused a spectrum of conditions ranging from severe global neurodevelopmental delay with hypomyelination and developmental brain abnormalities to pure spastic paraplegia. Some patients presented immunological deficits or genito-urinary abnormalities. Functional analyses by western blotting and immunofluorescence showed decreased PI4KA levels in the patients' fibroblasts. Immunofluorescence and targeted lipidomics indicated that PI4KA activity was diminished in fibroblasts and peripheral blood mononuclear cells. In conclusion, we report a novel severe metabolic disorder caused by PI4KA malfunction, highlighting the importance of phosphoinositide signalling in human brain development and the myelin sheath., (© The Author(s) (2021). Published by Oxford University Press on behalf of the Guarantors of Brain.)

The coronavirus disease (COVID-19) pandemic has had an unprecedent impact on the world of sport and society at large. Many of the challenges with respect to integrity previously facing competitive sport have been accentuated further during the pandemic. Threats to the integrity of sporting competition include traditional doping, issues of technological fairness, and integration of transgender and intersex athletes in elite sport. The enforced lull in competitive sport provides an unprecedented opportunity for stakeholders in sport to focus on unresolved integrity issues and develop and implement long-lasting solutions. There needs to be a concerted effort to focus on the many technological innovations accelerated by and perfected during COVID-19 that have enabled us to work from home, such as teaching students on-line, applications for medical advice, prescriptions and referrals, and treating patients in hospitals/care homes via video links and use these developments and innovations to enhance sport integrity and anti-doping procedures. Positive sports integrity actions will require a considered application of all such technology, as well as the inclusion of "omics" technology, big data, bioinformatics and machine learning/artificial intelligence approaches to modernize sport. Applications include protecting the health of athletes, considered non-discriminative integration of athletes into elite sport, intelligent remote testing to improve the frequency of anti-doping tests, detection windows, and the potential combination with omics technology to improve the tests' sensitivity and specificity in order to protect clean athletes and deter doping practices.

Sport is historically designated by the binary categorization of male and female that conflicts with modern society. Sport's governing bodies should consider reviewing rules determining the eligibility of athletes in the female category as there may be lasting advantages of previously high testosterone concentrations for transwomen athletes and currently high testosterone concentrations in differences in sex development (DSD) athletes. The use of serum testosterone concentrations to regulate the inclusion of such athletes into the elite female category is currently the objective biomarker that is supported by most available scientific literature, but it has limitations due to the lack of sports performance data before, during or after testosterone suppression. Innovative research studies are needed to identify other biomarkers of testosterone sensitivity/responsiveness, including molecular tools to determine the functional status of androgen receptors. The scientific community also needs to conduct longitudinal studies with specific control groups to generate the biological and sports performance data for individual sports to inform the fair inclusion or exclusion of these athletes. Eligibility of each athlete to a sport-specific policy needs to be based on peer-reviewed scientific evidence made available to policymakers from all scientific communities. However, even the most evidence-based regulations are unlikely to eliminate all differences in performance between cisgender women with and without DSD and transwomen athletes. Any remaining advantage held by transwomen or DSD women could be considered as part of the athlete's unique makeup.

Purpose  The treatment of acromioclavicular joint (ACJ) osteoarthritis during shoulder arthroscopy is a discussed topic. The aim of this scoping review is to report the current recommendations regarding the management of this disorder in patients undergoing surgery for rotator cuff tears. Methods  A scoping review was performed in Pubmed\Medline and Embase in March 2017, restricted to English language literature. The following keywords were used: ("rotator cuff tear" OR " rotator cuff" OR "rotator cuff repair") AND ("acromioclavicular joint arthritis" OR "ac joint arthritis" OR "ac joint" OR "acromioclavicular joint"). Inclusion criteria were randomized controlled trials, prospective cohort studies, retrospective trials, and therapeutic case series. Exclusion criteria were reviews, meta-analyses, and expert opinions. Results  Two retrospective studies and three randomized controlled trials were identified. Clinical studies reported results of 443 shoulders, with an average age of 60.48 years and a mean follow-up of 31.7 months. Many differences were found regarding the design of the studies, patient's selection, surgical procedures, and instrumental and clinical evaluations. No statistically significant differences were found in clinical outcome scores between patients that underwent rotator cuff repair in association with distal clavicular resection and patients with isolated rotator cuff repair. Conclusion  Results of this scoping review underline a lack of evidence-based recommendations about the management of ACJ osteoarthritis in association with arthroscopic rotator cuff repair. Surgical procedures such as distal clavicle resection (DCR) should be performed carefully in this cohort of patients. More prospective randomized studies are needed to reach a consensus about the correct surgical approach to DCR in patients with signs of ACJ osteoarthritis and rotator cuff tears. Level of Evidence  Level III., Competing Interests: Conflict of Interest P.R. declares consultation for Arthrex and Depuy (Johnson&Johnson), outside the submitted work. All other authors report no conflict of interest., (The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution-NonDerivative-NonCommercial-License, permitting copying and reproduction so long as the original work is given appropriate credit. Contents may not be used for commercial purposes, or adapted, remixed, transformed or built upon. ( https://creativecommons.org/licenses/by-nc-nd/4.0/ ).)

Most countries affected by the COVID-19 pandemic have repeatedly restricted public life to control the contagion. However, the health impact of confinement measures is hitherto unclear. We performed a multinational survey investigating changes in mental and physical well-being (MWB/PWB) during the first wave of the pandemic. A total of 14,975 individuals from 14 countries provided valid responses. Compared to pre-restrictions, MWB, as measured by the WHO-5 questionnaire, decreased considerably during restrictions (68.1 ± 16.9 to 51.9 ± 21.0 points). Whereas 14.2% of the participants met the cutoff for depression screening pre-restrictions, this share tripled to 45.2% during restrictions. Factors associated with clinically relevant decreases in MWB were female sex (odds ratio/OR = 1.20, 95% CI: 1.11-1.29), high physical activity levels pre-restrictions (OR = 1.29, 95% CI 1.16-1.42), decreased vigorous physical activity during restrictions (OR = 1.14, 95% CI: 1.05-1.23), and working (partially) outside the home vs. working remotely (OR = 1.29, 95% CI: 1.16-1.44/OR = 1.35, 95% CI: 1.23-1.47). Reductions, although smaller, were also seen for PWB. Scores in the SF-36 bodily pain subscale decreased from 85.8 ± 18.7% pre-restrictions to 81.3 ± 21.9% during restrictions. Clinically relevant decrements of PWB were associated with female sex (OR = 1.62, 95% CI: 1.50-1.75), high levels of public life restrictions (OR = 1.26, 95% CI: 1.18-1.36), and young age (OR = 1.10, 95% CI: 1.03-1.19). Study findings suggest lockdowns instituted during the COVID-19 pandemic may have had substantial adverse public health effects. The development of interventions mitigating losses in MWB and PWB is, thus, paramount when preparing for forthcoming waves of COVID-19 or future public life restrictions., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Wilke, Hollander, Mohr, Edouard, Fossati, González-Gross, Sánchez Ramírez, Laiño, Tan, Pillay, Pigozzi, Jimenez-Pavon, Sattler, Jaunig, Zhang, van Poppel, Heidt, Willwacher, Vogt, Verhagen, Hespanhol and Tenforde.)

In an effort to reduce transmission and number of infections of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2 or COVID-19) virus, governments and official bodies around the world have produced guidelines on the use of face masks and face coverings. While there is a growing body of recommendations for healthcare professionals and the wider population to use facial protection in "enclosed spaces" where minimal distancing from other individuals is not possible, there is a dearth of clear guidelines for individuals undertaking exercise and sporting activity. The present viewpoint aims to propose recommendations for face coverings while exercising during the COVID-19 pandemic that consider physical distancing, the environment, the density of active cases associated with the specific sports activity, and the practical use of face coverings in order to reduce potential viral transmission. Recommendations are provided on the basis of very limited available evidence in conjunction with the extensive collective clinical experience of the authors and acknowledging the need to consider the likelihood of the presence of the SARS-CoV-2 in the general population. We recommend that face coverings should be used in any environment considered to be of a high or moderate transmission risk, where tolerated and after individual risk assessment. In addition, as national caseloads fluctuate, individual sporting bodies should consider up to date guidance on the use of face coverings during sport and exercise, alongside other preventative measures.

Governments have restricted public life during the COVID-19 pandemic, inter alia closing sports facilities and gyms. As regular exercise is essential for health, this study examined the effect of pandemic-related confinements on physical activity (PA) levels. A multinational survey was performed in 14 countries. Times spent in moderate-to-vigorous physical activity (MVPA) as well as in vigorous physical activity only (VPA) were assessed using the Nordic Physical Activity Questionnaire (short form). Data were obtained for leisure and occupational PA pre- and during restrictions. Compliance with PA guidelines was calculated based on the recommendations of the World Health Organization (WHO). In total, n = 13,503 respondents (39 ± 15 years, 59% females) were surveyed. Compared to pre-restrictions, overall self-reported PA declined by 41% (MVPA) and 42.2% (VPA). Reductions were higher for occupational vs. leisure time, young and old vs. middle-aged persons, previously more active vs. less active individuals, but similar between men and women. Compared to pre-pandemic, compliance with WHO guidelines decreased from 80.9% (95% CI: 80.3-81.7) to 62.5% (95% CI: 61.6-63.3). Results suggest PA levels have substantially decreased globally during the COVID-19 pandemic. Key stakeholders should consider strategies to mitigate loss in PA in order to preserve health during the pandemic.

Background: Failure of conservative treatment in patients over 70 years of age with a rotator cuff tear makes surgery a possible option, considering the increase in life expectancy and the high functional demands of elderly patients. The purpose of this systematic review of the literature was to evaluate the subjective and objective outcomes after arthroscopic rotator cuff repair in patients over 70 years of age., Methods: A systematic review was performed to identify all the studies reporting subjective and objective outcomes in patients aged 70 years or older undergoing arthroscopic rotator cuff repair. Constant Murley Score (CMS), visual analog scale (VAS), American Shoulder and Elbow Surgeons Score (ASES), and Simple Shoulder Test (SST) were used to detect any clinical improvement after surgery. Retear and satisfaction were also analyzed., Results: Out of 941 studies identified, only 6 papers have been included in the review. All studies reported improvements in postoperative functional outcome scores that exceed the minimal clinically relevant difference. The mean retear rate amounts to 21.9%, which is in line with the failure rate of rotator cuff repair in general population. Moreover, postoperative satisfaction is very high (95%)., Conclusion: This systematic review suggests that arthroscopic rotator cuff repair in patients over 70 years of age could be a valid treatment option after failure of conservative approach., Level of Evidence: 4 Trial registration The study was registered on PROSPERO (registration ID: CRD42018088613).

Background In athletes with ventricular arrhythmias (VA) and otherwise unremarkable clinical findings, cardiac magnetic resonance (CMR) may reveal concealed pathological substrates. The aim of this multicenter study was to evaluate which VA characteristics predicted CMR abnormalities. Methods and Results We enrolled 251 consecutive competitive athletes (74% males, median age 25 [17-39] years) who underwent CMR for evaluation of VA. We included athletes with >100 premature ventricular beats/24 h or ≥1 repetitive VA (couplets, triplets, or nonsustained ventricular tachycardia) on 12-lead 24-hour ambulatory ECG monitoring and negative family history, ECG, and echocardiogram. Features of VA that were evaluated included number, morphology, repetitivity, and response to exercise testing. Left-ventricular late gadolinium-enhancement was documented by CMR in 28 (11%) athletes, mostly (n=25) with a subepicardial/midmyocardial stria pattern. On 24-hour ECG monitoring, premature ventricular beats with multiple morphologies or with right-bundle-branch-block and intermediate/superior axis configuration were documented in 25 (89%) athletes with versus 58 (26%) without late gadolinium-enhancement ( P <0.001). More than 3300 premature ventricular beats were recorded in 4 (14%) athletes with versus 117 (53%) without positive CMR ( P <0.001). At exercise testing, nonsustained ventricular tachycardia occurred at peak of exercise in 8 (29%) athletes with late gadolinium-enhancement (polymorphic in 6/8, 75%) versus 17 athletes (8%) without late gadolinium-enhancement ( P =0.002), ( P <0.0001). At multivariable analysis, all 3 parameters independently correlated with CMR abnormalities. Conclusions In athletes with apparently idiopathic VA, simple characteristics such as number and morphology of premature ventricular beats on 12-lead 24-hour ambulatory ECG monitoring and response to exercise testing predicted the presence of concealed myocardial abnormalities on CMR. These findings may help cost-effective CMR prescription.

Alzheimer's Disease (AD), one of the main causes of death in elderly people, is characterized by Mild Cognitive Impairment (MCI) at prodromal stage. Nevertheless, only part of MCI subjects could progress to AD. The main objective of this paper is thus to identify those who will develop a dementia of AD type among MCI patients. 18 F-FluoroDeoxyGlucose Positron Emission Tomography ( 18 F-FDG PET) serves as a neuroimaging modality for early diagnosis as it can reflect neural activity via measuring glucose uptake at resting-state. In this paper, we design a deep network on 18 F-FDG PET modality to address the problem of AD identification at early MCI stage. To this end, a Multi-view Separable Pyramid Network (MiSePyNet) is proposed, in which representations are learned from axial, coronal and sagittal views of PET scans so as to offer complementary information and then combined to make a decision jointly. Different from the widely and naturally used 3D convolution operations for 3D images, the proposed architecture is deployed with separable convolution from slice-wise to spatial-wise successively, which can retain the spatial information and reduce training parameters compared to 2D and 3D networks, respectively. Experiments on ADNI dataset show that the proposed method can yield better performance than both traditional and deep learning-based algorithms for predicting the progression of Mild Cognitive Impairment, with a classification accuracy of 83.05%.

The revised European consensus defined sarcopenia as a progressive and generalized skeletal muscle disorder that is associated with an increased likelihood of adverse outcomes including falls, fractures, physical disability and mortality. The aim of this study was to determine the prevalence of sarcopenia and analyse the influence of diet, physical activity (PA) and obesity index as risk factors of each criteria of sarcopenia. A total of 629 European middle-aged and older adults were enrolled in this cross-sectional study. Anthropometrics were assessed. Self-reported PA and adherence to the Mediterranean diet were evaluated with the Global Physical Activity Questionnaire (GPAQ) and Prevention with Mediterranean Diet questionnaire (PREDIMED), respectively. The functional assessment included handgrip strength, lower body muscle strength, gait speed and agility/dynamic balance. Of the participants, 4.84% to 7.33% showed probable sarcopenia. Sarcopenia was confirmed in 1.16% to 2.93% of participants. Severe sarcopenia was shown by 0.86% to 1.49% of participants. Male; age group ≤65 years; lower body mass index (BMI); high levels of vigorous PA; and the consumption of more than one portion per day of red meat, hamburgers, sausages or cold cuts and/or preferential consumption of rabbit, chicken or turkey instead of beef, pork, hamburgers or sausages (OR = 0.126-0.454; all p < 0.013) resulted as protective factors, and more time of sedentary time (OR = 1.608-2.368; p = 0.032-0.041) resulted as a risk factor for some criteria of sarcopenia. In conclusion, age, diet, PA, and obesity can affect the risk of having low muscle strength, low muscle mass or low functional performance, factors connected with sarcopenia.

Background: The aetiology of Parkinson's disease (PD) is still very controversial, with a peculiar lack of established risk factors or protective behavior., Methods: We carried out a case-control study of 634 idiopathic PD patients admitted from 2011 to 2015 to two hospitals located in central Italy and 532 controls matched by hospital, gender and age (± 5 years). The study questionnaire included questions on host factors, family history, residence, occupation and lifestyle. Odds ratios (ORs) for PD and 95% confidence intervals (CIs) were estimated with logistic regression, adjusting for actual and potential confounders., Results: A lower OR was observed in females (0.74; 95%CI:0.58-0.96), while older age classes showed a constantly increased risk for PD (p<0.005) starting from the class 65-69 years. Subjects who reported a first degree relative affected by PD showed a borderline increase which was more evident in those enrolled in the urban center of Rome (OR = 1.65; 95%CI: 1.09-2.50). Significant reduction of the risk was associated to current smoking (OR = 0.48; 95%CI: 0.24-0.54), and to vegetables consumption (p<0.03), while borderline increases were associated to meat and cold cut consumption. Occupational activities classified according to ISCO-08 categories did not show increased risk, while higher ORs' were found for pilots and physicians., Conclusions: The results from this study confirmed the higher risk of PD in males and in elderly, and the inverse association with smoking habit. The possible etiological role of familial clustering, dietary habit, and some job tasks is suggested., Competing Interests: The authors have declared that no competing interests exist.

Despite the recent advances in surgical techniques, the percentage of painful shoulder arthroplasties is still high (more than 10%). The causes of residual pain after shoulder arthroplasty, and the resulting treatment solutions, are many and different. The most common complications of shoulder prosthesis are infections, aseptic loosening, modular components disassembling, metal hypersensitivity, and instability. There are also implant-related complications such as glenoid wear in hemiarthroplasty, rotator cuff tear in anatomical total shoulder arthroplasty, scapular notching, and acromion fracture in reverse shoulder arthroplasty. Several of these complications can be avoided with a careful selection of the implants, a proper surgical technique and a precise implant positioning. The execution of a more accurate preoperative planning and the possible use of patient-specific implants are expected to translate into better clinical results in the future. We provide the reader with recent evidence on the causes and therapeutic options of this condition.

Confinement measures during the COVID-19 pandemic have caused substantial reductions in global physical activity (PA) levels. In view of the manifold health benefits of PA, the development of interventions counteracting this trend is paramount. Our survey with 15,261 participants (38 ± 15 years, 58.5% females) examined preferences towards digital home exercise programs in 14 countries affected by COVID-19. More than two-thirds of the sample (68.4%, n = 10,433) indicated being interested in home exercise, and most participants were willing to work out at least three times per week (89.3%, n = 9328). Binary logistic regression revealed that female sex, working part-time, younger age, and being registered in a gym were associated with willingness to exercise. Flexibility (71.1%, n = 7377), resistance (68.6%, n = 7116), and endurance training (62.4%, n = 6478) were the most preferred types of exercise. Our results may guide health providers in developing individually tailored PA interventions during the current and future pandemics.

Celiac disease (CD) screening in patients with Williams-Beuren Syndrome (WBS) is suggested, although data described in literature are discordant regarding CD prevalence in WBS. We retrospectively collected data from 101 WBS Italian patients [mean age: 13.5 years], to clarify the CD prevalence in a large cohort. All patients underwent a CD biochemical screening: IgA and anti-transglutaminase reflex antibodies (tTGA). CD-specific HLA typing was available for 42 patients. Small intestinal biopsy was performed in patients according to ESPGHAN guidelines. In 7 WBS patients an overt celiac disease was diagnosed. In 3 patients CD was confirmed by symptoms, HLA-DQ heterodimers and CD specific antibodies title, whereas in 4 patients, it was confirmed by a small intestinal biopsy. CD prevalence in our cohort is 6.9% (7/101). In 42/101 patients the CD-specific HLA typing was available, detecting 29/42 (69%) patients genetically predisposed to CD. The CD prevalence and CD-specific HLA prevalence are both higher than in the general population (p < 0.001; p < 0.001). Our cohort is the most numerous described confirming that the CD risk in WBS patients is significantly greater than in general population. Moreover, our HLA typing results, as well as scientific literature, suggest that the higher CD prevalence in WBS patients might not be intrinsically related to the genetic disease itself but with the higher HLA prevalence. However, HLA typing should be performed in bigger WBS cohorts to confirm this hypothesis. Our data confirms that HLA typing is mandatory in WBS patients and that CD screening should be performed only if genetically predisposed., (Copyright © 2020 Elsevier Masson SAS. All rights reserved.)

Cornelia de Lange syndrome Spectrum (CdLSp) is characterized by intellectual disability, facial dysmorphisms, and growth impairment. Although eating difficulties are a well-known feature of the disease, there is no data regarding the nutritional deficiencies of these patients. The food intake was tracked using a dietary transcription provided by the family/caregivers, biochemical nutritional parameters were measured with laboratory tests and through an accurate clinical evaluation of the incidence of qualitative and quantitative imbalances in a cohort of 73 patients with CdLSp ware determined. Of these 73, 62 (85%) subjects provided a complete and detailed dietary transcription. In the studied population, a quantitative caloric imbalance in 47/62 (76%) subjects was observed. The caloric intake was low in 27/62 (43%) subjects whereas excessive in 20/62 (33%). Only 15/62 (24%) had an optimum caloric intake. Regarding micronutrients, a calcium intake deficiency in 32% of the patients (20/62) was observed. Blood tests revealed a low iron level in 22/73 (30%) of the patients and 25(OH)D deficiency in 49/73 (67%). Serum hypocalcemia was not evidenced. Qualitative and quantitative imbalances resulted in more frequent than expected in CdLSp patients. A qualitative imbalance was more prevalent in younger patients while in older patients prevailed mainly a quantitative disproportion. We found no statistically meaningful correlation between dietary imbalances, genetic, or clinical parameters. Our findings highlight the need for further studies to evaluate the basal metabolic rate of CdLSp patients and find a correlation with their growth impairment., (© 2020 Wiley Periodicals LLC.)

The aims of this systematic review and meta-analysis were to evaluate the effects of physical exercise on static and dynamic balance in the elderly population, and to analyze the number of falls and fallers. A systematic literature search was conducted using PubMed-Medline, Cochrane Central, and Google Scholar to select randomized clinical trials that analyzed the role of exercise on balance and fall rate in patients aged 65 or older. Sixteen articles were included in this review. Applying the Cochrane risk-of-bias tool, three studies were determined to be at low risk of bias, nine at unclear risk of bias, and four at high risk of bias. The meta-analysis showed improvements in dynamic balance ( p = 0.008), static balance ( p = 0.01), participants' fear of falling ( p = 0.10), balance confidence ( p = 0.04), quality of life ( p = 0.08), and physical performance ( p = 0.30) in patients who underwent physical exercise compared to controls. The analysis of the total numbers of falls showed a decreased likelihood of falls in patients who participated in exercise programs ( p = 0.0008). Finally, the number of patients who fell at least once was significantly reduced in the intervention group ( p = 0.02). Physical exercise is an effective treatment to improve balance and reduce fall rates in the elderly.

In recent years, scientific interest has been developed towards irisin, a novel molecule of the family of myokines, which is directly involved in body mass composition balance, chronic diseases susceptibility and physiologic resilience to stressful events, including surgery. In the context of musculoskeletal disease, the role of this molecule has been associated to the balance of lean and fatty mass, and the production of irisin is subordinated to a healthy lifestyle and exercise. The mechanism of action of irisin on tissues is complex, and several studies described the molecular pathways in animal model and human subjects. In particular, in adipose cells, the key-role of irisin is to stimulate the differentiation of white adipose tissue to brown adipose tissue, through the action on the uncoupling protein 1. Furthermore, in the bony tissue, irisin stimulates osteogenesis through expression of Sost and Opn genes. These features make irisin a suitable molecule to use as a biomarker of the overall musculoskeletal health of the elderly, before undergoing orthopaedic surgery. Further research on this topic should be carried out to highlight the possible clinical role and predictive value of irisin in a multidisciplinary approach to the elderly before musculoskeletal surgery., (Copyright 2020 Biolife Sas. www.biolifesas.org.)

Cornelia de Lange spectrum (CdLSp) is a rare genetic condition characterized by intellectual disability, facial dysmorphisms, major malformations, growth impairment, and development delay. Approximately 80% of CdLSp patients have gastroesophageal reflux disease (GERD) with a varied clinical presentation. The aim of this study is to define potential clinical/genetic risk factors based on the clinical phenotype description of CdLSp patients with severe GERD who underwent surgical treatment. We retrospectively collected data from 23 CdLSp patients, 13 females and 10 males. Mean age of the patients undergoing surgical treatment was of 4 years. 21/23 (91%) had a molecular characterization, of which 21/21 (100%) had a NIPBL gene mutation, while 2/23 (9%) did not have a genetical characterization, only a clinical diagnosis. Most of our patients presented a moderate-severe severity score (21/23, 91%) with limb malformations evidenced in 10/23 (44%) of our patients and a moderate-severe intellectual disability in 20/23 (87%). Therefore, CdLSp patients harboring NIPBL variants, upper limb malformations and severe psychomotor delay are more likely to suffer from severe GERD, not responsive to proton pump inhibitors treatment. These features should be considered as clinical markers for potentially severe GERD that might require surgical treatment., (© 2020 Wiley Periodicals, Inc.)

The aim of this systematic review and meta-analysis was to evaluate the rate of return to sport in elderly patients who underwent anatomic (ATSA) and reverse (RTSA) total shoulder arthroplasty, to assess postoperative pain and functional outcomes and to give an overview of postoperative rehabilitation protocols. A systematic search in Pubmed-Medline, Cochrane Library, and Google Scholar was carried out to identify eligible randomized clinical trials, observational studies, or case series that evaluated the rate of return to sport after RTSA or ATSA. Six retrospective studies, five case series, and one prospective cohort study were included in this review. The overall rate of return to sport was 82% (95% CI 0.76-0.88, p < 0.01). Patients undergoing ATSA returned at a higher rate (90%) (95% CI 0.80-0.99, p < 0.01) compared to RTSA (77%) (95% CI 0.69-0.85, p < 0.01). Moreover, the results showed that patients returned to sport at the same or a higher level in 75% of cases. Swimming had the highest rate of return (84%), followed by fitness (77%), golf (77%), and tennis (69%). Thus, RTSA and ATSA are effective to guarantee a significative rate of return to sport in elderly patients. A slightly higher rate was found for the anatomic implant.

Hip and knee replacement is an effective treatment for symptomatic, end-stage hip and knee osteoarthritis, aiming to relieve pain and restore joint function. Several postoperative rehabilitation protocols and physical activities are proposed in routine clinical practice. However, their effect on clinical outcome and implant revision in patients undergoing joint replacement is still unclear. A systematic review of the literature was performed through a comprehensive search on online databases including Pubmed-Medline, Cochrane central, and Google scholar. We included all the available studies on postoperative physical activity and rehabilitation protocols after total knee and total hip arthroplasty in patients older than 65 years. The primary endpoint was to evaluate the effect of physical activity and rehabilitation on clinical outcome; the secondary outcome was to determine the effect on patients' quality of life (QoL) and implant survival. Although the heterogeneity of the rehabilitation protocols and outcome measures did not allow to draw definitive conclusions, most studies suggested that aquatic therapy, ergometer cycling, and fast-track protocols have a beneficial effect on muscle strength, gait speed, and main clinical scores after total hip arthroplasty. Similarly, enhanced rehabilitation protocols produced an improvement in primary and secondary outcomes after total knee arthroplasty.

: The aim of this systematic review and meta-analysis is to determine the role of physical activity as a conservative treatment for older people with knee or hip osteoarthritis. The effect on pain, physical function, stiffness, quality of life, and dynamic balance of Aquatic Exercise, Land-based Exercise, and Sports were compared in a specific population composed of osteoarthritic patients aged 65 or over. A systematic search using Pubmed-Medline, Google Scholar, and the Cochrane Library was carried out to select randomized clinical trials, observational studies, or case series that evaluated outcome measures after physical activity. Twenty randomized controlled trials (RCTs) and two case series were included in this review. Four trials were at low risk of bias (A), 12 at unclear risk of bias (B), and four at high risk of bias (C). Compared to controls, Aquatic Exercise, Land-based Exercise, Tai Chi, and Yoga showed a small to high effect for improving pain, physical function, quality of life, and stiffness. Active exercise and sport are effective to improve pain and physical function in elderly people with osteoarthritis. Nevertheless, further studies are required to validate the use of land-based exercise, aquatic exercise, or sport to treat the symptoms of older adults that suffer from knee and hip osteoarthritis., Competing Interests: The authors declare no conflict of interest.

In the scientific landscape, there is a growing interest in defining the role of several biomolecules and humoral indicators of the aging process and in the modifications of these biomarkers induced by physical activity and exercise. The main aim of the present narrative review is to collect the available evidence on the biohumoral indicators that could be modified by physical activity (PA) in the elderly. Online databases including Pubmed, Web of science (Medline), and Scopus were searched for relevant articles published in the last five years in English. Keywords and combination of these used for the search were the following: "biological", "indicators", "markers", "physical", "activity", and "elderly". Thirty-four papers were analyzed for inclusion. Twenty-nine studies were included and divided into four categories: cardiovascular (CV) biomarkers, metabolic biomarkers, inflammatory markers-oxidative stress molecules, and other markers. There are many distinct biomarkers influenced by PA in the elderly, with promising results concerning the metabolic and CV indexes, as a growing number of studies demonstrate the role of PA on improving parameters related to heart function and CV risk like atherogenic lipid profile. Furthermore, it is also a verified hypothesis that PA is able to modify the inflammatory status of the subject by decreasing the levels of pro-inflammatory cytokines, including interleukin-1 (IL-1), interleukin-6 (IL-6), and tumor necrosis factor-alpha (TNF-α). PA seems also to be able to have a direct effect on the immune system. There is a strong evidence of a positive effect of PA on the health of elderly people that could be evidenced and "quantified" by the modifications of the levels of several biohumoral indicators., Competing Interests: The authors declare no conflict of interest.

Total hip arthroplasty (THA) and total knee arthroplasty (TKA) represent two of the most common procedures in orthopedic surgery. The growing need to avoid physical impairment in elderly patients undergoing this kind of surgery puts the focus on the possibility to undertake a preoperative physical activity program to improve their fit and physical health at the time of surgery. A systematic review has been carried out with online databases including PubMed-Medline, Cochrane Central and Google Scholar. The aim was to retrieve available evidence concerning preoperative physical activity and exercise, before total knee or total hip arthroplasty in patients older than 65 years, and to clarify the role of this practice in improving postoperative outcomes. Results of the present systematic analysis showed that, for TKA, most of the studies demonstrated a comparable trend of postoperative improvement of Visual Analogue Scale (VAS), range of movement (ROM) and functional scores, and those of quality of life. There is insufficient evidence in the literature to draw final conclusions on the topic. Prehabilitation for patients undergoing TKA leads to shorter length of stay but not to an enhanced postoperative recovery. Concerning THA, although currently available data showed better outcomes in patients who underwent prehabilitation programs, there is a lack of robust evidence with appropriate methodology.

Ageing is accompanied by a severe muscle function decline presumably caused by structural and functional adaptations at the central and peripheral level. Although researchers have reported an extensive analysis of the alterations involving muscle intrinsic properties, only a limited number of studies have recognised the importance of the central nervous system, and its reorganisation, on neuromuscular decline. Neural changes, such as degeneration of the human cortex and function of spinal circuitry, as well as the remodelling of the neuromuscular junction and motor units, appear to play a fundamental role in muscle quality decay and culminate with considerable impairments in voluntary activation and motor performance. Modern diagnostic techniques have provided indisputable evidence of a structural and morphological rearrangement of the central nervous system during ageing. Nevertheless, there is no clear insight on how such structural reorganisation contributes to the age-related functional decline and whether it is a result of a neural malfunction or serves as a compensatory mechanism to preserve motor control and performance in the elderly population. Combining leading-edge techniques such as high-density surface electromyography (EMG) and improved diagnostic procedures such as functional magnetic resonance imaging (fMRI) or high-resolution electroencephalography (EEG) could be essential to address the unresolved controversies and achieve an extensive understanding of the relationship between neural adaptations and muscle decline.

Background: Neurodegenerative diseases (ND) as Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis represent a growing cause of disability in the developed countries. The underlying physiopathology is still unclear. Several lines of evidence suggest a role for oxidative stress and NADPH oxidase 2 (NOX2) in the neuropathological pathways that lead to ND. Furthermore, recent studies hypothesized a role for gut microbiota in the neuroinflammation; in particular, lipopolysaccharide (LPS) derived from Gram-negative bacteria in the gut is believed to play a role in causing ND by increase of oxidative stress and inflammation. The aim of this study was to assess NOX2 activity as well as serum 8-iso-prostaglandin F2 α (8-iso-PGF2 α (8-iso-PGF2., Methods: One hundred and twenty-eight consecutive subjects, including 64 ND patients and 64 controls (CT) matched for age and gender, were recruited. A cross-sectional study was performed to compare serum activity of soluble NOX2-dp (sNOX2-dp), blood levels of isoprostanes, serum H 2 O 2 , and LPS in these two groups. Serum zonulin was used to assess gut permeability., Results: Compared with CT, ND patients had higher values of sNOX2-dp, 8-iso-PGF2 α (8-iso-PGF2 p < 0.001), zonulin (Rs = 0.411; p < 0.001), zonulin (Rs = 0.411; p < 0.001), zonulin (Rs = 0.411; α (8-iso-PGF2 p < 0.001), zonulin (Rs = 0.411; p < 0.001), zonulin (Rs = 0.411; α (8-iso-PGF2 p < 0.001), zonulin (Rs = 0.411; β , 0.459; p < 0.001), zonulin (Rs = 0.411; α (8-iso-PGF2 β , 0.459; p < 0.001), zonulin (Rs = 0.411; R 2 = 57%)., Conclusion: This study provides the first report attesting that patients with ND have high NOX2 activation that could be potentially implicated in the process of neuroinflammation., Competing Interests: All the authors have no conflicts of interest to disclose., (Copyright © 2020 Lorenzo Loffredo et al.)

Collection of an adequate amount of autologous haematopoietic stem progenitor cells (HSPC) is required for ex vivo manipulation and successful engraftment for certain inherited disorders. Fifty-seven paediatric patients (age 0.5-11.4 years) underwent a bone marrow harvest for the purpose of HSPC gene therapy (GT), including adenosine deaminase-severe combined immunodeficiency (ADA-SCID), Wiskott-Aldrich syndrome (WAS) and metachromatic leukodystrophy (MLD) patients. Total nucleated cells and the percentage and absolute counts of CD34+ cells were calculated at defined steps of the procedure (harvest, CD34+ cell purification, transduction with the gene transfer vector and infusion of the medicinal product). A minimum CD34+ cell dose for infusion was 2 × 10 6 /kg, with an optimal target at 5-10 × 10 6 /kg. Median volume of bone marrow harvested was 34.2 ml/kg (range 14.2-56.6). The number of CD34+ cells collected correlated inversely with weight and age in all patients and particularly in the MLD children group. All patients reached the minimum target dose for infusion: median dose of CD34+ cells/kg infused was 10.3 × 10 6 /kg (3.7-25.9), with no difference among the three groups. Bone marrow harvest of volumes > 30 ml/kg in infants and children with ADA-SCID, WAS and MLD is well tolerated and allows obtaining an adequate dose of a medicinal product for HSPC-GT.

Aims: While several generic preparations of levodopa/carbidopa and levodopa/benserazide (LBD) are currently available, pharmacokinetic (PK) equivalence and therapeutic equivalence studies with levodopa generics are not available in Italy. Lack of data on generic formulations is a critical factor for their limited use in this country and often lead patients to refuse the generic version of the branded drug., Methods: An experimental, 2-centre, randomized, double-blind, 2-sequence, noninferiority cross-over study was designed to evaluate both the PK equivalence and clinical equivalence of multiple doses of the generic preparation of LDB, Teva Italia, compared to the originator (Madopar). Forty-three out-patients with a diagnosis of idiopathic Parkinson's disease on LDB, were recruited and randomly assigned to 1 of 2 study sequences: generic-originator or originator-generic. Clinical evaluations were performed at the end of each study period. A PK study with an LDB fixed dose (100 + 25 mg) was performed in a subpopulation of 14 subjects., Results: Clinical data showed a reduction of 0.49 and 1.54 in the mean UPDRS III scores for the LDB and the originator, respectively. The 95% CIs [-2.21: 0.11] of the mean difference original vs LDB are smaller than the clinically significant difference of 3 UPDRS III points, supporting the conclusion that the treatment with LDB is not inferior to the originator. No statistically significant differences were found with respect to area under the curve to last dose, half-life, maximum concentration, time to maximum concentration and last observed concentration., Conclusion: These findings prove the therapeutic clinical equivalence as well the PK equivalence of the generic LDB and the originator (Madopar)., (© 2019 The British Pharmacological Society.)

Background and Objective: 18 F-FluoroDeoxyGlucose Positron Emission Tomography ( 18 F-FDG PET) is one of the imaging biomarkers to diagnose Alzheimer's Disease (AD). In 18 F-FDG PET images, the changes of voxels' intensities reflect the differences of glucose rates, therefore voxel intensity is usually used as a feature to distinguish AD from Normal Control (NC), or at earlier stage to distinguish between progressive and stable Mild Cognitive Impairment (pMCI and sMCI). In this paper, 18 F-FDG PET images are characterized in an alternative way-the spatial gradient, which is motivated by the observation that the changes of 18 F-FDG rates also cause gradient changes., Methods: We improve Histogram of Oriented Gradient (HOG) descriptor to quantify spatial gradients, thereby achieving the goal of diagnosing AD. First, the spatial gradient of 18 F-FDG PET image is computed, and then each subject is segmented into different regions by using an anatomical atlas. Second, two types of improved HOG features are extracted from each region, namely Small Scale HOG and Large Scale HOG, then some relevant regions are selected based on a classifier fed with spatial gradient features. Last, an ensemble classification framework is designed to make a decision, which considers the performance of both individual and concatenated selected regions., Results: the evaluation is done on ADNI dataset. The proposed method outperforms other state-of-the-art 18 F-FDG PET-based algorithms for AD vs. NC with an accuracy, a sensitivity and a specificity values of 93.65%, 91.22% and 96.25%, respectively. For the case of pMCI vs. sMCI, the three metrics are 75.38%, 74.84% and 77.11%, which is significantly better than most existing methods. Besides, promising results are also achieved for multiple classifications under 18 F-FDG PET modality., Conclusions: 18 F-FDG PET images can be characterized by spatial gradient features for diagnosing AD and its early stage, and the proposed ensemble framework can enhance the classification performance., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Comprehensive facial injury (CFI) score is a powerful and extremely simple scale used to grade the clinical severity of all facial injuries, and is expressed in terms of the overall surgical time needed for definitive treatment. Its statistical validation was previously reported in 2019. The aim of this study was to investigate further the link with duration of surgery, applying the score to a larger sample of patients, and to evaluate the relationship between CFI score and other extremely relevant dependent variables: length of stay (LOS) in high care units (HCU) and in intensive care units (ICU). 1406 patients with diagnosis of at least one facial bone fracture, and treated by the same team in two highly specialized trauma centers, were studied. For each patient a specific CFI score is assigned and overall surgical time, length of stay, and presence of associated injuries were recorded. Data were divided into six clusters according to CFI score: (1) 0-5, (2) 6-10, (3) 11-15, (4) 16-20, (5) 21-25, and (6) >25. Regressions between CFI clusters and duration of surgery (minutes), LOS in ICU (days), and in HCU (days) were established. In addition, the presence of associated head and/or somatovisceral injuries was analyzed and related to CFI score. Statistical analysis confirmed linear regression existing between each CFI cluster and overall surgical time (p < 0.00001), with improved significance of the results using median values of surgical duration for each cluster (p = 0.0001). It also demonstrated the existence of linear regression between all CFI clusters and LOS in HCU (p = 0.0001) and between CFI clusters 3-6 and median values of LOS in ICU (p = 0.0001). Finally, associated injuries were observed to be more frequent in high CFI score clusters, occurring in around 90% of patients with a CFI score >25 (p < 0.00001). Association of head and facial injuries play a major role in high LOS in ICU values, whereas coexistence of facial, head and somatovisceral involvement increases LOS in ICU to over twice that for single association. Surgical time and length of stay are outcomes traditionally used to assess the statistical significance of many new proposed trauma score. The strong correlation demonstrated between CFI score and each of these variables confirms its value and reliability. CFI score is proven to be an ideal, simple, informative, and reproducible tool for measuring severity of facial injuries and their clinical impact. It allows correlation with associated head and somatovisceral injuries, focusing attention on the interesting field of reciprocal influences in simultaneous, multidistrectual involvement. None of the previously proposed facial injury severity scales have offered such informative and statistically significant features., (Copyright © 2019 European Association for Cranio-Maxillo-Facial Surgery. Published by Elsevier Ltd. All rights reserved.)

Using a single imaging modality to diagnose Alzheimer's disease (AD) or mild cognitive impairment (MCI) is a challenging task. FluoroDeoxyGlucose Positron Emission Tomography (FDG-PET) is an important and effective modality used for that purpose. In this paper, we develop a novel method by using single modality (FDG-PET) but multilevel feature, which considers both region properties and connectivities between regions to classify AD or MCI from normal control. First, three levels of features are extracted: statistical, connectivity, and graph-based features. Then, the connectivity features are decomposed into three different sets of features according to a proposed similarity-driven ranking method, which can not only reduce the feature dimension but also increase the classifier's diversity. Last, after feeding the three levels of features to different classifiers, a new classifier selection strategy, maximum Mean squared Error (mMsE), is developed to select a pair of classifiers with high diversity. In order to do the majority voting, a decision-making scheme, a nested cross validation technique is applied to choose another classifier according to the accuracy. Experiments on Alzheimer's Disease Neuroimaging Initiative database show that the proposed method outperforms most FDG-PET-based classification algorithms, especially for classifying progressive MCI (pMCI) from stable MCI (sMCI).

Background: The aim of this study was to compare the acute effects produced by a single bout of three different exercise modalities on short-term blood pressure variability., Methods: The study enrolled 21 sedentary male patients with hypertension and a mean age of 63 ± 7.2 years. Blood pressure variability was evaluated through ambulatory blood pressure monitoring that was performed twice: during an ordinary daily activity and after an exercise session lasting 60 minutes. Patients were divided into three groups according to the different exercise modality performed during the session: aerobic continuous training, interval training or combined training including aerobic and resistance training., Results: Twenty-four-hour systolic blood pressure variability increased in the interval training group, was unchanged in the aerobic continuous training group and decreased in the combined training group (intergroup P  = 0.03). Daytime systolic blood pressure variability increased in the interval training and aerobic continuous training groups while it decreased in the combined training group (intergroup P  = 0.0006). Twenty-four-hour diastolic blood pressure variability decreased in the aerobic continuous training and combined training groups while it increased in the interval training group (intergroup P  = 0.002)., Conclusion: Different training modalities have similar hypotensive action but exert different acute effects on blood pressure variability. Combined training seems to be the most suitable training modality for sedentary men with hypertension.

The role of oxidative stress, an imbalance between reactive oxygen species production (ROS) and antioxidants, has been described in several patho-physiological conditions, including cardiovascular, neurological diseases and cancer, thus impacting on individuals' lifelong health. Diet, environmental pollution, and physical activity can play a significant role in the oxidative balance of an organism. Even if physical training has proved to be able to counteract the negative effects caused by free radicals and to provide many health benefits, it is also known that intensive physical activity induces oxidative stress, inflammation, and free radical-mediated muscle damage. Indeed, variations in type, intensity, and duration of exercise training can activate different patterns of oxidant-antioxidant balance leading to different responses in terms of molecular and cellular damage. The aim of the present review is to discuss (1) the role of oxidative status in athletes in relation to exercise training practice, (2) the implications for muscle damage, (3) the long-term effect for neurodegenerative disease manifestations, (4) the role of antioxidant supplementations in preventing oxidative damages.

Background: Wiskott-Aldrich syndrome is a rare, life-threatening, X-linked primary immunodeficiency characterised by microthrombocytopenia, infections, eczema, autoimmunity, and malignant disease. Lentiviral vector-mediated haemopoietic stem/progenitor cell (HSPC) gene therapy is a potentially curative treatment that represents an alternative to allogeneic HSPC transplantation. Here, we report safety and efficacy data from an interim analysis of patients with severe Wiskott-Aldrich syndrome who received lentiviral vector-derived gene therapy., Methods: We did a non-randomised, open-label, phase 1/2 clinical study in paediatric patients with severe Wiskott-Aldrich syndrome, defined by either WAS gene mutation or absent Wiskott-Aldrich syndrome protein (WASP) expression or a Zhu clinical score of 3 or higher. We included patients who had no HLA-identical sibling donor available or, for children younger than 5 years of age, no suitable 10/10 matched unrelated donor or 6/6 unrelated cord blood donor. After treatment with rituximab and a reduced-intensity conditioning regimen of busulfan and fludarabine, patients received one intravenous infusion of autologous CD34+ cells genetically modified with a lentiviral vector encoding for human WAS cDNA. The primary safety endpoints were safety of the conditioning regimen and safety of lentiviral gene transfer into HSPCs. The primary efficacy endpoints were overall survival, sustained engraftment of genetically corrected HSPCs, expression of vector-derived WASP, improved T-cell function, antigen-specific responses to vaccinations, and improved platelet count and mean platelet volume normalisation. This interim analysis was done when the first six patients treated had completed at least 3 years of follow-up. The planned analyses are presented for the intention-to-treat population. This trial is registered with ClinicalTrials.gov (number NCT01515462) and EudraCT (number 2009-017346-32)., Findings: Between April 20, 2010, and Feb 26, 2015, nine patients (all male) were enrolled of whom one was excluded after screening; the age range of the eight treated children was 1·1-12·4 years. At the time of the interim analysis (data cutoff April 29, 2016), median follow-up was 3·6 years (range 0·5-5·6). Overall survival was 100%. Engraftment of genetically corrected HSPCs was successful and sustained in all patients. The fraction of WASP-positive lymphocytes increased from a median of 3·9% (range 1·8-35·6) before gene therapy to 66·7% (55·7-98·6) at 12 months after gene therapy, whereas WASP-positive platelets increased from 19·1% (range 4·1-31·0) to 76·6% (53·1-98·4). Improvement of immune function was shown by normalisation of in-vitro T-cell function and successful discontinuation of immunoglobulin supplementation in seven patients with follow-up longer than 1 year, followed by positive antigen-specific response to vaccination. Severe infections fell from 2·38 (95% CI 1·44-3·72) per patient-year of observation (PYO) in the year before gene therapy to 0·31 (0·04-1·11) per PYO in the second year after gene therapy and 0·17 (0·00-0·93) per PYO in the third year after gene therapy. Before gene therapy, platelet counts were lower than 20 × 10 9 per L in seven of eight patients. At the last follow-up visit, the platelet count had increased to 20-50 × 10 9 per L in one patient, 50-100 × 10 9 per L in five patients, and more than 100 × 10 9 per L in two patients, which resulted in independence from platelet transfusions and absence of severe bleeding events. 27 serious adverse events in six patients occurred after gene therapy, 23 (85%) of which were infectious (pyrexia [five events in three patients], device-related infections, including one case of sepsis [four events in three patients], and gastroenteritis, including one case due to rotavirus [three events in two patients]); these occurred mainly in the first 6 months of follow-up. No adverse reactions to the investigational drug product and no abnormal clonal proliferation or leukaemia were reported after gene therapy., Interpretation: Data from this study show that gene therapy provides a valuable treatment option for patients with severe Wiskott-Aldrich syndrome, particularly for those who do not have a suitable HSPC donor available., Funding: Italian Telethon Foundation, GlaxoSmithKline, and Orchard Therapeutics., (Copyright © 2019 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)