Overuse-Related Injuries of the Musculoskeletal System: Systematic Review and Quantitative Synthesis of Injuries, Locations, Risk Factors and Assessment Techniques.

Overuse-related musculoskeletal injuries mostly affect athletes, especially if involved in preseason conditioning, and military populations; they may also occur, however, when pathological or biological conditions render the musculoskeletal system inadequate to cope with a mechanical load, even if moderate. Within the MOVIDA (Motor function and Vitamin D: toolkit for risk Assessment and prediction) Project, funded by the Italian Ministry of Defence, a systematic review of the literature was conducted to support the development of a transportable toolkit (instrumentation, protocols and reference/risk thresholds) to help characterize the risk of overuse-related musculoskeletal injury. The PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) approach was used to analyze Review papers indexed in PubMed and published in the period 2010 to 2020. The search focused on stress (overuse) fracture or injuries, and muscle fatigue in the lower limbs in association with functional (biomechanical) or biological biomarkers. A total of 225 Review papers were retrieved: 115 were found eligible for full text analysis and led to another 141 research papers derived from a second-level search. A total of 183 papers were finally chosen for analysis: 74 were classified as introductory to the topics, 109 were analyzed in depth. Qualitative and, wherever possible, quantitative syntheses were carried out with respect to the literature review process and quality, injury epidemiology (type and location of injuries, and investigated populations), risk factors, assessment techniques and assessment protocols.

Robotic-Assisted Anastomosis in Orthoplastic Surgery: Preliminary Data.

BACKGROUND: The evolution of microsurgery has relied on advancements in operating microscopes and surgical instruments. Pioneering advancements, however, especially within the domain of "super-microsurgery", challenge the limits of human dexterity by dealing with anastomoses between vessels smaller than 0.8 mm. Based on these premises, the Symani robotic system was designed and developed. This platform utilizes teleoperation and motion-scaled movement to provide surgeons with precision and accuracy in manipulating millimetre and submillimetre-sized anatomical structures. In this study, we present our experience in performing robotic-assisted anastomoses using the Symani Surgical System in free flap reconstruction. METHODS: We present a comprehensive analysis of all reconstructive procedures involving microsurgical free flaps performed using the Symani robotic platform at the orthoplastic unit of the Rizzoli Orthopaedic Institute from 1 October 2022 to 1 May 2023. RESULTS: Sixteen microsurgical reconstructions using free flaps were performed, involving a total of 40 anastomoses on vessel calibres ranging from 0.6 mm to 2.5 mm. In each case, the anastomosis was executed with the assistance of the robotic platform, achieving a 100+% success rate in patent anastomoses, and no major complications occurred.Conclusion The Symani system has proven to be safe and reliable in performing microsurgical anastomoses. While this platform demonstrated successful in various vessel calibres, its most promising potential lies in anastomoses below the size of a millimetre. Larger patient cohorts and extended investigation periods will be essential to explore whether robotics in microsurgery offers advantages across all microsurgical procedures or should be reserved for selected cases.

Sublingual sufentanil for patient-controlled analgesia during labor induction for pregnancy termination: an effective and well-tolerated approach.

BACKGROUND: Effective pain management during labor induction for pregnancy termination is essential. However, to date, no effective treatment has been identified. The primary aim of this study was to measure the analgesic efficacy of a sufentanil sublingual tablet system during pregnancy termination and patient satisfaction by comparing nulliparous and multiparous women. The secondary aims were to characterize the safety profile by reporting any side effects or adverse events and to determine the need for rescue therapy. METHODS: We conducted an observational, retrospective, single-center study involving 48 women. The data retrieved for analysis included the total and hourly doses of sublingual sufentanil, evaluations of pain management satisfaction using a 5-point rating scale (ranging from 1, indicating "not satisfied" to 5, denoting "completely satisfied"), occurrence of side effects and adverse events, and the rate of rescue analgesic use. Categorical and numerical variables were compared between the two groups, and a correlation analysis was performed. RESULTS: The median total dose of sufentanil required was 60 mcg. Nulliparous women required a higher dose of sufentanil compared with multiparous women (105 mcg vs. 45 mcg; P = 0.01). Additionally, they underwent a longer labor, indirectly measured by the time of device usage (625 min vs. 165 min; P = 0.05). Regarding satisfaction, 40 patients (83.4%) were satisfied or completely satisfied, whereas only 8 patients (16.6%) reported dissatisfaction. Multiparous women exhibited higher satisfaction levels than did nulliparous women (P = 0.03). No adverse events were reported, and the most common side effects were nausea and vomiting (31.2%). Four patients (12%) required acetaminophen due to insufficient analgesia, with only one patient necessitating a switch to intravenous morphine. CONCLUSIONS: Sublingual sufentanil was effective in both nulliparous and multiparous women with minimal side effects. Therefore, sublingual sufentanil can be considered a valid strategy for analgesia during labor induction for pregnancy termination.

Unveiling intrinsic material and extrinsic pinning dimensionality in superconductors: Why Fe(Se,Te) is able to mimic YBCO.

Discovery of iron-based superconductors paved the way to a competitor of high-temperature superconductors, easier to produce, better performing in high fields, and promising to be less expensive. Critical parameters are investigated by resistivity measurements as a function of temperature, field, and angle R(T,H,θ). This work presents a deep analysis of H-θ phase diagram of PLD-processed Fe(Se,Te) superconducting films, thus revealing material and pinning anisotropy at once. By selecting different thresholds along the R(T,H,θ) curves, all possible regimes emerge. Surprisingly, anisotropy arises moving from the upper critical field toward the irreversibility line: gradually a non-monotonous transition from 3D to 2D, and backward to 3D occurs. Although Fe(Se,Te) appears as a 3D superconductor, its anisotropic pinning landscape shows up similarities with an intrinsic layered superconductor and Fe(Se,Te) definitively mimics YBCO. We propose a general method to disentangle, in any other superconductor, material dimensionality and pinning anisotropy that are key constraints for applications.

Evaluation of a textile-based wearable system for the electrocardiogram monitoring in cardiac patients.

AIMS: We developed a textile-based wearable system, named MagIC, for the unobtrusive monitoring of one electrocardiogram (ECG) lead, respiratory frequency and motion. In the present study, we investigated the ability of this system to monitor cardiac rhythm and arrhythmic events in cardiac patients. METHODS AND RESULTS: The study was carried out by comparing ECG tracings simultaneously recorded by MagIC and traditional ECG devices (Trad-ECG) in 40 cardiac patients at rest and during physical exercise. Data were manually scored by two cardiologists. At rest the artefact rates observed with MagIC and Trad-ECG were virtually identical (1.4% of the registered signal); while during physical exercise the artefact rate observed with MagIC was much lower than with Trad-ECG (4.07 vs. 17.31%). Recordings from MagIC allowed a correct identification of the type of rhythm in the vast majority of patients (92.5%) and an estimation of PQ interval and QRS duration similar to Trad-ECG (<0.016 s). MagIC displayed a good performance in detecting arrhythmias, with only 14 misclassified events out of 3618, and both specificity and sensitivity being above 99%. No practical difference was observed in the estimation of the beat-by-beat RR interval by the two methods. CONCLUSION: This study indicates that in static condition MagIC has a capability of monitoring cardiac rhythm and arrhythmic events which is comparable with what obtainable by a traditional one-lead ECG recorder. During movement MagIC provides an ECG signal of better quality.

Intracoronary Pacing during "Chimney Technique" in Transcatheter Aortic Valve-in-Valve Implantation: An Alternative Temporary Rapid Ventricular Stimulation?

Temporary rapid ventricular pacing (TRVP) is required during transcatheter aortic valve implantation (TAVI) in order to reduce cardiac output and to facilitate balloon aortic valvuloplasty, prosthesis deployment, and post-deployment balloon dilation. The two most frequently used TRVP techniques are right endocardial (RE)-TRVP and retrograde left endocardial temporary rapid ventricular pacing (RLE)-TRVP. The first one could be responsible for cardiac tamponade, one of the most serious procedural complications during TAVI, while the second one could often be unsuccessful. Intracoronary (IC)-TRVP through a coronary guidewire has been described as a safe and efficient procedure that could avoid such complications. We describe two clinical cases in which IC-TRVP has been effectively used during valve-in-valve TAVI with coronary protection via the "chimney technique", after unsuccessful RLE-TRVP.

A Newly Developed Exergame-Based Telerehabilitation System for Older Adults: Usability and Technology Acceptance Study.

BACKGROUND: Telerehabilitation has gained significance as a tool to deliver and supervise therapy and training as effective as traditional rehabilitation methods yet more accessible and affordable. An exergame-based telerehabilitation system has recently been developed within the scope of the international Continuum-of-Care (COCARE) project. The system comprises training devices for use in clinics (Dividat Senso) and at home (Dividat Senso Flex), an assessment system, and a rehabilitation cockpit, and its focus lies on home-based motor-cognitive training, which is remotely managed by health care professionals (HPs). OBJECTIVE: This study aims to analyze the usability, acceptance, and enjoyment of the COCARE system from the perspective of primary (older adults [OAs]) and secondary (HPs) end users. METHODS: At 3 trial sites (located in Switzerland, Italy, and Cyprus), participants engaged in a single-session trial of the COCARE system, including testing of exergames and assessments. Mixed methods encompassing qualitative approaches (eg, think aloud) and quantitative measures (eg, Exergame Enjoyment Questionnaire [EEQ], System Usability Scale [SUS], and Unified Theory of Acceptance and Use of Technology [UTAUT] questionnaire) were used to analyze participants' perceptions of the system and identify potential barriers to its implementation in a home setting. In addition, the associations of performance during gameplay and assessments, demographics, and training motivation (Behavioral Regulation in Exercise Questionnaire-3 [BREQ-3]) with usability, acceptance, and enjoyment were explored. RESULTS: A total of 45 OAs and 15 HPs participated in this study. The COCARE system achieved good acceptance ratings (OAs: 83%, range 36%-100% and HPs: 81%, range 63.8%-93.3% of the maximum score), and OAs indicated high enjoyment (mean 73.3, SD 12.7 out of 100 points in the EEQ) during the exergame session. The system's usability, assessed with the SUS, received scores of 68.1 (SD 18.8; OAs) and 70.7 (SD 12.3; HPs) out of 100 points, with substantial differences observed between the trial sites. Several requirements for improvement were identified. Commonly mentioned barriers to adoption included the movement-recognition sensitivity of the Senso Flex, its limited markings, and difficulties in understanding certain instructions for assessments and games. Performance in games and assessments showed the highest significant correlations with the SUS (Spearman ρ=0.35, P=.02 to ρ=0.52, P<.001). The BREQ-3 had significant correlations with all usability measures, thereby even large significant correlations with enjoyment (Spearman ρ=0.58; P<.001). Age had moderately significant correlations with the SUS (Spearman ρ=-0.35; P=.02) and the UTAUT total score (ρ=-0.35; P=.02) but no significant correlation with the EEQ. Concerning sex and years of education, no significant correlations were found. CONCLUSIONS: The study's findings will inform the further development of the COCARE system toward a user-friendly and widely accepted version, enhancing cognitive and physical functions in OAs. Future randomized controlled trials should evaluate the system's feasibility and effectiveness.

Feasibility and Effectiveness of a Personalized Home-Based Motor-Cognitive Training Program in Community-Dwelling Older Adults: Protocol for a Pragmatic Pilot Randomized Controlled Trial.

BACKGROUND: Exergame-based motor-cognitive training in older adults has been associated with improvements in physical, cognitive, and psychological functioning. The novel Cocare system (Dividat GmbH), developed through a user-centered design process, allows motor-cognitive training in a telerehabilitation setting. It includes (1) a stationary stepping platform for supervised exergame training (Dividat Senso; Dividat GmbH), (2) a home-based version (Dividat Senso Flex, which is a rollable pressure-sensitive mat; Dividat GmbH), (3) an assessment system (including motor-cognitive tests), and (4) a rehabilitation cockpit for remote training supervision and management. OBJECTIVE: The aim of this study is to test the feasibility and effectiveness of this novel training system. METHODS: A total of 180 older adults from Switzerland, Italy, and Cyprus aged ≥60 years with a prescription for rehabilitation are randomly allocated to an intervention group or a control group. Both groups continue with their usual care, whereas participants in the intervention group additionally perform a 2-week supervised exergame training program at rehabilitation centers, followed by a 10-week home training program under remote supervision. The assessment system is used to indicate the start level of each participant, and, in both intervention periods, standardized progression rules are applied. The measures of feasibility include adherence, attrition, exergame enjoyment, willingness to perform such a training program, and the number and types of help requests. Effectiveness is assessed in terms of cognitive and physical functioning, balance confidence, and quality of life. RESULTS: Data collection started in February 2023 and is ongoing. Final measurements are expected to be performed in January 2024. CONCLUSIONS: Owing to the user-centered design approach, the Cocare system is expected to be user-friendly and offers several novel features to cover the whole continuum of care. This pragmatic trial will provide valuable information regarding final necessary adaptations and subsequent implementation efforts. TRIAL REGISTRATION: ClinicalTrials.gov NCT05751551; https://www.clinicaltrials.gov/study/NCT05751551. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/49377.

Surgical Mortality Risk Scores in Transcatheter Aortic Valve Implantation: Is Their Early Predictive Value Still Strong?

BACKGROUND: Surgical mortality risk scores, even if not properly designed and rarely tested in the transcatheter aortic valve implantation (TAVI) setting, still guide the heart team in managing significant aortic stenosis. METHODS: After splitting 1763 consecutive patients retrospectively based on their mortality risk thresholds, the composite endpoint early safety (ES) was adjudicated according to Valve Academic Research Consortium (VARC)-2 and -3 consensus documents. RESULTS: ES incidence was higher if VARC-2 rather than VARC-3 defined. Despite only patients showing VARC-2 ES had significantly lower absolute values of all three main risk scores, these last still failed to foresee both VARC-2 and -3 ES in intermediate-risk patients. The receiver operating characteristic analysis also showed a significant correlation, but with poor diagnostic accuracy, among the three scores and only VARC-2 ES; moreover, the absence of VARC-2 ES and low-osmolar contrast media administration were identified as independent predictors of 1-year mortality and absence of VARC-3 ES, respectively. Finally, even a single complication included in the ES definition could significantly affect 1-year mortality. CONCLUSION: Currently, the most used mortality risk scores do not have adequate diagnostic accuracy in predicting ES after TAVI. The absence of VARC-2, instead of VARC-3, ES is an independent predictor of 1-year mortality.

Long-term longitudinal study on swine VML model.

BACKGROUND: Volumetric Muscle Loss (VML), resulting from severe trauma or surgical ablation, is a pathological condition preventing myofibers regeneration, since skeletal muscle owns the remarkable ability to restore tissue damage, but only when limited in size. The current surgical therapies employed in the treatment of this pathology, which particularly affects military personnel, do not yet provide satisfactory results. For this reason, more innovative approaches must be sought, specifically skeletal muscle tissue engineering seems to highlight promising results obtained from preclinical studies in VML mouse model. Despite the great results obtained in rodents, translation into human needs a comparable animal model in terms of size, in order to validate the efficacy of the tissue engineering approach reconstructing larger muscle mass (human-like). In this work we aim to demonstrate the validity of a porcine model, that has underwent a surgical ablation of a large muscle area, as a VML damage model. RESULTS: For this purpose, morphological, ultrasound, histological and fluorescence analyses were carried out on the scar tissue formed following the surgical ablation of the peroneus tertius muscle of Sus scrofa domesticus commonly called mini-pig. In particular, the replenishment of the damaged area, the macrophage infiltration and the vascularization at different time-points were evaluated up to the harvesting of the scar upon six months. CONCLUSION: Here we demonstrated that following VML damage, there is an extremely poor regenerative process in the swine muscle tissue, while the formation of fibrotic, scar tissue occurs. The analyses performed up to 180 days after the injury revealed the development of a stable, structured and cellularized tissue, provided with vessels and extracellular matrix acquiring the status of granulation tissue like in human.

Older adults' needs and requirements for a comprehensive exergame-based telerehabilitation system: A focus group study.

Introduction: Telerehabilitation in older adults using information and communication technologies (ICTs) provides therapy, which is potentially equally effective as traditional rehabilitation, yet more accessible. This study aimed to analyze the needs and requirements of older adults (OA) and healthcare-professionals (HP) toward ICTs and telerehabilitation in general as well as toward a specific novel exergame-based telerehabilitation system (COCARE system, Dividat). Materials and methods: The COCARE telerehabilitation system enables individual training based on exergames, as well as an assessment system and a digital centralized case management. Six focus groups with in total 34 participants were conducted. A mixed-methods approach was used comprising questionnaires and semi-structured interviews. Results: Both OA and HP would engage to an exergame-based telerehabilitation program. Major motivating factors are the relevance of such a training for health and the entertainment component of exergames. Main requirements are simplification of the system, variety, a personalized training, a constantly available contact person, and comprehensive instructions for use. Besides, HP praised the system's motivational effect, but remained concerned about risk of falls and social isolation. Conclusion: ICTs for telerehabilitation are accepted by OA and HP but should be adapted hardware- and software-wise to address OA' age-stemming vulnerabilities (e.g., risk of falls) and low ICT literacy.

Bioinspired Helicoidal Composite Structure Featuring Functionally Graded Variable Ply Pitch.

Composite laminated materials have been largely implemented in advanced applications due to the high tailorability of their mechanical performance and low weight. However, due to their low resistance against out-of-plane loading, they are prone to generate damage as a consequence of an impact event, leading to the loss of mechanical properties and eventually to the catastrophic failure of the entire structure. In order to overcome this issue, the high tailorability can be exploited to replicate complex biological structures that are naturally optimised to withstand extreme impact loading. Bioinspired helicoidal laminates have been already studied in-depth with good results; however, they have been manufactured by applying a constant pitch rotation between each consecutive ply. This is in contrast to that observed in biological structures where the pitch rotation is not constant along the thickness, but gradually increases from the outer shell to the inner core in order to optimise energy absorption and stress distribution. Based on this concept, Functionally Graded Pitch (FGP) laminated composites were designed and manufactured in order to improve the impact resistance relative to a benchmark laminate, exploiting the tough nature of helicoidal structures with variable rotation angles. To the authors' knowledge, this is one of the first attempts to fully reproduce the helicoidal arrangement found in nature using a mathematically scaled form of the triangular sequence to define the lamination layup. Samples were subject to three-point bending and tested under Low Velocity Impact (LVI) conditions at 15 J and 25 J impact energies and ultrasonic testing was used to evaluate the damaged area. Flexural After Impact (FAI) tests were used to evaluate the post-impact residual energy to confirm the superior impact resistance offered by these bioinspired structures. Vast improvements in impact behaviour were observed in the FGP laminates over the benchmark, with an average reduction of 41% of the damaged area and an increase in post-impact residual energy of 111%. The absorbed energy was similarly reduced (-44%), and greater mechanical strength (+21%) and elastic energy capacity (+78%) were demonstrated in the three-point bending test.

Statins and immunotherapy: Togetherness makes strength The potential effect of statins on immunotherapy for NSCLC.

BACKGROUND: Recent researches suggested that statins, beside their role in inhibiting endogenous cholesterol synthesis and in cardiovascular prevention, could influence several processes in cancer biology. In fact, a recent meta-analysis demonstrated that statins could positively influence OS in lung cancer patients. AIM: There is a lack of large cohort studies that could support a potential antineoplastic role of statins in clinical practice. We collected data from 162 patients treated with immunotherapy for Nonsmall Cell Lung Cancer (NSCLC) in first- and second-line setting to investigate the impact of these drugs on survival parameters. METHODS AND RESULTS: In our observational study, we enrolled 162 patients who received immunotherapy for lung cancer between October 2015 and April 2020. We used descriptive statistics to analyze patients' baseline features. Tumor response was evaluated using RECIST version 1.1 guidelines. Uni and multivariate analysis were conducted to investigate the relationship between statin use and response to immunotherapy, using the χ2 -test. We used Kaplan-Meier curves to estimate OS and PFS in statin and nonstatin users. We included 122 patients in the final analysis. Median PFS was 17.57 months in the statin group and 9.57 months in the nonstatin group, with a P = <.001. Moreover, median OS was superior in the statin-users group, with a statistically significant difference (19.94 vs 10.94 months, P = <.001). CONCLUSION: Although in our study, statin use positively correlates with PFS and OS in lung cancer patient treated with immunotherapy, these results require a further validation with randomized clinical trials.

The War after War: Volumetric Muscle Loss Incidence, Implication, Current Therapies and Emerging Reconstructive Strategies, a Comprehensive Review.

Volumetric muscle loss (VML) is the massive wasting of skeletal muscle tissue due to traumatic events or surgical ablation. This pathological condition exceeds the physiological healing process carried out by the muscle itself, which owns remarkable capacity to restore damages but only when limited in dimensions. Upon VML occurring, the affected area is severely compromised, heavily influencing the affected a person's quality of life. Overall, this condition is often associated with chronic disability, which makes the return to duty of highly specialized professional figures (e.g., military personnel or athletes) almost impossible. The actual treatment for VML is based on surgical conservative treatment followed by physical exercise; nevertheless, the results, in terms of either lost mass and/or functionality recovery, are still poor. On the other hand, the efforts of the scientific community are focusing on reconstructive therapy aiming at muscular tissue void volume replenishment by exploiting biomimetic matrix or artificial tissue implantation. Reconstructing strategies represent a valid option to build new muscular tissue not only to recover damaged muscles, but also to better socket prosthesis in terms of anchorage surfaces and reinnervation substrates for reconstructed mass.

Experimental study protocol of the project "MOtor function and VItamin D: Toolkit for motor performance and risk Assessment (MOVIDA)".

Musculoskeletal injuries, a public health priority also in the military context, are ascribed to several risk factors, including: increased reaction forces; low/reduced muscle strength, endurance, body mass, Vitamin D level, and bone density; inadequate lifestyles and environment. The MOVIDA Project-funded by the Italian Ministry of Defence-aims at developing a transportable toolkit (assessment instrumentation, assessment protocols and reference/risk thresholds) which integrates motor function assessment with biological, environmental and behavioural factors to help characterizing the risk of stress fracture, stress injury or muscle fatigue due to mechanical overload. The MOVIDA study has been designed following the STROBE guidelines for observational cross-sectional studies addressing healthy adults, both militaries and civilians, with varying levels of physical fitness (sedentary people, recreational athletes, and competitive athletes). The protocol of the study has been designed and validated and is hereby reported. It allows to collect and analyse anamnestic, diagnostic and lifestyle-related data, environmental parameters, and functional parameters measured through portable and wearable instrumentation during adapted 6 minutes walking test. The t-test, one and two-way ANOVA with post-hoc corrections, and ANCOVA tests will be used to investigate relevant differences among the groups with respect to biomechanical parameters; non-parametric statistics will be rather used for non-normal continuous variables and for quantitative discrete variables. Generalized linear models will be used to account for risk and confounding factors.

Risk factors for postoperative eye pain in patients with non-painful eye disease undergoing pars plana vitrectomy: the VItrectomy Pain (VIP) study.

BACKGROUND: Pars plana vitrectomy (PPV), a surgical procedure used to treat different ophthalmic pathologies, could be associated with moderate to severe eye pain. The aim of the present study was to evaluate the incidence of postoperative eye pain and its risk factors following PPV in a selected population of patients with non-painful eye disease, receiving regional anesthesia and moderate sedation with benzodiazepines, without use of narcotics. METHODS: Single-center, prospective observational cohort study. We recorded the presence of pain at operating room discharge, at 6 and 24 hours, using the numeric rating scale (NRS). We recorded also age, sex, ethnic origin, American Society of Anaesthesia physical status (ASA PS) classification, Charlson Comorbidity Index, the etiology of the vitreoretinal pathology, length of surgery, and type of surgical procedure performed. RESULTS: Eye pain (NRS>3) was present in three patients (0.7%) at operating room discharge, 59 (13.2%) at six and 65 (14.6%) at 24 hours after surgery. LASSO logistic regression analysis identified age, ASA PS, race, along with tamponade as independent risk factors for eye pain at six hours. Scleral buckling was selected for eye pain at 24 hrs. CONCLUSIONS: A protocol for pain control after PPV should be considered, especially in younger, non-Caucasian people, and patients with high ASA PS grade. Moreover, attention must be paid when additional surgical procedures are requested, restricting them to selected patients, and using the appropriate agent for intraocular tamponade.

Efficacy of immunotherapy in lung cancer with co-occurring mutations in NOTCH and homologous repair genes.

BACKGROUND: Immune checkpoint inhibitors (ICIs) provide significant survival benefits in non-small cell lung cancer (NSCLC). Nevertheless, while some patients obtain a prolonged benefit, a non-negligible fraction of patients experiences an ultrarapid disease progression. Identifying specific molecular backgrounds predicting opposite outcomes is instrumental to optimize the use of these agents in clinical practice. METHODS: We carried out an observational study with prospective design envisioning targeted next-generation sequencing (NGS) with an approved assay in 55 patients with metastatic NSCLC (Rome cohort), of whom 35 were treated with ICIs. Data from three clinically comparable datasets were collected and combined into a metadataset containing 779 patients. The datasets were related to the Memorial Sloan Kettering Cancer Center (MSKCC) cohort (tissue-based NGS) and the randomized phase II and III POPLAR and OAK trials (blood-based NGS). RESULTS: In patients treated with ICIs in the Rome cohort, co-occurring mutations in NOTCH1-3 and homologous repair (HR) genes were associated with durable clinical benefit. Using the MSKCC/POPLAR/OAK metadaset, we confirmed the relationship between the NOTCHmut/HRmut signature and longer progression-free survival (PFS) in ICI-treated patients (multivariate Cox: HR 0.51, 95% CI 0.34 to 0.76, p=0.001). The NOTCHmut/HRmut genomic predictor was also associated with longer survival (log-rank p=0.008), despite patients whose tumors carried the NOTCHmut/HRmut signature had higher metastatic burden as compared with their negative counterpart. Finally, we observed that this genomic predictor was also associated with longer survival in patients with other tumor types treated with ICIs (n=1311, log-rank p=0.002). CONCLUSIONS: Co-occurring mutations in the NOTCH and HR pathways are associated with increased efficacy of immunotherapy in advanced NSCLC. This genomic predictor deserves further investigation to fully assess its potential in informing therapeutic decisions.

Cardiac, Respiratory and Postural Influences on Venous Return of Internal Jugular and Vertebral Veins.

It is known from physiology that heartbeat and respiration influence venous return, but little is known regarding the extent to which these two factors affect flow. In this study, we estimated the prevalence of cardiac- and breathing-induced venous flow modulations in the internal jugular vein (IJV) and vertebral vein (VV) and the effects of posture. In 19 healthy patients, neck vein flow was examined with pulsed wave Doppler. Electrocardiogram and respiratory signals were simultaneously acquired. In supine position, heart contraction always influenced venous flow, whereas breathing influenced 68% of IJV and 34% of VV flow. In sitting position, heart contraction influenced 74% of IJV and 42% of VV flow; breathing influenced 68% of IJV and 61% of VV measures. Thus, cardiac influence is greatly present in supine position, whereas breathing influence prevails in the VV while sitting. This setup allowed us to observe that in some patients, expiration may cause an unexpected increase in venous flow.

MAGnesium-oral supplementation to reduce PAin in patients with severe PERipheral arterial occlusive disease: the MAG-PAPER randomised clinical trial protocol.

INTRODUCTION: Magnesium exerts analgaesic effects in several animal pain models, as well as in patients affected by acute postoperative pain and neuropathic chronic pain. There is no evidence that magnesium can modulate pain in patients with peripheral arterial occlusive disease (PAOD). We describe the protocol of a single-centre randomised double-blind clinical trial aimed at assessing the efficacy of oral magnesium supplementation in controlling severe pain in patients with advanced PAOD. METHODS AND ANALYSIS: Adult patients affected by PAOD at stages III and IV of Lèriche-Fontaine classification, who are opioid-naïve, and who have been admitted to our Acute Pain Service for intractable pain, will be eligible. Patients will be randomised to the control group, treated with standard therapy (oxycodone and pregabalin) plus placebo for 2 weeks, or to the experimental group (standard therapy plus magnesium oxide). Patients will be evaluated on days 0, 2, 4, 6, 8, 12 and 14; the following information will being collected: daily oxycodone dose; average and maximum pain (Numerical Rating Scale); pain relief (Pain Relief Scale); characteristics of the pain (Neuropathic Pain Scale); impact of pain on the patient's daily activities (Brief Pain Inventory). The primary outcome will be oxycodone dosage needed to achieve satisfactory analgaesia on day 14. Secondary outcomes will be pain relief on day 2, time needed to achieve satisfactory analgaesia and time needed to achieve a pain reduction of 50%. A sample size calculation was performed for the primary outcome, which estimated a required sample size of 150 patients (75 per group). ETHICS AND DISSEMINATION: Ethical approval of the study protocol has been obtained from Comitato Etico Provinciale di Brescia, Brescia, Italy. Trial results will be disseminated through scientific journal manuscripts and scientific conference presentations. TRIAL REGISTRATION NUMBER: NCT02455726.