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The role of mitochondria as the electric engine of cells is well established. Over the past two decades, accumulating evidence has pointed out that, despite the presence of a highly active glycolytic pathway (Warburg effect), a functional and even upregulated mitochondrial respiration occurs in cancer cells to meet the need of high energy and the biosynthetic demand to sustain their anabolic growth. Mitochondria are also the primary source of intracellular ROS. Cancer cells maintain moderate levels of ROS to promote tumorigenesis, metastasis, and drug resistance; indeed, once the cytotoxicity threshold is exceeded, ROS trigger oxidative damage, ultimately leading to cell death. Based on this, mitochondrial metabolic functions and ROS generation are considered attractive targets of synthetic and natural anticancer compounds. Tocotrienols (TTs), specifically the δ- and γ-TT isoforms, are vitamin E-derived biomolecules widely shown to possess striking anticancer properties since they regulate several intracellular molecular pathways. Herein, we provide for the first time an overview of the mitochondrial metabolic reprogramming and redox homeostasis perturbation occurring in cancer cells, highlighting their involvement in the anticancer properties of TTs. This evidence sheds light on the use of these natural compounds as a promising preventive or therapeutic approach for novel anticancer strategies.

Background : The evolution of technology has continuously redefined the landscape of rehabilitation medicine. Researchers have long incorporated virtual reality (VR) as a promising intervention, providing immersive therapeutic environments for patients. The emergence of the metaverse has recently further expanded the potential applications of VR to augment the possibilities in rehabilitation. Rehabilitation is a crucial aspect of healthcare, and technological advancements have allowed new approaches to aid in this process. One such approach is the metaverse, a virtual world where users can interact with each other and their surroundings in a simulated environment. This comprehensive review aimed to analyze the scientific evidence using the term "metaverse" in rehabilitation and its potential patient benefits. Methods : We conducted a comprehensive literature search from the inception to September 2024 in PubMed, Scopus, Web of Science, and Cochrane Database to identify studies investigating the term "metaverse" and its role in rehabilitation. We then assessed these studies based on their methodology, patient population, technology used, and therapeutic outcomes. Results : Out of 81 articles, 55 remained after removing duplicates. After screening the title, abstract, and full text, we included five articles. Conclusions : Results from these studies suggested potential benefits in various rehabilitative areas, such as cerebral palsy, intellectual disabilities, pain management, and physical performance improvement among the elderly. The metaverse presents promising avenues for enhancing rehabilitation outcomes. While VR's effectiveness is well established, the metaverse, being a newer concept, necessitates further studies for a more comprehensive understanding.

Background: Age-related loss of skeletal muscle strength and mass is linked to adverse postoperative outcomes in older individuals with sarcopenia. Half of patients suffer from severe associated osteoarthritis requiring orthopedic interventions. Mitigating the onset and progression of sarcopenia before surgery is essential to improve the prognosis and reduce surgical complications. The aim of this research was to innovatively explore whether the preoperative period could be the appropriate timeframe to empower surgical resilience, through prehabilitation and dietary supplementation, in older sarcopenic patients undergoing knee arthroplasty., Methods: The current literature concerning the effectiveness of prehabilitation and dietary supplementation before knee arthroplasty in sarcopenic older individuals was reviewed, following the SANRA criteria, between December 2023 and February 2024. The study inclusion criteria were as follows: (1) prehabilitation and/or dietary supplementation interventions; (2) human participants aged 65 years and older; (3) relevant outcome reporting (functional status, postoperative complications, and patient-reported outcomes); and (4) articles written in English The extracted information included study characteristics, demographics, intervention details, outcomes, and the main findings., Results: Merged prehabilitation and dietary supplementation strategies extrapolated from the current literature and involving strength, resistance, balance, and flexibility training, as well as essential amino acids, iron, vitamin D, adenosine triphosphate, and glucosamine sulphate supplementation, could improve the functional capacity, ability to withstand the upcoming surgical stressors, and postoperative outcomes in older people undergoing knee arthroplasty., Conclusions: Addressing complex links between knee osteoarthritis and sarcopenia in older individuals undergoing knee arthroplasty requires a multidimensional approach. Prehabilitation emerges as a crucial preliminary step, allowing the optimization of surgical outcomes. Nutraceutical integration, included in a comprehensive care plan, could have a synergic effect in achieving prehabilitation goals. Those interventions are essential for surgical resilience, in terms of muscle function preservation, recovery acceleration, and overall quality of life enhancement. Intensive collaboration among specialists could advance knowledge and the sharable consensus concerning the critical and evolutive field of perioperative care.

Background and Purpose: Assessing appendicular skeletal muscle (ASM) mass is crucial for the diagnosis of numerous pathologies related to the decline of muscle mass in old age, such as sarcopenia, malnutrition, or cachexia. The dual-energy X-ray absorptiometer (DEXA) radiological technique, which is the gold standard for its assessment, is particularly costly and not routinely used in clinical practice. The aim of this study was to derive computationally simple equations capable of estimating the DEXA-measured ASM at zero cost in older adult populations., Methods: We used the cross-sectional data collected by the National Health and Nutrition Examination Survey (NHANES) over 7 years (1999-2006). The study sample included 16,477 individuals aged 18 years and over, of which 4401 were over 60 years old. We considered 38 nonlaboratory variables. For the derivation of the equations, we employed the Brain Project, an innovative artificial intelligence tool that combines genetic programming and neural networks. The approach searches simultaneously for the mathematical expression and the variables to use in the equation. The derived equations are useful to estimate the DEXA-measured ASM., Results and Discussion: A simple equation that includes the body weight of the patient as the sole variable can estimate the outcome of DEXA with an accuracy equivalent to previously published equations. When used to identify individuals over 60 years old with muscle mass loss, it achieved an area under the curve (AUC) value of 0.85 for both males and females. The inclusion of sex and anthropometric data (thigh and arm circumference) improved the accuracy for male individuals (AUC 0.89). The model is also suitable to be applied to the general adult population of 18 years of age or older. Using more than 3 variables does not lead to better accuracy., Conclusions: The newly proposed equations have better diagnostic accuracy than previous equations for the estimation of DEXA-measured ASM. They are readily applicable in clinical practice for the screening of muscle mass loss in the over 60-year-old population with nearly zero-cost variables. The most complex model proposed in this study requires only the inspection of a simple diagnostic chart to estimate the status of muscle mass loss., (Copyright © 2024 APTA Geriatrics, An Academy of the American Physical Therapy Association.)

Cutaneous melanoma still represents a significant health burden worldwide, being responsible for the majority of skin cancer deaths. Key advances in therapeutic strategies have significantly improved patient outcomes; however, most patients experience drug resistance and tumor relapse. Cancer stem cells (CSCs) are a small subpopulation of cells in different tumors, including melanoma, endowed with distinctive capacities of self-renewal and differentiation into bulk tumor cells. Melanoma CSCs are characterized by the expression of specific biomarkers and intracellular pathways; moreover, they play a pivotal role in tumor onset, progression and drug resistance. In recent years, great efforts have been made to dissect the molecular mechanisms underlying the protumor activities of melanoma CSCs to provide the basis for novel CSC-targeted therapies. Herein, we highlight the intricate crosstalk between melanoma CSCs and bystander cells in the tumor microenvironment (TME), including immune cells, endothelial cells and cancer-associated fibroblasts (CAFs), and its role in melanoma progression. Specifically, we discuss the peculiar capacities of melanoma CSCs to escape the host immune surveillance, to recruit immunosuppressive cells and to educate immune cells toward an immunosuppressive and protumor phenotype. We also address currently investigated CSC-targeted strategies that could pave the way for new promising therapeutic approaches for melanoma care.

Objective: This study aims to assess the impact of proprioceptive training strategies with dual-task exercises on gait in people with chronic stroke., Study Design: Systematic review., Patients: Chronic stroke., Methods: Searches were conducted in accordance with PRISMA guidelines and PICOS criteria. PubMed, Web of Science, and Scopus databases were systematically searched from November 2020 to February 2022, for eligible clinical trials. Two independent reviewers thoroughly screened potential articles for relevance and assessed the methodology quality. In accordance with the GRADE, PICOS criteria, and Cochrane risk of bias tools, the authors included articles concerning the effectiveness of dual-task in proprioceptive training on gait parameters in people with chronic stroke., Results: Of 3075 identified studies, 11 articles met the inclusion criteria: 7 were randomized clinical trials, 1 was not randomized, and 3 were observational studies. The overall quality of evidence, assessed using the GRADE framework, was high, indicating a high level of confidence in the systematic review's findings. The papers involved 393 stroke patients; 241 underwent dual-task in proprioceptive training, with 152 participants in other stroke rehabilitation; within the dual-task group, 71 engaged in cognitive tasks, and 170 participated in motor tasks. dual-task in proprioceptive training improved gait speed, cadence, stride time, stride length, and step length. The best effects were observed with training 3 times a week for 4 weeks, with each session lasting 30 minutes, on speed, cadence, stride length, and step length., Conclusion: Current evidence suggests that proprioceptive training strategies with dual-task exercises improved walking abilities in people with chronic stroke. Specifically, it enhanced gait speed, a key indicator of clinical severity.

Background: High-flow nasal therapy is widely used in patients with respiratory failure in different clinical settings, but the effect of high-flow nasal therapy on respiratory-swallow coordination is unknown. Understanding this relationship is crucial, considering the necessity for patients to maintain adequate nutrition during daytime high-flow nasal therapy. This scoping review aims to synthesise available data on the effects of high-flow nasal therapy flow rates on swallowing function and the possible risk of aspiration during treatment, focusing on knowledge and evidence gaps., Methods: PubMed, Scopus, Web of Science and Google Scholar databases were searched from inception to 30 May 2023 for studies reporting data on swallowing assessment in healthy adults or patients with acute or chronic respiratory failure receiving high-flow nasal therapy. Data on study design, patients' characteristics and quality outcomes were extracted., Results: Eight studies were included, four including cohorts of healthy volunteers (n=148) and four including patients with acute or chronic respiratory failure (n=151). Study designs, patient populations and quality outcome measures were heterogeneous. Two studies indicated improvement while four articles showed impairment in swallowing function during high-flow nasal therapy; two studies showed that patients' overall clinical picture and underlying medical conditions influenced swallowing-breathing coordination rather than high-flow nasal therapy per se ., Conclusion: This scoping review found limited and controversial evidence on the impact of high-flow nasal therapy on swallowing function. Remarkably, methods for swallowing function assessment were quite heterogeneous. Additional research is required to test the effect of high-flow nasal therapy on respiratory-swallowing coordination., Competing Interests: Conflict of interest: C. Crimi reports honoraria for lectures from AstraZeneca, GSK, Sanofi, Novartis, Resmed, Fisher & Paykel and Vitalair, outside the submitted work; and a patent pending (number 102023000013077) not discussed in the present study. Conflict of interest: C. Gregoretti reports honoraria for lectures from Vivisol, Vyare and Philips, outside the submitted work; a patent in association with the University of Palermo (number 102019000020532, Italian Ministry of Economic Development) and a patent pending (number 102023000013077), not discussed in the present study. Conflict of interest: A. Carlucci reports honoraria for lectures from Breas, Resmed, Fisher & Paykel and Vitalaire, outside the submitted work. Conflict of interest: A. Cortegiani reports honoraria for lectures from Fisher & Paykel outside the submitted work; and a patent in association with the University of Palermo (number 102019000020532, Italian Ministry of Economic Development) not discussed in the present study. Conflict of interest: The remaining authors have nothing to disclose., (Copyright ©The authors 2024.)

Objective: To show the effectiveness of goal-oriented proprioceptive training in subacute stroke for balance, autonomy, and fall risk., Methods: Out a total of 35 patients, consistent in age (75.31±8.65 years), type of stroke (ischemic, 3 to 11 weeks before), and motor impairment, 18 patients underwent solely proprioceptive rehabilitation, the other 17 dual task exercises. The study assessed autonomy using Barthel Index, fall risk with Timed Up and Go Test (TUG), balance through Berg Balance Scale (BBS) and Tinetti test., Results: After two months, significant improvements were recorded in Barthel Index, BBS (p<0.0001), Tinetti test (p<0.0001 in dual task group, p=0.0029 in single task group), and TUG (p=0.0052 in dual task group, p=0.0020 in single task group) in both groups. Comparing the two groups, dual task group showed a significant difference in Tinetti balance assessment (p=0.0052), between the total score of Tinetti test and TUG in single (p=0.0271), and dual task (p=0.0235). Likewise, Tinetti gait test was significantly related to TUG in single (p=0.0536), and dual task (p=0.0466), while Tinetti balance test to Barthel Index (p=0.0394), BBS (p<0.0001), and TUG in single (p=0.0219), and dual task (p=0.0196). Lastly, there is a positive correlation of the use of aids with BBS (p=0.0074), and total score of Tinetti test (p=0.0160)., Conclusion: In subacute stroke, goal-oriented proprioceptive training improved balance, but only partially autonomy. Furthermore, the use of aids after dual-task exercises improved recovery of balance, but did not reduced falls.

Introduction: Sport-specific adaptations of the glenohumeral joint may arise in adolescent overhead athletes who begin high-performance sports early in life. Research mainly addresses overuse injuries, leaving gaps in prevention, with adults studied more than youths., Objective: This study aims to investigate sport-adaptations of the glenohumeral joint in asymptomatic adolescent volleyball players to identify potential shoulder injury risk factors., Design: Observational study., Setting: Clinical screening campaign conducted at the Physical Medicine and Rehabilitation Unit of Policlinic Hospital in Catania, Italy., Participants: Forty asymptomatic under-16 athletes were evaluated., Interventions: Shoulder internal rotation (IR) and external rotation (ER), range of motion (ROM), total-rotation ROM, glenohumeral IR deficit (GIRD), general joint laxity using Beighton score, apprehension, relocation, O'Brian tests, and ultrasound (US) glenohumeral distance were tested bilaterally. Variables such as the player's position, the age they began the sport, limb dominance, weight, and height were also considered., Results: The median US glenohumeral distance was at 0.42 ± 0.26 cm, which is consistent with the range found in non-dislocated shoulders of a healthy non-athletic population. The ER ROM was significantly greater in the dominant shoulder than the contralateral one (P = 0.0001), and there was a significant correlation between the ER ROM of attackers and their US glenohumeral distance (P = 0.0413). Furthermore, shoulder IR ROM and US glenohumeral distance were not significantly different between the dominant and contralateral limbs (P = 0.05). None of the athletes presented GIRD. Other tests, including the Beighton score, apprehension, and relocation tests, yielded no significant differences between the dominant and contralateral limbs., Conclusions: Despite an increased shoulder ER in the dominant limb, the glenohumeral joint remains stable, suggesting that greater ROM in ER does not equate to instability in overhead athletes without hyperlaxity. Nevertheless, increased ER impacts glenohumeral distance in attacker volleyball players. This finding suggests that the shoulder morphological adaptation process starts early in attackers., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 Published by Elsevier Ltd.)

Our world is made of plastic. Plastic waste deeply affects our health entering the food chain. The degradation and/or fragmentation of plastics due to weathering processes result in the generation of nanoplastics (NPs). Only a few studies tested NPs effects on human health. NPs toxic actions are, in part, mediated by oxidative stress (OS) that, among its effects, affects bone remodeling. This study aimed to assess if NPs influence skeleton remodeling through OS. Murine bone cell cultures (MC3T3-E1 preosteoblasts, MLOY-4 osteocyte-like cells, and RAW264.7 pre-osteoclasts) were used to test the NPs detrimental effects on bone cells. NPs affect cell viability and induce ROS production and apoptosis (by caspase 3/7 activation) in pre-osteoblasts, osteocytes, and pre-osteoclasts. NPs impair the migration capability of pre-osteoblasts and potentiate the osteoclastogenesis of preosteoclasts. NPs affected the expression of genes related to inflammatory and osteoblastogenic pathways in pre-osteoblasts and osteocytes, related to the osteoclastogenic commitment of pre-osteoclasts. A better understanding of the impact of NPs on bone cell activities resulting in vivo in impaired bone turnover could give more information on the possible toxicity consequence of NPs on bone mass and the subsequent public health problems, such as bone disease., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: Vertebral fragility fractures (VFFs) commonly result from low bone mass and microarchitecture deterioration of bone tissue. spinal orthoses are common non-pharmacological options for managing vertebral fracture pain. However, the effects of spinal orthoses on pain, physical functioning, and quality of life (QoL) are still debated., Objective: This survey aimed to investigate the patients-reported outcomes of a dynamic spinal orthosis prescribed in the routine clinical practice of VFFs management., Methods: This multi-center national-wide prospective cohort study assessed older patients (aged > 60 years) diagnosed with acute VFFs and prescribed with a dynamic spinal orthosis (Spinfast®). A survey questionnaire was realized and included sections on patient characterization, osteoporosis characterization, spinal orthosis, clinical outcomes, pain medications, and osteoporosis medications. The questionnaire was administered at baseline and after three months. A total of 68 patients completed the questionnaire at three months. Most patients had one or two VFFs and were treated with pain medications and osteoporosis medications. Compliance and tolerability of the spinal orthosis were assessed, and clinical outcomes such as pain intensity, physical functioning, and QoL were measured., Results: The results showed no significant differences in outcomes between age subgroups. Italian physical medicine and rehabilitation physicians were commonly involved in the management of VFFs patients. Sixty-six patients completed the questionnaire. The results showed that pain intensity, physical functioning and QoL improved after three months of spinal orthosis wearing (p< 0.0001)., Conclusion: The correct management of VFFs is mandatory to improve pain and reduce disability, and our findings suggested a positive role of dynamic spinal orthosis to improve the comprehensive management of VFFs patients. However, high-quality research trials are warranted to provide clear recommendations for the correct clinical management of VFF.

DIS3 gene mutations occur in approximately 10% of patients with multiple myeloma (MM); furthermore, DIS3 expression can be affected by monosomy 13 and del(13q), found in roughly 40% of MM cases. Despite the high incidence of DIS3 mutations and deletions, the biological significance of DIS3 and its contribution to MM pathogenesis remain poorly understood. In this study we investigated the functional role of DIS3 in MM, by exploiting a loss-of-function approach in human MM cell lines. We found that DIS3 knockdown inhibits proliferation in MM cell lines and largely affects cell cycle progression of MM plasma cells, ultimately inducing a significant increase in the percentage of cells in the G0/G1 phase and a decrease in the S and G2/M phases. DIS3 plays an important role not only in the control of the MM plasma cell cycle, but also in the centrosome duplication cycle, which are strictly co-regulated in physiological conditions in the G1 phase. Indeed, DIS3 silencing leads to the formation of supernumerary centrosomes accompanied by the assembly of multipolar spindles during mitosis. In MM, centrosome amplification is present in about a third of patients and may represent a mechanism leading to genomic instability. These findings strongly prompt further studies investigating the relevance of DIS3 in the centrosome duplication process. Indeed, a combination of DIS3 defects and deficient spindle-assembly checkpoint can allow cells to progress through the cell cycle without proper chromosome segregation, generating aneuploid cells which ultimately lead to the development of MM.

The NOTCH ligands JAG1 and JAG2 have been correlated in vitro with multiple myeloma (MM) cell proliferation, drug resistance, self-renewal and a pathological crosstalk with the tumor microenvironment resulting in angiogenesis and osteoclastogenesis. These findings suggest that a therapeutic approach targeting JAG ligands might be helpful for the care of MM patients and lead us to explore the role of JAG1 and JAG2 in a MM in vivo model and primary patient samples. JAG1 and JAG2 protein expression represents a common feature in MM cell lines; therefore, we assessed their function through JAG1/2 conditional silencing in a MM xenograft model. We observed that JAG1 and JAG2 showed potential as therapeutic targets in MM, as their silencing resulted in a reduction in the tumor burden. Moreover, JAG1 and JAG2 protein expression in MM patients was positively correlated with the presence of MM cells in patients' bone marrow biopsies. Finally, taking advantage of the Multiple Myeloma Research Foundation (MMRF) CoMMpass global dataset, we showed that JAG2 gene expression level was a predictive biomarker associated with patients' overall survival and progression-free survival, independently from other main molecular or clinical features. Overall, these results strengthened the rationale for the development of a JAG1/2-tailored approach and the use of JAG2 as a predictive biomarker in MM.

Background: Chemotherapy, as well as opioid and antiemetic drugs, can contribute to constipation in oncological patients. This systematic review aims to analyse the potential of specific rehabilitation strategies and alternative strategies for improving constipation symptoms, with the goal of incorporating these strategies into a dedicated protocol for managing cancer-related constipation. This could potentially reduce the dosages of or eliminate the need for constipation medications., Methods: A systematic search was conducted on PubMed, Scopus and Web of Science. The review included studies analysing constipation complaints in cancer patients treated with rehabilitation, acupuncture and osteopathy., Results: The review included 16 studies in line with PRISMA and PICOS criteria. Most studies showed that physical exercise, abdominal massage, TENS, acupuncture and education on the correct defecation position positively impacted the management of constipation and quality of life in oncological patients. A physiotherapy program involving massages as well as aerobic and resistance training improved constipation in oncological women, regardless of age, sex and frailty. A combination of abdominal massage, abdominal muscle stretching and education on proper defecation position alleviated the severity of constipation and related depression. However, the outcomes regarding TENS were yet inconsistent. Another technique, becoming increasingly common for constipation, and demonstrating positive results, involved stimulating trigger points through acupressure and acupuncture. Conversely, osteopathic and superficial manipulations more frequently required constipation medications than did the other alternative approaches. However, no existing studies have proposed a specific protocol to manage cancer-related constipation., Conclusions: The results of the studies confirm the positive influences of rehabilitation, osteopathy and acupuncture on constipation and pain in oncological patients. Nevertheless, further studies are required to establish the best type, timing and duration of treatment, as well as how the stage and location of the cancer and the cause of constipation (drug-induced or functional) impact the results.

Background: Sarcopenia is a risk factor for morbidity and preventable mortality in old age, with consequent high costs for the national health system. Its diagnosis requires costly radiological examinations, such as the DEXA, which complicate screening in medical centers with a high prevalence of sarcopenia., Objectives: Developing a nearly zero-cost screening tool to emulate the performance of DEXA in identifying patients with muscle mass loss. This can crucially help the early diagnosis of sarcopenia at large-scale, contributing to reduce its prevalence and related complications with timely treatments., Methods: We exploit cross-sectional data for about 14,500 patients and 38 non-laboratory variables from successive NHANES over 7 years (1999-2006). Data are analyzed through a state-of-the-art artificial intelligence approach based on decision trees., Results: A reduced number of anthropometric parameters allows to predict the outcome of DEXA with AUC between 0.92 and 0.94. The most complex model derived in this paper exploits 6 variables, related to the circumference of key corporal segments and to the evaluation of body fat. It achieves an optimal trade-off sensitivity of 0.89 and a specificity of 0.82. Restricting exclusively to variables related to lower limb, we obtain an even simpler tool with only slightly lower accuracy (AUC 0.88-0.90)., Conclusions: Anthropometric data seem to contain the entire informative content of a more complex set of non-laboratory variables, including anamnestic and/or morbidity factors. Compared to previously published screening tools for muscle mass loss, the newly developed models are less complex and achieve a better accuracy. The new results might suggest a possible inversion of the standard diagnostic algorithm of sarcopenia. We conjecture a new diagnostic scheme, which requires a dedicated clinical validation that goes beyond the scope of the present study., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2023 The Authors. Published by Elsevier Ltd.)

Background: The purpose of this study is to evaluate the impact of total knee arthroplasty (TKA) with the aid of Navio Robot, comparing it with standard prosthetic surgery on the functional outcomes of patients after an intensive rehabilitation program., Method: A case-control observational study was conducted on patients undergoing TKA for severe KOA. All patients underwent the same intensive hospital rehabilitation program of 14 daily sessions lasting 3 h. The following rating scales were administered: Numeric Rating Scale (NRS), Knee Society Score (KSS) and 12-Item Short Form Survey scale. Patient assessments were performed 1 week post-surgery (T0), 1 month post-surgery (T2), and 3 months post-surgery (T3). The primary outcomes were active knee extension and flexion and pain severity. The secondary outcomes were functional capacity and quality of life., Results: Using repeated measures ANOVA, we observed at T1 a statistically different difference for the treatment group compared to the control group about KSS (p < 0.05), pain (p < 0.05), and knee flexion (p < 0.05). No statistically significant difference between the two groups was observed for knee extension (p = 0.09) and the SF-12 scale (p = 0.52). At T2 instead, we observed a statistically significant difference for the treatment group compared to the control group as regards KSS (p < 0.05) and knee flexion (p < 0.05), while no statistically significant difference was observed for pain (p = 0.83), knee extension (p = 0.60), and the SF-12 scale (0.44)., Conclusions: Our study has demonstrated that robot-NAVIO assisted knee prosthesis surgery, associated with a specific intensive rehabilitation treatment, in the short and medium term, determines good pain control, better flexion recovery and a improvement of functional capacity., (© 2023. The Author(s).)

Background: The various mechanisms involved in peripheral nerve regeneration, induced by exercise and electrical nerve stimulation, are still unclear., Objective: The aim of this review was to summarize the influence of physical exercise and/or electrical stimulation on peripheral nerve repair and regeneration and the variation of impact of intervention depending on timing, as well as kind and dosage of the intervention. A literature survey was conducted on PubMed, Scopus, and Web of Science, between February 2021 to July 2021, with an update in September 2022., Methodology: The literature search identified 101,386 articles with the keywords: "peripheral nerve" OR "neuropathy" AND "sprouting" OR "neuroapraxia" OR "axonotmesis" OR "neurotmesis" OR "muscle denervation" OR "denervated muscle" AND "rehabilitation" OR "physical activity" OR "physical exercise" OR "activity" OR "electrical stimulation". A total of 60 publications were included. Eligible studies were focused on evaluating the process of nerve repair (biopsy, electromyographic parameters or biomarker outcomes) after electrical stimulation or physical exercise interventions on humans or animals with peripheral sensory or motor nerve injury., Synthesis: This study shows that the literature, especially regarding preclinical research, is mainly in agreement that an early physical program with active exercise and/or electrical stimulation promotes axonal regenerative responses and prevents maladaptive response. This was evaluated by means of changes in electrophysiological recordings of CMAPs for latency amplitude, and the sciatic functional index (SFI). Furthermore, this type of activity can cause an increase in weight and in muscle fiber diameter. Nevertheless, some detrimental effects of exercising and electrical stimulation too early after nerve repair were recorded., Conclusion: In most preclinical studies, peripheral neuropathy function was associated with improvements after physical exercise and electrical stimulation. For humans, too little research has been conducted on this topic to reach a complete conclusion. This research supports the need for future studies to test the validity of a possible rehabilitation treatment in humans in cases of peripheral neuropathy to help nerve sprouting.

Treating chronic hyponatremia by continuous renal replacement therapy (CRRT) is challenging because the gradient between a replacement fluid's [sodium] and a patient's serum sodium can be steep, risking too rapid of a correction rate with possible consequences. Besides CRRT, other gains and losses of sodium- and potassium-containing solutions, like intravenous fluid and urine output, affect the correction of serum sodium over time, known as osmotherapy. The way these fluids interact and contribute to the sodium/potassium/water balance can be parsed as a mixing problem. As Na/K/H 2 O are added, mixed in the body, and drained via CRRT, the net balance of solutes must be related to the change in serum sodium, expressible as a differential equation. Its solution has many variables, one of which is the sodium correction rate, but all variables can be evaluated by a root-finding technique. The mixing paradigm is proved to replicate the established equations of osmotherapy, as in the special case of a steady volume. The flexibility to solve for any variable broadens our treatment options. If the pre-filter replacement fluid cannot be diluted, then we can compensate by calculating the CRRT blood flow rate needed. Or we can deduce the infusion rate of dextrose 5% water, post-filter, to appropriately slow the rise in serum sodium. In conclusion, the mixing model is a generalizable and practical tool to analyze patient scenarios of greater complexity than before, to help doctors customize a CRRT prescription to safely and effectively reach the serum sodium target., (© 2023 The Authors. Physiological Reports published by Wiley Periodicals LLC on behalf of The Physiological Society and the American Physiological Society.)

Long non-coding RNA NEAT1 is the core structural component of the nuclear paraspeckle (PS) organelles and it has been found to be deregulated in multiple myeloma (MM) patients. Experimental evidence indicated that NEAT1 silencing negatively impacts proliferation and viability of MM cells, both in vitro and in vivo, suggesting a role in DNA damage repair (DDR). In order to elucidate the biological and molecular relevance of NEAT1 upregulation in MM disease we exploited the CRISPR/Cas9 synergistic activation mediator genome editing system to engineer the AMO-1 MM cell line and generate two clones that para-physiologically transactivate NEAT1 at different levels. NEAT1 overexpression is associated with oncogenic and prosurvival advantages in MM cells exposed to nutrient starvation or a hypoxic microenvironment, which are stressful conditions often associated with more aggressive disease phases. Furthermore, we highlighted the NEAT1 involvement in virtually all DDR processes through, at least, two different mechanisms. On one side NEAT1 positively regulates the posttranslational stabilization of essential PS proteins, which are involved in almost all DDR systems, thus increasing their availability within cells. On the other hand, NEAT1 plays a crucial role as a major regulator of a molecular axis that includes ATM and the catalytic subunit of DNA-PK kinase proteins, and their direct targets pRPA32 and pCHK2. Overall, we provided novel important insightsthe role of NEAT1 in supporting MM cells adaptation to stressful conditions by improving the maintenance of DNA integrity. Taken together, our results suggest that NEAT1, and probably PS organelles, could represent a potential therapeutic target for MM treatment.

To evaluate the reasons for inadequate adherence to osteoporosis therapy and to describe the strategies for improving adherence to and persistence with regular medications, we conducted a review of the literature. The primary outcome of the study was the determination of the factors adverse to the onset and maintenance of anti-osteoporosis therapies. Secondly, we focused on studies whose efforts led to finding different strategies to improve adherence and persistence. We identified a total of 26 articles. The most recurrent and significant factors identified were aging, polypharmacy, and smoking habits. Different strategies to guide patients in their osteoporosis care have been identified, such as monitoring and follow-up via telephone calls, email, and promotional meetings, and proactive care interventions such as medication monitoring, post-fracture care programs, and decision aids. Changes in the drugs regimen and dispensation are strategies tried to lead to better adherence and persistence, but also improved satisfaction of patients undergoing anti-osteoporosis treatment. Patient involvement is an important factor to increase medication persistence while using a flexible drugs regimen.

A hyponatremic patient with the syndrome of inappropriate antidiuresis (SIAD) gets normal saline (NS), and the plasma sodium decreases, paradoxically. To explain, desalination is often invoked: if urine is more concentrated than NS, the fluid's salts are excreted while some water is reabsorbed, exacerbating hyponatremia. But comparing concentrations can be deceiving. They should be converted to quantities because mass balance is key to unlocking the paradox. The [sodium] equation can legitimately be used to track all of the sodium, potassium, and water entering and leaving the body. Each input or output "module" can be counterbalanced by a chosen iv fluid so that the plasma sodium stays stable. This equipoise is expressed in terms of the iv fluid's infusion rate, an easy calculation called the ratio profile. Knowing the infusion rate that maintains steady state, we can prescribe the iv fluid at a faster rate in order to raise the plasma sodium. Rates less than the ratio profile may risk a paradox, which essentially is caused by an iv fluid underdosing. Selecting an iv fluid that is more concentrated than urine is not enough to prevent paradoxes; even 3% saline can be underdosed. Drinking water adds to the ratio profile and is underestimated in its ability to provoke a paradox. In conclusion, the quantitative approach demystifies the paradoxical worsening of hyponatremia in SIAD and offers a prescriptive guide to keep the paradox from happening. The ratio profile method is objective and quickly deployable on rounds, where it may change patient management for the better., Competing Interests: R. Chiaramonte has ownership interest in BioPharma Credit/Pharmakon, ITB-MED/Zelarion, ProKidney, and Royalty Pharma; patents or royalties with Royalty Pharma; and an advisory or leadership role with ITB-MED/Zelarion. J. Shey reports being an employee of West Coast Kidney Institute and has ownership interest in Fresenius Kidney Care. The remaining author has nothing to disclose., (Copyright © 2022 by the American Society of Nephrology.)

Multiple myeloma (MM) is an incurable hematologic neoplasm, whose poor prognosis is deeply affected by the propensity of tumor cells to localize in the bone marrow (BM) and induce the protumorigenic activity of normal BM cells, leading to events associated with tumor progression, including tumor angiogenesis, osteoclastogenesis, and the spread of osteolytic bone lesions. The interplay between MM cells and the BM niche does not only rely on direct cell-cell interaction, but a crucial role is also played by MM-derived extracellular vesicles (MM-EV). Here, we demonstrated that the oncogenic NOTCH receptors are part of MM-EV cargo and play a key role in EV protumorigenic ability. We used in vitro and in vivo models to investigate the role of EV-derived NOTCH2 in stimulating the protumorigenic behavior of endothelial cells and osteoclast progenitors. Importantly, MM-EV can transfer NOTCH2 between distant cells and increase NOTCH signaling in target cells. MM-EV stimulation increases endothelial cell angiogenic ability and osteoclast differentiation in a NOTCH2-dependent way. Indeed, interfering with NOTCH2 expression in MM cells may decrease the amount of NOTCH2 also in MM-EV and affect their angiogenic and osteoclastogenic potential. Finally, we demonstrated that the pharmacologic blockade of NOTCH activation by γ-secretase inhibitors may hamper the biological effect of EV derived by MM cell lines and by the BM of MM patients. These results provide the first evidence that targeting the NOTCH pathway may be a valid therapeutic strategy to hamper the protumorigenic role of EV in MM as well as other tumors.

This systematic review aims to reveal the effectiveness of proprioceptive exercise combined with dual-task training in stroke patients. The research was conducted using PubMed, Cochrane Library, Web of Science, and Scopus databases to evaluate studies of rehabilitation interventions with proprioceptive and dual-task exercises in patients with stroke. The keywords for the search were: "stroke" AND "proprioception" OR "proprioceptive" AND "rehabilitation" OR "training" OR "exercises" AND "dual-task" OR "task-performance" with the following inclusion criteria: comparative studies of rehabilitation interventions with proprioceptive and dual-task exercises in stroke patients. Of the 104,014 studies identified, 23 were included according to the inclusion criteria. Proprioceptive and dual-task exercises stimulate and promote postural balance, gait, and quality of life and reduce the risk of falls in stroke patients compared with traditional rehabilitation programs. In conclusion, this systematic review suggests that proprioceptive exercise combined with dual-task training is needed to improve balance and recover gait. Moreover, it provides a comprehensive overview of the literature on the various proprioceptive treatments with contextual dual-task exercises for imbalance after stroke, providing a guide for choosing a complete rehabilitation protocol that combines these two techniques.

Senescence is a stress-response process characterized by the irreversible inhibition of cell proliferation, associated to the acquisition of a senescence-associated secretory phenotype (SASP), that may drive pathological conditions. Lymphangioleiomyomatosis (LAM) is a rare disease in which LAM cells, featuring the hyperactivation of the mammalian Target of Rapamycin Complex 1 (mTORC1) for the absence of tuberin expression, cause the disruption of the lung parenchyma. Considering that LAM cells secrete SASP factors and that mTOR is also a driver of senescence, we deepened the contribution of senescence in LAM cell phenotype. We firstly demonstrated that human primary tuberin-deficient LAM cells (LAM/TSC cells) have senescent features depending on mTOR hyperactivation, since their high positivity to SA-β galactosidase and to phospho-histone H2A.X are reduced by inducing tuberin expression and by inhibiting mTOR with rapamycin. Then, we demonstrated the capability of LAM/TSC cells to induce senescence. Indeed, primary lung fibroblasts (PLFs) grown in LAM/TSC conditioned medium increased the positivity to SA-β galactosidase and to phospho-histone H2A.X, as well as p21 WAF1/CIP1 expression, and enhanced the mRNA expression and the secretion of the SASP component IL-8. Taken together, these data make senescence a novel field of study to understand LAM development and progression.

Introduction: The aim of the study was to investigate the efficacy of rehabilitation programs for bladder disorders in patients with multiple sclerosis (MS) and to guide physicians in delineating therapeutic tools and programs for physiatrists, using the best current strategies., Evidence Acquisition: A search was conducted on PubMed, EMBASE, the Cochrane Library and Web of Science. Studies were eligible if they included adults with bladder disorders related to MS and described specific treatments of rehabilitation interest. The search identified 190,283 articles using the key words "multiple sclerosis" AND "rehabilitation" AND "urinary" OR "bladder," of which the reviewers analyzed 81 full-texts; 21 publications met the criteria and were included in the systematic review., Evidence Synthesis: The systematic review identified the specific rehabilitation treatments reported in the current literature. The meta-analysis compared the scores and scales used to quantify bladder disorders due to MS, both before and after rehabilitation or in a comparison with a control group., Conclusions: The present study suggests the need of a specific therapeutic protocol, based on the degree of disability and symptom complexity in patients with MS-related neurogenic lower urinary tract dysfunction (NLUTD). Particularly, the meta-analysis shows the effectiveness of peripheral tibial nerve stimulation (PTNS) and pelvic floor muscle training (PFMT) for neurogenic detrusor overactivity (NDO). However, the goal of physiotherapy is to treat incontinence without making urinary retention worse and vice-versa, reducing the loss of urine urgency, while ensuring the emptying of the bladder.

Background: Recreation, transportation and sport are the most common uses of bicycles. Unfortunately, repetitive bicycle use can also cause injuries, such as osteoarticular direct and undirect traumatisms and sometimes compression nerve entrapment caused by an extrinsic compressive force., Purpose: The aim of the study is to define diagnostic process, preventive strategies, and treatment of ulnar and median neuropathies in cyclists., Study Design: Systematic review., Methods: A search was conducted on PubMed, EMBASE, the Cochrane Library, and Web of Science. Two reviewers independently reviewed articles and came to a consensus about which ones to include. The authors excluded all duplicates, articles involving individuals with other sport-related injuries than cycling, and articles unrelated to peripheral neuropathies. Articles were included if hand palsy was due to peripheral compression of ulnar or median nerve in cyclists., Results: The search identified 15,371 articles with the keywords "Peripheral Nervous System Diseases" OR "neuropathy" OR "ulnar palsy" OR "median palsy" AND "bicycling" OR "bike" OR "bicycle" OR "cyclist". The reviewers analyzed 48 full texts. There were 20 publications that met the criteria and were included in the systematic review. These articles were used to describe the main methods used for diagnosis, prevention and treatment of hand neuropathy of cyclists., Conclusion: Despite the range of treatment available for peripheral neuropathies, a unique and common protocol is lacking on this specific topic. For this reason, we delineate a definitive recovery protocol to show the best therapeutic methodologies present in the current literature. Preventive strategies, period of rest since the beginning of the symptomatology, rehabilitation training with muscle strengthening, orthoses at night are the first strategies, but if the symptoms persist, pharmacologic treatment and eventual surgical decompression are sometimes the unique solution., (Copyright © 2021. Published by Elsevier Inc.)

[Creatinine] was proved to change in the opposite direction of the kinetic GFR (GFR K ), but does the [creatinine] also change in the opposite direction of the volume rate? If volume is administered and the [creatinine] actually goes up, then the two changes move in the same direction and their ratio is positive, paradoxically. The equation that describes [creatinine] as a function of time was differentiated with respect to the volume rate. This partial first derivative has a global maximum that can be positive under definable conditions. Knowing what makes the maximum positive informs when the derivative will be positive over some continuous domain of volume rate inputs. The first derivative versus volume rate curve has a maximum and a minimum point depending on the GFR K . If GFR K is below a calculable value, then the curve's minimum vanishes, letting it descend to - ∞ and not allowing the derivative to ever be positive. If GFR K lies between a lower and a higher calculable value, then the curve's maximum vanishes, letting the derivative diverge to + ∞ , though the clinical scenario is unrealistic. If GFR K is above the higher calculable value, then the curve's absolute maximum can become positive by decreasing the creatinine generation rate or increasing the initial [creatinine]. The derivative is potentially positive under these clinically realizable circumstances. The combination of parameters above can align in septic patients (low creatinine generation rate) with kidney failure (high initial [creatinine]) who are put on continuous dialysis (high GFR K ). If a first derivative is positive, removing more volume can improve the [creatinine] and, dismayingly, giving more volume can worsen the [creatinine]. This paradox is explained by a covert interplay between the ambient [creatinine] and GFR K that excretes creatinine faster than its volume of distribution declines., (© 2022 The Authors. Physiological Reports published by Wiley Periodicals LLC on behalf of The Physiological Society and the American Physiological Society.)

Matrix metalloproteinase (MMP) dysregulation is implicated in several diseases, given their involvement in extracellular matrix degradation and cell motility. In lymphangioleiomyomatosis (LAM), a pulmonary rare disease, MMP-2 and MMP-9 have been detected at high levels in serum and urine. LAM cells, characterized by a mutation in the tuberous sclerosis complex (TSC)1 or TSC2, promote cystic lung destruction. The role of MMPs in invasive and destructive LAM cell capability has not yet been fully understood. We evaluated MMP-2 and MMP-7 expression, secretion, and activity in primary LAM/TSC cells that bear a TSC2 germline mutation and an epigenetic modification and depend on epidermal growth factor (EGF) for survival. 5-azacytidine restored tuberin expression with a reduction of MMP-2 and MMP-7 levels and inhibits motility, similarly to rapamycin and anti-EGFR antibody. Both drugs reduced MMP-2 and MMP-7 secretion and activity during wound healing and decreased their expression in lung nodules of a LAM mouse model. In LAM/TSC cells, MMP-2 and MMP-7 are dependent on tuberin expression, cellular adhesion, and migration. MMPs appears sensitive to rapamycin and anti-EGFR antibody only during cellular migration. Our data indicate a complex and differential modulation of MMP-2 and MMP-7 in LAM/TSC cells, likely critical for lung parenchyma remodeling during LAM progression.

Environmental stimuli, including sex hormones and oxidative stress (OS), affect bone balance, modifying the epigenetic profiles of key osteogenic genes. Nonetheless, the interplay between sex steroids, epigenome and OS has yet be fully elucidated. This paper aims to study in vitro the role of sex steroids in OS-induced alteration in bone cells' homeostasis, and to assess the possible contribution of epigenetic modifications. Toward this purpose, osteoblast (MC3T3-E1) and osteocyte (MLOY-4) cell lines were exposed to two different sources of free oxygen radicals, i.e., tert-butyl hydroperoxide and dexamethasone, and the protective effect of pre-treatment with androgens and estrogens was evaluated. In particular, we analyzed parameters that reflect bone cell homeostasis such as cell viability, cell migration, transcriptomic profile, transcriptional activity, and epigenetic signature. Our findings indicate that estrogens and androgens counteract OS effects. Using partially overlapping strategies, they reduce OS outcomes regarding cell viability, cell migration, the transcriptomic profile of gene families involved in bone remodeling, and epigenetic profile, i.e., H3K4me3 level. Additionally, we demonstrated that the protective effect of steroids against OS on bone homeostasis is partially mediated by the Akt pathway. Overall, these results suggest that the hormonal milieu may influence the mechanisms of age-related bone disease.

L-carnitine supplementation improves body strength, sports endurance and exercise capacity, as well as delaying the onset of fatigue. The aim of this study was to identify the correct dosage of supplementation to obtain improvements in physical performance and evaluate the changes related to L-carnitine supplementation in specific metabolic parameters, such as serum lactate, VO 2 , serum total and free carnitine at rest and after physical activities, in healthy subjects. The search was conducted on PubMed, EMBASE, Cochrane Library, Scopus and Web of Science and identified 6404 articles with the keywords: "carnitine" AND "exercises" OR "rehabilitation" OR "physical functional performance" OR "physical activity" OR "sports" OR "health" OR "healthy". A total of 30 publications met the inclusion criteria and were included in the systematic review. The meta-analysis did not show any significant differences in serum lactate values at rest and after exercise in healthy subjects who took L-carnitine supplementation ( p > 0.05). On the contrary, L-carnitine administration significantly changed maximal oxygen consumption (VO 2 ) at rest ( p < 0.005), serum free and total carnitine at rest and after exercise ( p < 0.001). The dosage of supplementation that obtained a significant change in serum total carnitine was 2 g/dL for 4 weeks at rest, 1 g/dL for 3 weeks after exercise, and in serum free carnitine was 2 g/dL for 3 weeks and 2 g/dL for 4 weeks at rest. Based on our study, serum total and free carnitine at rest and after exercise, and VO 2 at rest could be used to clinically follow individuals during physical activity and rehabilitation programs. Moreover, the supplementation should have a correct dosage to have maximum effect. Other robust trials are needed to find the best dosage to obtain positive results in metabolic parameters and in physical performance.

Introduction: When the serum [creatinine] is changing, creatinine kinetics can still gauge the kidney function, and knowing the kinetic glomerular filtration rate (GFR) helps doctors take care of patients with renal failure. We wondered how the serum [creatinine] would respond if the kinetic GFR were tweaked. In every scenario, if the kinetic GFR decreased, the [creatinine] would increase, and vice versa. This opposing relationship was hypothesized to be universal., Methods: Serum [creatinine] and kinetic GFR, along with other parameters, are described by a differential equation. We differentiated [creatinine] with respect to kinetic GFR to test if the two variables would change oppositely of each other, throughout the gamut of all allowable clinical values. To remove the discontinuities in the derivative, limits were solved., Results: The derivative and its limits were comprehensively analyzed and proved to have a sign that is always negative, meaning that [creatinine] and kinetic GFR must indeed move in opposite directions. The derivative is bigger in absolute value at the higher end of the [creatinine] scale, where a small drop in the kinetic GFR can cause the [creatinine] to shoot upward, making acute kidney injury similar to chronic kidney disease in that regard., Conclusions: All else being equal, a change in the kinetic GFR obligates the [creatinine] to change in the opposite direction. This does not negate the fact that an increasing [creatinine] can be compatible with a rising kinetic GFR, due to differences in how the time variable is treated., (© 2021 The Authors. Physiological Reports published by Wiley Periodicals LLC on behalf of The Physiological Society and the American Physiological Society.)