AR) gene (Ensembl number ENSG00000169083) may lead to reduced fertility. Our objective was to determine the association of CAG and GGC repeats with altered sperm parameters in male infertile subjects.Infertility is a global problem that brings about serious sexual and social consequences that strain the health sector and society. The expansion of CAG and GGC repeats in androgen receptor  and group B (N = 168) were comprised of subjects with normal and altered sperm parameters, respectively, from 18 to 60 years. The numbers of CAG and GGC repeats were determined by using PCR amplification and sequence analysis using the Molecular Evolutionary Genetic Analysis (MEGA) software version 6.0. Statistical analysis was performed using the SPSS version 20 and the P-value of <0.05 was considered significant.The mean androgen receptor gene CAG repeats were significantly longer in males with altered sperm parameters as compared to male subjects with normal sperm parameters (P < 0.001). There was no significant difference found for GGC repeats for subjects with altered sperm parameters.Longer CAG length corresponded to greater severity of spermatogenic defect and may lead to subfertility recommendations. The WHO defines infertility as “a disease of the reproductive system defined by the failure to achieve a clinical pregnancy after 12 months or more of regular unprotected sexual intercourse” [The environmental causes of male infertility include prolonged exposure to heat , noise pThe genetic causes underlying male infertility include Y chromosome microdeletions , sex chrAR) gene (Ensembl number ENSG00000169083) is located on chromosome Xq11-12 and has 8 exons and 7 introns, out of which exon 1 has CAG and GGC repeats and is associated with transcription [Androgen is indispensable for the male sex differentiation and spermatogenesis . Testostcription ,16.Polymorphic trinucleotide repeat segment (CAG)n encodes a polyglutamine tract in which n usually ranges from 11 to 31. This CAG repeat tract has been the basis of unprecedented attention in current years because it has been found that the expansion of the CAG segment to more than 40 repeats leads to spinal bulbar muscular atrophy, a mortal neuromuscular disease. Trinucleotide repeat expansions are now associated with many diseases .AR gene is susceptible to one of the largest number of mutations in a steroid receptor, documented at up till 300 mutations [AR gene essentially consists of three main functional domains as the N-terminal transcriptional regulation domain, the DNA-binding domain, and the ligand-binding domain. Androgens bind to the AR gene and exert their actions either through DNA binding-dependent manner, regulating gene transcription, or non-DNA binding-dependent manner, causing phosphorylation of the secondary messenger system [AR gene is expressed on a multitude of tissues in the body such as prostate, bone, adipose tissue, muscle, etc., and plays an important role in the immune, hematopoietic, respiratory, cardiovascular, and neural systems [The utations . The AR r system . The AR  systems ,20.AR gene [The CAG trinucleotide repeat length is normally between 16 and 29 . The varAR gene  since thAR gene .AR resistance is reported to account for 40% of male infertility cases [AR gene has been correlated with male infertility owing to a decreased transcription of the AR gene and diminished spermatogenesis [AR gene [ty cases . Increasogenesis . Therefo[AR gene . Most of[AR gene . Even th[AR gene ,28,29. A[AR gene . An incr[AR gene ,32. Howe[AR gene .AR gene protein levels, suggesting that the GGC repeat length of 13 produced 2.7 times more AR proteins than the GGC repeat length of 17 did. A shorter GGC repeat length has also been linked to prostate cancer [AR gene, while also having an association with the prostate and endometrial cancers [AR gene and altered sperm parameters in our population of male subjects with infertility problems.The transactivation domain of AR also contains a polyglycine tract, encoded by GGT/GGC six-glycine tract proceeded by a polymorphic GGC repeat of a length of 10 to 35 nucleotides. In spite of the limited studies showing the association between GGC repeat polymorphism and male fertility, there have been certain studies  showing  cancers . Hence, This cross-sectional study was conducted from July 2017 to July 2018 at the Department of Biological and Biomedical Science, Aga Khan University, in collaboration with the Sindh Institute of Reproductive Medicine after acquiring the ethical approval of the institutional ethical review board (2019-1226-3970). The sample size was calculated on the Open Epi software version 3.01. A sample size of 398 was estimated to find the CAG and GGC repeat polymorphism in both groups adjusted for 10% nonresponse rate. We assumed a level of significance of 5%, an odds ratio of 2, and power for detecting the true effect of 80%. However, the final recruitment was 376 males on account of a number of refusals to provide semen samples.All the male subjects were recruited from the Sindh Institute of Reproductive Medicine based on nonconception after regular, unprotected intercourse for a period of at least 1 year. Possible genetic causes of male infertility were excluded by Y chromosome microdeletions and Karyotype analysis. The infertile subjects were divided into two groups (A and B) on the basis of normal or altered semen parameters, respectively. All the subjects were collected via convenience sampling after obtaining written and informed consent.6, sperm motility of more than 50%, and normal morphology 34% with age ranging from 18 to 60 years from all ethnic backgrounds [6, a sperm motility less than 50%, and a normal morphology £4% [At the time of recruitment, a data collection form was filled to record clinical data such as age, height, weight, the calculation of body mass index (BMI), the estimation of body fat percentage, blood pressure, smoking habits, hormonal treatment, and clinical history. Group A  comprised of male subjects with a sperm count more than 39 × 10kgrounds . The mallogy £4%  between Blood samples were collected for DNA extraction from antecubital vein in 2 tubes, serum gel tube (3 mL) and EDTA tube (2 mL). Serum was centrifuged at 3500 rpm for 5 min, separated into two aliquots, and stored at −70 °C. DNA was extracted from 2 mL of blood in EDTA tube using the standard protocol of Promega Genomic DNA Extraction Kit Cat# A1125. The steps included taking 6 mL of cell lysis solution with 2 mL of blood (centrifuged at 3500 rpm for 10 min), adding 2 mL of nuclei lysis solution and 660 μL of protein precipitation solution (centrifuged at 3500 rpm for 10 min), transferring the supernatant to a tube of 2 mL cold isopropanol, aspirating and adding 200 μL of rehydration solution, incubating for 24 h at 4 °C, vortex before aliquoting the extracted DNA, and keeping it at −80 °C for further analysis. The extracted DNA was quantified by measuring the ultraviolet absorbance and determining the absorbance ratio (A280/A260) for 2-μL samples using a Nanodrop-ND1000 . The extracted DNA was considered pure at an absorbance ratio of ~1.8.AR gene. Polymerase chain reaction (PCR) for CAG repeats was performed using 2× PCR HotStart Master Mix ) as per the manufacturer’s instructions. The PCR conditions were 1 cycle for 5 min at 95 °C for the initial denaturation followed by 30 cycles at 95 °C for 30 s, 60 °C for 45 s, 72 °C for 45 s followed by a final extension of 10 min at 72 °C. PCR was performed for GGC repeats using GoTaq HotStart Master Mix  as per the manufacturer’s instructions. The PCR conditions were 1 cycle for 5 min at 95 °C for the initial denaturation followed by 30 cycles at 95 °C for 30 s, 50 °C for 45 s, 72 °C for 45 s followed by a final extension of 10 min at 72 °C. The amplified products were electrophoresed on 2% agarose gel. The purification of the PCR products was performed using PCR Clean Up for DNA Sequencing  following the manufacturer’s protocol.The primers were designed using Primer 3 output primer designing tool for CAG  and GGC  repeat region of the AR gene can be detected by PCR amplification and direct sequencing in the published article [AR gene in the samples of Group A and B and the PCR products were sent to the sequencing company Operon (Canada). The samples were sequenced to obtain accuracy in finding the number of repeats in polymorphic trinucleotide repeat segment of the AR gene. The obtained sequences were directly compared to the previously published CAG and GGC repeat region of the AR gene sequence using the MEGABLAST search tool in the National Center for Biotechnology Information (NCBI) database. The sequence files were imported into Chromas Lite, and then assembled using Molecular Evolutionary Genetic Analysis (MEGA) version 6.0.Sanger sequencing is a classical method for sequencing and CAG polymorphism in the  article . This meStatistical analysis was performed with the SPSS version 20 software using the Mann–Whitney U test, and Spearman’s rank correlation tests . Logistic regression analysis with 95% confidence intervals (CIs) was performed to report odds ratios (OR). The sequences were analyzed using Molecular Evolutionary Genetics Analysis (MEGA) software version 6.0.A total of 376 males presenting to infertility centers were enrolled in the study. The subjects in Group A (168) had normal semen parameters, whereas 208 male subjects in Group B had abnormal semen parameters.The mean values of the CAG lengths in infertile men with altered sperm parameters (27) were significantly higher than the ones who had normal sperm parameters (24) as shown in AR gene.However, GGC length alone did not show any significant association with male infertility as demonstrated by our results. The mean values of GGC length in the Group B subjects (17) were comparable with the Group A (16) subjects. The increased prevalence of infertility with psychological and economic burdens of developing countries has motivated researchers to look for the relationship of infertility with genetic factors. The main observation in this study was that infertile males have significantly longer CAG lengths compared with fertile male subjects.Increased fat in the scrotum leads to the production of gonadal heat, which impairs sperm production since sperms need an optimum temperature range of 34–35 degrees. This accounts for the higher BMI among infertile men compared to fertile men in our study. Heat production causes oxidative stress to sperm, the fragmentation of sperm DNA, and diminished sperm motility .AR gene [An increased CAG trinucleotide repeat length has been associated with male infertility . This isAR gene . IncreasAR gene . ShorterAR gene . Thus, oThe total sperm count and sperm motility of the infertile men recruited in our study was reported to be lower than that of the fertile men recruited, which corroborates the negative effect of the increased CAG length (>26) on sperm parameters. Furthermore, there are studies such as Mengual et al., who showed that men with greater than 26 CAG repeats had a risk of being azospermic . Xiao etAR gene is a polymorphism that may be associated  with male infertility, and its clinical relevance is still debated. The limitations of the present study are that the occupational status of each subject was not determined and we did not correlate smoking status with polymorphism. All triplet repeat disorders show anticipation and a significant correlation between age at the onset of the disease and the length of the expanded repeat [AR CAG expansion may transfer infertility to their descendants. This CAG triplet repeat disorder (Group B), however, is anticipated to be expressed in future generations in terms of an alteration in sperm count, motility, and morphology, hence contributing to male infertility. AR CAG polymorphism is not recommended in the routine setting, yet the test may become imperative on the basis of clinical relevance, pharmacogenetic implications, theoretical possibility of transmission to next generation, and tailoring of testosterone replacement therapy on the basis of length of CAG repeat in hypogonadal men.However, GGC length alone did not show any significant association with male infertility as demonstrated by our results. Even though studies such as Gao et al.’s show the deletion of polyglycine tract and the reduction of androgen receptor transcriptional activity, there is little evidence to prove the impact of GGC length and male infertility ,47. Studd repeat ,49. The Longer AR CAG repeat lengths cause decreased sperm motility, corresponding to a greater severity of spermatogenic defect that can lead to disturbance in reproductive functions, thus causing male infertility. However, GGC did not reflect any association with male infertility.


The purpose of this review was to analyze the evidence on the role of augmented reality (AR) in the improvement of minimally invasive surgical (MIS) procedures. A scoping literature search of the PubMed and ScienceDirect databases was performed to identify articles published in the last five years that addressed the direct impact of AR technology on MIS procedures or that addressed an area of education or clinical care that could potentially be used for MIS development. A total of 359 studies were screened and 31 articles were reviewed in depth and categorized into three main groups: Navigation, education and training, and user-environment interfaces. A comparison of studies within the different application groups showed that AR technology can be useful in various disciplines to advance the development of MIS. Although AR-guided navigation systems do not yet offer a precision advantage, benefits include improved ergonomics and visualization, as well as reduced surgical time and blood loss. Benefits can also be seen in improved education and training conditions and improved user-environment interfaces that can indirectly influence MIS procedures. However, there are still technical challenges that need to be addressed to demonstrate added value to patient care and should be evaluated in clinical trials with sufficient patient numbers or even in systematic reviews or meta-analyses. Advances in surgery have the potential to significantly improve patient outcomes and reduce hospital length of stay (LOS) . HealthcThe overall definition of MIS includes surgical procedures that reduce the morbidity of conventional surgical trauma . These tOne of the major disadvantages of MIS is the extended surgical “learning curve” . with coThe development of new technologies has come to the forefront, especially during the Corona pandemic . VirtualAR is a technology that overlays computer-generated images or videos onto real-world objects and environments . The useTo address the question of the role of AR in improving MIS procedures, a scoping literature search was conducted in the PubMed and ScienceDirect databases to identify all relevant studies and reviews available from January 2018 to February 2023. Different areas of application were identified and the potential advantages and disadvantages of AR were evaluated.This review article was designed and conducted according to the enhancing transparency in reporting the synthesis of qualitative research (ENTREQ) guidelines  to reveaThe search strategy followed the identification and screening guidelines by the preferred reporting items for systematic reviews and meta-analyses (PRISMA) statements . The folArticles were screened for relevance by two authors (PB and BW) based on title and abstract. In case of uncertainty, full-text screening was performed. A total of 31 articles were independently reviewed by both authors. All articles with questionable relevance were reviewed independently by both authors to reach a consensus. In case of disagreement, a third author (HS) was involved.Articles were included if they were considered relevant to the advancement of MIS through AR technologies if they were relevant to the practice of MIS , or its subspecialties if the method used to study AR could be applied to MIS  and if they had potential educational or didactic value for MIS.Articles were excluded if they were not directly relevant to MIS techniques, did not address AR, or were not published in English. A total of 31 studies relevant to both AR and MIS promotion were identified. Articles were accessed through the University of Goettingen library system.Due to the small number of randomized clinical trials, a risk of bias analysis was not required and was not performed.A total of 31 articles from the last five years (2018–2023) were included in the review. The role of AR in the improvement of MIS procedures was identified in three main areas: AR-guided navigation, improving education and training conditions, and building improved user-environment interfaces . Some arOf the 31 papers included a total of 16 articles addressed the topic of AR-based navigation. Six studies were experimental or proof-of-concept approaches. One study was a prospective multicenter clinical approach, one study was a retrospective analysis of clinical data, one study was a prospective case-controlled study, one study was a case report, one study was a clinical investigation, and five studies were review articles. Of these, two articles were systematic reviews. Existing studies and their reported outcome data showed a high degree of heterogeneity , which iIn an experimental approach, Zadeh et al. analyzed the impact of artificial intelligence (AI) concepts using the Uteraug system, an AR-based guidance application for laparoscopic uterine surgery . A datasIn their review, Xu et al. analyzed current surgical tracking systems, one of the most important technologies for MIS navigation, and evaluated the advantages and disadvantages of different solutions . The proButler and colleagues described the first in vivo use of AR-guided percutaneous MIS placement of pedicle screws in the setting of spine surgery . A totalZhu et al. proposed an AR-based neuroendoscopic navigation system to assist surgeons in the localization and removal of intracerebral hematomas . Dual-moLecointre and colleagues developed and tested an AR-based robotic assistance system that performed a real-time multimodal and temporal fusion of laparoscopic images with preoperative medical images in a porcine model . It enabp = 0.0007) and lower blood loss  than the patients in the conventional surgery group. The authors concluded that AR and 3D plate library-assisted posterior MIS is an effective and reliable method for the treatment of scapular fractures, allowing precise preoperative planning and intraoperative navigation. It also saves time and allows for a more individualized treatment plan, resulting in a safer reduction procedure [Guo et al. evaluated the feasibility, accuracy, and efficacy of AR technology and 3D plate library assisted posterior MIS for scapular fractures . They rerocedure .Felix et al. placed a total of 124 thoracolumbar pedicle screws under AR guidance in seven cadavers . Sixty-fIn their review, Yuk et al. present recent advances and innovations in the use of simulation methods in spine surgery . These iChen and colleagues proposed a novel in situ AR navigation system with enhanced arthroscopic information for knee surgery . In an eIn their systematic review, Benmahdjoub et al. examined AR technology and its utility in craniomaxillofacial surgery . From a In their review, Hussain and colleagues evaluate the benefits and challenges of AR systems in skull base surgery . The autHussain and colleagues reviewed relevant features of AR navigation in MIS and examined its evolution over time . They dip < 0.001) and had a shorter operative time  during entry point identification and local anesthesia, which began with the registration of the skin entry point at the lesion site and ended with identification of the bony entry point. In terms of accuracy, the ARCASS group had a significantly higher percentage of “good” entry points in the lateral view  and in the anteroposterior view  than the control group. The authors concluded that the AR system is clinically feasible for PVP and provides a more precise bone entry point with reduced operative time and unnecessary radiation exposure [Hu et al. evaluated the clinical application of the augmented reality computer-assisted spine surgery (ARCASS) system for percutaneous vertebroplasty (PVP) in their prospective case-control study . A totalexposure .Gribaudo et al. presented an approach for developing real-time AR solutions for navigation in robotic surgery . A modulChauvet and colleagues reported the first two clinical cases of real-time AR technology in a laparoscopic myomectomy, in which uterine muscle fibers were visualized with diffusion tensor imaging (DTI) after MRI tractography to help surgeons decide whether to proceed with incision . The autBrebant et al. presented a simplified method of supermicrosurgical lymphovenous anastomosis (LVA) in 30 patients with secondary upper extremity lymphedema . A surgiOf the 31 articles identified, six dealt with education and training. One study was a web-based survey, one study was a randomized controlled trial, one study was a clinical investigation, and three studies were review articles (non-systematic) with insufficiently reported quantitative measures.In their article, Balla and colleagues investigated the current knowledge and use of AR, VR, and MR technology to improve MIS procedures in surgical training in Italy . A web-bWild et al. described the iSurgeon system designed for visual guidance in the operating room via telemetry with AR . Novice Gholizadeh and colleagues present a literature review on image guidance in liver surgery, with particular emphasis on information on AR techniques . The resIn their paper, Godzik et al. described how the disruptive technologies of VR and AR are being used in spine surgery and education . AccordiBenčurik and colleagues described the clinical use of near-infrared (NIR) fluorescein angiography, a technique of AR, in the context of anastomotic leak rate (ALR) in rectal resections . Data anIn their review, Pratt et al. describe a number of important new imaging technologies, including AR technologies, that are more or less integrated with transoral robotic surgery (TORS) . The autOf the 31 articles identified, nine addressed the user-environment interface. Of these, seven were experimental or proof-of-concept approaches and two were review articles with no specified search strategy and insufficiently reported quantitative measures.In their work, Thabit et al. developed an AR-based suture visualization system and evaluated the accuracy and applicability of AR-based navigation for surgical guidance during minimally invasive spring-assisted craniectomy . The autStewart et al. hypothesized that an AR headset that provides a 3D intracorporeal view while pointed at the surgical field could shorten the time and improve the accuracy of robotic bedside tasks . BedsideIn their report, Rush et al. describe institutional experiences with the use and implementation of some of the current AR products in spine surgery . SuggestPrevious AR applications for robotic minimally invasive surgery have mainly focused on overlaying preoperative 3D images with patient anatomy. The article by Forte and colleagues presents alternative interactive AR tools for robotic surgery . They deIn their review, Wendler et al. presented the use of novel molecular imaging as one of the pillars of precision surgery . These dLi and colleagues addressed the current challenges of AR and MR in MIS navigation . The surJia et al. pointed out that real-time AR for MIS without additional tracking devices is a valuable but challenging task, especially in dynamic surgical environments . NumerouWang et al. showed that tracking is a critical step in achieving accurate AR during MIS . In addiChen and colleagues point out that previous research on the use of AR technology in monocular surgical MIS scenes has mainly focused on superimposing information without addressing proper spatial calibration, which could lead to mislocalization of annotations and labels, as well as inaccurate depth information and tumor measurements . The autAR technology is gaining increasing interest in the development of minimally invasive surgery today . This isMost of the developments have been made in spine surgery/orthopedic surgery ,35,36,40To answer the question of how AR technology can help improve MIS procedures, we have identified three main areas of application. Most research today is focused on intraoperative AR-guided navigation. AR technology is also being used to improve education and surgical training and to develop and improve new user-environment interfaces.While the studies discussed here indicate some potential of AR technology in the context of improving MIS navigation solutions ,41,42,43Although AR is predicted to revolutionize surgery, there are several challenges that need to be addressed to ensure widespread adoption ,56,57,58Several studies have addressed the benefits of AR technology and its ability to enhance surgical education and training by providing students and professionals with an immersive, interactive, and engaging learning experience ,46,47,51The interface between users and different surgical environments can be improved by using AR technology to provide relevant and contextual information in real-time ,23,51,53AR technology is currently being investigated for MIS approaches in various medical disciplines. Most studies to date have been limited to experimental developmental approaches, while the number of clinical trials and systematic reviews is low. Most articles on AR-guided navigation are limited to endoscopic/laparoscopic MIS approaches. Intraoperative tracking is still considered cumbersome and error prone. In addition, processing large amounts of data in real-time is computationally intensive and requires improved hardware and software solutions. However, AR technology has been shown to improve ergonomics and visualization, as well as reduce operation time and blood loss. AR can also be used to improve education and surgical training and to create and improve new user interfaces that may indirectly improve MIS procedures. However, to date, controlled studies with large case numbers and standardized outcome parameters and reporting are lacking to confirm the added value for clinical use.


The COVID-19 sequelae have been shown to affect respiratory and cardiological functions as well as neuro-psychological functions, and, in some cases, metabolic/nutritional aspects. The Italian National Institute for Insurance against Accidents at Work  recorded that, until December 2022, 315,055 workers were affected by COVID-19; therefore, there is a need to identify an effective approach to treat such patients. Robotic and technological devices could be integrated into the rehabilitation programme of people with long COVID conditions. A review of the literature showed that telerehabilitation may improve functional capacity, dyspnoea, performance, and quality of life in these patients, but no studies were found evaluating the effects of robot-mediated therapy or virtual reality systems. Considering the above, Fondazione Don Carlo Gnocchi and INAIL propose a multi-axial rehabilitation for workers with COVID-19 sequelae. To accomplish this goal, the two institutions merged the epidemiological information gathered by INAIL, the expertise in robotic and technological rehabilitation of Fondazione Don Carlo Gnocchi, and the literature review. Our proposal aims to facilitate a multi-axial rehabilitation approach customized to meet the unique needs of each individual, with a particular emphasis on utilizing advanced technologies to address the current and future challenges of patient care. On 11 February 2020, the WHO announced the name of the respiratory disease caused by the new coronavirus: COVID-19. This novel coronavirus disease, induced by the virus SARS-CoV-2, originated in Wuhan (China) and spread worldwide, with 757,264,511 confirmed cases and 6,850,594 deaths (WHO update on 21 February 2023). Since the start of the COVID-19 outbreak in China, and its subsequent global spread, Italy has been one of the first countries to be affected, and the number of recorded cases has been among the highest in the world: after 3 years from the beginning of the pandemic, 25,547,414 confirmed cases and 187,850 deaths  were reported.On 9 March 2020, in response to the increase in COVID-19 cases in the country, the Italian government decreed urgent measures promoting social distancing to limit the spread of the virus. From 11 March 2020, all non-essential activities, such as social interaction, sporting, retail, and recreational activities, were suspended and, when possible, most organisations had to introduce remote work: citizens were forced to stay at home and travelling was drastically reduced. People’s freedom to move was limited to urgent health circumstances or working in healthcare. A similar lockdown was never experienced before in Italy. Due to the rapid spread of the virus, China first and later Italy, went into a full lockdown, while other countries used social distancing as the principal strategy to limit the number of new cases .,51.50,51During the pandemic, FDG continued to provide rehabilitation services to patients, particularly by utilising various technologies. In order to accomplish this, FDG acquired a specific CE-certified platform that gave it access to patients’ homes throughout the lockdown. Following a training period, telerehabilitation sessions based on real-time interactivity (synchronous interaction) now make up around 10% of outpatient rehabilitation sessions .In the last year, Fondazione Don Carlo Gnocchi has started a collaboration with INAIL to ensure multi-axial rehabilitation for COVID-19-affected workers integrated with technological and robotic devices. The protocol is characterised by a multiperspective approach, including respiratory and cardiological rehabilitation, neuromotor rehabilitation, cognitive rehabilitation, and psychological and nutritional treatment. The protocol takes advantage of the beneficial effects of robotics and technologies on sensorimotor and cognitive deficits , which h2) in the recovery phase, and the reduction of the level of lactates produced during the exercise and the share of non-metabolic carbon dioxide (CO2) generated by the bicarbonate system to buffer its effects on pH.Respiratory function rehabilitation can be divided into two main categories: (a) rehabilitation of respiratory function and motor performance; and (b) bronchial disruption. The rehabilitation of respiratory function and motor performance involves motor training exercises aimed at improving the strength and endurance of the upper and lower limbs, and respiratory muscles ,54,55,56Bronchial unblocking is an important element of rehabilitation, especially for patients with hypersecretion. The techniques used are: (a) the Active Cycle of Respiratory Techniques (ACBT), (b) the Total Slow Expiration with Open Glottis in Lateral Decubitus (ELTGOL) , (c) theFinally, the continuation of such a rehabilitation programme, also through telerehabilitation and the telemonitoring of heart rate, body pressure, pulse oximetry, and hemoglobin, is recommended since exercise’s physiological effects decay if ad hoc maintenance programmes are not provided .Therefore, we suggest using the following outcome indicators to assess the impact of respiratory and cardiovascular rehabilitation: Barthel Dyspnoea ; InstrumThe focus of neuromotor rehabilitation in patients with SARS-CoV2 outcomes relies on the treatment of the central and/or peripheral nervous system. Neuromotor rehabilitation should be performed by the integration of conventional techniques with new advanced technological and robotic devices.Conventional rehabilitation allows for functional recovery of the limbs and trunk, as well as the complex tasks that rely on them, such as walking, balance, coordination, and postural control, all with the goal of regaining autonomy in ADLs.sensorimotor training to restore normal motor programmes, maintain joint mobility of the upper and lower limbs through passive and active assisted mobilisations, and control pain when present;programmes to increase muscle strength and endurance with incremental exercises appropriate to the patient’s performance, and programmes to recover segmental movement and then more complex motor functions;training from autonomies in safe postural transitions;postural control exercises;balance and gait recovery exercise;activities aimed at family and social reintegration.Conventional re-education protocols should promote:intensified treatment;objective measurement of patient’s achieved goals;personalised treatment;stimulation of neurocognitive as well as motor aspects .The robotic device can be:End-effector, where movements are generated from the most distal segment of the extremity and no alignment between patient-robot joints is required ;Exoskeletons, which have a one-to-one correspondence between robots and human joints, and every single joint is guided along a pre-programmed trajectory . They caThere are also advanced technological systems such as:sensor-based systems that allow for the control of a wide range of limb movements, but also of the whole body in space (trunk and gait control);electromechanical systems with body weight or a district relief system .Robotic rehabilitation grants treatment of both upper and lower limbs; they represent an innovative rehabilitation approach that allows:Robotic rehabilitation approaches can be useful for post-COVID symptoms such as disabling balance disorders and insufficient postural control using technological/robotic platforms. Stabilometric and dynamic platforms can also be used to carry out evaluative tests of the patient’s condition before and after the rehabilitation course. Moreover, exoskeleton or end-effector robotic devices (that safely sustain the patient using a weight body support system), allowing more physiological gait training even in the presence of a significant lower limb strength deficit, can be utilised for gait training.Some sensor-based and robotic devices have been found to be useful not only for inpatient rehabilitation, but also for home-based rehabilitation with caregivers (telerehabilitation and telerobotic programmes through telemonitoring). Through monitoring systems, the therapist evaluates the patient’s progress every day and adjusts the treatment to suit the patient’s needs. Furthermore, telerehabilitation systems also allow for the simultaneous treatment of patients in small groups.We propose to evaluate the effects of neuromotor rehabilitation using the following outcome measures: the Motricity Index , to evalLong COVID’s cognitive deficits, including memory loss and moderate cognitive impairment, might last for months after recovery from the acute phase.The most experienced symptoms are memory issues, multitasking deficits, processing speed reduction, and lack of concentration. These symptoms can prevent the return to normal activities of daily living. Therefore, early interventions aimed at limiting short- and long-term damage are important.It is first necessary to conduct a neuropsychological assessment to highlight cognitive deficits and to characterise their impact on the individual, with the aim of guiding treatment. The assessment will be carried out through a cognitive screening test and, later, with specific tests for individual impaired areas.Therapy will be trained according to the functions that are most affected on the assessment tests or experienced as more debilitating by the patient.targeted reinforcement of deficit skills through the administration of exercises of increasing difficulty ;adaptation of the patient’s behaviours and setting of new compensation strategies ;evaluation of the results obtained is mandatory at the end of the treatment.Cognitive training aims at reducing symptoms and will be based on two works conducted in parallel:The first interview and administration of standardised tests should be conducted in person; cognitive training could be conducted in telerehabilitation or mixed regimens.To assess the effectiveness of the proposed intervention, we suggest using the following outcome measures: the Montreal Cognitive Assessment , to evalThe lockdown has had an impact on the whole community, particularly in terms of family separation. This mostly affected those who were unable to spend the lockdown period with their family. This situation led to psychological distress for patients .To overcome this distress, adequate psychological support for patients should be conceived, and “technological” solutions, such as video calls, can be used to maintain communication with patients also after dismission.In this context, we suggest evaluating anxiety, using the Beck Anxiety Inventory , depressSignificant weight loss (sarcopenia) is common in post-COVID patients with severe symptoms due to a long ICU stay. Nutritional problems need particular attention as they result in reduced exercise tolerance, susceptibility to infection, and consequently, to worse outcomes. Therefore, it is critical to employ nutritional status screening tools to identify people who are malnourished or at risk of malnutrition, and to implement procedures to monitor and regulate daily nutritional intake in these circumstances.For this purpose, we propose the use of the Mini Nutritional Assessment  to gradeScientific evidence shows that SARS-CoV-2 infection may affect health at different levels. Due to the COVID-19 multi-organ sequelae, an exceptional number of workers underwent medical complications and lost their ability to work and conduct a normal life.In this scenario, INAIL plays a crucial role in supporting Italian Public Healthcare to guarantee optimal multi-axial rehabilitation assistance in terms of the appropriateness and timeliness of the rehabilitation intervention.As an institution created to protect and support workers’ wellbeing integrity, INAIL provides multi-axial rehabilitation assistance for those whose health has been affected by the occurrence of the pandemic. These services are dispensed in specific rehabilitation institutes such as the centres of Fondazione Don Carlo Gnocchi. These centres provide professional expertise, specialised structures, and up-to-date technologies, such as robotic devices, to rehabilitate different types of disabilities.An optimal multi-axial rehabilitation approach entails stepping in at the earliest stages of the pathological process to promote healing and improve clinical conditions, selecting the most effective treatments according to scientific evidence and good practice. This requires including multiple district interventions and contemplating the possibility of repeated treatments (deferred rehabilitation).As we described in this proposal, both conventional and technological treatments should be applied. Technological-robotic rehabilitation has been proven to be a promising tool for both physical therapy and remote interventions (telerehabilitation).Telerehabilitation has expanded its applications in the last 25 years due to the development of new computer science technologies . During Whatever type of treatment we intend to apply, reintegrating workers with long COVID sequelae in their jobs, families, and social activities will undoubtedly have a positive impact on their quality of life and will reduce the costs related to days of absence from work and medical complications. In order to ascertain the efficacy of the proposed treatment in individuals experiencing long COVID outcomes, it is imperative that experimental studies be undertaken. These investigations should involve rigorous clinical trials or observational studies, employing robust methodologies and a sufficiently large sample size. By carefully monitoring the response of patients to the treatment, including its impact on various symptom domains, functional outcomes, and quality of life measures, researchers can acquire valuable evidence regarding its effectiveness. Additionally, long-term follow-up assessments should be conducted to evaluate the durability and sustainability of the treatment outcomes over an extended period. The findings derived from such studies will not only contribute to the existing body of knowledge, but also provide crucial insights for healthcare professionals and policymakers when determining the most appropriate therapeutic interventions for patients suffering from long COVID.The COVID pandemic has been a hard test for Italian healthcare professionals, patients, and their caregivers in terms of the management of the medical emergency and because of the human and social costs that it caused to the country.Aside from providing adequate assistance to the affected workers, our proposal intends to promote a multi-axial rehabilitation approach that is effectively tailored to individual needs, taking into special account the availability of advanced technologies and their application to the current and future challenges of patient care.


Objective Breast cancer (BC) biomarkers, such as hormone receptors expression, are crucial to guide therapy in BC patients. Antiandrogens have been studied in BC; however, limited data are available on androgen receptor (AR) expression test methodology. We aim to report the core needle biopsy (CNB) accuracy for AR expression in BC.Methods Patients diagnosed with stage I-III invasive BC from a single institution were included. Androgen receptor expression was evaluated by immunohistochemistry (IHC) using 1 and 10% cutoff and the AR expression in surgical specimens (SS) was the gold standard. Kappa coefficients were used to evaluate the intraprocedural agreement.Results A total of 72 patients were included, with a mean age of 61 years old and 84% were Luminal A or B tumors. The prevalence of AR expression in all BC samples was 87.5% using a cutoff ≥ 10% in SS. With a cutoff value ≥ 1%, CNB had an accuracy of 95.8%  and 86.1%  when ≥ 10% cutoff was used for AR positivity. Androgen receptor expression in CNB (cutoff ≥ 1%) had a sensitivity of 98.5%, specificity of 60%, positive predictive value of 97.0%, and a negative predictive value of 76.9% in the detection of AR expression in SS.Conclusion Core needle biopsy has good accuracy in evaluating AR expression in BC. The accuracy of CNB decreases with higher cutoff values for AR positivity. Breast cancer (BC) is a heterogeneous disease. Immunohistochemistry (IHC) is the routine pathological technique used to evaluate hormone receptor (HR) status, HER2 expression, among other markers to better stratify BC subtypes.Androgen receptor (AR) expression in breast cancer is often associated with better prognostic tumors, was identified as a subtype of triple negative breast cancer (TNBC) and as a potential therapeutic target, especially in TNBC.The primary goal of the present study is to describe the CNB accuracy for the evaluation of AR expression in BC in a Brazilian population.We conducted a cross-sectional study to evaluate biomarkers expression in BC specimens. Clinical data from consecutive patients diagnosed with invasive BC treated in the Surgical Breast Unit of Hospital São Lucas of the Pontifícia Universidade Católica do Rio Grande do Sul (PUCRS) in Brazil, from March 2017 to March 2018, were retrospectively collected. All patients underwent CNB and subsequently had surgical procedure in our institution. Women ≥18 years old who have agreed to participate in our study and have signed a written informed consent were included in the analysis. Patients who received neoadjuvant treatment and for whom material from surgical specimens was sufficient for AR, estrogen receptor (ER) and progesterone receptor (PR) status evaluation were also included. Neoadjuvant treatment may impair the biomarker analysis once intratumoral heterogeneity and different responses of cellular clones may result in discordant IHC. The exclusion criteria were in situ or microinvasive BC, because this subgroup of carcinomas was not included in the trials that evaluated the role of anti-androgens as a potential therapeutic target. We also excluded multicentric or multifocal tumors to make sure that we analyzed the same tumor by core biopsy and surgical specimen, to evaluate the accuracy properly. The Local Ethics Committee approved the study under the Certificate of Ethical Assessment (CAAE) registration number 60989316.0.0000.5336. Clinical data such as patient age, menopausal status, surgical treatment type, neoadjuvant treatment history, number of fragments obtained from CNB and main pathological findings from both CNB and SS, which included tumor size, tumor grade, and tumor biomarkers expression, were collected through retrospective review of medical records and pathologic reports.Percutaneous CNB was performed under local anesthesia with a semiautomated biopsy gun with a 14 Gauge (14-G), 10 cm long needle. A mean of 6 core samples per lesion (range 2–11) were obtained. In 58 cases, ultrasound guidance was performed and in 14 cases the guidance was performed by the assistant physician, because the tumor was easily palpable. Fragments of CNB were placed immediately into an adequate volume of 10% buffered formaldehyde. A minimum fixation time of 6 hours and a maximum of 72 hours were ensured, according to the American Society of Clinical Oncology and the College of American Pathologists (ASCO/CAP) guidelinesThe tumor was incised after painting of the surgical margins to facilitate fixation of breast conserving surgery specimens and the mastectomy specimens were inked and cut into 1-cm-thickness slices before fixation. Sampled tissue blocks were fixed in an adequate volume of 10% buffered formaldehyde for between 12 and 24 hours, processed in a Shandon Excelsior ES  and then embedded in paraffin. Three-μm-thickness paraffin sections were cut for hematoxylin-eosin staining and IHC analysis.The evaluation of AR, PR, and ER by IHC was performed using the following validated primary antibodies: anti-AR, clone AR441, dilution 1:100 ; anti-ER, clone EP1, ready-to-use  and anti-PR, clone 636, ready-to-use . Material was processed in an automated system for immunohistochemical reactions  and IHC analysis was done by a trained pathologist with qualitative and semiquantitative image analysis. The IHC uses labeled antibodies to localize specific activations of antigen proteins in the tissue sections. The qualitative image analysis consists in simple observation of the presence and darkness of specific stains within the tissue, while the semiquantitative method estimates the quantity of proteins on chromogen-labeled immunohistochemical (IHC) tissue sections via computer-aided methods. Material from both CNB and SS were processed and analyzed in the same institution.The ASCO/CAP guidelineBreast surgery was categorized as breast conserving surgery or mastectomy. The later includes simple mastectomy (without immediate reconstruction procedure), nipple sparing mastectomy, and skin-sparing mastectomy (both with immediate reconstruction procedure).Surgical specimens were classified into molecular subtypes according to the 12th St. Gallen International Breast Cancer Conference [4] as: luminal A, luminal B (HER2 negative or HER2 positive), HER2 positive nonluminal , and triple negative.The primary endpoint was to describe the CNB accuracy for the evaluation of AR expression in BC by IHC. The secondary endpoint was to perform the same evaluation for ER and PR expression. Definitive histological diagnosis and biomarkers on SS served as the gold standard in subsequent analyzes.p-values < 0.05 were considered statistically significant. The statistical analysis was performed using IBM SPSS Statistics for Windows version18 .Sample size calculation was performed with R/R Studio software. It was estimated that, in different Kappa coefficients, 80 patients would provide a margin of error between 0.10 and 0.11 for agreement evaluation. We also took into consideration the consecutive sample available with AR analysis in our institution, a limited sample. Data were presented as mean ± standard deviation (SD) or frequency and percentage. Kappa coefficients were used to evaluate the intraprocedural agreement. Its interpretation was conducted based on the following parameters: Kappa of 0.01 indicates “poor” agreement; Kappa ranges from 0.01 to 0.20 indicate “slight” agreement; Kappa from 0.21 to 0.40 indicate “fair” agreement; Kappa from 0.41 to 0.60 indicate “moderate” agreement; Kappa from 0.61 to 0.80 indicate “substantial” agreement, and Kappa ranging from 0.81 to 1.00 indicate “almost perfect” agreement.The study included 72 patients with a mean age of 61 years old; 78% were postmenopausal. The mean number of samples in each CNB was 6 ± 2; 51 (71%) patients underwent breast conserving surgery and 21 (29%) underwent mastectomy. The majority had Luminal A (44%) and Luminal B HER2 negative (40%) tumors. There were no HER-enriched breast carcinomas in our sample. For all patients included independent of BC subtype, the frequency of AR expression was 87.5% using a cutoff point of ≥ 10% and 94.4% when the cutoff point was ≥ 1%. Patient characteristics are summarized onp < 0.001). A lower accuracy of 86.1% for AR expression was found when using a cutoff ≥ 10% . For hormone receptor status, the accuracy of ER expression was 943% , and 88.5% for PR expression , which were similar to AR.The AR expression accuracy was 95.8% using a cutoff ≥ 1%  is used. Five (6.9%) of the 72 patients had AR negative in CNB and positive in SS (2 received neoadjuvant chemotherapy). On the other hand, 5 (6.9%) patients who had positive AR in CNB turned out to have a negative result in the SS (1 received neoadjuvant chemotherapy). Therefore, it is expected that a small number of patients will have discordant results possibly due to intratumoral heterogeneity and exposure to neoadjuvant chemotherapy.Estrogen receptor and PR expression remain the most important biomarkers in breast cancer over the last decades, even though the definition of the optimal threshold to define HR positivity remain controversial. Recently, the ASCO/CAP guideline for estrogen and progesterone receptor testing in breast cancer was updated [1]. Results with 1 to 10% of cells staining positive should be reported using a new category (“low positive”). The limited data on endocrine therapy benefit in this subgroup tailored the new reporting recommendation, but it should not change the patient eligibility for endocrine therapies. The same issue is important regarding the evaluation of the AR expression.The AR is a steroid-hormone activated transcription factor belonging to the nuclear receptor superfamily, which also includes the ER and PR. The AR pathway is associated with regulation of normal breast development, as it appears to balance the estrogen-induced cell proliferation, and also with breast tumor carcinogenesis.Neoadjuvant therapies have been increasingly used in breast oncology not only as a clinical tool to allow tumor downstaging and less extensive surgeries, but also as a scientific tool to the evaluation of biomarkers and development of targeted therapies. In this case, the systemic therapy that will be offered will depend on disease staging and tumor biomarkers, such as HR evaluated on CNB.p < 0.01).Androgen receptor expression was associated with chemoresistance in TNBC and endocrine therapy resistance in Luminal tumors.In our study, the prevalence of AR expression was 87.5% in SS using a cutoff ≥ 10% and 94.4% with a cut-off ≥1%, which are similar to previous data.p < 0.001).Nonetheless, the AR expression in BC has no standard procedure and evaluation and results are variable depending on the cutoff levels for positivity ,Two ongoing studies  evaluating the role of antiandrogen drugs in a neoadjuvant setting selected patients to receive therapy with enzalutamide using AR positivity based on CNB IHC, each study using a different cutoff for AR positivity (1 and 10%), which clearly highlight the lack of consensus in methodology and the potential implications of trial results in practice.Several studies have shown a high concordance between ER and PR status evaluated on CNB and SS. The concordance found in these studies ranged from 92 to 96% for ER and from 88 to 94% for PR.The AR expression is usually not evaluated in current clinical practice but the increasing interest in this biomarker as a predictive and therapeutic target corroborates the need of an accurate evaluation and consensus regarding the threshold to define positivity as it may be used for BC classification subtype and therapeutic decision. It is also important to address the potential harm of indicating the use of antiandrogen drugs in false-positive cases. It includes adverse effects (AE) like headache, muscular weakness, and anxiety, mostly grade 1 or 2 (slight to mild), which are usually tolerable for the patients.The present study has some limitations. We evaluated a relatively small sample size, which impair a sub-analysis in different BC subtypes, and there was a higher proportion of Luminal A and B tumors, which may impact the results of AR expression prevalence. Furthermore, we have included a subgroup of patients who have received neoadjuvant treatment (chemotherapy or endocrine therapy), which may impact biomarker analysis. Nevertheless, our study contributes to the very limited data regarding AR expression accuracy in terms of CNB and SS, also to add validity to our methodology, we performed analysis of ER and PR expression, which showed consistent accuracy results.Our study shows that evaluation of AR expression by IHC using CNB samples is feasible and has a high accuracy. Using a cutoff ≥ 10% for AR expression decreases the agreement between CNB and SS. This finding has implications for the pathological analysis of AR especially in clinical trials evaluating antiandrogen agents.


Serious games (SGs) about Chemistry have the potential to cope with challenges, such as students’ low performance and lack of motivation for the subject. However, the majority of existing SGs for Chemistry have the form of educational applications infused with some elements of entertaining games. The aim of the study presented was to design and evaluate a new SG with rich game mechanics for Chemistry. The game is called Elementium and revolves around basic topics of Chemistry, such as chemical elements and compound terminology, creation and everyday usage of such elements. The main goal of the game is to familiarize junior high school students with the aforementioned subjects. The design of Elementium was carried out implementing the dimensions described in the Four-Dimensional framework, as proposed by de Freitas and Jarvis in 2006. After the development process, Elementium was evaluated by people in the field of education that are currently teaching or have taught Chemistry in the past. The participants play-tested the game at leisure in their homes and evaluated it based on the key criteria for SGs design proposed by Sanchez in 2011, as well as other quality indicators established in the literature. Elementium was positively evaluated by Chemistry teachers in terms of its acceptance, usability, didactic utility, and game environment. The positive results concluded from this evaluation show that Elementium is fulfilling its main purpose and can be used as a supplementary tool in the teaching process. However, its true didactical effectiveness has to be confirmed through a study with high school students. Serious games (SGs) comprise a dedicated category of video games whose primary objective is not entertainment, rather educating individuals through entertainment Zyda, . Nowaday“more value-added research is needed to identify more effective game design features and instructional design features and provide design guidelines for chemistry GBL”  that are tightly connected with the educational content through the game’s scenario, having as an ultimate goal to familiarize users with the basic concepts and terminology of Chemistry. The game, called Elementium, incorporates material based on the textbooks of Chemistry courses that are currently being taught in junior high schools in Greece. The conceptual understanding in Chemistry contains the ability of someone to think both at a macroscopic and microscopic level. That, in combination with the vast number of chemical elements and compounds that the student has to memorize, can often trouble both the educator and the learner. Our aspiration for developing this SG is to provide supplementary material that will enrich the learning experience and will act as a motivation for students to self-study and improve their knowledge. In this article, a pilot study is carried out in order to investigate teachers’ perceptions regarding the game in terms of its acceptability, usability, didactic utility, and game environment using the key criteria proposed by Sanchez , as wellWhat are teachers’ perceptions on the acceptability, usability, didactic utility, game features, and balance between game and learning of the RPG Chemistry game Elementium?The rest of the article is structured as follows. Section Four-Dimensional design framework for Serious Games, as proposed by de Freitas and Jarvis  or other online players, asking them questions about the experiments that need to be conducted. These ‘self-generated’ questions are, according to the author, of higher value, when compared to passive listening during traditional teaching.Shui  presenteMolecule Madness, a gamification of the software ChemDraw, aiming to aid the teaching and social interaction of a class during the COVID-19 pandemic. The game, in the form of a single-elimination tournament, is hosted online with the help of web-conferencing software. The results of this study showed that using Molecule Madness as a substitute for the postponed laboratory sessions can improve the wellness of the classroom and have a positive impact on student morale.Fontana  developeWorld of Chemistry, a virtual reality SG with narrative elements, meant to motivate students to study Chemistry. A study was conducted with the participation of volunteers that played the game and the results showed that the game was a good motivational influence for the majority of them.Soares et al.  implemenFour-Dimensional framework for Serious Games ; preferences; skills in Information and Communication Technologies and game experience.Representation. This dimension deals mainly with: the ways that immersion is achieved; the level of fidelity both in terms of the graphics and the representation of the game world; the interaction of the player with the game. The elements in this dimension of the framework are clearly connected to the game features  that are considered not only to entertain, but also to motivate . The first scene of the game shows the main character studying in his room, while a message prompts the player to interact with the environment around him by clicking the right mouse button (representation: interactivity). After clicking on the open book on the desk, a dialogue sequence starts following the scenario of the game and at the end the character is transported to the main scene. Besides the contribution to the story, the purpose of the first scene is to familiarize a new player (context: support) with the main character’s movement and interaction system and with the dialogue and question windows . The main scene of the game is set on a uniform map consisting of six areas, labeled 0–5 in Fig. The first area is enclosed inside the walls of the town of Mendeleev, where the player encounters the first NPC character that explains the basic functionality of the inventory, the crafting system and the help window (context: support). In order to leave the town, the player must find the key to the main entrance which comes as a reward after the three interlocked quests are completed (representation: immersion). The quests are carefully chosen as representatives of the three types of collection quests that the player will face during the game: crafting quests, gathering quests and quests that the player has to find a quest item . After the main gate is unlocked, the player encounters another gate and a ‘teacher’ NPC, which holds Chemistry questions (pedagogy: cognitive). If the player answers all of the questions correctly, the door can be unlocked. At all times, the player can press the escape button on the keyboard, to reveal the game menu window (context: support), containing gameplay info. In the game menu there is also a checkbox to mute the in-game music, a button that opens the save menu and a button that opens a webpage containing a more detailed gameplay tutorial (context: support) Fig. .In the second area the player gets introduced to Treelings, the enemies of the game and obstacles that block the path . Treelings come in three types, namely normal, ranged and fast, as well as boss variations of each. The obstacles are implemented in the form of NPCs, so it is easier for the user to navigate through the tasks. At the end of this area there is again a teacher NPC with Chemistry based questions (pedagogy: cognitive). The rest of the game follows the same pattern of increasing difficulty Chemistry related quests and questions at the end of each area, with few exceptions of interconnected quests from different areas (representation: immersion). At the end of the final area, the player must face the final enemy that guards the portal to Earth. After activating the portal, the character returns to his room and immediately goes to his classroom for the Chemistry exam. There, the player must answer 15 final questions in the form of an exam, to complete the game .The main character of the game can move using either the W, A, S, D keys or the keyboard arrows and can execute two ranged attacks (representation: interactivity). The attacks can only be executed if two conditions are met: the player has to select an enemy with a mouse click and the character has to face the enemy. When a spell is casted a horizontal progress bar appears and fills based on the casting time of the spell and an amount of mana points is consumed. The main character starts at level 1 and gains experience points (XP) by completing quests  or eliminating enemies (learner: game experience).By selecting an enemy, a UI element appears at the top of the screen, informing the player about the enemy level (context: support) and real-time health points. Enemies try to deal damage to the main character, if they get attacked or if the character walks in their attack range and in both situations the character enters the combat state. The health points of a character and an enemy replenish when out of combat. If the character’s health points reach zero, he immediately respawns at the starting point, in the town. Respectively, if its health points reach zero, the enemy enters a sleeping state from which it recovers after 2.5 min. When the enemy is in the sleeping state, the player can take its loot, which is crucial for the progression of the story (representation: immersion). Loot includes elements, potions and quest items and it is only available the first time the enemy is eliminated (learner: skills).One of the main components of the gameplay is the inventory Fig. . The chaDuring the game, the player has to complete a number of quests . Those quests are of two types: collection quests (including gathering or crafting quests) or elimination quests. The player can refer to the quest window . The player can view the crafting objective of a quest from the quest window and find the recipe at the recipes window. By clicking on a recipe title, information is displayed, along with the components required for the craft (context: support). If the player has the number of components required in his inventory, the crafting can be initiated by pressing the corresponding button. When the button is pressed, the progress bar pops up, in the same manner as with the casting of a spell, previously described. After the countdown, the newly crafted item can be found in the inventory, while the required constituents are consumed.Another important component of Elementium is the questions system presented in Fig. Lastly, the saving system is responsible for saving and loading the game (context: place). The save menu, accessed via the game menu, contains three slots that are initially empty. If a player clicks the save button next to a slot, a game instance is saved and the slot is occupied with the main characters stats, like health, mana and experience points, gold, active quests etc. Fig. .For an early evaluation of the game, teachers were invited to play-test the game at leisure in their homes and evaluate it through an anonymous questionnaire. The questionnaire included:demographic questions.questions regarding the proper execution of the game.questions based on the acceptability, usability and didactic utility dimensions of key criteria of the game design model proposed by Sanchez .questions on the game environment proposed in other game design and evaluation frameworks , where 1 equals ‘strongly disagree’ and 5 equals ‘strongly agree’.https://alexpheeuom.github.io/elementium/Elementium.html), while it remained open to submissions for one month. The first author made an announcement about the game, its availability and an invitation for its anonymous evaluation by Physics and Chemistry teachers through his social media.The questionnaire was created using Google forms and was linked through the game’s webpage  and 29–39 (57.7%). This research has been conducted following the ethical requirements established by Greece national board of ethics. All the participants hold a Bachelor degree in Physics (76.9%) or Chemistry (23.1%) and have experience in teaching Chemistry. Specifically, the majority of the participants (69.3%) have 3 to 10 years of experience in teaching Chemistry. As for the game execution, all of the participants finished the game, which ran on their PCs with no problems. From the whole of the participants, 7.7% finished the game in approximately 1 h, 53.8% in approximately 2 h and 38.5% needed more than two hours for completing the game.Data was collected through an anonymous questionnaire (Google form) and was statistically analyzed using MS Excel. We calculated the mean value (x̄), standard deviation (σ) and median (x͂) for each question.acceptance of the game  regarding the possibility of using the game in school classes, affecting the mean value for the acceptability Fig. : 4.17 anOne of the most important results of the study refers to the balance between game components and the achievement of the educational objective (Bellotti et al., “the acceptance of the game by teachers and their intention to utilize it in the classroom is considered important taking into account the scepticism of instructors to incorporate games in their courses”. In the case that a teacher evaluates positively the added value of a game in the learning process, then the game can be utilized in the classroom or be proposed to students as a learning aid that can be used for studying at home (Ibrahim & Jaafar, Elementium is a serious game for Chemistry targeted at high school students. As is the case with any game-based learning approach, three dimensions have to be taken into account in order to ensure its effective application in an educational context Sanchez, . These dIn this sense, the pilot evaluation of Elementium was carried out by teachers that have experience in teaching Chemistry. Since the participants are experts in the area of the game, it is considered that the results of the evaluation are trustworthy. Specifically, as noted by Nielsen and Molich  two to tIt is clear that both the approach and the sample of the study pose limitations on the conclusions drawn. Taking into account the positive evaluation of the game by the teachers, the next step in the process is the evaluation of the game by students or anyone interested in learning Chemistry in order to draw safe conclusions about its didactical effectiveness. This could be accomplished through a study carried out with junior high school students in a formal educational setting. Specifically, an experimental group of students could utilize Elementium in the classroom or at home and a control group could be taught without it, while a pretest and posttest design could be utilized for investigating potential changes that could be attributed to the use of game.This article presents the results of a pilot study that followed the design and implementation of a SG for familiarizing junior high school students with the basics of Chemistry. Several SGs for Chemistry have been developed, but most of them fall short in the essential fun factor that characterizes a SG. Our goal was to incorporate the educational content into the mechanics of a video game and deliver an entertaining game that will be attractive to students. Elementium’s design was guided by the Four-Dimensional framework (de Freitas & Jarvis,


Two million people in the UK are experiencing long COVID (LC), which necessitates effective and scalable interventions to manage this condition. This study provides the first results from a scalable rehabilitation programme for participants presenting with LC.601 adult participants with symptoms of LC completed the Nuffield Health COVID-19 Rehabilitation Programme between February 2021 and March 2022 and provided written informed consent for the inclusion of outcomes data in external publications. The 12-week programme included three exercise sessions per week consisting of aerobic and strength-based exercises, and stability and mobility activities. The first 6 weeks of the programme were conducted remotely, whereas the second 6 weeks incorporated face-to-face rehabilitation sessions in a community setting. A weekly telephone call with a rehabilitation specialist was also provided to support queries and advise on exercise selection, symptom management and emotional wellbeing.p < 0.001), with the 95% confidence intervals (CI) for the improvement in each of these outcomes exceeding the minimum clinically important difference (MCID) for each measure . Significant improvements exceeding the MCID were also observed for sit-to-stand test results . On completion of the rehabilitation programme, participants also reported significantly fewer GP consultations (p < 0.001), sick days (p = 0.003) and outpatient visits (p = 0.007) during the previous 3 months compared with baseline.The 12-week rehabilitation programme significantly improved Dyspnea-12 (D-12), Duke Activity Status Index (DASI), World Health Orginaisation-5 (WHO-5) and EQ-5D-5L utility scores  in its aim of controlling the impacts of COVID-19 and delivering on its long-term plan.https://www.isrctn.com/ISRCTN14707226, identifier 14707226. COVID-19 is a highly infectious respiratory disease that has elicited catastrophic health, care and economic effects. Officially declared as a global pandemic by the World Health Organization (WHO) in March 2020, there have since been 523 million cases of COVID-19, of which six million cases have resulted in death (as of May 2022) (The most frequently reported symptoms of long COVID (LC) include breathlessness and fatigue, as well as impaired pulmonary function and reductions in health-related quality of life (HR-QoL) , 5. In MThe purpose of this study was to assess the clinical effectiveness of a novel 12-week blended community rehabilitation programme for individuals experiencing LC. These are the first results from a scalable rehabilitation programme for participants presenting with LC. The findings demonstrate substantial improvements in LC symptoms and suggest that this rehabilitation model can support the NHS  in its aim of controlling the impacts of COVID-19 and delivering on its long-term plan.This study was conducted according to the guidelines laid down in the Declaration of Helsinki, and all procedures were approved by the Ethics Advisory Committee at Manchester Metropolitan University (Ref: 25307). Participants were able to enroll into the rehabilitation programme online via self-referral or referral from an NHS practitioner. Following enrollment, participants underwent triage with a physiotherapist to assess eligibility for inclusion in the study. Eligible participants were then assigned a start date for the programme.All participants reported in this manuscript provided written informed consent for the inclusion of outcomes data in external publications.This service evaluation used baseline and follow-up data (at 12 weeks) from 601 people with LC undertaking the Nuffield Health COVID-19 Rehabilitation Programme between February 2021 and March 2022. This trial is registered at the ISRCTN Registry (ID: 14707226). A full overview of inclusion and exclusion criteria is provided in The LC rehabilitation programme aims to improve symptoms of LC, functional capacity, personal well-being and HR-QoL. The LC rehabilitation programme is a 12-week, group-based programme split into two 6-week phases consisting of 3 × 45-min exercise sessions per week and continued support from a programme lead, with a maximum of 10 participants per group. Throughout the 12-week programme participants completed three exercise sessions per week: (1) group rehabilitation exercise session lasting 45 min; (2) on-demand exercise session lasting 45 min, using a pre-recorded guided exercise session located on a dedicated online platform ; (3) a “build your own” exercise session whereby participants selected from a menu of activities provided within their rehabilitation workbook to populate a session commensurate with their personal threshold. An overview of the components included in the 12-week programme are presented in ®), with the programme lead delivering the session.The first phase of the programme was conducted remotely in Weeks 1–6. The group exercise session was performed via an online live-streaming platform . Following exercise sessions, participants were advised to record their perceived effort score on a scale which ranged from 0 (no effort) to 10 (extremely hard). Self-recording exercise effort allowed for participants to monitor their progress and adjust effort accordingly over the 12-week programme. Participants were also encouraged to progress movement complexity, range of motion, stability, and volume where possible.1 which contained the on-demand exercise sessions, webinars, and resources relevant to the programme. Participants were provided with a printed copy of the Nuffield Health LC rehabilitation journal which contained information on physical and emotional wellbeing, and an activity record to log exercise sessions completed each week.Participants also received a weekly telephone call with a rehabilitation specialist lasting up to 45 min to support with any queries on the programme and provide advice on exercise selection, symptom management and emotional wellbeing. Participants had access to a web-based LC rehabilitation hubThe LC programme was conducted at 51 Nuffield Health Fitness and Wellbeing Centres, all of which were registered with the Care Quality Commission (England) or the Care Inspectorate (Scotland). Nuffield Health Fitness and Wellbeing centres are commercial gyms, available to the public. The LC rehabilitation programme was free to participants.Full details of the rehabilitation programme are provided in the published study protocol .All sessions were delivered by Nuffield Health Rehabilitation Specialists . On successful completion of the LC course, the Rehabilitation Specialist has access to an online platform containing relevant materials for delivering the programme. This ensures that the delivery of the LC remains consistent in Nuffield Health Fitness and Wellbeing Centres across the UK.Outcome data were collected for all participants at baseline and on completion of the rehabilitation programme at Week 12 via a digital application . Data were objectively measured by the Rehabilitation Specialist or self-reported and stored on a web-based platform .Breathlessness was measured using the Dyspnea-12 tool (D-12) . The D-1Functional capacity was assessed using the Duke Activity Status Index (DASI) . The DASPhysical fitness was assessed using the 30-s sit-to-stand test . The 30-Mental wellbeing was assessed using The World Health Organization- Five Well-Being Index (WHO-5) . The WHOHealth status was assessed using the EuroQoL Five Dimension Five Level (EQ-5D-5L) and visual analog scale (VAS) . The desAt baseline and Week 12, participants also reported the number of general practitioner (GP) consultations, outpatient hospital episodes, inpatient hospital episodes and days absent from work due to illness (“sick days”) experienced during the past 3-months (for participants who were engaged in employment at baseline). This enabled a comparison of illness burden during the rehabilitation programme compared with the preceding 3-month period.The primary analyses were conducted in 601 participants who completed the LC rehabilitation programme and provided outcome measures at Week 0 and 12. A subgroup of 539 participants provided D-12, DASI, WHO-5, EQ-5D-5L and sit-to-stand test outcomes at the midpoint of the intervention. The outcomes for these participants were analyzed at Weeks 0, 6, and 12 to understand the time-course of changes in response to the programme.t-tests were used to determine significant differences between timepoints. Additionally, the 95% CIs of differences between timepoints were compared against the minimum clinically important difference (MCID) thresholds identified for relevant outcomes from the wider research literature. Where the 95% CIs of a difference between timepoints exceeded the MCID, this demonstrated that the change was significantly greater than the MCID. Two-sided 95% CIs were used for all analyses and all significance tests were performed at the 5% alpha level.Graphical representations of the results are provided as mean . Descriptions of data in the text for individual timepoints are provided as mean (SD), with the difference between timepoints provided as mean (95% CI). Paired samples The MCID for each outcome was obtained from the research literature, as follows: D-12 score (2.83 points) , WHO-5 sAll analyses were performed using R version 4.1.2 .Complete case analysis was conducted for the 601 participants who completed the Nuffield Health COVID-19 Rehabilitation Programme and provided the relevant outcome measures at Weeks 0 and 12.All participants had been previously diagnosed with COVID-19 and were currently experiencing symptoms of LC, with a mean period of 9.8 (SD 5.0) months between COVID-19 diagnosis and commencing the rehabilitation programme. During COVID-19 infection 13.3% of participants were admitted to hospital, with a mean hospital stay duration of 10 (SD 16) days and 16.5% of these participants being admitted to an intensive care unit. On programme enrollment, participants had a mean age of 47 (SD 10) years and 2.9 (SD 1.7) comorbidities. The majority of participants were female (77.4%) and of White British ethnicity (88.6%). Participant characteristics are presented in p < 0.001). Additionally, the 95% CIs for the improvement in each of these outcomes exceeding the MCID for each measure . Significant improvements in EQ-5D VAS  and sit-to-stand test results  were also observed, with the 95% Cis of the improvements exceeding the MCID for each measure .The 12-week rehabilitation programme significantly improved D-12, DASI, WHO-5 and EQ-5D-5L utility values (p < 0.001), sick days (p = 0.003) and outpatient visits (p = 0.007) during the previous 3 months compared with baseline. The number of inpatient episodes experienced during the past 3 months did not change in response to the rehabilitation programme but was limited by the small number of episodes at baseline (p = 0.235).On completion of the rehabilitation programme, participants reported significantly fewer GP consultations (p < 0.001), and further significant improvements from Week 6 to 12  (p < 0.001) and sit-to-stand test results .A subgroup of patients with measures collected at Weeks 0, 6, and 12 demonstrated significant improvements in D-12, DASI, WHO-5 and EQ-5D-5L utility values from Week 0 to 6  . SignifiChanges in the individual components of the D-12, DASI, WHO-5 and EQ-5D-5L questionnaires are available in the Supplementary material for the primary analysis (Week 0 to 12) and time-course analysis (Week 0 to 6 to 12).This is the first evaluation of the effectiveness of a scalable community rehabilitation programme for participants presenting with LC. The outcomes demonstrate significant and clinically meaningful improvements in dyspnea, functional capacity, wellbeing and HR-QoL at programme completion. A reduced number of GP consultations, sick days and outpatient admissions were also observed during the programme compared with the preceding 3-month period. These findings suggest that the Nuffield Health COVID-19 Rehabilitation Programme can meet the urgent need for an effective and scalable LC rehabilitation model.The improvements in functional capacity in response to the rehabilitation programme were demonstrated via a mean 9.2 point (37%) improvement in DASI score and a 4.1 score (36%) improvement in the 30-s sit-to-stand test. While the precise mechanisms of LC remain largely unknown , these fConsistent with the improvements in physical symptoms, significant and clinically meaningful increases in mental wellbeing and HR-QoL were observed in response to the 12-week rehabilitation programme. Participants demonstrated a mean 20.3 point (68%) improvement in WHO-5 score as a marker of mental wellbeing, alongside marked improvements in EQ-5D-5L utility and VAS scores. The mental wellbeing benefits of exercise are well documented in various chronic diseases including cardiovascular disease, diabetes and obesity, with regular physical activity shown to improve overall mood and symptoms of anxiety and depression . These eThe improvements in physical and mental health and HR-QoL appeared to translate into reduced healthcare utilization during the rehabilitation programme. In this regard, participants reported significantly fewer GP consultations, sick days, and outpatient admissions during the 12-week rehabilitation programme compared with the 3-month period preceding the programme. This aligns with previous research in COPD patients showing reduced hospital readmission rates and medical costs during the 6 months after completion of a pulmonary rehabilitation programme, compared with patients who did not initiate rehabilitation . It is iImportantly, beneficial effects of the rehabilitation programme for physical and mental health and HR-QoL were observed after 6 weeks, with further improvements then observed at 12 weeks. This finding strengthens the theory that pulmonary rehabilitation programs for LC may benefit from a duration of 12 weeks, rather than the 6–8 week duration seen in some studies . During The present study has demonstrated the clinical effectiveness of a scalable LC rehabilitation model for improving physical, mental, and HR-QoL outcomes. This is particularly striking considering current evidence that LC does not appear to improve over time in the absence of targeted therapies . NeverthIn conclusion, this evaluation demonstrated significant and clinically meaningful improvements in dyspnea, functional capacity, mental wellbeing and HR-QoL in response to a 12-week rehabilitation programme for participants presenting with LC. A reduced number of GP consultations, sick days and outpatient admissions was also observed during the 3-month programme. The blended and community design of this rehabilitation model makes it scalable and meets the urgent need for an effective intervention to support patients experiencing LC. Improvements observed during the first 6 weeks of the programme also demonstrate the effectiveness of remote programme delivery. This rehabilitation model is well placed to support the NHS  in its aim of controlling the impacts of COVID-19 and delivering on its long-term plan.The original contributions presented in this study are included in the article/The studies involving human participants were reviewed and approved by the Manchester Metropolitan University. The patients/participants provided their written informed consent to participate in this study.AI, MH, LM, ZL, PD, GW, JK, DD, and BK contributed to the design and coordination of the intervention. KD performed the statistical analysis. JS and KD drafted the manuscript. BK accepted the full responsibility for the work and the decision to publish and attested that all authors meet authorship criteria and no others meeting the criteria have been omitted. All authors contributed to the final manuscript.


Indigenous Peoples around the globe make up approximately six percent of the global population, yet they sustainably care for around eighty percent of the world’s remaining biodiversity. Despite continued political, economic, and racial marginalization, as well as some of the worst health inequities on the planet, Indigenous Peoples have worked hard to maintain their cultures and languages against all odds. Indigenous Peoples’ close connections to land, water, and ecosystems, however, have placed them at increasing vulnerability from the effects of climate change. With this, the health risks from climate change have unique considerations within Indigenous Nations for both mitigation and adaptation responses that are largely unappreciated. This Indigenous narrative review will synthesis the current climate and health landscape of Indigenous Peoples at a global, high-level scale, including relevant international mechanisms and considerations for Indigenous Peoples’ health. This Indigenous narrative review will also explore and reflect on the strengths of Indigenous traditional knowledges as it pertains to climate change and health. To see from one eye with the strengths of Indigenous ways of knowing, and to see from the other eye with the strengths of Western ways of knowing, and to use both of these eyes together …”  recognises data as a cultural and economic asset” [c asset” .Settler-colonialism: “… is a distinct type of colonialism that functions through the replacement of Indigenous populations with an invasive settler society that, over time, develops a distinctive identity and sovereignty” [reignty” .Solastalgia: “… is the distress that is produced by environmental change impacting on people while they are directly connected to their home environment” [ronment” .Traditional ecological knowledges (TEK): “… is the on-going accumulation of knowledge, practice and belief about relationships between living beings in a specific ecosystem that is acquired by Indigenous Peoples over hundreds or thousands of years through direct contact with the environment, handed down through generations, and used for life-sustaining ways” [ng ways” . “TEK isng ways” . TEK plang ways” .Traditional knowledge systems (TKS): Are systems of knowledge, know-how, skills and practices that are developed, sustained, and passed on from generation to generation within a community, often forming part of its cultural or spiritual identity [identity .