Glioblastomas are the most common primary brain tumors in adults. They harbor a dismal prognosis and intrinsic resistance to treatment. Nonetheless, around 5% of glioblastomas present a unique genetic alteration, the FGFR3-TACC3 gene fusion, that drives tumor transformation and could represent a therapeutic opportunity. In this review, we discuss the state-of-the-art knowledge regarding glioblastomas with FGFR3-TACC3 gene fusions. We present their unique features and the methods for their identification. Targeted therapies aimed at inhibiting the protein resulting from the gene fusion have been developed with moderate clinical efficacy. An integrated effort is ongoing to improve the treatment results for these patients.FGFR3 and TACC3 genes as the main oncological driver in a subset of human glioblastomas. Since then, FGFR3-TACC3 fusions have been identified in several other solid cancers. Further studies dissected the oncogenic mechanisms of the fusion protein and its complex interplay with cancer cell metabolism. FGFR3-TACC3 fusion-driven gliomas emerged as a defined subgroup with specific clinical, histological, and molecular features. Several FGFR inhibitors were tested in FGFR3-TACC3 fusion-positive gliomas and proved some efficacy, although inferior to the results seen in other FGFR3-TACC3 fusion-driven cancers. In this review, we summarize and discuss the state-of-the-art knowledge resulting from a 10-year research effort in the field, its clinical implications for glioma patients, the potential reasons for targeted therapy failures, and the perspective of emerging treatments.In 2012, whole-transcriptome sequencing analysis led to the discovery of recurrent fusions involving the  Isocitrate dehydrogenase (IDH) wild-type (thereafter IDHwt) diffuse gliomas, of which glioblastoma (GBM) represents the most malignant and prototypical form, are the most frequent primary brain tumors in adults [fibroblast growth factor receptor 3 (FGFR3) and transforming acidic coiled-coil protein 3 (TACC3) genes [FGFR3 is a component of the FGFR family of transmembrane receptor tyrosine kinases (RTK), which are physiologically involved in the regulation of several cellular processes, including development, survival, migration, and angiogenesis [RAS/mitogen-activated protein kinase (MAPK), phosphoinositide 3-kinase (PI3K)/Akt, and Signal transducer and activator of transcription 3 (STAT3) pathways [TACC3 is a protein involved in mitotic spindle stabilization during cell division [n adults . They arn adults . Nonethe3) genes ,5. FGFR3ogenesis . In physpathways . An aberpathways , includipathways . TACC3 idivision ,10. Bothdivision .FGFR3-TACC3 (thereafter F3T3) fusions were detected from the transcriptome of cultured glioma cells obtained from nine GBM patients [TACC3 [FGFR3 was fused in-frame upstream to the coiled-coil (C-C) domain of TACC3  staining using antibodies that recognize the N-terminal portion of  protein ,27. Subs3T3 GBMs ,29,30,313T3 GBMs ). Indeed3T3 GBMs  as well 3T3 GBMs .FGFR3 IHC. Its 100% negative predictive value [A cost-effective, time-saving approach for the prospective screening of F3T3 fusions in glioma patients includes a first step with ve value  excludesve value .IDH mutant glioma cases. In an expanded cohort of more than 950 unselected gliomas, we later confirmed a prevalence of 3–4% in both histologically grade 2–3 and grade 4 IDHwt diffuse gliomas [IDH mutant gliomas so far.The first large screening for F3T3 fusions in glioma patients included 795 cases from different institutions . In thisFGFR3 TK domain fused in-frame, with variable sequences of TACC3 always retaining the C-C domain [TACC3 exons are involved in the fusion breakpoint. While a recent panglioma study (including circumscribed glioma entities such as ganglioglioma) suggests a better outcome for patients harboring the FGFR3ex17-TACC3ex10 isoform compared to FGFR3ex17-TACC3ex11 cases [The breakpoint position on the fusion protein appears to range widely ,12,27. NC domain ,5,31. ThC domain , with inC domain ; this se11 cases .FGFR3 TK and TACC3 C-C domains are always retained in the fusion protein [FGFR3 TK activity is required for oncogenicity [TACC3 C-C domain induces protein dimerization with consequent transphosphorylation of key FGFR3 tyrosine residues and constitutive activation of the FGFR TK [We have clear evidence that the F3T3 gene fusion is highly oncogenic. F3T3-transfected cells proliferate and display anchorage-independent growth ,13,34. T protein , suggest FGFR TK .FGFR3  remains controversial. In the first paper reporting the presence of F3T3, the authors did not detect increased phosphorylation of ERK and Akt proteins [MAPK/ERK and STAT3 pathways but not Akt [The activation of canonical downstream signaling pathways of  not Akt ,34,36,37 not Akt .TACC3 to the oncogenicity of F3T3. Indeed, even if TACC3 is by far the most common (>80% of cases) gene partner in FGFR3 rearrangements in cancer [TACC3 serves merely as a donor for the self-interacting domain required for the constitutive activation of FGFR3, and its higher frequency could be explained by the proximity of the two genes on the genome and the presence of microhomology [Another matter of debate is the contribution of n cancer ,39, seven cancer ,30,38,39homology ), or if TACC3 component could drive the intracellular location of the fusion protein, with F3T3 positioning at spindle poles at metaphase and relocating to the midbody in the late stages of mitosis [TACC3 protein at the mitotic spindle via the binding to the C-C domain present in the fusion protein and subsequent sequestration [TACC3 would eventually result in chromosome segregation errors and aneuploidy [In this regard, Singh et al. noticed that the stration . The impeuploidy . It is reuploidy .TACC3 being responsible for its nuclear localization [MAPK pathway activation and oncogenicity, suggesting that membrane localization and canonical FGFR3 downstream pathways are required for the oncogenic function of F3T3 [Subsequent works showed that the F3T3 protein can relocate to the nucleus, with the presence of the C-C domain of lization . This delization ,34. Thislization . Converslization . The add of F3T3 .FGFR3 transcript [FGFR2, regardless of the presence of a gene fusion partner with self-dimerization properties [FGFR2, both the loss of exon 18 and a fusion partner with self-interacting properties are required for FGFR3 oncogenicity [FGFR3 in the fusion transcript. In normal conditions, FGFR3 expression is negatively regulated by microRNA mirR-99a, which is highly expressed in the brain. F3T3 escapes miR-99a regulation via 3′-UTR loss [Another putative mechanism contributing to the oncogenicity of the fusion protein is the loss of the terminal part of the anscript ,39,42. TUTR loss . HoweverUTR loss , arguingPeptidylprolyl Cis/Trans Isomerase, NIMA-Interacting 4 (PIN4) [PIN4 results in peroxisome biogenesis and the accumulation of reactive oxygen species (ROS) [Peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α)-Estrogen-related receptor γ (ERRγ) complex, which acts as a master regulator of mitochondrial biogenesis. This rewires the metabolism of the cancer cells, eventually inducing the activation of mitochondrial metabolism and oxidative phosphorylation (OXPHOS) in F3T3 cancers [A crucial step in the downstream signaling of F3T3 appears to be the phosphorylation of 4 (PIN4) . Phosphoes (ROS) . ROS acc cancers .F3T3 GBMs display recurrent clinical, morphologic, and molecular features  that canF3T3 GBMs display Olig2 and GFAP immunopositivity, maintained ATRX expression, and low p53 positivity. Extravascular CD34 positivity is present in more than half of cases ,31, a feBielle and colleagues first reported that F3T3 GBMs present recurrent morphological features (RMF) . These iF3T3 GBMs show a male predominance and peak in the sixth and seventh decades of life ,5, similWe previously extensively explored the radiological profile of F3T3 GBMs . F3T3 GBIDH1/2 and histone H3K27M mutations [EGFR, PDGFRA, KIT, and MET [MDM2 and/or CDK4, two oncogenes located closely on chromosome 12q13.15 [MDM2 and/or CDK4 amplifications may have a better survival compared to other F3T3 GBMs [FGFR3 K650T activating mutation have been reported [pTERT mutations, CDKN2A and PTEN inactivations, chromosome 7 gain, and chromosome 10 loss, are seen with frequencies comparable to F3T3 negative cases [MGMT promoter, a marker of response to alkylating agents, is present in around 32–53% of cases [The molecular landscape of F3T3 GBMs is characterized by the absence of other truncal alterations, such as utations . F3T3 fu and MET ,12,30,3112q13.15 . Patientreported ; the reaof cases .Recently, methylation profiling has emerged as a powerful tool for the identification of novel tumor entities in neuro-oncology ,54. TumoVoltage-dependent anion-selective channel 1 (VDAC1) and NADH:ubiquinone oxidoreductase subunit S4 (NDUFS4) [A recent pathway-based analysis of a single glioma cell transcriptome identified four cellular states distributed along metabolic and neurodevelopmental axes . The met(NDUFS4) . Indeed,(NDUFS4) . This asFGFR inhibitors (FGFRi) fexagratinib (AZD4547) or erdafitinib (JNJ-42756493) inhibits the growth of glioma stem cells expressing F3T3 at low nanomolar concentrations (<10 nM) [The presence of F3T3 fusions as the main oncogenic driver in a subset of GBMs suggests a specific vulnerability of these tumors to FGFR inhibition. Indeed, the treatment with nib JNJ-456493 inhnib JNJ-456493 inhA crucial question for the effective clinical translation of any novel candidate target alteration is its frequency in the cancer cell population, thus discriminating between clonal and subclonal events . In factGiven its actionability, F3T3 is acknowledged as a target of potential interest in current EANO guidelines . On the FGFR3-TACC3 fusions (The first evidence of an antitumor effect of FGFRi in F3T3 gliomas came from two patients with recurrent F3T3 GBM who were treated with erdafitinib (previously JNJ-42756493) in a first-in-human phase I trial . Both pa fusions .The first-in-human study NCT01703481) with erdafinitib for patients with advanced solid tumors showed a stronger signal of activity in patients with FGFR1-4 gene fusions compared to patients with other alterations (gene amplifications or point mutations) . Among t3481 withThe subsequent phase II RAGNAR trial (NCT04083976) recruited patients affected by recurrent solid tumors  with FGFR1–4 mutations or fusions . Data frAn NCI-sponsored phase II trial is planned to test erdafitinib specifically in patients with recurrent or progressive gliomas with FGFR-TACC fusions (NCT05859334)Infigratinib (BGJ398) is an oral inhibitor of FGFR1-3 tyrosine kinases. It has received FDA accelerated approval for the treatment of FGFR2-rearranged cholangiocarcinoma with FGFR2 rearrangements . InfigraFexagratinib (AZD4547) is a potent oral FGFR1-3 inhibitor that demonstrated antitumor activity in preclinical models of F3T3 gliomas . It has n = 9), and F3T3 was the most common molecular alteration (n = 9). The results are available in abstract form [Pemigatinib (INCB054828) is an oral FGFR1–3 inhibitor. In the FIGHT-101 phase I/II study (NCT02393248), including refractory advanced malignancies, responses were seen in 12 (9%) of 128 patients, of whom five had cholangiocarcinoma. The following results confirming its activity in patients with cholangiocarcinoma  led to pact form ,75 and dact form .Zoligratinib (Debio-1347) is another oral ATP-competitive FGFR1-3 inhibitor; it has been tested in patients with FGFR1-3 fusion-positive advanced solid tumors in a phase I trial (NCT01948297). Among the 18 patients included in the expansion cohort, five presented with an F3T3-positive brain tumor. Disease control was obtained in 79% of patients with systemic tumors versus 0% in the brain tumor patients . PrimaryFutibatinib (TAS120) is an irreversible FGFR1-4 inhibitor predicted to be more resistant to the emergence of resistance mutations compared to other ATP-competitive inhibitors. Futibatinib was tested in a phase I basket trial NCT02052778) that included a brain tumor cohort . Among t that incIn conclusion, FGFRi displays moderate antitumor activity in patients with F3T3 gliomas, particularly when compared to the remarkable results obtained in other FGFR-rearranged cancers such as urothelial carcinoma  or cholaGiven the limited results seen in clinical trials of FGFR inhibition in F3T3 gliomas, new approaches are actively investigated to improve the management of these patients.The OXPHOS metabolism of F3T3 gliomas has emerged as a promising therapeutical target. The reliance of MTC tumors upon the OXPHOS metabolism as a source of energy  can reprThere is little emerging evidence regarding the use of MEK inhibitors (MEKi) against the FGFR-dependent MAPK pathway activation in FGFR-altered gliomas. Trametinib reduces MAPK phosphorylation and focus formation in F3T3-transfected HEK cells . The useInnovating approaches proposed for the treatment of patients with F3T3 include RNA interference  and CRISGliomas harboring F3T3 fusions emerged as a distinct niche among IDH wild-type gliomas. They present peculiar features from the molecular  to the macroscopic  levels. More importantly, F3T3 fusions can be targeted with specific FGFRi. Such inhibitors have shown, so far, a signal of activity but overall moderate results in dedicated phase I and II clinical trials dedicated to the recurrent stage of the disease. However, given the lack of effective therapies for recurrence in this population, systematic screening for F3T3 gene fusions in newly diagnosed IDHwt diffuse glioma patients is warranted, as recently recommended by EANO guidelines (ESCAT level 2). Further efforts are ongoing to optimize the effectiveness of specific TK inhibitors and/or develop alternative therapeutic approaches, such as metabolic manipulation.


Repetitive DNA sequences accounts for over 80% of maize genome. Although simple sequence repeats (SSRs) account for only 0.03% of the genome, they have been widely used in maize genetic research and breeding as highly informative codominant DNA markers. The genome-wide distribution and polymorphism of SSRs are not well studied due to the lack of high-quality genome DNA sequence data.In this study, using data from high-quality de novo-sequenced maize genomes of five representative maize inbred lines, we revealed that SSRs were more densely present in telomeric region than centromeric region, and were more abundant in genic sequences than intergenic sequences. On genic sequences, tri- and hexanucleotide motifs were more abundant in CDS sequence and some mono- and dinucleotide motifs were more abundant in UTR sequences. Median length and chromosomal density of SSRs were both narrowly range-bound, with median length of 14-18 bp and genome-wide average density of 3355.77 bp/Mbp. LTR-RTs of < 0.4 Mya had higher SSR density (4498-4992 bp/Mbp). The genome-specific and motif-specific SSR polymorphism were studied. Their potential breeding applications were discussed.We found that the median length of SSR sequences of different SSR motifs was nearly constant. SSR density in genic regions was much higher than intergenic regions. In addition, SSR density at LTR-RTs of different evolutionary ages varied in a narrow range. The SSRs and their LTR-RT carriers evolved at an equal rate. All these observations indicated that SSR length and density were under control of yet unknown evolutionary forces. The chromosome region-specific and motif-specific SSR polymorphisms we observed supported the notion that SSR polymorphism was invaluable genome resource for developing highly informative genome and gene markers in maize genetic research and molecular breeding.The online version contains supplementary material available at 10.1186/s12864-023-09156-0. Maize is one of the most important crops. Breeding new varieties more effectively for better commercial values to end users have always been the goal and primary task of maize breeders. Great effort has been made in genetic and genome research to provide molecular markers for breeding and gene discovery for trait development –3. More Simple sequence repeats (SSRs) or microsatellites, are DNA segments with a tandem repeat motif of 1–6 nucleotides . SSRs arIn the past, SSRs were considered to be non-functional and therefore subject to little selection pressure, and are evolutionarily insignificant repetitive elements . HoweverPrevious studies have shown that transposons serve as carriers for SSR expansion, and this type of expansion is still going on in the shrimp genome . StudiesSince different species may have evolved different SSR patterns , studying the SSR patterns at different species might bring different insight to genome evolution of different species , 23.In addition, SSR is widely used as a molecular marker, and SSR is highly polymorphic . Unlike Due to the lack of high-quality genomic sequence data, the distribution of SSR in the genic and intergenic region have not been systematically studied. Eighty percent of maize genome is repetitive sequence, which is a major challenge to DNA sequencing, the NGS sequencing technology is not capable to read the repetitive sequence to build complete reference genome . In receUsing high-quality de novo-sequenced maize genome data we have examined the pattern and variation of SSRs in different genome regions in five genomes of modern commercial maize inbred lines. We hope our findings would shed light on maize genome evolution, genetic research and molecular breeding.Five maize genomes were selected in this study because of their high de novo sequencing quality and their representativeness in maize heterotic group pattern and germplasm diversity Table S. The fivhttps://ngdc.cncb.ac.cn/), LT2357 was from Beijing Lantron Seed, and other genomes were downloaded from Maize GDB (https://www.maizegdb.org/).Among these genomes, the SK genome was downloaded from National Genomics Data Center (http://pgrc.ipk-gatersleben.de/misa/), was used for the identification and localization of perfect microsatellites, compound microsatellites and imperfect microsatellites which were interrupted by a certain number of bases [Microsatellite search module (MISA), a SSRs motif scanning tool written in Perl , untranslated regions (UTR), genic regions  and intergenic regions were extracted from GFF or GTF files of each maize genome. Python scripts were developed to identify SSRs and their quantity and length in the different genomic regions.− 8 per site per year [Since most retroviral genomes, or retrotransposons are flanked by LTR , in this study, we focus on retrotransposons with LTR. Full-length LTR-RTs  were identified in maize genome using software tool: LTR_Finder with the following parameters: ‘-D 20000 -d 1000 -L 7000 -l 100 -p 20 -C -M 0.9’, LTRharvest, and LTR_retriever  with defper year . To studAll repeat units of mono-, di-and trinucleotide SSR motifs and the top 10 repeat units of tetra-, penta- and hexanucleotide SSR motifs were collected. Their relative proportion and variation among five maize genomes, referred as genome-specific variation, were plotted using Tukey’s Box-plot . We showed that LTR-RTs carried a large number of SSRs and the SSR density differs in LTR-RT of different age. In the LTR-RT groups younger than 0.4 Mya Fig. , we saw  of SSRs . Our res of SSRs .SSR is a very important DNA molecular marker in plant breeding and widely used in crop molecular breeding, parentage identification, variety genuineness or authenticity identification and variety intellectual property protection , 48–51. We have found that both mononucleotide and dinucleotide SSR motifs had the largest quantity in maize genome. They also had the largest genome-specific variation in genic region Fig. B. HoweveIn this study, we analyzed the distribution and evolution of SSR in maize genome, and preliminarily discussed the relationship between LTR-RT and SSR. With the progress of sequencing assembly and bioinformatics analysis methods, the reference genomes of many plants have been released. Not only in maize, SSR and other repeats in other species are still worthy of our in-depth study. SSR is no longer the “non-functional sequence” previously thought, nor is it a field difficult to explore by bioinformatics methods. SSR is widely used in genetic analysis of maize and other species. Studying the distribution and evolution of SSR is conducive to the detailed exploration of the potential function of SSR in maize and other species in the future.Additional file 1: Table S1. De novo Sequenced Maize Genomes used in the study.Additional file 2: Figure S1. Length variation of simple sequence repeats (SSRs) in different Maize genomes.Additional file 3: Table S2. SSR Length polymorphism in six SSR motifs and five maize inbred genomes .Additional file 8: Figure S3. Distribution of the number (A) and length (B) of dinucleotide SSRs with specific repeat units in different maize genomes.Additional file 9: Script for analyzing GC content of SSR.Additional file 10: The SSR identification script in different genomic regions.


Due to the growth of sensor technology, more affordable integrated circuits, and connectivity technologies, the usage of wearable equipment and sensing devices for monitoring physical activities, whether for wellness, sports monitoring, or medical rehabilitation, has exploded. The current literature review was performed between October 2022 and February 2023 using PubMed, Web of Science, and Scopus in accordance with P.R.I.S.M.A. criteria. The screening phase resulted in the exclusion of 69 articles that did not fit the themes developed in all subchapters of the study, 41 articles that dealt exclusively with rehabilitation and orthopaedics, 28 articles whose abstracts were not visible, and 10 articles that dealt exclusively with other sensor-based devices and not medical ones; the inclusion phase resulted in the inclusion of 111 articles. Patients who utilise sensor-based devices have several advantages due to rehabilitating a missing component, which marks the accomplishment of a fundamental goal within the rehabilitation program. As technology moves faster and faster forward, the field of medical rehabilitation has to adapt to the time we live in by using technology and intelligent devices. This means changing every part of rehabilitation and finding the most valuable and helpful gadgets that can be used to regain lost functions, keep people healthy, or prevent diseases. It has been observed in recent years that remarkable progress has been made in the development of sensors. These advancements in sensor technology provide opportunities that have never been available before for the early diagnosis and prevention of human diseases by detecting critical biomarkers and health assessments via monitoring and analysing human physiological signals in healthcare and biomedical applications .The development and integration of materials science, sensing methods, wireless technologies, and the Internet of Things (I.o.T.) have considerably helped the evolution of wearable gadgets. Wearable technology has emerged as an innovative new approach to leading a healthy lifestyle. The amount of wearable technology worldwide has been on the rise, as shown by research conducted by the International Data Corporation (I.D.C.) . Over thWearable gadgets, also known as devices that can be worn on the body and monitor many activities and characteristics, are becoming more popular among the general public and are seeing increased sales and use. Wearable technology has many applications, but one of the most important ones is in medicine, namely, in biomedical research, clinical treatment, personal health practices and monitoring, technological development, and engineering. In this setting, the use of wearables for medical purposes has been linked to several promises and advantages for more digital, individualised, preventative care . The availability of consumer and medical products that use wearable sensor technology has progressively increased over the last several years. This includes a broad range of well-established consumer products. Wearable technologies can offer real-time feedback on a person’s health status. As a result, they may provide an objective alternative to manage and monitor the course of chronic diseases, such as in the case of the elderly, within rehabilitation, and for people who suffer from various impairments. Because of its hardware capability, compact size, and reduced cost compared to analogous medical tools capable of monitoring the same vital signs, wearable sensors have widespread use in healthcare . In addiThe research community and the industry are using I.o.T. applications with real-time integrated devices to improve the lives of average users. The I.o.T. is increasingly used everywhere, especially in the healthcare system. This is because the healthcare system offers clinical facilities, nursing for patients, cutting-edge searching and monitoring of medical challenges, computer-based treatment, and constant backup facilities for patients .With the evolution of body area sensing and network technologies, wearable rehabilitation technology has opened up the possibility of independent training, which has many advantages over traditional rehabilitation services. Inertial measurement units (IMUs), including accelerometers and gyroscopes, have been widely used in technology-assisted rehabilitation with sufficient effectiveness. However, despite the potential use of IMU-based sensors in neurorehabilitation and for treating musculoskeletal impairments, some such sensors have been used in clinical trials .Image-based and wearable sensor systems have been used to assess exercise and body movements, applying methods developed in human activity recognition. Image-based systems have many challenges  that may limit their suitability for home rehabilitation assessment and posture monitoring. Portable sensors with inertial measurement units (IMUs) have been widely used in various scenarios. IMUs are easy to incorporate, compatible with a variety of contexts, and present fewer privacy problems. This device seems to be a potential solution for monitoring adherence to rehabilitation protocols and posture ,10.This study aims to analyse the role and importance of using sensor-based devices in medical rehabilitation, evaluating their effects on the quality of patients’ rehabilitation, as well as the pact of using smart devices on patients and physiotherapists. Also, this study aims to evaluate the use of advanced technology in medical rehabilitation and its usefulness at the expense of classical methods and techniques used since ancient times by physiotherapists.The degree of novelty of this review consists of addressing a current issue in physical therapy, namely, the use of smart devices based on sensors on the quality of rehabilitation of various pathologies and dysfunctions of patients. Their use nowadays has become a beneficial and frequently used alternative, both due to the pandemic context we have gone through and the accelerated advancement of technology.Using the databases PubMed, Web of Science, and Scopus, the current literature review was compiled between October 2022 and February 2023 in compliance with the P.R.I.S.M.A. guidelines .EndNote X9, a reference management application, was used to construct the records recognised from the databases using the abovementioned keywords. It was also used to help delete articles that were duplicated.After that, depending on the designs of the studies, we attempted to include all articles of the following types: a systematic review, a meta-analysis, a case–control study, a cross-sectional study, a literature review, and a case report. However, we did not include expert opinions, letters to the editor, or conference reports.The data were obtained via the use of a word form. In order to develop the current literature review, we went through each article that was chosen for evaluation and extracted the material that we felt was relevant to the respective sub-chapter.We want to mention the high number of duplicate articles because many are found in two or even three databases. n = 69), because the articles dealt exclusively with rehabilitation and orthopaedics (n = 41), because only the abstracts of 28 articles were visible, and because 10 articles dealt exclusively with other sensor-based devices and not medical ones; the inclusion phase resulted in 111 articles being included in the study. The complete P.R.I.S.M.A. diagram is seen in The first search turned up 337 different titles in the databases mentioned above; the database software deleted 78 duplicate articles, and 2 more articles were brought in from external sources. After performing a relevancy check on the titles and abstracts of the remaining 259 papers, we eliminated 78 research papers. At the screening stage, studies were eliminated because of items that did not fit the themes developed in all subchapters of the study , combines a number of different factors in order to treat and prevent diseases. These factors include natural elements  and manufactured elements . The effects of their action include a reduction in pain, stimulation of restoration processes, increased range of motion, activation of immunological systems, and improved biochemical performance. When compared to other treatments, physical therapy is not only less expensive but also less intrusive and more straightforward to put into practice ,14,15.Physicians such as Hippocrates, and later Galen, are believed to have been the first physiotherapy practitioners. Around 460 BC, some practitioners advocated using massage, manual therapy methods, and hydrotherapy to treat individuals. Due to the creation of orthopaedics in the 18th century, devices such as the Gymnasticon were first designed to treat gout and other ailments of a similar kind through systematic joint exercise, similar to later developments in physiotherapy .Various factors impair a person’s physical abilities; many stem from a muscle, an accident, a surgical procedure, degenerative diseases, cardiovascular disease, and ageing . NeuroloAs a result of recent technology breakthroughs, virtual reality (V.R.) is becoming an increasingly popular tool for use in healthcare settings. These improvements present opportunities for diagnosis and therapy. V.R. is a technology that creates the appearance that the user is physically present in a simulated environment by means of the usage of a headset to mimic a reality in which the user is immersed in a simulated setting. V.R. provides users with a wide variety of options for how they may engage with a virtual environment or with virtual characters. A better feeling of realism and the ability to have meaningful interactions may be provided to the user through virtual characters, also known as avatars .The term “virtual reality” refers to a computer-generated, three-dimensional virtual environment that users are able to interact with. A user’s many senses will be engaged by the technology, which will then enable the user to interact with realistic 3D virtual surroundings. V.R. is a kind of extended reality technology that differs from augmented reality (A.R.), which is another sort of extended reality technology. Whereas AR superimposes digital data onto the actual world, V.R. blocks off the real world and allows interaction with a simulated virtual environment. Delivering simulated virtual worlds may either be achieved in a non-immersive way or in an immersive way. In non-immersive virtual reality, the virtual world is implemented by projecting it onto a big display or wall screen . On the other hand, in immersive virtual reality, a head-mounted display is often used to offer complete immersion and interaction with the virtual environment .Motion capture (Motion Capture Tech) refers to the process of documenting movement, whether of people or things. It has applications in the armed forces, the entertainment industry, sports and medicine, computer vision, and robot validation applications .Tracking the mobility of human bodies is now one of the study fields that are seeing the highest growth. The word “motion capture” (MoCap) has been defined in various ways by various researchers, each according to the particular study domain they specialise in. The process of identifying and establishing the nature of a patient’s illness or condition is known as medical diagnosis. This process, which plays an essential part in the area of healthcare, is essential. Historically, diagnosing a medical condition mainly depended on the knowledge and experience of experts working in healthcare. Nevertheless, there has been a dramatic shift in how diagnoses are made in recent years due to technological developments and the rise of artificial intelligence (A.I.) and Motion Capture Tech (MCT). A medical diagnosis based on A.I. and MCT uses machine learning algorithms to examine massive volumes of patient data, such as medical records, imaging scans, and genetic information, to aid medical practitioners in making accurate and fast diagnoses .In the last five years, for instance, mobile gaming has experienced exponential growth in every country, accompanied by the appearance of powerful processors with stunning graphics and high-speed performance. These technological advancements guarantee that each patient possesses the necessary equipment for the physical therapist to prescribe highly engaging treatment plans .In light of this, recent advancements in gaming technology and telerehabilitation are shifting the proportion of a therapist’s time spent on motor practice as opposed to behavioural intervention. This innovative form of therapy allocates most of the therapist’s time to behavioural interventions to improve arm usage. These interventions may be carried out remotely through telerehabilitation, which increases accessibility. Patients may use gaming technology designed for rehabilitation to manage their own intense motor practice at home. The games increase in complexity over time, provide quick feedback, and keep track of patients’ progress. This reversed approach to patient care was shown to be risk-free and doable, and the patients favoured it. However, in order to evaluate whether or not dedicating therapist time almost exclusively to behavioural intervention may be just as beneficial as typical rehabilitation, which predominantly employs therapist time for motor practice, a definite pragmatic randomised controlled study is still required. In addition, this self-managed, time-efficient strategy’s success must be compared with the efficacy of a complete time-intensive intervention (CI therapy), in which a therapist gives both motor practice and behavioural treatment to the patient .In this demanding era of usage, outcomes research, and cost efficiency, it is necessary to have open-ended medical practice management systems that are efficient with both time and resources and have the ability to enhance patient care. As a result, medical practice offices in developing nations are going through significant micro-processing shifts, a crucial standard for recording and conveying patient care that has emerged over the last decade.The patient management system (P.M.S.) and the electronic medical record (E.M.R.) are currently considered the most important types of medical software in emerging nations’ medical informatics. An electronic medical record (E.M.R.) is a repository of information regarding the health of a subject of care that is in a form that a computer can process, can be stored and transmitted in a secure manner. On the other hand, medical practice management software, often known as P.M.S.s, is a form of medical software used to manage the day-to-day activities in a hospital, physical therapy at home, or doctors’ clinic. This is accomplished by dealing with the day-to-day operations of a medical practice at a physician’s office .At the moment, robots for rehabilitation are driving a significant amount of research and development, and a great number of exciting new avenues are developing, both directly related to mechanical instruments and in the assistance of a rehabilitation process that is much more extensive.There is potentially a good number of benefits that may come from providing rehabilitation with the application of mechanical technology. To be more specific, it makes it possible for more rigorous and patient-specific rehabilitation operations and services . In addition, it enables all team members  to establish and administer specific work parameters in order to personalise and optimise the patient’s rehabilitation process  .Physical therapists are discussing telehealth in physical therapy more frequently, regardless of whether or not they have a well-known work system or are seeking to operationalise a new telehealth base . As an oPatients who live in distant places, such as rural populations in poor nations, who often have limited access to healthcare, may benefit from the increased availability of healthcare that is made possible via telemedicine. In addition to this, it is able to swiftly deploy large numbers of physicians, which helps with triage and supplies clinical services in situations when health institutions are unable to fulfil demand . MoreoveThe importance and especially the benefits of using sensor-based devices in medical rehabilitation is an issue entirely addressed by physiotherapists and other specialists in the field of rehabilitation; as technology advances at a significantly accelerated pace and devices are created for the rehabilitation of lost functions, the devices have become very complex and require advanced training of the specialists who will use them  31]..31].Sensor-based devices appeared relatively recently in medical rehabilitation, incorporating many techniques that physical therapists can use to achieve a series of goals established at the beginning of the rehabilitation protocol .Sensor-based devices appear in many forms and can be used in many ways, aiming to rehabilitate some lost functions . Thanks Telerehabilitation represents a topical technique that will be around for a while . With thPatients in rural areas can easily connect with specialists, parents can enjoy physical therapy sessions without dropping their kids off at daycare, and others who struggle to go out/have social anxiety can be treated from the comfort of home .In fact, in countries such as Poland and Germany, telerehabilitation is reimbursed as part of health plans for citizens .Gamified rehabilitation applications help to engage patients, which plays a crucial role in deciding the success or failure of treatment . Even thThese two phrases are more than buzzwords, and they can change the image of the healthcare industry . These mPulsed Electromagnetic Field P.E.M.F. therapy is a promising solution to reduce the adverse effects of chronic stress –which is highly prevalent today . PhysiotUsing sensor-based devices has many benefits for patients because the rehabilitation of a missing part represents the achievement of a fundamental objective within the rehabilitation program  49,50].,50.49,50Medical devices that use immersive virtual reality use neuro-motor and cognitive rehabilitation techniques for patients of any age  with neurological disease disorders such as stroke, cerebral palsy, Parkinson’s, and autism ,52. SpecSensor-based systems may generate environments on the walls or floors where the patient can engage with the delivered stimuli. The analysis equipment monitors the patient’s motion and behaviour to adjust the projected environment appropriately. These adjustments include the delivery of powerful incentives and rehabilitative audio–visual feedback via full-body immersion . The proUtilising sEMG sensors in addition to IMU sensors to monitor individuals while they exercise is one method used for remote evaluation of the characteristics of rehabilitative exercise described by some authors . The autNumerous studies  have exaBoth Yu et al.  and HaywIntegration of small sensor components into on-chip electronic systems with ultra-low power consumption has been made possible by recent technology breakthroughs for the automated detection of functional activities of daily living in patients who have had a stroke. This has led to the creation of “hybrid” wearable sensors, which integrate in a single capsule (i) motion sensing and (ii) E.M.G. detection of muscle activity. These sensors have been made possible because of the rise of hybrid computing. When evaluating and treating patients with motor impairments, hybrid sensors may be especially beneficial for detecting the quality of their movement. In point of fact, evaluating the features of the wearer’s movement and the underlying muscle activity responsible for controlling the movement allows for a more comprehensive analysis of movement dysfunction. An electromyography (E.M.G.) recording component and a motion component, such as an accelerometer or IMU, are included in modern hybrid sensors used for movement monitoring ,69,70,71Roossien et al. (2021)  devised Prasanth et al. (2021)  conducteValidated as a Class I medical device, the D.M.D.   is a kneMonitoring the human body and its dynamics supports exercise, clinical interventions, and physical therapy in terms of patient rehabilitation ,78. BasePhysiotherapists are specialists in the field of human biomechanics, and they play an essential part in the prevention, diagnosis, evaluation, treatment, and (re)habilitation of persons whose mobility and function are threatened or hindered as a result of ageing, injury, illness, conditions, or environmental factors ,83,84. PIn a multidisciplinary team, physiotherapists can work individually with patients with musculoskeletal and neurological conditions, provide fall prevention, and educate patients and caregivers about preventing and managing chronic diseases . PhysiotThe impact of using sensor-based devices on physiotherapists and specialists in rehabilitation medicine has been discussed and analysed from several perspectives over time . As wellAs a primary benefit of using sensor-based devices on physiotherapists, we mention the reduced therapy time; many recovery goals are achieved with the help of these devices, shortening both the recovery period of lost functions and the duration of a recovery session ,97. The Regarding telerehabilitation and robot-assisted rehabilitation, physiotherapists may face several issues related to the need for a team, as these devices can be coordinated and guided by a reliable specialist . This caUsing sensor-based devices in physical therapy has become increasingly popular . AlthougHowever, the availability of these sensor-based devices is quite limited because they are expensive, most of them being quite challenging to acquire or requiring advanced training of physiotherapists in their correct and effective use ,105.Although the benefits of using sensor-based devices in medical rehabilitation have been demonstrated, their use in rehabilitation and rehabilitation programs is still in its infancy, with many physiotherapy specialists opting for classical methods and techniques over advanced technology ,106.At the same time, the use of sensor-based devices also has several limitations for physical therapists . AlthougRegarding the rehabilitation of the elderly, the use of sensor-based devices may be limited by their willingness to try this type of therapy . At the The use of sensor-based devices today represents a highly beneficial alternative to the rehabilitation of lost functions, facilitating both the work of physiotherapists and maintaining the active attention of the patient during a rehabilitation session. Sensor-based devices help patients’ functional rehabilitation thanks to software specially created by specialists, but also by creating interactive activities, adopting a new approach to medical rehabilitation, and using advanced technology, which keeps patients’ attention throughout a rehabilitation session.The increasingly accelerated advancement of technology makes the field of medical rehabilitation adapt to the era in which we live, based on technology and smart devices, adapting every aspect of rehabilitation and discovering the most valuable and beneficial devices that can be used for regaining some lost functions, maintaining well-being, or preventing some pathologies.The use of sensor-based devices in medical rehabilitation is undoubtedly one of the current therapies used more and more often in rehabilitation programs and physiotherapy clinics, having numerous benefits both in the restoration of lost functions and in maintaining the active attention of patients, facilitating the work of physiotherapists.


The SPADI, DASH, and EQ5D5L scores demonstrate group×time interactions . However, no significant differences over time are observed between the groups in terms of pain, ROM, muscle strength, and handgrip strength. The outcomes show significant improvement in both groups . No adverse events are reported during the interventions. AR-based rehabilitation shows better improvement in terms of shoulder function after RCR compared to conventional rehabilitation. Therefore, as an alternative to the conventional rehabilitation, the digital healthcare system is effective for postoperative rehabilitation.A digital healthcare system based on augmented reality (AR) has promising uses for postoperative rehabilitation. We compare effectiveness of AR-based and conventional rehabilitation in patients after rotator cuff repair (RCR). This study randomly allocates 115 participants who underwent RCR to digital healthcare rehabilitation group (DR group) and conventional rehabilitation group (CR group). The DR group performs AR-based home exercises using UINCARE Home+, whereas the CR group performs brochure-based home exercises. The primary outcome is a change in the Simple Shoulder Test (SST) score between baseline and 12 weeks postoperatively. The secondary outcomes are the Disabilities of the Arm, Shoulder and Hand (DASH) score; Shoulder Pain And Disability Index (SPADI) score; EuroQoL 5-Dimension 5-Level (EQ5D5L) questionnaire score; pain; range of motion (ROM); muscle strength; and handgrip strength. The outcomes are measured at baseline, and at 6, 12, and 24 weeks postoperatively. The change in SST score between baseline and 12 weeks postoperatively is significantly greater in the DR group than in the CR group ( The predominant symptoms are pain and functional limitations in activities of daily living2. The first-line treatment for a rotator cuff tear is conservative management3; surgical rotator cuff repair (RCR) is required in cases of failed conservative management4.Rotator cuff tear is one of the most common shoulder disorders. It affects almost 30% of individuals older than 60 years, its prevalence is nearly doubles to 60% in individuals aged 80 years5. Postoperative rehabilitation is initiated with immobilization and passive movements for 4–6 weeks. Active movements and resumption of light work are recommended at 7–12 weeks. Progressive functional recovery, including the ability to perform physical activities and sports, is achieved from 13 weeks onward6. Several attempts have been made to perform postoperative rehabilitation at patients’ homes; the need for home-based postoperative rehabilitation has particularly increased over the past few years8. During the COVID-19 pandemic, telerehabilitation was urgently required to minimize the infection risk and physical contact. There was no significant difference in functional outcomes between telerehabilitation and face-to-face rehabilitation, and telerehabilitation was more cost-effective10. However, there are technical limitations to the use of telerehabilitation, particularly in terms of its implementation, the need for a stable internet connection, and ease of use11.Rehabilitation is essential for a good functional outcome after RCR12. For these reasons, AR-based rehabilitation has been evaluated for various uses, mainly including neurorehabilitation14. However, few studies have evaluated AR-based postoperative rehabilitation of the upper limb, particularly for patients with RCR.With advances in augmented reality (AR), it has been adopted for use in clinical medicine. AR combines artificial and real reality by creating images based on digital information and implementing them in real environments. AR-based rehabilitation allows real-time interaction, increasing participation by patients, and improves physical outcomesThe aim of this study was to compare the effectiveness of rehabilitation using an AR-based digital healthcare system and conventional rehabilitation for patients after RCR.n = 58) and CR (n = 57) groups. The intention-to-treat analysis included 108 participants, after excluding the 7 who withdrew consent before the intervention was initiated. During intervention, 14 and 4 participants in the DR and CR groups dropped out of the study. The Consolidated Standards of Reporting Trial flow diagram is presented in Fig. A total of 230 patients who underwent RCR were screened for eligibility. Of those, half were excluded; most of the excluded patients declined to participate, 10 did not fulfil the inclusion or exclusion criteria, 1 was unable to install device, and 5 provided other reasons. Finally, 115 participants were randomized into the DR   Table . Althoug5) Table . Additio5) Table .Table 2Pp = 0.001). Compared to the participants in the CR group, those in the DR group had greater improvements in the DASH (Δ24 weeks), SPADI , and EQ5D5L (Δ12 and 24 weeks) scores. Additionally, there were significant group × time interactions for the DASH, SPADI, and EQ5D5L scores  .The secondary outcomes are presented in Table y) Table , Fig. 3.y) Table . No groue DASH Δ2 weeks, SParticipants in the DR group answered eight questions related to their satisfaction level on a scale of 1  to 4 (Extremely). The 36 respondents reported a high level of satisfaction with the use of the digital healthcare system and services, with an average score of 3.2 out of 4. The highest-scoring items were “Did the services help you to effectively solve the problems?” and “Would you like to participate in this program again, if needed?” , self-care , and usual activities  . However, no differences were observed between groups in their pain-related subscales scores. Thus, an AR-based digital healthcare system is effective for improvement in shoulder function, such as the return to activities of daily living and improvement of the quality of life, after RCR.Our results indicate significant improvement in the self-reported functional outcome with AR-based rehabilitation compared to conventional rehabilitation. Notably, there were significant differences between the groups in terms of disability  . Additio15. PROMs are a major target for digital healthcare systems to achieve better outcomes.The DASH, SPADI, and EQ5D5L are patient-reported outcome measurements (PROMs) that evaluate patient’s perception of their own health. Based on the abovementioned results, participants in the DR group perceived themselves to be well-recovered, which was related to satisfaction with rehabilitation services and self-efficacy. The DR group participants reported high satisfaction levels with the use of the digital healthcare system in terms of real-time feedback, programs supported by experts, and rehabilitation service without transportation concerns. These findings are in line with those of a previous study that showed a high satisfaction level with a home-based strengthening and stabilization system after shoulder surgery16. Technologies used in telerehabilitation are diverse, such as videoconference19, mobile applications21, and virtual reality (VR)23. Of these, AR, derived from VR, provides a better sense of reality by blending the real environment and virtual objects. AR-based rehabilitation provides better proprioceptive feedback through interactions with the surrounding environment24. Previous studies have reported that AR-based rehabilitation was effective for maintaining balance and preventing falls in the geriatric population26 and lower and upper extremity function in stroke patients27. Similarly, the current trial showed that AR-based rehabilitation was effective for the improvement of shoulder function after RCR.Recently, there is increasing demand for telerehabilitation . The use of telerehabilitation can reduce healthcare-related costs and improve the accessibility of rehabilitation services in rural and remote areas30. On the other hand, studies evaluating the use of digital healthcare rehabilitation system after RCR were relatively rare. Comparing the effect of this study with previously reported MCID , the mean changes for SST, DASH, SPAID and EQ5D5L in this study during 12 weeks postoperatively were clinically significant in both groups . That is, the study was conducted among participants who had a relatively high functional level at baseline compared to our study sample.Digital healthcare for postoperative rehabilitation including RCR, is still emerging area and previously published studies have mainly demonstrated the feasibility after lower extremity surgery, with some studies showing superior results compared to conventional rehabilitation. are demonstrating feasibilityThe number of dropouts differed between the groups. Most dropouts occurred in the DR group at the time of 6 weeks postoperatively. Seven participants discontinued the intervention due to refusal of device installation. The main reasons were reluctance to have someone visit their home, particularly during the COVID-19 pandemic, and install a motion tracking device in their home. These reasons for withdrawal were observed in the DR group only, suggesting a need to improve the digital healthcare system in the future. Two participants in the CR group discontinued the intervention because of falls and medical reasons; the reasons were not related to our intervention. Falls occurred during routine activities, not during exercise, and the medical reasons for discontinuation  were related to the underlying disease. There were no significant adverse events in the study, suggesting that AR-based rehabilitation is clinically safe.This study had several limitations. First, the outcomes were measured postoperatively. Because the baseline assessment was performed between 1 and 14 days after surgery, there was a lack of data on the objective physical outcomes at baseline, which might have affected out study results. Second, there was difference between two groups in SPADI score at baseline despite randomly allocation. Nevertheless, the DR group showed greater improvement at each time point than the CR group, and the group×time interaction showed significant results. Third, although participants in both groups were provided instructions to perform the exercises for the same duration, the actual exercise duration differed between the group, which could have affected out study results. These differences are due to differences in the methods of counting the number of exercise days. The exercise quantity was recorded by the Internet server after the entire session was completed in the DR group, participants in the CR group recorded whether the exercises were performed and the number of repetitions in an exercise diary.In conclusion, AR-based digital healthcare rehabilitation showed better improvement than conventional rehabilitation in terms of shoulder function and quality of life after RCR. No adverse events were noted. Participants in the DR group reported high satisfaction rates. Our results suggest that AR-based rehabilitation is effective and safe compared to conventional rehabilitation.This prospective, single-center, assessor-blinded, randomized controlled trial, randomly assigned participants to digital healthcare rehabilitation group (DR group) and conventional rehabilitation group (CR group) Fig. . Both grhttp://clinicaltrials.gov/ct2/show/NCT04511377) on August 10, 2020 under the title “Rehabilitation Exercise Using Digital Healthcare System in Patients with Rotator Cuff Repair”. Written informed consent was obtained from the participants. With respect to Fig. 35.The study protocol was approved by the Institutional Review Board of Seoul National University at Bundang Hospital (SNUBH) (IRB no.: B-2005-612-001), and it was registered on ClinicalTrials.gov  between August 2020 to November 2021. The medical records of patients were searched 1-3 days postoperatively to determine whether they fulfilled the eligibility criteriaParticipants were randomly allocated at a 1:1 ratio to the DR or CR group using SAS version 9.4 program . Randomization was performed using a computer-generated sequence with a block size of four. An unblinded coordinator, who did not participate in enrollment and assessment, allocated the participants. The nature of the study did not allow blinding of participants. The assessments were performed by two experienced investigators who were blinded to the groups and the participants were instructed not to reveal their group allocation during assessments.37. Prior to discharge, the participants were educated by an experienced physical therapist and provided with a brochure that illustrated the exercises and included brief written summaries of each motion. The exercise protocol has been published previously35. Both groups performed the same type and duration of exercises. In addition, usual care, such as medication or physical therapy for pain relief, were allowed in both groups.Participants were enrolled in a 12-week rehabilitation program, consisting of three phases: on-brace phase (from immediate to 6 weeks postoperatively), off-brace phase (6-9 weeks postoperatively), and active mobilization phase (9–12 weeks postoperatively)Participants in the DR group began with brochure-based exercises in the on-brace phase. During this phase, low-intensity whole body exercise and upper extremity mobilization exercise were performed, similar to the CR group. Next, in the off-brace phase, an AR-based digital healthcare system  was installed at the participants’ homes by a technician on the research team. Technical support was also provided if a monitor or Wi-Fi was unavailable. Installation took about 10–20 min, after installation, the technician showed participants how to use the system for 20–30 min and, in turns, participants followed that. The digital healthcare system is designed with an easy and simple interface that allows participants to activate the program, click the “Today’s Session button”, and start the exercises for the day. Participants received a telephone number of the manufacturer in case of technical error or unstable connections.®, Microsoft, Redmond, WA, USA), a computer, and a display (TV or monitor) device. A three-dimensional camera sensor, a universal serial bus plug-and-play device that translates the scene geometry into depth information, tracks the movements of 25 joints of the upper and lower extremities. Before starting an exercise, participants were positioned to recognize their bodies on the screen. Each exercise was displayed on the screen as an avatar’s actual motion and written summaries. When participants performed the exercise, they were provided with real-time feedback on the screen , 6, 12, and 24 weeks postoperatively. Because the baseline assessment was performed during the on-brace phase, range of motion (ROM) and muscle strength were not measured.38. The SST consists of 12 questions, rated as “yes” (1) or “no” (0), and each question asking whether specific activity can be performed. The total score ranges from 0 (worst) to 12 (best)39. It shows high test-retest reliability (intraclass correlation coefficient > 0.90)41.The primary outcome was the change in simple shoulder test (SST) score between baseline and 12 weeks postoperatively. The SST is self-reported shoulder-specific questionnaire that measure functional limitation of shoulder, such as pain, ROM, and strengthThe secondary outcomes included the shoulder function with disabilities of arm, shoulder and hand (DASH) and shoulder pain and disability index (SPADI); quality of life with EuroQoL 5-Dimension 5-Level questionnaire (EQ5D5L); pain measured using a numeric pain rating scale (NRS); and objective functional outcomes .42. The SPADI consists of 13 questions related to pain (5 items) and disability (8 items). Each item is marked on a 10-point scale from 0  to10 (worst pain imaginable or need for help). The total score ranges from 0 to 10043. The EQ5D5L comprises five dimensions: mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. Each dimension has 5 levels: no, slight, moderate, severe, and extreme problems44. Pain intensity during activity on the affected side was measured using a NRS, rating from 0 (no pain) to 10 (worst pain imaginable)45. The active ROM on the affected side was measured within the pain-free range in four directions: shoulder forward flexion (0–180°), abduction (0–180°), external rotation (0–90°), and internal rotation (0–70°)46. Muscle strength of the affected shoulder during abduction and external rotation was assessed using a Lafayette Hand-held Dynamometer 47. Handgrip strength on the affected side was measured using a Takei Handgrip Dynamometer . Participants were asked to squeeze the dynamometer with maximal effort in a standing position with the elbow fully extended, without moving the hand and arm48.The DASH survey consists of 30 questions related to difficulty in performing physical activities (21 items), severity of pain, activity-related pain, tingling sensation, weakness, and stiffness (5 items), and problems with social activities, work, sleep, and self-image (4 items). Each item is rated on a 5-point scale. The total scores ranges from 0 (no disability) to 100 (most severe disability)49. The size of the rotator cuff tear was measured in two planes  on a sagittal T2-weighted MRI sequence. Perioperative tear size was measured intraoperatively and categorized similar to a previous study by DeOrio and Cofield50: small, ≤1 cm; medium, 1–3 cm; large, 3–5 cm; and massive, >5 cm or involving more than one tendon.The other recorded variables included acromion thickness, fatty degeneration of rotator cuff muscles , and tear size based on preoperative magnetic resonance imaging (MRI) and perioperative findings. The acromion thickness was measured on the oblique sagittal view by MRI. Fatty degeneration was graded on a scale of 0 to 4 according to the Goutallier classification system51. The mean SST score 3 months postoperatively was 6.34 (standard deviation52 = 3.7)53. The minimum sample size was calculated based on a 2.15-point difference in SST score , SD of 3.7, probability of a type 1 error of 5%, and statistical power of 80%. A minimum of 49 participants were required in each group. Assuming 15% attrition per group; a total of 115 participants were required to be enrolled.The minimal clinically important difference in SST score for patients with a rotator cuff tear was reported as 4.354. Differences in the clinical and demographic variables of the two groups were assessed using an independent t-test or chi-square test. The primary and secondary outcomes were compared between the groups using an independent t-test for each time point and changes from baseline. Additionally, a repeated measures analysis of variance was used to analyze the differences in outcomes between the groups over time. P < 0.05 was considered statistically significant. Statistical analyses were performed using IBM SPSS software .Statistical analyses were performed using an intention-to-treat approach. Missing outcome data were addressed using multiple imputationsFurther information on research design is available in the Reporting SummarySupplementary file


Lastly, we also found that the saracatinib-enzalutamide combination reduced DNA replication compared to the saracatinib-docetaxel combination, resulting in marked increased apoptosis. By elucidating this combination strategy, we provide pre-clinical data that suggests combining SRC kinase inhibitors with enzalutamide in select patients that express both AR-FL and AR-Vs.Prostate cancer (PCa) remains the most diagnosed non-skin cancer amongst the American male population. Treatment for localized prostate cancer consists of androgen deprivation therapies (ADTs), which typically inhibit androgen production and the androgen receptor (AR). Though initially effective, a subset of patients will develop resistance to ADTs and the tumors will transition to castration-resistant prostate cancer (CRPC). Second generation hormonal therapies such as abiraterone acetate and enzalutamide are typically given to men with CRPC. However, these treatments are not curative and typically prolong survival only by a few months. Several resistance mechanisms contribute to this lack of efficacy such as the emergence of AR mutations, AR amplification, lineage plasticity, AR splice variants (AR-Vs) and increased kinase signaling. Having identified SRC kinase as a key tyrosine kinase enriched in CRPC patient tumors from our previous work, we evaluated whether inhibition of SRC kinase synergizes with enzalutamide or chemotherapy in several prostate cancer cell lines expressing variable AR isoforms. We observed robust synergy between the SRC kinase inhibitor, saracatinib, and enzalutamide, in the AR-FL+/AR-V+ CRPC cell lines, LNCaP95 and 22Rv1. We also observed that saracatinib significantly decreases AR Y When primary prostate cancer is diagnosed in patients, many clinicians will either prescribe surgery, radiotherapy, and/or androgen deprivation therapy (ADT) that interfere with androgen synthesis such as leuprolide (GnRH agonist) . While pPTEN, and TMPRSS-ERG fusions , loss of  fusions –7. One k fusions . AR-Vs a fusions . Recent  fusions . Yet, th534  CRPC. We find that enzalutamide plus saracatinib was strongly synergistic in AR-full length positive (AR-FL+) cell lines, regardless of AR-V positive (AR-V+) status. Meanwhile, docetaxel plus saracatinib was not as effective, especially in cell lines expressing AR-Vs, supporting the potential failure of dasatinib in the previously mentioned clinical trial with docetaxel. We also found that saracatinib ablated AR Y22.1via Bliss Independence (BI) and the Combination Index (CI) equation via Chou-Talalay method through CompuSyn 1.1  in both 22Rv1 and LNCaP-95 cells . Cells were harvested after 48 hours and RNA sequencing was performed. We initially focused on changes in steroid receptor mRNA expression as it had been reported that the inhibition of AR can induce expression of another steroid receptor as a mechanism of resistance to AR targeted therapies, such as with the glucocorticoid receptor (NR3C1) and mineralocorticoid receptor (NR3C2) (Based on previous literature that stated phosphorylation on AR Y (NR3C2) , 30 We a (NR3C2)  and obse (NR3C2)  and Nels (NR3C2)  AR-regul (NR3C2)  more tha2.4via apoptosis and suppression of cell growth . AD1 and R1D567 cells were obtained from Dr. Scott Dehm at the University of Minnesota Medical School and cultured as described previously (4.2Cells were seeded at the following densities: DU-145 (500 cells/0.1 mL), AD1 , R1D567 , LNCaP95 , 22Rv1  in 96 well plates in RPMI media (Sigma-Aldrich) with 10% FBS, 1% penicillin-streptomycin, and 1% Glutamax (Corning). After an overnight incubation at 37°C and 5% CO2, media in the wells was replaced with fresh RPMI media with 5% charcoal-stripped (CSS)-FBS, 1% penicillin-streptomycin, and 1% Glutamax (Corning). Cells were then grown in the media for 3 days. One of the following three drug groups is then administered: enzalutamide, saracatinib, ranging from 0.39-100μM, and docetaxel 0.04-10nM. All drugs were obtained from Selleckchem. Treatment lasted for 6 days with replenishment of the media and drug after 3 days. Cell viability was measured using WST-1 at 1:10 dilution with CSS-FBS media at absorbance of 450 nm (Tecan 1100 Plate Reader). IC50 dosage was calculated using GraphPad Prism. Each data point was conducted in technical and biological triplicate.4.3via Combination Index . Measured absorbance was converted in percentile and inputted in the Bliss Independence equation  as well on Index  between 4.4For cell-cycle analysis of 22Rv1 cells, a quantitative image-based cytometry method was used as described previously . BrieflyZ-stack images were captured using a Leica DMi8 microscope (Leica Microsystems). Image segmentation of nuclei and whole cells was performed using the cellpose algorithm implemented in Python. The cyto2 and nuclei models were further trained on the images in this study to achieve high-quality segmentation. Nuclear and/or cellular masks were exported to ImageJ to measure total intensity, mean intensity, and pixel areas of defined regions within max-projected images.4.5To measure caspase 3/7 activation, Invitrogen CellEvent Caspase-3/7 green detection reagent  was used as stated in manufacturer’s protocol. 22Rv1 cells were seeded in 96 well plates at 4,000 cells/ 0.1 ml in FBS media overnight. Media in the wells was then replaced with CSS-FBS media and grown for 3 days. The following drug groups were then administered for 24 hours at IC50 dosage: DMSO Vehicle, enzalutamide, saracatinib, docetaxel, enzalutamide plus saracatinib, docetaxel plus saracatinib. After 24 hours, the caspase reagent, diluted to 4 μM was added to the cells for 1 hour. Fluorescence was observed using Spark Cyto Multimode Plate Reader. Excitation and emission settings were 488 and 590/50 nm respectively. The intensity of fluorescence was analyzed with Spark Cyto Imaging software. Each data point was conducted in biological triplicate.4.6Cells were lysed with RIPA buffer supplemented with protease inhibitor tablets and phosphatase inhibitor cocktail. Protein concentration was quantified using Pierce BCA protein assay kit following manufacturer’s protocol. 40 micrograms of protein were loaded into GenScript SurePage 4%-12% polyacrylamide gel, transferred to both nitrocellulose and PVDF membranes, blocked in 5% BSA or 5% milk in 1x TBST for one hour, before incubating the membranes with primary antibodies overnight at 4°C in 1% BSA solution. Membranes were washed with 1x TBST 3 three times before incubating the membranes in LI-COR IR-conjugated secondary antibodies  for 2 hours at room temperature. Membranes were washed three times with 1x TBST and imaged using the LI-COR Odyssey System. Membranes were adjusted and quantified with the LI-COR Image Studio Lite software (v5.2). The following antibodies were used for Western Blot Analysis: At 1:1000 Total AR (rabbit CST: #5153), Total SRC (rabbit CST: #2109), Total β-actin (mouse Santa Cruz: 4970S), ARpY534 (rabbit Invitrogen: #PA5-64643), SRCpY416 (rabbit CST: #2101), FKBP5 (rabbit CST: #8245), NKX3.1 (rabbit CST: #83700) cleaved PARP (mouse CST: #32563), total PARP (rabbit CST: #9532). At 1:500, ARpS81 (rabbit Sigma-Aldrich: #07-1375), AR-V7 (rabbit CST: #19672). Blots are results in triplicate.4.7via RNeasy Mini Kit . Messenger RNA was purified from total RNA using poly-T oligo-attached magnetic beads. After fragmentation, the first strand cDNA was synthesized using hexamer primers followed by second strand cDNA synthesis. Library sequencing was conducted on Novaseq6000 S4 flowcell for PE150 sequencing . Transcriptome sequence data processing and analysis were performed using pipelines at the Minnesota Supercomputing Institute (MSI) and University of Minnesota Informatics Institute (UMII) at the University of Minnesota. Raw reads were trimmed, aligned to the GRCh38 human genome, and gene-level read counts were generated using the CHURP pipeline  was determined using GraphPad Prism 9 with the tests indicated in the figure legends. P < 0.05 was considered to indicate a statistically significant difference. P values were determined with significance indicated as follows: *, P < 0.05; **, P < 0.01; ***, P < 0.001; and ****, P < 0.0001. Tukey’s multiple comparisons test and Kruskal-Wallis test were performed after one-way ANOVA.The data presented in the study are deposited in the Gene Expression Omnibus (GEO) repository, accession number GSE229805.RW and JD conceived the project. RW and VT designed, conducted experiments and analysed data under supervision of JD. MB performed microscopy, quantitative image-based cytometry analysis, and analysed data under the supervision of RW and HD. HB, AD and JH performed RNA sequencing analysis and provided project discussion. RW wrote the manuscript draft with support from JD. All authors provided constructive critiques in editing the manuscript. All authors contributed to the article and approved the submitted version.


Novel medical technologies are necessary to support virtual health in low bandwidth environments. When tele-mentoring is not possible, advanced clinical decision support tools can deliver essential medical knowledge to assist novice clinicians. These tools can fill knowledge gaps in specialty fields, like burn. We developed the Augmented Reality Burn Assist Manager (ARBAM), a novel, comprehensive augmented reality (AR)-based burn management platform to address key tasks in burn care.A randomized 2x2 cross-over design was used to investigate if ARBAM could enhance a user’s ability to care for a simulated burn patient as compared to standard clinical practice guidelines (CPGs). We developed the software for use on a mixed reality, head-mounted device. Participants were clinicians with little to no burn care experience, and were asked to complete 4 key tasks, twice each, using either paper copies of the Joint Trauma System’s CPGs and supplemental worksheets first (Paper) or our AR technology. Tasks included calculating burn size (TBSA), performing medication dosage calculations (MC), managing a burn fluid resuscitation (FR), and performing a simulated escharotomy (EC). All tasks were evaluated for completion time and accuracy. Cross-over analysis of treatment effects used a two-sided, two-sample t-test or Wilcoxon Rank-Sum test as appropriate.Eleven participants were randomized: 5 started with Paper and 6 started with AR. Time to perform FR was statistically different (p< 0.05) with AR taking less time than Paper . FR clinical performance was also better in the AR group with a mean accuracy score of 99% vs. 52% for Paper (p< 0.001). EC completion times were not clinically or statistically different. However, EC accuracy was 93% for AR compared to 55% for Paper (p< 0.001). Although not statistically different, MC performance accuracy was considerably better for AR (91%) than for Paper (66%). No differences between groups were observed for TBSA or MC completion times nor TBSA accuracy.Compared to traditional tools, AR may enhance a clinician's ability to complete key tasks in the initial management of a burn patient. This technology may be helpful during disasters when tele-mentoring is not available. Limitations of this study include a small sample size, limited user training on the AR device, and potential carry-over effects. Therefore, generalizations cannot be made about wide-scale usage. Nonetheless, this study showed that AR may be helpful in managing lifesaving burn tasks.ARBAM may enhance decision making by novice clinicians when caring for burn patients. Our data demonstrate the potential for AR-based support tools to improve burn care delivery and reduce error rates for novice clinicians, which could lead to reductions in morbidity and mortality. Future research is needed to investigate how AR technology can be used for other lifesaving interventions.