In the dynamic realm of spinal surgery, the integration of virtual reality (VR) and augmented reality (AR) technologies is heralding a transformative era. These cutting-edge tools are not only reshaping the training landscape for surgical trainees, offering immersive and interactive experiences but are also enhancing the surgical precision of seasoned professionals in the operating room. While the potential of VR and AR is vast, their adoption is tempered by significant costs and challenges in seamless integration. As the spinal surgery community looks ahead, it becomes imperative to emphasize the validation, reliability, and thorough cost-benefit analysis of these technologies. This article delves into the current applications, benefits, challenges, and future trajectories of VR and AR in spinal surgery, underscoring their pivotal role in the evolution of immersive healthcare. IntroductionSpinal surgery represents a unique convergence of precision, coordination, and extensive anatomical knowledge. The steep learning curve and the high stakes of error are well-known challenges in this field. . Yet, thVR has the potential to create highly accurate, immersive simulations, thereby crafting a realistic training environment for surgical residents outside of the operating room. These technologies offer unique advantages to surgical training, such as the ability to review quantified performance measures using sophisticated analytics and algorithms. Additionally, VR technology immerses the trainees in the surgical process via head-mounted displays and handheld devices with haptic feedback, enhancing the realism of the experience. By rehearsing surgical procedures in the simulation environment, trainees have the opportunity to introduce and develop surgical skills in a flexible setting.In other orthopedic surgery subspecialties, VR technology's value is already well-established, particularly in arthroscopy training. Compared to traditional training methods, VR provides distinctive advantages like three-dimensional anatomy visualization, simulation of inter-operative complications, and performance recording and analysis. A myriad of studies corroborates the effectiveness of VR in enhancing surgical performance and outcomes.Current developmentsVR and AR in Spinal Surgery: From Simulation to OperationThough similar to VR and AR, navigation technologies have been effectively used in spinal procedures, notably pedicle screw placements. Current intraoperative navigation platforms  utilize monitors to provide visual feedback coupled with CT data. AR goes a step further by superimposing a layer of digital information onto the real world, essentially blending the virtual and the physical. There are several emerging products that have begun the transition into AR (such as the Xvision system by Augmedics), integrating headset-mounted visual feedback. This allows for a visual overlay directly onto the patient. AR holds the potential to employ holographic imaging to guide surgeons, though no commercially available products are currently available.With improved visual cues offered by VR and AR, the surgeon gains provide an additional layer of information when encountering difficult anatomy that could make the difference between a successful surgery and a problematic one -5. DespiWith VR, surgeons are afforded an immersive, interactive environment that supplements the baseline surgical visualization. One of the key advantages of VR is that it can provide visual cues and feedback to the surgeon in real-time during the procedure, increasing surgical precision . StudiesBeyond Pedicle Screws: The Broadening Scope of VR and AR in Spinal SurgeryThe applications of VR and AR technologies in spinal surgery extend beyond pedicle screw placements. These cutting-edge tools are finding use in a variety of spinal procedures, from decompression to tumor resection to deformity correction surgeries. AR can provide surgeons with real-time, 3D visualizations of the patient's spinal anatomy during spinal decompression surgeries, allowing for more accurate identification and resection of compressive pathology. Similarly, in tumor resection procedures, VR and AR can help visualize the tumor's exact location and its relationship with surrounding structures, enabling a more targeted and safer surgical approach. As more patients request less-invasive and minimally invasive treatment options, AR and VR-assisted approaches in the field of endoscopic spine surgery may help reduce the learning curve to this newly emerging procedure.In spinal deformity correction surgeries, these technologies can aid in preoperative planning by providing 3D visualizations of the patient's spinal alignment and providing more detailed and reliable osteotomy landmarks. The AR overlay can help surgeons visualize the final alignment before making any surgical cuts, leading to more accurate and reproducible surgical execution. Studies have shown that the use of VR and AR in these procedures can lead to better patient outcomes, with fewer complications and revisions -5.Integration of VR and AR into surgical practice: opportunities and challengesThe integration of VR and AR technologies into everyday surgical practice presents unique opportunities and challenges. On the one hand, these technologies have shown significant potential in improving surgical outcomes by increasing precision, reducing complications, and enhancing patient safety . On the One of the primary obstacles to wider adoption is the high cost associated with these technologies. The adoption of VR and AR technologies often requires a substantial initial investment, primarily due to the cost of hardware, software, and maintenance ,7. This The integration of VR into residency training programs has seen a mix of enthusiasm and hesitation . In a suThe global disparity in access to advanced medical technologies is a well-documented challenge ,11. WhilConclusion: future developments and directionsDespite these challenges, as these technologies continue to evolve and become more streamlined, it's expected that their use in spinal surgery will become more widespread. With improved accessibility and reduced costs, VR and AR technologies have the potential to become integral and indispensable tools in spinal surgical practice, helping surgeons navigate the complex anatomical landscape of the spine with increased confidence and precision. As we venture further into the 21st century, the influence of VR and AR in spinal surgery is set to grow. We expect that as more data becomes available that supports the benefits of VR and AR in enhancing surgical outcomes, their use in spinal surgery is expected to increase. Careful assessment and consideration are needed to ensure the potential of this technology is harnessed without compromising the rigorous standards of surgical practice. As technology is refined and the implication of its utilization is better understood, it becomes clear that the future of spinal surgery may well be alongside the virtual.


Since prostate cancer (PCa) was described as androgen-dependent, the androgen receptor (AR) has become the mainstay of its systemic treatment: androgen deprivation therapy (ADT). Although, through recent years, more potent drugs have been incorporated, this chronic AR signaling inhibition inevitably led the tumor to an incurable phase of castration resistance. However, in the castration-resistant status, PCa cells remain highly dependent on the AR signaling axis, and proof of it is that many men with castration-resistant prostate cancer (CRPC) still respond to newer-generation AR signaling inhibitors (ARSis). Nevertheless, this response is limited in time, and soon, the tumor develops adaptive mechanisms that make it again nonresponsive to these treatments. For this reason, researchers are focused on searching for new alternatives to control these nonresponsive tumors, such as: (1) drugs with a different mechanism of action, (2) combination therapies to boost synergies, and (3) agents or strategies to resensitize tumors to previously addressed targets. Taking advantage of the wide variety of mechanisms that promote persistent or reactivated AR signaling in CRPC, many drugs explore this last interesting behavior. In this article, we will review those strategies and drugs that are able to resensitize cancer cells to previously used treatments through the use of “hinge” treatments with the objective of obtaining an oncological benefit. Some examples are: bipolar androgen therapy (BAT) and drugs such as indomethacin, niclosamide, lapatinib, panobinostat, clomipramine, metformin, and antisense oligonucleotides. All of them have shown, in addition to an inhibitory effect on PCa, the rewarding ability to overcome acquired resistance to antiandrogenic agents in CRPC, resensitizing the tumor cells to previously used ARSis. Prostate cancer (PCa) is the most common tumor diagnosed in men in the Western World, the third leading cause of cancer death in Europe, and the second in the United States ,2. Most Castration-resistant prostate cancer (CRPC) had been considered “androgen-independent” or “hormone-refractory” in the past, but today, we know that acquiring castration-resistant status does not mean tumor cells are nonresponsive to hormone inhibition. In fact, CRPC remains highly dependent on the AR signaling axis, so it is recommended to maintain ADT indefinitely as the mainstay of treatment ,7. FurthThe exact mechanisms underlying the transition from androgen-dependent PCa to CRPC are yet to be fully understood. AR reactivation in CRPC occurs despite the androgen deprivation induced by ADT, and although the main mechanism triggering CRPC is through the AR signaling pathway, AR-independent pathways have also been detected ,9. SeverSince the beginning of this century, many drugs with different mechanisms of action have been approved and managed to prolong advanced PCa patient survival. Clinical options include: (1) cytostatic agents ; (2) newer-generation androgen receptor signaling inhibitors (ARSis) such as the AR antagonists enzalutamide, darolutamide, and apalutamide, or the androgen biosynthesis inhibitor abiraterone acetate; (3) bone-targeted therapies (Radium 223); 4) immunotherapy (sipuleucel-T); (5) radioisotopes (lutetium-177–PSMA-617) and (6) poly ADP-ribose polymerase (PARP) inhibitors (olaparib and rucaparib) . Incorpo immunoth-Finding new drugs with different mechanisms of action from those previously used;-Using combination therapies to boost synergies, enhancing the action of each drug;-Research treatments that can resensitize tumor cells to previously used mechanisms of action.Therapeutic resistance not only occurs in prostate cancer, but it is a constant challenge in oncology. Castration resistance results from adaptive pathways created by PCa cells to elude current therapies. By identifying these pathways and inhibiting them, researchers could overcome treatment resistance and significantly improve patient survival and quality of life. Research on advanced PCa specifically focuses on the following:In this sense, it may be possible to resensitize tumor cells to antiandrogens, maintaining or restoring the dependence of the AR signaling axis. This re-expression of AR in AR-negative cells could revitalize the activity of AR inhibitors.This rechallenge is a well-known strategy in oncology. It consists of using again an oncological line that was considered exhausted on initially suitable responder patients. In this article, we will review all those strategies and drugs that have been demonstrated to be able to resensitize CRPC cells to previously used antiandrogens. The one with the strongest scientific evidence is bipolar androgen therapy (BAT).BAT is a concept that was born years ago but is now being established as an emerging treatment strategy for patients with metastatic CRPC (mCRPC). This method involves cycling serum testosterone from supraphysiologic down to near-castrate levels every month . AlthougA recently published systematic review focuses on the efficacy and safety of BAT in mCRPC after abiraterone or enzalutamide . HoweverThese other compounds have demonstrated their activity against CRPC cells in vitro and in vivo. Though, in some cases, this effect has yet to be shown in patients on monotherapy, and in other cases, the agent results in unacceptable toxicity. However, all these molecules show a promising alternative pathway that would involve sensitizing to prior antiandrogen treatments or reversing intrinsic or acquired resistance to second-generation antiandrogens . This isThis article aims to review the mechanisms that allow cancer cells to switch from an AR-positive to an AR-negative disease, focusing on potential strategies to overcome these mechanisms and successfully resensitize these CRPC cells to antiandrogen therapy. BAT has proved to be the most effective of all antiandrogen resensitization mechanisms. Therefore, we will review the most recent literature on BAT and will provide interesting data on other agents, such as niclosamide, indomethacine, metformine, lapatinib, panobinostat, and ipatasertib.To the best of our knowledge, this is the first article to extensively review this interesting antiandrogen resensitization or rechallenge strategy.In January 2023, a comprehensive database search was performed based on PICO  criteria ,18. StudThe population consisted of castration-resistant prostate cancer cells (P). Treatment of interest was androgen deprivation therapy (I). We considered eligible single or multiple arms studies, so no comparator was mandatory (C). Main outcomes of interest were the mechanism of castration resistance and strategies to resensitize cells to antiandrogen therapies (O).Studies identification: 42 articles using the terms “resensitizing to antiandrogen” AND “prostate cancer” were found. Out of them, 6 were reviews and systematic reviews, while 36 were original articles. The consistency of this revision is affected by the inherent lack of robust evidence in urology.Screening: No articles were duplicated, so 42 articles were screened by title and abstract. Out of them, 24 full-text articles were assessed for eligibility.Eligibility: The selection criteria were (a) reviews, original articles, and preclinical studies, (b) studies about castration resistance mechanisms and strategies to resensitize cells to androgen deprivation therapy. Exclusion criteria were (a) non-English/Spanish literature, (b) editorials, comments, and letters, and (c) studies published before 2012, as they were not updated enough for our purpose.Study analysis: After applying the above eligibility criteria, 19 studies about castration resistance mechanism and strategies to resensitize cells to androgen deprivation therapy were selected. In total, 16 articles with the highest level of relevance to the discussed topics were selected with the consensus of the authors. A review from the selected studies was conducted.AR is a protein encoded by the AR gene, which is located on the X chromosome at Xq11-12. It has several functional domains: (1) NTD ; (2) DBD ; (3) the hinge region ; and (4) LBD  ,19.AR is a ligand-dependent transcription factor whose main function is to respond to androgenic steroid hormones, such as testosterone and DHT. After binding them, it causes a conformational change in AR that originates a nuclear translocation and induction of androgen-responsive gene expression, which allows the development of prostate cells .Like normal prostate cells, PCa cells require androgens for continued growth. ADT reduces testosterone levels by 90–95% and is initially effective in PCa patients by suppressing gonadal testosterone production. Nevertheless, intraprostatic levels of DHT decline by only about 50%.Stimulation of intraprostatic DHT and other androgens, such as those from the adrenal gland, can be blocked by adding a first- or second-generation antiandrogen drug.In the absence of one of these androgenic ligands, testosterone or DHT, AR is sequestered in the cytoplasm where it is inactive, but in a conformation with a high ligand-binding affinity.Inhibition of the AR induces both cell cycle arrest and apoptosis of PCa cells .Following androgen binding to the LBD of the AR, the receptor leaves the cytoplasm and translocates to the nucleus, where it dimerizes with a second AR to regulate the transcription of androgen-dependent target genes. Transcriptional regulation of these target genes through persistent RA signaling contributes to PCa proliferation and survival.CRPC is defined as cancer that progresses despite effective suppression of testosterone below castrate levels (≤50 ng/dL) and encompasses a broad spectrum, from an asymptomatic localized disease where the only sign of progression is an elevated prostate-specific antigen (PSA) to rapidly progressive metastatic disease that leads to death.The term “castration resistant” is justified by the intracrine production of androgens, which is at least partially responsible for ADT resistance .The reduction in circulating testosterone levels caused by ADT causes the AR to remain inactive and, thus, no longer activates androgen-dependent target genes that drive the PCa viability and proliferation.However, AR reactivation, despite effective suppression of testosterone below castrate levels, leads to a CRPC phenotype in all patients with PCa treated with ADT, with or without antiandrogens. Other mechanisms independent of AR also drive CRPC ,23.One mechanism of AR reactivation in CRPC is increasing AR expression through genomic amplification of the AR locus or upregulation of AR protein levels. In both cases, increased AR expression can sensitize PCa cells to low levels of androgens .This overexpression of the AR mRNA is the most frequent alteration in CRPC (up to 81% of cases) ,26.Studies have shown a range of AR mutations in androgen-dependent tumors from 2% to 25%, while the incidence in CRPC tumors is around 10–40% .These AR mutations may confer hypersensitivity to androgens, broaden ligand specificity , or leadThe most frequent AR mutation is T878A, which correlates with decreased specificity of the AR ligand, allowing the receptor to be activated by other molecules, such as estrogens and glucocorticoids .This mutation occurs more frequently in response to drugs targeting androgen synthesis, such as abiraterone , and thiWhen there is testicular testosterone deficiency due to ADT, PCa cells themselves are capable of transforming adrenal cholesterol and androgen precursors into testosterone to activate AR signaling.These cells have been shown to contain all the essential components to carry out androgen biosynthesis, and an elevation of many of the key enzymes to carry out this synthesis in recurrent or metastatic tumors has been objectified .AR splice variants (AR-Vs) are caused by alternative gene splicing or rearrangement of the AR gene, which results in AR LBD loss ,34.Approximately 20–40% of patients present with primary resistance to second-generation antiandrogens, such as enzalutamide and abiraterone , and eveExpression of these AR variants is strongly associated with resistance to both abiraterone and enzalutamide, the most widely studied of these variants, AR-V7, being particularly important, and is associated with worse results in these patients ,39.In the absence of androgens or when androgens are present at low levels, numerous growth factors, cytokines, and hormones may activate AR . Some ofFor example, cyclin D1b, an isoform that does not possess an AR inhibitory function, is elevated in clinical PCa specimens .Similarly, the retinoblastoma (Rb) tumor suppressor gene induces an increase in AR mRNA and protein levels, which promotes castrate-resistant progression in PCa cells .The aberrant activation of PI3K-Akt may induce PCa proliferation since the PI3K-Akt-mTOR pathways regulate important cellular processes, such as cell growth and programmed cell death . Loss ofWhen AR interacts with PI3K subunits, the Akt pathway is activated, and therefore the cell proliferation .In fact, it has been demonstrated that synergistic targeting of the PI3K/Akt pathway and the androgen receptor axis delays CRPC progression ,50.It has been described that alternative signaling pathways allow the proliferation of CRPC bypassing AR. These AR bypass pathways remain active even in the absence of AR expression .When AR signaling is blocked by antiandrogens, those clones that can bypass the AR are selected. An example is the glucocorticoid receptor (GR), which has a DNA-binding domain similar to that of the AR.The GR may be able to bind to androgen response elements (AREs) and drive PCa cell survival under certain circumstances ; for exaAccording to the cancer stem cell or tumor-initiating cells (TICs) theory, only a population of tumor cells that possess stem cell properties can trigger tumor initiation ,54.Cancer stem cells are resistant to most therapies and are capable of developing a tumor with increased metastatic capacity .Several populations of PCa stem-like cells (PCSCs) have been described, such as CD44+/α2β1+/CD133+, TRA-1-60/CD151/CD166, ALDH, and PSA-/lo, for example. It appears that PCSCs are AR-negative or express very low levels of AR, and, therefore, tumors consisting of these cells would have a poor response to antiandrogens and other AR-targeted therapies ,57.The mechanism that would explain the relationship between PCSC and CRPC would involve the expansion of a residual AR-negative/low stem-like cell population remaining after androgen deprivation and potentially repopulating tumors with castrate-resistant tumor cells .Neuroendocrine prostate cancer (NEPC) is the most common type of AR-negative tumor . NeuroenNEPC can be classified as de novo or treatment-related. De novo NEPC is rare, typically less than 2% of all primary PCa, and very aggressive . More frInterestingly, it has been shown that the neuroendocrine subtype is not entirely foreign to AR-positive cells and partly originates from AR-positive conventional adenocarcinoma through a transdifferentiation process.Zou et al. have demonstrated that nearly all tumors with neuroendocrine markers have a luminal-epithelial origin . MoreoveBluemn et al., detected a subtype of PCa associated with ARSis treatment, whose incidence has increased from 5% to 20% in recent years, and that are negative for AR and neuroendocrine markers . In addiSince the AR pathway is an essential therapeutic key in PCa, many researchers have focused on finding ways to restore AR signaling in AR-negative PCa. It would be interesting to find out the functional consequences of AR re-expression and if AR reactivation will suppress the oncogenic potential of AR-negative PCa cells revitalizing the activity of AR inhibitors.Of all the compounds and strategies currently under study to resensitize CRPC cells to antiandrogens, BAT accumulates the most scientific evidence and promising results.BAT is based on the observation that the growth of some AR-expressing “androgen sensitive” human PCa cells can be inhibited by supraphysiologic levels of testosterone followed by a rapid drop of testosterone to castrate levels.This “bipolar androgen therapy” will not allow time for PCa cells to adapt their AR expression in response to environmental conditions .Different mechanisms have been proposed to explain this, including the induction of genomic instability through DNA double-strand breaks (DSBs) and the stabilization of the link between DNA and the AR, which prevents AR degradation and DNA relicensing during the cell cycle. Other postulated mechanisms are the modulation of oncogene expression, the inhibition of AR-V7 expression, and the reversal of transition to the neuroendocrine phenotype Among the proposed mechanisms, one of the most important is that high-dose testosterone can induce double-strand DNA damage .Supraphysiological concentrations of DHT induce DNA breaks and result in the activation of DNA damage response pathways, and these androgen-induced DSBs are independent of androgen-induced cell cycle progression .When PCa cells are acutely exposed to supraphysiologic androgen levels, AR is saturated. This induces a paradoxical cancer cell death via over-stabilizing AR, preventing full relicensing in the next cell cycle .Different proposed mechanisms of action are: the repression of SKP2 and MYC  and the Probably, there may be no single mechanism that explains the effectiveness of BAT, and several mechanisms of action coexist.BAT involves giving sequential cycles alternating periods of acute supraphysiologic androgen followed by acute ablation.The BAT concept uses the adaptive increase in AR that occurs in the CRPC cell after ADT to make it vulnerable to high androgen levels exposure , and after that lowers back the testosterone to castration levels.In this way, it is possible to damage two types of CRPC cells: those with very high levels of AR, which will be sensitive to supraphysiological levels of testosterone, and those with very low levels of AR, which will be sensitive to very low levels of testosterone. See The first studies on the concept of BAT emerged in the 1990s when it was observed that supraphysiological androgen levels could paradoxically suppress the growth of some PCa cell lines and xenograft models ,72,73.After that, some studies showed that it was an effective and safe treatment in patients with metastatic PCa and CRPC ,75.Subsequently, it was described that BAT could also resensitize to antiandrogen therapy .As pioneers of this treatment, Denmeade et al. conducted a pilot study on 16 asymptomatic CRPC patients. They demonstrated the safety and efficacy of BAT in combination with etoposide, achieving objective responses defined as PSA decreases ≥50% vs. baseline and Response Evaluation Criteria in Solid Tumors (RECIST).Two very interesting ideas can also be extracted from this study. The first one comes from the post hoc exploratory analysis of the effect of BAT on subsequent hormonal therapies. This analysis revealed that 12 of 13 patients who had received at least one antiandrogen prior to BAT treatment experienced a PSA response when retreated with AR-directed therapy after BAT. The other idea is that BAT can improve the quality of life of patients undergoing treatment .The following paper published by this group included a larger number of patients and focused on the ability of BAT to resensitize to antiandrogen therapy.RESTORE (REsensitizing With Supraphysiologic Testosterone to Overcome Resistance) was a phase II study designed to evaluate the activity of BAT in asymptomatic mCRPC patients progressing on AR-targeted therapy.The most exciting conclusions of this study came from its multicohort design. It evaluated the responses to abiraterone or enzalutamide upon rechallenge after BAT.The trial enrolled four cohorts of patients: Cohort A: 30 men with mCRPC who had progressed on enzalutamide, Cohort B: 30 men who progressed on abiraterone acetate, Cohort C: 30 on first-line castration-only therapy, and Cohort D: 20 mCRPC men with inactivating somatic or germline gene mutations.The coprimary endpoints were number of participants with PSA drop ≥50% from preBAT level, and after enzalutamide or abiraterone acetate post-BAT from baseline .p = 0.001).The authors did not find statistically significant difference in PSA50 response to BAT between both cohorts, although one of the most interesting results of the study was that PSA50 responses to ARSi rechallenges were higher in the post-enzalutamide cohort . Moreover, AR-V7-positive patients got worse outcomes with this strategy.The other interesting finding was that the time to progression following rechallenge was more than four months longer in the post-enzalutamide vs. post-abiraterone cohort  trial was to compare BAT vs. enzalutamide in asymptomatic CRPC men after progression on abiraterone. The impact of sequential exposure to AR agonists or antagonists was also assessed since crossover to the opposite treatment upon progression was allowed.Regarding primary endpoint, clinical or radiographic progression-free survival (PFS), BAT was not superior to enzalutamide.Nevertheless, the interesting finding was that the most significant benefit from BAT was seen in patients experiencing progression on prior abiraterone.Approximately 40% of patients crossed over to the opposite treatment at progression.Those who crossed to enzalutamide post-BAT experienced a significantly greater response compared to those who did not use BAT as a bridging therapy. Median time to PSA progression was 10.9 months in the first group vs. 3.8, PSA50 response was 78% vs. 25%, and objective response (OR) improved to 29% in the post-BAT cohort vs. 4%.Although the trial failed to demonstrate superior PFS with BAT over enzalutamide in post-abiraterone CRPC, the most important finding from our point of view is that post-abiraterone, BAT can significantly improve the magnitude and duration of response to enzalutamide ; see FigOther authors have also proven through multicenter studies with real-world evidence that BAT may play a role in CRPC resensitization after multiple treatment lines .Although the core of this revision is to further examine the ability of BAT to resensitize mCPRC to antiandrogen therapy aiming to improve the efficacy and duration of response to BAT, ongoing studies are evaluating the combined treatments of BAT with other treatments, such as the DNA-repair inhibitor olaparib (NCT03516812), the bone-targeted radiation therapy radium 223 (NCT04704505), and carboplatin (NCT03522064).Interestingly, BAT has also been shown to have a role in the sensitization of PCa cells to ionizing radiation (IR). It has been demonstrated that high doses of androgens have a synergetic effect when combined with ADT and radiotherapy, causing DNA damage and inhibiting PCa cells growth ,83.Other lines of research dive into the hypothesis that treatments that induce DNA double-strand breaks, such as BAT, may modify the immune microenvironment, improving subsequent immunotherapy outcomes .AR has been shown to be expressed in some types of immune cells , and ADTLikewise, it has been shown that natural killer (NK) cells target androgen-dependent PCa stem-like cells .All these findings strengthen the hypothesis that supraphysiological doses of androgens can affect the immune response. In fact, in vitro and in vivo studies in animals suggest that the combination of BAT with PD-1/PD-L1 checkpoint inhibitors can inhibit the growth of CRPC cells .The COMBAT study was carried out to demonstrate this hypothesis. This is a phase 2 clinical trial designed to evaluate the clinical activity of BAT in mCRPC patients progressing on ARSis, followed by a combination treatment of BAT and the anti-PD1 nivolumab.The combination met the pre-specified primary endpoint of confirmed PSA50 response, which was 40.0%, and the objective response rate (ORR) for patients with measurable disease was 23.8%.BAT plus nivolumab was well tolerated, considering it was a heavily treated population, and durable responses were observed in a subset of patients .Unfortunately, not all patients respond to BAT, and the degree and durability of the response are unpredictable. However, some men are exceptional responders. For this reason, like in other treatments, it is essential to identify prognostic and predictive biomarkers .Moreover, it has been suggested that resistance to this treatment is mediated by changes in AR levels and activity .Although there most likely are multiple molecular mechanisms responsible for the clinical response to BAT, one the researchers have studied recently is that BAT suppresses the oncogene MYC in responding patients .Sena et al. showed that growth inhibition of prostate cancer models during BAT requires high AR activity, which is partly driven by the downregulation of MYC, a potent driver of growth and proliferation highly expressed in PCa .The authors demonstrated that high pretreatment AR activity predicts a better clinical response and prolongs progression-free and overall survival for patients on BAT through the downregulation of MYC expression .MW score.In addition, they used samples from combat clinical trial  patientsMW scores than non-responders (p = 0.011), leading to the conclusion that ARAMW is a potential biomarker that may stratify BAT responders from non-responders [Notably, responders had significantly higher preBAT ARAsponders ,95,96,97BAT is well tolerated. Most adverse events (AEs) are low grade and well tolerated . Grade 3 to 4 AEs rarely described are hypertension, pulmonary embolism, and back pain .Targeting AR variant expression is one way to achieve restoring sensitivity to antiandrogens .Niclosamide, an anti-helminthic drug, has demonstrated preclinical efficacy in reducing AR-V7 expression in enzalutamide-resistant cells ,100.Liu et al. established that niclosamide could induce AR-V7 protein degradation and reduce AR-V7 recruitment to promoter regions of target genes, resulting in reduced transcriptional activity and thus resensitizing resistant cells to enzalutamide and abiraterone treatment.The combination of niclosamide and either enzalutamide or abiraterone produced maximal tumor inhibition in a xenograft model.After that, they demonstrated that a combination of niclosamide and bicalutamide overcomes treatment resistance to enzalutamide in vitro .Based on these preclinical data, a phase I/II study established the safety of abiraterone in combination with niclosamide in CRPC patients .However, these findings differ from the study phase I, which evaluated the combination of enzalutamide and niclosamide in patients with mCRPC finding high toxicity .Another mechanism by which niclosamide could reverse resistance to enzalutamide is through the downregulation of the androgen receptor-STAT3 signaling axis .MAOAIs have been shown to inhibit the growth and development of PCa metastasis due to high concentrations of MAOA in the prostate. MAOAI combined with enzalutamide synergizes and sensitizes cells to enzalutamide treatment .Inhibitors of gamma-secretase, which regulates cleavage of cell surface receptors, including Notch receptors, have been demonstrated to inhibit PCa cell growth in vitro in combination with enzalutamide or abiraterone and are also capable of resensitizing enzalutamide-resistant cells and xenografts to enzalutamide treatment .Indomethacin, a nonsteroidal anti-inflammatory drug, acts as an inhibitor of AKR1C3 enzymatic activity and, when elevated, is linked to enhanced PCa progression, aggressiveness, and resistance to antiandrogens and radiation therapy , and it Based on these preclinical studies, a single-arm phase II trial showed the efficacy and tolerability of the indomethacin and enzalutamide combination to treat CRPC .Abiraterone-resistant xenograft models have increased ErbB2 activity. It has been demonstrated that lapatinib blocks ErbB2 and, in combination with abiraterone, can enhance treatment response .Furthermore, it has also been established that lapatinib can enhance enzalutamide response by inhibiting the HER2 signaling axis .Histone deacetylases (HDACs) are required for AR mRNA transcription and protein stability and transcriptional activation of AR target genes. HDAC inhibitors (HDACIs) are promising anticancer drugs targeting epigenetic modes .Panobinostat, an HDACI, has been proven to reduce AR mRNA levels, including ARV7, as well as cell proliferation in vitro and tumor growth in vivo in all CRPC model systems .Unfortunately, these promising preclinical observations have yet to translate into beneficial clinical activity of HDACI monotherapy in CRPC, maybe because low concentrations were used due to its toxicity.However, researchers found an alternative use for panobinostat when they discovered its ability to overcome the prevalent acquired resistance to antiandrogenic agents in CRPC.They demonstrated a synergetic inhibition of PCa cell growth between panobinostat and bicalutamide in culture cells resistant to bicalutamide , and whaThese promising results of panobinostat in combination with bicalutamide encourage authors to design new trials in combination with more powerful antiandrogen enzalutamide, which also works by binding to the AR LBD and develops resistance linked to AR overexpression and ARV7.As explained before, AR-V7 expression after enzalutamide or abiraterone therapy correlates with a high percentage of resistance to treatment and worse response . TherefoEPI-001 is a bisphenol A-derived antagonist that binds the AR N-terminal domain to block the transcriptional activity of AR and several AR-Vs, including AR-V7. It has been shown that EPI can inhibit the proliferation of enzalutamide-resistant cells in vivo and in vitro . Based oUnfortunately, it showed minor PSA declines, bringing to light the need for more potent and metabolically stable NTD inhibitors.The next generation of NTD inhibitors, EPI-7386, is more active and metabolically stable than EPI-506 ,120, andAutophagy is a process associated with drug resistance in different cancers. It is an adaptative response to maintain cell survival under metabolic stress, including androgen deprivation. It is an essential mechanism of resistance to ARSis in CRPC .Although the exact mechanism remains unknown, ADT has been shown to promote autophagy.Clomipramine and metformin are autophagy inhibitors and have proven to overcome enzalutamide resistance in vitro and in vivo, significantly reducing tumor growth in enza-resistant prostate cancer cells . In addiEpigenetic modifications in CRPC are being studied, specifically epigenetic inhibitors, for their ability to render CRPC cells sensitive to enzalutamide.Numerous investigations are focused on targeting epigenetic mediators since it is known that epigenetic aberrations are associated with PCa progression and drug resistance .Antisense oligonucleotides (ASO) inhibit the histone lysine-N-methyltransferase (EZH2), which correlates with poor prognosis in PCa.Xiao et al. observed that ASO may have a strong influence on the AR pathway, causing redistribution of AR binding and upregulated AR signaling, and demonstrated that treatments that inhibit EZH2 may resensitize tumor cells to AR-targeting treatments in CRPC . In factBased on all these findings, ASO is postulated as a possible strategy to restore sensitivity to antiandrogen therapy.The bromodomain and extra-terminal (BET) family proteins can regulate DNA transcription. Some proteins of this family can interact with AR in the nucleus, acting as a mediator of AR and AR-Vs transcription.The inhibition of BET pathways is being studied as an attractive option to overcome resistance to androgen inhibition ,63. The The SRC gene encodes the proto-oncogene tyrosine protein kinase Src, and there is increasing evidence about its correlation with AR pathways and the development of castration-resistant status. Src can favor the development of CRPC by sensitizing AR to intracrine androgen levels by developing canonical and non-canonical AR binding site-associated genes. Src inhibitor dasatinib has been demonstrated to reduce the expression of the splice variant AR-V7, helping to overcome antiandrogen resistance ,131.Ipatasertib is an Akt inhibitor that has been demonstrated to resensitize CRPC cells to antiandrogens when combined with enzalutamide, inducing apoptosis and leading to remarkable tumor cell growth inhibition, both in vitro and in vivo ,133.Even in the advanced stages of the disease, AR is the key therapeutic target of PCa.For this reason, several studies focus on an alternative concept beyond the inhibition of tumor growth.This concept focuses on the ability of different agents to resensitize CRPC cells to previously used antiandrogen treatments that have lost their effectiveness, allowing them to overcome antiandrogen resistance and achieving prolonged responses in multidrug-treated patients.It has been demonstrated that BAT can restore sensitivity to ARS is in CRPC patients. These findings represent a major step toward this use of BAT, although since not all patients respond uniformly to this maneuver, it is essential to determine predictors of response and resistance mechanisms to this interesting therapy.In this vein, other agents have been studied, and studies are at different stages of development. In any case, these findings open the door to the interesting possibility of using specific drugs as a hinge to effectively reuse treatments for which the tumor had already developed resistance.


Interprofessional rehabilitation programs have demonstrated effectiveness at improving health-related quality of life, function, work abilities, and reducing pain, for patients with chronic low back pain (CLBP). However, the characteristics of interprofessional rehabilitation programs vary widely across studies. Therefore, clarifying and describing key characteristics of interprofessional rehabilitation programs for patients with CLBP will be valuable for future intervention design and implementation. This scoping review aims to identify and describe the key characteristics of interprofessional rehabilitation programs for patients with CLBP.Our scoping review will follow the framework developed by Arksey and O'Malley, further enhanced by Levac et al. and the Joanna Briggs Institute (JBI). Electronic databases, including MEDLINE, EMBASE, CINAHL, PsycINFO, SCOPUS, PubMed, Web of Science, and Cochrane Library, will be searched to identify relevant published studies. Our scoping review will consider all primary source peer-reviewed published articles that evaluated interprofessional rehabilitation programs for adults with CLBP from all countries and any therapeutic settings.The Covidence software will be used to remove duplicates, article screening, record the step-by-step selection process, and data extraction. The analysis will involve a descriptive numerical summary and narrative analysis. Data will be presented in graphical and tabular format based on the nature of the data.This scoping review is expected to provide a source of evidence for developing and implementing interprofessional rehabilitation programs in new settings or contexts. As such, this review will guide future research and provide key information to health professionals, researchers and policymakers interested in designing and implementing evidence and theory-informed interprofessional rehabilitation programs for patients with CLBP.https://osf.io/rquxv. Low back pain (LBP) is a major public health problem globally , 2, incuCLBP is among the leading cause of years lived with disabilities (YLDs) worldwide , 14. AccThe complex, dynamic and multifactorial nature of CLBP makes it challenging to manage . IncreasFurthermore, heterogeneity in the contents, intensity of the interventions, and choice of outcomes may hamper comparisons between studies, knowledge synthesis, and conclusiveness of the evidence. To our knowledge, there is no published scoping review on descriptions and components of interprofessional rehabilitation programs for patients with CLBP. A synthesis of the key characteristics of interprofessional rehabilitation programs may facilitate the design and implementation of future interprofessional rehabilitation programs . Hence, A scoping review is selected as an appropriate and rigorous evidence synthesis approach for reviewing a heterogeneous body of evidence and mapping rapidly the key concepts underpinning a research area –24. A prThe evidence on the effectiveness of interprofessional rehabilitation programs for CLBP has been synthesized in systematic reviews of randomized controlled trials , 26. HowThis scoping review aims to provide a fulsome description of characteristics of interprofessional rehabilitation programs for CLBP evaluated in the peer-reviewed literature to support the development of interprofessional rehabilitation programs in new settings or contexts without limiting the search to particular trial designs. We anticipate the scoping review findings will provide a comprehensive overview of the characteristics of interprofessional rehabilitation programs, including professions involved, program components or interventions, frequency, duration, and theoretical foundations of interprofessional rehabilitation programs. Our scoping review will follow the framework developed by Arksey and O'Malley , which hOur research team includes researchers from multiple disciplines, including team members with expertise in low back pain, interprofessional rehabilitation, and knowledge syntheses.Through discussion with the research team, the overarching research question guiding this review is: what are the key characteristics of interprofessional rehabilitation programs for patients with CLBP that have been evaluated in the peer-reviewed literature?What types of interventions have been included in interprofessional rehabilitation programs used to treat patients with CLBP?How are interprofessional rehabilitation programs for patients with CLBP described across the studies?What is the duration and intensity/frequency of visits included in interprofessional rehabilitation programs for patients with CLBP?What health professionals have been involved in interprofessional rehabilitation programs for patients with CLBP?What health outcomes have been assessed in interprofessional rehabilitation programs for patients with CLBP?In what setting have interprofessional rehabilitation programs for patients with CLBP been provided?More specifically, this scoping review will try to address the following research questions:The JBI updated guidance for scoping review  recommenAll primary published studies with any methodological approach  will be the sources of evidence considered in this scoping study. The scoping review will include all studies that evaluate interprofessional rehabilitation programs for CLBP. The reference lists of systematic reviews and relevant studies identified through our search will be scanned to identify relevant primary research articles. However, we will not consider grey literature due to the time constraints we have in searching a large volume of grey literature, the lack of resources to manage a large volume of information found, and the inability to cover all grey literature repositories. As it is known, grey literature is less formally archived evidence, and searching will be time-consuming and inefficient. In addition, we wanted to include peer-reviewed high-quality evidence with a robust methodology and low risk of bias. In addition, opinion papers, all types of systematic reviews, and undergrad students’ theses not published in peer-reviewed journals will be excluded. In addition, commentaries, book reviews, and studies focusing on single-model interventions will also be excluded.Electronic databases like MEDLINE, EMBASE, CINAHL, PsycINFO, SCOPUS, and Web of Science will be searched to identify relevant published studies.A systematic approach will be followed to search for relevant articles using a combination of medical subject heading (MeSH) and keywords related to an interprofessional rehabilitation program and CLBP. A Queen’s University librarian (AP) helps to refine the search strategy, keywords, and MeSH terms for each database. In addition, titles of articles from an initial search will also be checked to refine search terms. The following initial key search terms are developed by the research team and refined with the support of Queen’s University librarian (AP):Concept 1: Chronic low back pain, Low Back Pain [MeSH Term], Low back ache, Back pain, Low backache, Lumbago, Mechanical low back pain, Lumbar painConcept 2: Multidisciplinary, Interdisciplinary, Interprofessional, Team, Transdisciplinary, Team-based, Collaborative, Multi-professionalConcept 3: Rehabilitation, Treatment, Management, Intervention, Approach, Care, TherapyA comprehensive search strategy will be developed using Boolean operators and truncation to fit each database. First, each term identified under each concept will be entered into different databases to identify subject headings and similar keywords. Then, we will search one concept at a time, and terms within each concept will be connected with ‘OR’ Boolean operator. Finally, we will search all identified MeSH terms and keywords together in different databases. We will use the Boolean operator ‘AND’ between each concept. An iterative process will be applied to identify and develop a list of key search terms. The librarian (AP) in our research team will test relevant MeSH terms, keywords, and filters to enhance the sensitivity and specificity within each database. A sample search strategy for OVID MEDLINE and CINAHL databases is found in The search will be limited to articles published in English due to the time and costs associated with translating articles published in other languages. However, there will be no date limits applied to our search.The reference lists and abstracts of articles found from each database will be retrieved and imported into Covidence software . The CovThe study selection process will be conducted independently by two reviewers. Disagreement will be resolved by mutual consensus or by a third reviewer through a two-step process using Covidence software to record the step-by-step selection process according to our inclusion criteria. First, the two reviewers will independently review all the titles and abstracts of articles against the inclusion and exclusion criteria. As Levac et al.  suggesteA flow chart will be prepared to show the study selection procedure at each stage of the review, including the reasons for exclusion. The study selection process will be reported using Preferred Reporting Items for Systematic Reviews and Meta-Analyses for Scoping Reviews (PRISMA-ScR) flow diagram . Since aTwo reviewers will independently extract the data from articles included in the scoping review using the data charting framework in the software program, Covidence. A draft extraction form is provided . We will only begin formal extraction when the percentage agreement is above 90% between the two reviewers. Inconsistency in extracted data between the two reviewers will be discussed until consensus is reached or resolved by a third reviewer .Data to be extracted from relevant selected studies will include information about the author, year of publication, the objective of the study, study design, detailed descriptions of the interventions, country, settings, targeted population, and types of outcomes assessed Table .The analysis will involve a descriptive numerical summary  and a narrative summary. First, we will apply a numerical description of the characteristics of included studies, including the overall number of studies included, years of publication, types of study designs, countries where studies were conducted, characteristics of the study population, detailed description of interventions, health professions involved in delivering the program, delivery mode, frequency and duration of the program, and settings of the intervention Table .The results will be reported through a thematic presentation and tables that align with the purpose of the scoping study. In addition, data will be presented in graphical representations such as pie charts and bar graphs when appropriate. Finally, we will discuss the meaning of the findings and implications for future research, policy, and clinical practice .In this analysis, we will compare and describe interprofessional rehabilitation programs for people with CLBP evaluated across studies. The analysis will also explore the types of outcomes that have been reported in interprofessional rehabilitation programs for people with CLBP. In addition, we will try to show gaps in the descriptions and contents of an interprofessional rehabilitation program and indicate areas where further analysis is required. This scoping review will adhere to the Preferred Reporting Items in Systematic Reviews and Meta-analyses extension for scoping reviews (PRISMA-ScR) . Any devAlthough Arksey and O'Malley  suggest that consultation is an optional stage in conducting a scoping review, Levac et al.  argue that it should be a required component to add methodological rigour. Accordingly, we will conduct consultation with stakeholders to share preliminary results, to help identify potential meaning from the findings, obtain their feedback about the findings not revealed by the scoping study, and identify additional references about potentially relevant studies which offer extra value to a scoping study. Hence, we will use a preliminary finding to inform the consultation, which enables stakeholders to build on the evidence and offer a higher level of meaning and perspective to the preliminary findings.Experts in CLBP, including healthcare providers and researchers in CLBP and interprofessional rehabilitation, will be consulted, thus offering important insights beyond what has been reported from the available evidence. We will conduct a focus group discussion (FGD) through a Zoom meeting with six to eight stakeholders. We will purposively recruit participants based on their expertise and lived experiences and send an invitation with a consent form through email. We will ask for any additional insights on how to interpret the findings of what has been reported in the literature and identify important gaps for future research. Focus groups will be video/audio-recorded, transcribed verbatim, and analyzed using a descriptive qualitative approach.This review aims to synthesize the characteristics of interprofessional rehabilitation programs for patients with CLBP evaluated in the literature. The characteristics described will include professions involved, program components or interventions, frequency, duration, the outcome evaluated, and theoretical foundations of interprofessional rehabilitation programs for patients with CLBP evaluated in the literature to date. Synthesizing and describing the characteristics and components of interprofessional rehabilitation programs is expected to provide valuable evidence to inform new program development and implementation. For example, this review will constitute the initial step in a multistage research project to identify and develop an evidence and theory-informed interprofessional rehabilitation program for patients with CLBP that can be implemented in Ethiopia. This scoping review is expected to provide evidence for this, and other initiatives aimed at developing and implementing interprofessional rehabilitation programs in new settings or contexts. As such, this review will be beneficial in guiding future research and providing key information to health professionals, researchers and policymakers interested in designing and implementing evidence and theory-informed interprofessional rehabilitation programs for patients with CLBP.


Augmented reality (AR) technology has been shown to be effective in displaying information and presenting three-dimensional objects. Although AR applications are commonly used by learners via mobile devices, plastic models or two-dimensional images are still commonly used in tooth carving practice. Learners practicing tooth carving face a challenge due to the three-dimensional features of teeth as there is a lack of tools available that provide sequential guidance. In this study, we developed an AR-based tooth carving practice tool (AR-TCPT) and compared it to a plastic model to evaluate its potential as a practice tool as well as its user experience.To model tooth carving, we created a three-dimensional object from sequential steps that included the maxillary canines and maxillary first premolars (16 steps), mandibular first premolars (13 steps), and mandibular first molars (14 steps). Image markers, created using Photoshop software, were assigned to each tooth. An AR-based mobile application was developed using the Unity engine. For tooth carving, 52 participants were randomly assigned to a control group  or an experimental group . User experience was evaluated using a 22-item questionnaire. Data were comparatively analyzed using the nonparametric Mann–Whitney U test via the SPSS program.The AR-TCPT detects image markers with the mobile device camera and displays three-dimensional objects for tooth fragmentation. Users can manipulate the device to view each step or examine the shape of a tooth. The results of the user experience survey revealed that the AR-TCPT experimental group scored significantly higher in tooth carving experience compared with the control group that used the plastic model.Compared with the conventional plastic model, the AR-TCPT provided a better user experience for tooth carving. The tool is highly accessible as it is designed to be used on mobile devices by users. Further studies are required to determine the educational impact of the AR-TCTP on quantitative scoring of carved teeth as well as individual user’s carving abilities. Dental morphology and practice class is an essential part of the dentistry curriculum. This course provides theoretical and practical instruction on the morphology, function, and direct carving of tooth structure , 2. The Beginner students in dental morphology practice face challenges interpreting and reproducing 2D images in three-dimensional (3D) form –10. TootAugmented reality (AR) technology has emerged as promising tool for enahncing learning experiences. By superimposing digital information onto the real environment, AR technology can provide learners with a more interactive and immersive experience . AccordiTo effectively guide learners in tooth carving using AR media, a sequential process should be followed. This approach can help reduce variation and facilitate skill mastery . Novice http://developer.vuforia.com). The AR application was implemented using the Unity engine  and subsequently installed and operated on a mobile device. To evaluate the effectiveness of the AR-TCPT as a practice tool for tooth carving, a control group and experimental group were formed by randomly selecting participants from a class of dental morphology practice in 2023. Participants in the experimental group used the AR-TCPT, whereas those in the control group used the plastic model from a Tooth Carving Step Model Kit . After completing the tooth carving task, user experiences for each practice medium were investigated and compared. The order of the research design is presented in Fig. The AR-TCPT was developed using AR technology for mobile devices. The tool was designed to create 3D models of the maxillary canine, maxillary first premolar, mandibular firt premolar, and mandibular first molar in a stepwise manner. Initial 3D modeling was completed using 3D Studio Max , whereas final modeling was performed using the Zbrush 3D package . Image markers were produced using Photoshop software  and were designed for stable recognition by mobile cameras, achieving a five-star rating in the Vuforia engine , and they distinguished each tooth using a circle–number symbol and a background of repeated patterns, as shown in Fig. Participants were recruited from the first-year dental morphology practice class at the department of dental hygiene at Seoyeong University in Gyeonggi-do. Potential participants were informed of the following: (1) participation was voluntary, without financial or academic grade reward; (2) the control group would use a plastic model while the experimental group would use the AR mobile application; (3) the experiment would take place over three weeks and involve carving three teeth; (4) Android users would receive an application installation link, whereas iOS users would be lent Android devices with AR-TCPT installed; 5) AR-TCTP would function in the same manner in both systems; (6) the control and experimental groups would be randomly assigned; (7) tooth carving would take place in separate labs; (8) after completion of the experiment, a survey consisting of 22 items would be conducted; and (9) the control group could use the AR-TCPT after the experiment. In total, 52 participants volunteered, and online consent forms were obtained from each participant. The control group (n = 26) and experimental group (n = 26) were randomly assigned using the random function in Microsoft Excel . Figure  AR-TCTP The experimental and control group carved three teeth each for three weeks, beginning on March 27, 2023, using the AR-TCPT and plastic model, respectively. Participants carved premolars and molars, including the mandibular first molar, mandibular first premolar, and maxillary first premolar, all with complex morphological features. The maxillary canines were not included in the carving. Participants were given a weekly time limit of 3 h to carve one tooth. After completing one tooth, the plastic model and image marker of the control and experimental groups, respectively, were retrieved. The 3D object of the tooth was not augmented via the AR-TCTP without image marker recognition. To prevent the use of other practice tools, the experimental and control groups practiced tooth carving in separate spaces. Feedback on tooth shape was provided for three weeks after the experiment concluded to limit the influence of instructor guidance. After completing the mandibular first molar carving in the third week of April, a questionnaire survey was conducted. The modified questionnaire of Saunders et al.  with 23 SPSS statistical software  was used for data analysis. A significant two-tailed test was conducted at a significance level of 0.05. Fisher’s exact test was used to analyze general characteristics, such as gender, age, place of residence, and tooth carving experience, to confirm the distribution of these characteristics between the control and experimental groups. The survey data did not follow a normal distribution (p < 0.05), as evidenced by the results of a Shapiro–Wilk test. Therefore, the nonparametric Mann–Whitney U test was used to compare the control and experimental groups.The tools used by the participants for tooth carving practice are depicted in Fig. The randomly allocated participants in the two groups showed no significant differences in gender, age, place of residence, and tooth carving experience (p > 0.05). The control group comprised 96.2% females (n = 25) and 3.8% males (n = 1), whereas the experimental group solely consisted of females (n = 26). The control group had 61.5% (n = 16) 20-year-old participants, 26.9% (n = 7) 21-year-old participants, and 11.5% (n = 3) ≥ 22-year-old participants, whereas the experimental group comprised 73.1% (n = 19) 20-year-old participants, 19.2% (n = 5) 21-year-old participants, and 7.7% (n = 2) ≥ 22-year-old participants. In terms of the place of residence, 69.2% (n = 18) of the control group lived in Gyeonggi-do, whereas 23.1% (n = 6) lived in Seoul. In contrast, 50.0% (n = 13) of the experimental group lived in Gyeonggi-do, whereas 46.2% (n = 12) lived in Seoul. The percentages of the control group and the experimental group living in Incheon were 7.7% (n = 2) and 3.8% (n = 1), respectively. Out of the control group, 25 participants (96.2%) had no prior tooth carving experience. Similarly, 26 participants (100%) in the experimental group had no prior experience in tooth carving.Table AR technology has become increasingly popular in various areas of dentistry, including clinical aesthetics, maxillofacial surgery, restorative techniques, dental morphology and implantology, and simulation –31. For The effect of 3D-printed plastic tooth models on tooth morphology education has been superior to that of textbooks with 2D pictures and explanations . HoweverInvestigating the user experience of AR applications is crucial for understanding the factors that impact media utilization . PositivAs shown in Fig. This comparative study suggests that the AR-TCPT has the potential to be a valuable alternative or complementary tool to the conventional plastic model for dental practice, as it received a superior evaluation score for user experience. However, to establish its superiority, further quantitative evaluations by instructors are required for intermediate and final carved teeth. Moreover, the impact of individual differences in spatial perception ability on the carving process and the final teeth must be analyzed. Dental ability varies among individuals, which may affect the carving process and final teeth. Therefore, additional research is needed to demonstrate the effectiveness of the AR-TCPT as a practice tool for tooth carving and understand the regulatory and mediating roles of AR applications in the carving process. Future studies should focus on evaluating the developmental and evaluative aspects of practice tools using advanced HoloLens AR technology for dental morphology.In conclusion, this study demonstrated the potential of the AR-TCPT as a practice tool for tooth carving, as it provided an innovative and interactive learning experience for students. Compared with the conventional plastic model group, the AR-TCPT group showed significantly higher scores in user experience, including benefits such as quick comprehension, improved learning, and reduced reliance on textbooks. With its familiar technology and ease of use, the AR-TCPT offers a promising alternative to conventional plastic tools and may assist beginners struggling with 3D carving. However, further research is required to evaluate its educational efficacy, including its effects on individual carving abilities and quantitative evaluations of carved teeth.


Most of the problems that appear after tibial plateau leveling osteotomy surgery are lameness. The dog exhibited mild lameness due to pain and inflammation, impeding full recovery. The purpose of this study is to collect objective data using walking analysis and digital thermal imaging to aid recovery from potential pain, inflammation, and lameness resulting from delayed rehabilitation after tibial plateau leveling osteotomy. The dog had not experienced rehabilitation until 42 h post-surgery. Gait analysis revealed insufficient weight support and the digital thermal imaging confirmed an increase in relative body heat within the medial stifle joint. After that, cold treatment, transcutaneous electrical nerve stimulation, and treadmill exercise were applied to promote recovery. Veterinary rehabilitation is often neglected post-surgery, despite its ability to enhance a dog’s quality of life.A 7-year-old neutered Maltese dog weighing 5.1 kg was presented, with a tibial plateau-leveling osteotomy (TPLO) on the right hindlimb 42 days prior. The patient’s right hind limb showed lameness, intermittent limping, and atrophy, and the patient had not experienced rehabilitation since TPLO surgery. The patient showed a pain reaction at the end of the stifle extension, and an increased body temperature was identified on the medial side of the right hindlimb when compared with the left hindlimb using a digital thermal imaging device. In addition, a type of lameness, only partial weight bearing in the right hindlimb, was also identified during the gait analysis. The pain was relieved by applying a cold pack and transcutaneous electrical nerve stimulation, and the patient’s weak muscles were strengthened through treadmill exercises. In this study, physical therapy and rehabilitation exercises controlled pain and induced rapid recovery, indicating that rehabilitative intervention is required after TPLO surgery. Cranial cruciate ligament deficits progress to secondary osteoarthritis and are the most common orthopedic diseases to cause lameness and limping ,2. TibiaA neutered 5.1 kg, 7-year-old Maltese dog, who underwent TPLO surgery 42 days prior for cranial cruciate ligament rupture of the right hind limb, presented for rehabilitation. After the surgery, the owner reported that the patient did not support weight well on the affected limb and seemed uncomfortable, had never undergone rehabilitation, and the owner was advised by a veterinary surgeon to perform passive range of motion exercises and walking at home for a short time. Based on video recordings of the dog walking and trotting, its lameness score was determined to be 1. The evaluation was performed using the method proposed by Millis and Levine . There w®, IR-Pad 320, INFRARED CAMERAS INC., Beaumont, TX, USA) with a spectral band between 7 and 14 µm and a resolution of 336 × 256 pixels. The dog had limited exercise, was maintained in temperature-controlled runs, and was measured at room temperature and moisture . All laboratory and radiographic evaluations, as well as physical examinations were conducted two days before thermal imaging to acclimate the dog and minimize the possible effects on his sympathetic nervous system that could alter thermal patterns. The dog was kept with his owner in a room designed to reduce stress and avoid physical responses for at least two hours. For better quality pictures, the owner held the front limbs while a detailed picture of the hind limb was taken at 50–60 cm from the camera to minimize environmental artifacts on the non-metallic platform.The unaffected and affected sides in the front and medial views were simultaneously measured using a digital thermal imaging device  with dimensions of 212 × 60.5 cm (L × W) and a sensor surface of 203 × 54.2 cm. For each measurement, the dog walked three times for one minute, and the average was measured and generated on the screen for analysis. The velocity ranged from 4.3 to 5.3 km/h.To establish a treadmill exercise plan, the evaluator asked the owner to leash the dog and walk as usual and the MVF and symmetry index (SI) were measured using a gait analysis device  at low current intensities, which is appropriate for pain control. Animals often do not tolerate high-intensity activities, and they are not recommended . The SI The HCPI is a valid, reliable, and responsive tool for assessing the response to osteoarthritis treatment in dogs . I totalThis study confirmed improvements using only thermal imaging and gait analysis. There is a limitation in that the improvement effect of the rehabilitative intervention was not evaluated using kinematics. It is thought that the effect of rehabilitation following TPLO can be clarified through various evaluation methods.Rehabilitation is frequently overlooked in clinical veterinary care. It is important to closely monitor pain and lameness following cranial cruciate ligament surgery in order to prevent chronic problems and return the animal to daily activities quickly. It is hopeful that future advances in rehabilitation will make it possible for animals suffering from pain to widely benefit from rehabilitative intervention.


Home is where much of the upper limb recovery after stroke takes place. This can be due to a variety of factors such as limits on the amount of inpatient rehabilitation, precedence of lower limb training in hospital, or the length of time it can take to regain functional arm and hand use. A trend toward moving inpatient rehabilitation services into the community and COVID-19 have also increased reliance on home-based rehabilitation. This raises many questions about home-based rehabilitation for the upper limb including optimal content and delivery, effects, and stroke survivors' experiences.Westlake et al. This showed little evidence of superiority of a purposively designed upper limb program over a more conventional one. The main reason for this neutral effect could be the low contrast between the groups. The review identified, however, eight promising interventions covering a range of home programs, such as the GRASP program, neuromotor stimulation, video games and use of a Music Glove or robotic arm.The effectiveness of home-based self-managed low-cost upper limb programs, when compared to other home programs, was investigated in a systematic review by Toh et al. compared home programs to conventional programs delivered in clinical settings. Interestingly, the non-technology programs  were superior or equal to conventional intervention provided either at clinic or home—with the exception of electrical stimulation, which provided significantly more improvement in upper limb function than treatment without electrical stimulation. These reviews show that home therapy when provided in a well-structured way using sufficient contrast can be beneficial in improving upper limb function and activity, but evidence to point out which specific intervention is most effective is limited.In contrast, A fundamental question is how best to facilitate engagement in rehabilitation after stroke. This is necessary for stroke survivors to build new routines that facilitate transfer of what has been learned in a rehabilitation program to meaningful activities in their daily lives. The papers in this Research Topic contribute to a deeper insight in the complexities of what facilitating engagement in rehabilitation may involve. They highlight that this needs to be carefully co-created, with input from the stroke survivor and their family/carers (if available) and professionals, and monitored.Schnabel et al.). This is needed to generate the drive to initiate, maintain and—where possible—progress practice toward an individual's personal goals.A crucial factor for engaging people with their home-based rehabilitation- especially where there is minimal or no professional input—is their intrinsic motivation .It is important that therapists take time to work with stroke survivors (and family/carers if available and appropriate) to gain an understanding of their views on the life roles and goals they wish (or need) to return to after their stroke, as well as salient physical and social aspects of their home environment. Any rehabilitation activities need to be clearly linked to their needs and daily lives in order to spark the intrinsic motivation necessary to initiate and sustain practice . Findings in the papers in this Research Topic underscore the Challenge Point Hypothesis  which posits that skill acquisition is maximized under an optimal challenge level. In cases where there is no professional input, rehabilitation technology needs to be designed in such a way that individual users can easily select (and then progress) the appropriate challenge level that yields a success rate of more than 90%—but <100% . Mastery experience is necessary for stroke survivors to boost their self-efficacy which, in turn, is needed to build new practice routines , and to transfer the learning to other skills they need. Mixed reality gaming interventions, such as the one piloted by Ham et al., are a promising development as they combine an immersive environment, where challenge levels can be carefully controlled and progressed, with activities that involve actual objects.A key requirement is to set the challenge, posed by the rehabilitation exercises and/or activities, at the appropriate level . Other factors  may also impede engagement in self-managed practice. Particularly in these circumstances, input from professionals may be pivotal .Persevering is associated with initiating self-practice , as shown by the work by De Jesus Ramos Muñoz et al.), but further research is needed to work out which formats are least burdensome. Self-report is common, but it is well known that this may be confounded by several factors (including memory), and therefore further research on objective measures of engagement .Regular follow-up, either by a professional or through logs, is necessary to review how well stroke survivors engage in their rehabilitation. Daily logs that are reviewed on a weekly basis were shown to be most commonly used (van Vliet et al. focuses on progressive functional task-specific practice in the home, with therapist visits being tapered down over the course of the intervention to facilitate engagement in self-managed practice. The protocol by Christie et al. comprises functional task practice and shaping techniques that align with the Challenge Point Hypothesis, as well as a transfer package to support engagement by stroke participants.It will be exciting to learn the findings from the two studies for which the protocols were described in this Research Topic; the protocol by Taken together, the work comprised within this Research Topic highlights the importance of collaborative working between healthcare professionals, stroke survivors and family/carers, as well as rehabilitation technology designers, to ensure that rehabilitation programs are meaningful, appropriate and engaging, to ultimately enable stroke survivors to achieve their goals.PV: Conceptualization, Writing—original draft, Writing—review and editing. MT: Conceptualization, Writing—original draft. FW: Conceptualization, Writing—original draft, Writing—review and editing. MA: Conceptualization, Writing—original draft, Writing—review and editing.


Allergic rhinitis, a common allergic disease affecting a significant number of individuals worldwide, is observed in 25% of children and 40% of adults, with its highest occurrence between the ages of 20 and 40. Its pathogenesis, like other allergic diseases, involves innate and adaptive immune responses, characterized by immunologic hypersensitivity to environmental substances. This response is mediated by type 2 immunity. Within type 2 allergic diseases, certain molecules have been identified as clinical biomarkers that contribute to diagnosis, prognosis, and therapy monitoring. Among these biomarkers, nitric oxide has shown to play a key role in various physiological and pathological processes, including neurotransmission, immunity, inflammation, regulation of mucus and cilia, inhibition of microorganisms, and tumor cell growth. Therefore, measurement of nasal nitric oxide has been proposed as an objective method for monitoring airway obstruction and inflammation in different settings  and in various clinical conditions, including upper airways diseases of the nose and paranasal sinuses. The purpose of this review is to analyze the potential mechanisms contributing to the production of nasal nitric oxide in allergic rhinitis and other related health issues. Additionally, this review aims to identify potential implications for future research, treatment strategies, and long-term management of symptoms. Allergic rhinitis (AR) is the most common allergic disease worldwide, impacting approximately 400 million people ,2,3. OveThe pathogenesis of AR, like other allergic diseases, involves innate and adaptive immune responses, characterized by immunologic hypersensitivity to environmental substances ,3,4. ThiIn the era of precision medicine, certain molecules have been identified as key biomarkers in the pathogenesis of AR, providing crucial information for precise diagnosis and treatment monitoring . These bThe objective of this review is to explore the potential mechanisms involved in nNO production in AR and their associations, particularly in the presence of comorbidities. The review aims to identify implications for pathophysiological mechanisms, treatment strategies, and long-term symptom management in AR.NO is a small diatomic molecule weighing 30 Da, known for its high reactivity caused by its unpaired electron, thus requiring precise enzymatic control for both activation and inactivation .2) [This molecule is synthesized by several forms of NO synthase (NOS) from the semi-essential amino-acid L-arginine and oxygen (O2) ,18. Thre2) . InsteadThe NO molecule derives from oxidation of extracellular L-arginine after its uptake. This pathway has been the target in several research for the development of NOS inhibitors, such as NG-monomethyl-L-arginine (L-NMMA) and NG-nitro-L-arginine-methyl-ester (L-NAME) ,21. ThesnNO plays different roles in many physiological and pathological processes. It inhibits the growth of microorganisms  and tumoral cells . Given iVarious functions of NO derive from its different concentrations ,25. A ThCells expressing iNOS include fibroblasts, natural killer cells (NK), chondrocytes and keratinocytes, monocytes and macrophages, and epithelial and endothelial cells ,26, whilMeasurement of FeNO has been a widely used and standardized method to detect eosinophil inflammation in lower airways diseases, particularly asthma ,34. In cAll the instruments enable nNO sampling, whether in parallel or in series ,34. In tTherefore, a new method to assess the patency of the osteo–meatal complex has been proposed by using nNO during humming, which is the production of a tone without opening the lips or forming words. Under normal conditions, humming causes a strong increase in nNO (humming responder), while, in the presence of obstruction of the osteo–meatal complex, this maneuver does not cause any increase in NO (humming non-responder) ,40.nNO has been studied in different clinical diseases of the upper airways, being a potential tool in diagnosis and monitoring AR in both adults and children ,42.In AR, as with FeNO in asthma, nNO appears to be related to the degree of eosinophilic inflammation , as it c® Mino, Aerocrine AB, Solna, Sweden), the same flow rate (0.3 L/min) and the same method (breath hold), two authors reported similar cut-off values (169.4 and 161.4 nL/min) with good specificity and sensitivity for nNO in AR [® Breath Analyzer, Sunvou-CA2122, Wuxi, China) instead, other authors reported cut-off values in AR and in healthy control subjects of 684.2 and 355.4 ppb, respectively [Using the same analyzer  induced by bradykinin, while partially inhibiting plasma extravasation mediated by platelet-activating factor (PAF), all mechanisms involved in AR ,64.Significant clinical evidence has emerged from the analysis of nNO levels after the administration of intranasal steroids (INS) and/or antihistamines (ATH) . In partThe levels of nNO in children with AR are influenced by their age, showing a positive association, which is likely explained by the increased development and pneumatization of the paranasal sinuses as children grow older . In chilHowever, it is worth noting that several studies utilizing nasal sprays might encounter a potential limitation due to the presence of substances that could influence the levels of nNO .The evaluation of nNO has shown potential as a useful biomarker in AR, as its levels increase in this condition and tend to decrease after treatment . HoweverIn the upper airways, NO acts as a biomarker of infections and inflammation, being produced by epithelial cells in the nose and so deposited in the paranasal sinuses ,31,75. I3/s [According to the recent literature evidence, NO comes from eosinophilic inflammation in patients affected by AR, being detected only in the presence of mild-to-moderate nasal obstruction, with an uncomplete closure of paranasal sinuses ostia or NAR lower than 0.65 Pa/cm3/s ,61. ConvIn conclusion, additional research is still needed to assess the usefulness of this biomarker in monitoring Th2 inflammation and enhancing treatments across various clinical environments such as community, hospital, and rehabilitation settings ,73. More