Computer as an integral part of continual advancements in medicine has experienced tremendous development to minimize the risks and improving the precision of the surgery. Our review included multi-disciplinary publications in English from 2014 to 2017 using Springer, Oxford library, Elsevier, PubMed, Google Scholar, and Springer search engines using terms of “augmented reality (AR), “plastic surgery,” and “surgery “ and “Augmented Reality Ethics and challenges”. It was shown that AR has been successfully effective in different branches of surgery, but with concerns and challenges like acceptance, privacy, different physical, security and behavioral threats. To come over them partially, a methodological approach for cyber threat landscape proactive exploration has been suggested. Surgeons are regularly looking for technologies that would enhance their operating environment and to offer a better surgical and patient experience.1The Continuance of Alvin Tofler‘s third wave, electronic age, which began after 2010, is the current virtual world with extremity enhancement in information technology (IT) , 3-D spaces as well as knowledge-based environment.2Examples of such innovations include fiber optics allowing the advent of minimal access and robotic surgery leading to developments of systems such as the da Vinci robot over a decade ago. These tools have historically come at a considerable cost, but over the last decade became cheaper and increasingly available. New computational paradigms are emerging with rapid advancement and miniaturization of real-time visualization platforms. Smartphones are now commonplace with micro-processing powers rivalling desktop computers. The near ubiquitous use of smartphones by doctors has driven an increasing use of technology in health care.2Medical applications and instant access to web-based resources now guide clinical practice. This has allowed for the development of powerful wearable technologies that can provide high fidelity audio-visual data to the surgeon whilst operating. The recent emerging role and integration of augmented reality (AR) in healthcare is ripe for translation into this data rich field and warrants consideration for future applications to enhance the surgical experience. This viewpoint aims to review the applications, limitations and legal pitfalls of these devices across surgical specialties and imagines what the future surgical landscape may reveal.3On the other hand, the whole history of humanity is an enormous accumulation of data. Information has been stored for thousands of years and data has become an integral part of history, politics, science, economics and business structures, and now even social lives. This trend is clearly visible in social networks such as Facebook, Twitter and Instagram, where users produce an enormous stream of different types of information daily . As data processing rates are growing continuously, a situation may appear when traditional analytical methods would not be able to stay up to date, especially with the growing amount of constantly updated data, which ultimately opens the way for Big Data technologies.3The current activity in the field of Big Data visualization is focused on the invention of tools that allow a person to produce quick and effective results working with large amounts of data. One of the more promising methods for improving upon current Big Data visualization techniques is its correlation with AR that is suitable for the limited perception capabilities of humans.Augmented reality (AR)4Have you ever played” Pokémon game?” or have you happened to use “Erase Brusher”, “Rewind videos”, “Type “hashtag#” or “Add effects” in Instagram? All are AR capabilities. AR  is the enrichment of the perceived reality by means of artiﬁcial virtual content. AR denotes a technique to combine a real world and virtual objects which are artificially generated digital content by a computer. AR can allow the user to see 3D virtual objects superimposed upon the real world. With the help of AR in medicine, a surgeon can see hidden organs inside a body and improve the perception of treatment procedure by interacting with the real world.AR components5A complete AR system requires at least three components including a tracking component, a registration component, and a visualization component. A fourth component, a spatial model  stores information about the real world and about the virtual world. The real-world model is required to serve as a reference for the tracking component, which must determine the user’s location in the real world. The virtual-world model consists of the content used for the augmentation. Both parts of the spatial model must be registered in the same coordinate system. AR uses a feedback loop between human user and computer system. The user observes the AR display and controls the viewpoint. The system tracks the user’s viewpoint, registers the pose in the real world with the virtual content, and presents situated visualizations.How does AR work?6,7AR combines real and digital elements in one of three ways including using a Head-Mounted Display (HMD), placing the visual information close in front of the user’s point of view; using handheld devices, most commonly smartphones and tablets; and computer-generated overlay that is placed directly on real objects using projects or devices known as Spatial Displays. AR has been used to make inroads in the medical domain. For example, AR has been used to give surgeons information about the position of internal organs and the adjustments needed for needle biopsy.AR Goals and Motivations8Augmented reality is used in many fields including medicine, education, manufacturing, and entertainment. Hardware components for augmented reality are processor, display, sensors and input devices. Modern mobile computing devices like smartphones and tablet computers contain these elements which often include a camera and MEMS sensors; such as accelerometer, GPS, and solid state compass, making them suitable AR platforms.8 (4) To shift through huge datasets to establish patterns and to manage bed space and medication tracking; (5) To read medical images and to integrate this information to be used in the vital services; and (6) To enhance one’s current perception of reality, whereas in contrast, virtual reality replaces the real world with a simulated one.9The goals of the AR are (1) to make the life of the user easier through providing the virtual information to his adjacent environment as well as to any indirect view of the real-world environment like the live-video stream; (2) to develop the user’s insight into and communications with the real world. The virtual reality or the virtual environment as named by Milgram engages users totally in an artificial world without seeing the real one; (3) To boost the sense of reality through laying virtual items over the real world in real time. AR not only adds items in real word but also represents useful digital information in real world;10 The Vein Viewer Vision system projects the patient’s vascular network onto the skin to help with needle insertion.11 The Speed-up Robust Feature (SURF) descriptor is applied to an endoscopic video of a liver.12,13The application of AR in healthcare is two-fold for doctors; firstly there is the training and education aspect, allowing trainee physicians to lift their heads from their textbooks and better visualize the health issues they will one day be treating; and secondly, the technology will monumentally enhance their ability to diagnose and treat conditions by allowing them to access real-time data and patient information faster than ever before.14 It is considered to be one of the most effective applications of AR. However, by the start of the 21st century, new instruments were available to study, diagnose and treat the body. Today, hospitals worldwide use complex, computerized machines to image the body or assist its function called “AR”. Medicine had always relied on technology such as scalpels, probes and materia medica .15Ten AR Apps for healthcare are (i) AccuVein helps providers locate patients’ veins more accurately for injections; (ii) VA-ST helps those with impaired vision to see; (iii) Brain Power works to teach life skills to children and adults on the autism spectrum; (iv) Eye Decide allows healthcare professionals to demonstrate how certain conditions impede eyesight; (v) Surgical Navigation Advanced Platform (SNAP) lets physicians demonstrate their plans for a surgery; (vi) Saagara is aimed at improving individuals’ overall physical/mental health and well-being using AR technologies; (vii) VR Dentist is a dental app that uses virtual and augmented reality for educational purposes; (viii) smARtsKin (in development) superimposes relevant patient to contour onto real-time camera feeds of patients undergoing radiation therapy; (ix) Anatomy 4D visualizes detailed bone structures and organ systems when the device is pointed at special downloaded templates; and (x) Google Glass, despite being discontinued, continues to play a vital role in the development of many of the AR applications in the medical field.16The traditional teaching of anatomy usually involves use of an anatomical atlas, time spent in the dissection room and fixed prosecutions. AR is being used to deliver a better appreciation of structures in virtual or real space to ease the transition from the learning to the clinical environment. An example of this is using Microsoft Kinect to produce an interactive ‘digital mirror’ of the leaner. This digital mirrored image is then augmented by anatomical datasets to visualize structures such as musculature, superimposed on the user’s own arm.16Telementoring would enable juniors to share a real time view of complex cases with an off-site senior member of the team for immediate advice. Specialities whereby visual review is required would benefit from, such as injury assessment, patient monitoring and trauma management. Telementoring is a safe option for providing expert diagnosis and opinion which can reduce the likelihood of mismanagement and unnecessary patient transfer. Likewise, Multidisciplinary Team Management (MDT) requires a careful coordination of different disciplines at one site and is often fraught with difficulties in accessibility.. However, real-time enhancement of the surgical procedure remains a slightly tentative application. It is not yet validated that surgery can be enhanced with AR and in some instances, it could be distracting. Some features may be useful of systems like GG where with voice activation the operator could communicate beyond the theatre environment, retrieve images and test results without breaking scrub. Real-time updates regarding the progress of the trauma list would reduce unnecessary fasting of patients in the event of a delay in theatre.16AR has the potential to impact on surgery in a number of novel ways as discussed above, especially in the arena of surgical training in the virtual surgical environment16Real-time augmentation of surgery usually involves the blending of acquired 3D imaging with surgical reference points. Novel applications of AR include use to project optimal port placement on the abdomen for laparoscopic surgery; using AR to identify the position of sentinel nodes with 3D freehand single photon emission computed tomography; and using this with near infra-red spectroscopy to provide visual guidance in lymph node dissection in cancer surgery. Specialized near infrared (NIR) devices have been developed for the detection of tissue vascularity using indocyanine green (ICG) dye. The use of ICG in lymphatic surgery is already well developed to help identify vessels and check for their patency hence the move from microscope to HMD is a likely future development. AR technology would also be able to seamlessly project diagnostic images intra-operatively for surgical planning to guide surgeons with optimal incisions and approach.16Companies are using the technology to provide patients with an augmented experience of what they can expect from surgery. Crisalix are promoting virtual aesthetics planning whereby after obtaining the patients attributes, the software can virtually demonstrate the likely changes in aesthetics such as breast enhancement. This improves documentation, communication, and education of clinicians, which will have implications for quality of service and patient safety. In addition, a case study demonstrated that using Oculus Rift  with distraction software reduced the level of pain experienced by a burns’ patient during occupational therapy. Other AR systems offered similar results for pain control in burns’ patients undergoing wound debridement.17All of those counted features of AR, arises following question in our minds: (a) Whether or not, AR is useful in surgery? (b) How AR services can help physicians? (c) What are AR application limits? (d) How we can overcome AR limitations? To answer above questions, some search engines and articles on “AR usages in surgery and healthcare” have been chosen to study: Despite its long history, AR has only recently made its debut in medical practice, being applied primarily to navigational surgery. This involves taking data from preoperative imaging and using anatomical anchors in the operating field to link or register the two representations in real time.17In a survey on “increasing intraoperative awareness to scattered radiation in interventional procedures by combining AR, Monte Carlo simulations and wireless dosimeters”, surgical staff performing image-guided minimally invasive surgical procedures are chronically exposed to harmful ionizing radiation. Currently, no means exist to intraoperatively depict the 3D shape and intensity of scattered radiation fields or to assess the body-part exposure of clinicians. A system for simulating and visualizing intraoperative scattered radiation using AR has been proposed.17A multi-camera RGBD system has been used to obtain a 3D point cloud reconstruction of the current room layout. The positions of the clinicians, patient, table and C-arm are used to build a radiation propagation simulation model and compute the deposited dose distribution in the room. Examiners have been worn wireless dosimeters to calibrate the simulation and to evaluate its accuracy at each time step. The computed 3D risk map is shown in an augmented reality manner by overlaying the simulation results onto the 3D model. Results showed that several 3D visualizations showing scattered radiation propagation, clinicians’ body-part exposure and radiation risk maps under different irradiation conditions are proposed. The system is evaluated in an operating room equipped with a robotized X-ray imaging device by comparing the radiation simulation results to experimental measurements under several X-ray acquisition setups and room configurations. Then the proposed system is capable to display intraoperative scattered radiation intuitively in 3D by using AR. This can have a strong impact on improving clinicians’ awareness of their exposure to ionizing radiation and on reducing overexposure risks.18AR can enhance viewing a fetus inside a mother’s womb. Siemens, Karl Storz and IRCAD have developed a system for laparoscopic liver surgery that uses AR to view sub-surface tumors and vessels. AR has been used for cockroach phobia treatment. Patients wearing AR glasses can be reminded to take medications. Surgical guidance can beneﬁt from AR by providing information from medical scan images to a surgeon in a convenient and intuitive manner. A useful review of mixed reality image guided surgery was previously provided and highlighted four key issues of the need to choose appropriate information for the augmented visualization; the use of appropriate visualization processing techniques; addressing the user interface; and evaluation/validation of the system. These remained important areas of research.19 The principles of AR was discussed in the context of laparoscopic surgical oncology before and the beneﬁts and limitations for clinical use were described. Using patient images from medical scanners, AR was shown to improve the visual capabilities of the surgeon and compensate for their otherwise restricted ﬁeld of view. Two main processes are useful in AR including the 3D visualization of the patient data; and registration of the visualization onto the patient.20AR has been used within neurosurgery area too. A systematic review showed that AR was a versatile tool for minimally invasive procedures for a wide range of neurological diseases and could improve the current generation of neuronavigation systems.21A study on “Preliminary trial of AR performed on a laparoscopic left hepatectomy” showed that the patient’s operating time was summed up to 205 min, where a blood loss of 300 mL was recorded. The postoperative course was simple. Histopathological analysis revealed the presence of a hepatocellular carcinoma with free margins. Results of intrahepatic visualization suggested that ARGS was beneficial in detecting the tumor, transection plane and medial hepatic vein prior to parenchymal transection, where it did not work due to the substantial changes to the liver’s shape.21In real surgery, it is important to have a thorough, accurate, and detailed knowledge of the anatomical structure of the surgical target. This aspect is especially important in plastic surgery, where most of the surgical outcomes are directly connected to the patient’s external appearance. With the development of computer graphics and sensors, VR and AR have become technologies that can bring new opportunities for development of the diagnostic and operative techniques used in reconstructive, plastic and aesthetic surgery.21The markerless AR-based technology was previously proposed to widely support oral and maxillofacial surgery. It matched a 3D patient teeth model to a real patient’s teeth in a real-time video image to track the patient’s position. It also overaided other 3D anatomical models such as the maxillofacial bone, nerves, and vessels. An AR-based surgical navigation system using a tablet PC with an embedded camera for bone tumor resection in the pelvic region was developed before. It overlaid and provided a 3D patient tumor model and planned resection margin information on the real surgical view. In AR-based display images, it was found to be hard for the user to recognize depth information.21This difficulty was overcome by switching AR display images and providing the closest distance information about a real surgical tool and a 3D patient mesh model. In addition, it was applied to spine surgery. Herein, we highlighted the main advantages of AR in plastic surgery, which are as follows: (1) AR allows the presentation of virtual objects to all human senses in a way identical to their natural counterparts; (2) As a diagnostic tool, the simulated 3D reconstruction of organs based on radiological data can provide a more naturalistic view of a patient’s appearance and anatomy; (3) Preoperative surgical planning can provide a more realistic prediction of the outcome, especially in craniofacial and aesthetic surgery; (4) Computerized 3D atlases of human anatomy, physiology, and pathology can provide better learning and training systems for plastic and reconstructive surgery; and (5) Intraoperative navigation reduces the possibility of major complications and increases the possibility of the best surgical results. Application of AR-based can be displayed in orthognathic surgery and the surgeon’s view of the segmented virtual maxilla in an AR environment.22A search on “navigation surgery using an AR for pancreatectomy” to evaluate the utility of navigation surgery using AR technology. The 3D reconstructed images from CT were created by segmentation. The initial registration was performed by using the optical location sensor. The reconstructed images were superimposed onto the real organs in the monitor display. Of the 19 patients who had undergone hepatobiliary and pancreatic surgery using AR-based NS, the accuracy, visualization ability, and utility of our system were assessed in five cases with pancreatectomy.22Results showed that the position of each organ in the surface-rendering image corresponded almost to that of the actual organ. Reference to the display image allowed for safe dissection, while preserving the adjacent vessels or organs. Then, AR-based NS contributed to accurate and effective surgical resection in pancreatectomy. The AR-based NS system displayed detailed, vivid, and comprehensible anatomical information around the pancreas, which contributed to margin-free and effective surgical resection in pancreatectomy.23A research on “effectiveness of a novel augmented reality-based navigation system in treatment of orbital hypertelorism”, AR technology could superimpose the virtual image generated by computer onto the real operating field to present an integral image to enhance surgical safety to develop a novel AR-based navigation system for craniofacial surgery. It focused on orbital hypertelorism correction, because the surgery required high preciseness and was considered tough even for senior craniofacial surgeon.23Twelve patients with orbital hypertelorism were selected. The preoperative computed tomography data were imported into 3-dimensional platform for preoperational design. The position and orientation of virtual information and real world were adjusted by image registration process. The AR toolkits were used to realize the integral image. Afterward, computed tomography was also performed after operation for comparing the difference between preoperational plan and actual operational outcome. Results showed that the AR-based navigation system was successfully used in these patients, directly displaying 3-dimensional navigational information onto the surgical field. A better appearance by the guidance of navigation image was achieved. This study reported an effective visualized approach for guiding orbital hypertelorism correction. The AR-based navigation system might lay a foundation for craniofacial surgery navigation. The AR technology could be considered as a helpful tool for precise osteotomy in craniofacial surgery.24AS in perforator flap transplantation, dissection of the perforator is an important, but difficult procedure because of the high variability in vascular anatomy. A research done on “A novel AR-based navigation system in perforator flap transplantation- a feasibility study”, preoperative imaging techniques could provide substantial information about vascular anatomy; however, it did not provide direct guidance for surgeons during the operation. In this study, a navigation system (NS) was established to overlie a vascular map on surgical sites to further provide a direct guide for perforator flap transplantation24Using this method, the NS was established based on computed tomographic angiography and AR techniques. A virtual vascular map was reconstructed according to computed tomographic angiography data and projected onto real patient images using AR Tool Kit software. Additionally, a screw-fixation marker holder was created to facilitate registration. With the use of a tracking and display system, the NS was conducted on an animal model and the system error was measured on a rapid prototyping model. Results showed that the NS assistance allowed for correct identification, as well as a safe and precise dissection of the perforator. AR-based NS could provide precise navigation information by directly displaying a 3-dimensional individual anatomical virtual model onto the operative field in real time. It allowed rapid identification and safe dissection of a perforator in free flap transplantation surgery.25A study on “Google Glass interface for sensory feedback in myoelectric hand prostheses” to provide sensory feedback to the user of the prosthesis is an important challenge. The common approach is to use tactile stimulation, which is easy to implement, but requires training and has limited information bandwidth. AN alternative approach based on AR has been suggested. The GLIMPSE, a Google Glass application was developed, which was connected to the prosthesis via a Bluetooth interface and rendered the prosthesis states  using AR (see-through display) and sound (bone conduction transducer).25The interface was tested in healthy subjects that used the prosthesis with (FB group) and without (NFB group) feedback during a modified clothespins test that allowed us to vary the difficulty of the task. The outcome measures were the number of unsuccessful trials, the time to accomplish the task, and the subjective ratings of the relevance of the feedback. The results showed that there was no difference in performance between FB and NFB groups in the case of a simple task . The GLIMPSE feedback did not increase the time to accomplish the task.25Therefore, the supplemental feedback might be useful in the tasks which are more demanding, and thereby, less likely to benefit from learning and feedforward control. The subjects integrated the supplemental feedback with the intrinsic sources (vision and muscle proprioception), developing their own idiosyncratic strategies to accomplish the task. This study demonstrated a novel self-contained, ready-to-deploy, wearable feedback interface. The interface was successfully tested and was proven to be feasible and functionally beneficial. The GLIMPSE could be used as a practical solution but also as a general and flexible instrument to investigate closed-loop prosthesis control.26A study on “Precise positioning of an intraoral distractor using augmented reality in patients with hemifacial microsomia” has been done on 20 patients with hemifacial microsomia who were randomly assigned to experimental and control groups. Pre-operative computed tomography was used in both groups, whereas AR was used in the experimental group. Afterwards, pre- and post-operative computed tomographic scans of both groups were superimposed, and several measurements were made and analyzed. Findings showed that both the conventional method and AR technique achieved proper positioning of the osteotomy planes, although the AR was more accurate. This study reported an efficient approach for guiding intraoperative distraction osteogenesis. AR tools such as the AR Toolkit may be helpful for precise positioning of intraoral distractors in patients with hemifacial microsomia in craniofacial surgery.27Despite the growing interest in AR and the large body of advances and research, several challenges and issue still exist and need to be addressed. Having all those gains and benefits does not come without concerns. Using this technology one may not be able to ignore some of the threats of the real, surrounding environment. AR will have an important role in image-based augmentation of the surgical environment. This will require increasingly powerful microcomputers to drive AR, which is currently limited but may improve with time.27As with electronic patient records, confidentiality and data management will be a major hurdle in the integration of recordable HMDs into medical practice. All should consider ethical and legal obligations, when using technology to either review, store or transfer patient data to prevent medical identity theft. Encryption improves but does not guarantee prevention from data hijacking. It is important that whichever system is developed meets the standards for health care information governance. With so many different healthcare systems, it is likely that there will be many different AR systems in use, which will have varying degrees of compatibility. As such, the healthcare market will capitalize on developing accessible price sensitive software and hardware to market. It is anticipated the global AR healthcare industry will be worth $641 million by 2018.28Here, we classify the limits that characterize the current state of the art of AR based on aspects of technology, social acceptance, and usability. (i) AR system has to deal with vast amount of information in reality. So the hardware used should be small, light, and easily portable and fast enough to display graphics; (ii) The battery life used by these complicated AR devices is another limitation for AR’s uses; (iii) AR tracking needs some system hardware such as GPS to provide accurate markers, ask them to be both accurate and reliable enough; (iv) AR systems usually obtain a lot of information, and need software to filter the information, retain useful information, discard useless data and display it in a convenient way; and (v) Despite the numerous benefits of AR in the medical field, some issues have arisen, including, for example, incorrect visualization of interposition between real and virtual objects.2829A challenge in surgery is that the position of organs and tissues cannot be estimated but the surgeon must know them exactly. AR projections do not always correspond the reality because of the structure of tissues in human body and patient’s subtle movements, such as aspiration and other tissue function. An attempt to provide more realistic real-time data was made before by integrating laparoscopy and 3D-ultrasound images, i.e. combining images inside and outside a body, provided by two different imaging methods.30The physical threats may come from the imperfection of devices like head-up displays, or their non-interference with the peripheral vision of the pilot/users as the displays present information only in the central field. Also there is the threat of misjudging relative motions, due to the poorer (or absent) peripheral field. In regard to the security threats, there are significant risks in the way augmented environments are deployed. The communications used in such platform, voice, position, messages have to be protected and encrypted.30AR is often used in training. There is also the issue that those technologies help reducing social and cultural barriers, giving the chance of some to participate at higher level in the educational process and often this is done using avatar. Regarding the behavioral threats, some individuals can assert a more destructive behavior, and show a non-proper conduct of behavior. Privacy threats are of concern even at present virtual societies like Facebook and Google+. Monitoring of presence, behavior and other issues of their users is alarming and stressful. While those technologies can bring a great benefit, jumping on their use and development might be costly for a number of companies. It might be better to start with pilot virtual/AR projects than spending a lot of money and not getting the expected advantage and value. Internet of things (IoT) has also a big security problem, sensors and other devices used in it are built with little or no security requirement. This could lead to serious vulnerabilities in applications at home, in cities, industry, etc.31Proper and adequate securing of AR is inevitably producing a significant challenge. Achieving a suitable reaction in this sense is a quite challenging task. Taking onto account the new understandings for “privacy space” and hybrid phenomena like “Advanced Persistent Threats” looks rather ambiguous and not quite certain. This directly reflects to a fast evolving cyber threats landscape for the human factor and environment of living.32A methodological approach for proactive exploration of the cyber threat landscape in the evolving digital environment is suggested. It should be noted here that the presented approach has been successfully developed and tested during the last five years in different cyber fields, ranging from social networks to smart environments implementing multiple IoT gadgets . The key ideas behind this model are accomplishing system modelling (based on expert knowledge), further analyzed in the discrete case and simulated in mixed reality environment.32The obtained results are validated with human biometrics monitoring, probabilistic assessment and questionnaire based multicriteria evaluation. Finally, the validated results are also verified in different digital reality projections  and are expected to be practically applied with overall global cyber trends landscape analysis, achieving proactive understanding of future cyber threats evolution.32As cyber threat context definition is difficult to be outlined, regarding its future evolution, the upcoming threats landscape in the cyber space (up to year 2020) will be strongly influenced by transformed privacy, biometric disturbances, and espionage, regarding the complete studied technological set . Whilst, social engineering and advanced malware are quite uncertain. Data breaches are expected to be weakened as threat, being already a quite exploited one.Practical support in this sense was achieved via monitoring of user multiple biometrics, Balanced Score Card post-simulation assessment and probabilistic machine simulation of cyber-attacks. Below these three approaches will be given with more details, regarding some successful implementation examples. 32Suitable results verification requires multiple scenarios and environments implementations and production comparison. Practical support in this sense was achieved via monitoring of user multiple biometrics, Balanced Score Card post-simulation assessment and probabilistic machine simulation of cyber-attacks.32Both psychological and physiological assessment of user complex characteristics, like emotions and behavior were organized for reliable hybrid simulation evaluation within different situational scenarios. Personality assessments of temperament, depression and sensation seeking evaluation of motivation have been also applied. Additional stress assessment has been studied through monitoring trainees’ response times. This is in close relation with human neural dynamics observations of different training process aspects in digital space.32The approach is extending the Balanced Score Card (BSC) tool with questionnaire-based assessment and Delphi filtering (A program for setting filters on tables and query result sets), similar to other security exercises assessment. During this process practical organization an important note is the participant motivation for proper questionnaires treating. Unfortunately, it is difficult to be directly measured and checked, together with correct question understanding. This naturally generates noisy data results from the user response monitoring perspective. A useful support in this sense could be the combination with indirect user feedback, based on stored activities biometrics analysis or other bench mark machine simulation results.We can conclude that despite of few resources on AR, especially in Iran, vast dealing with AR capabilities has been done in the realm of surgery as one important branches of medicine, while showing its benefits and shortcomings like different physical, educational and behavioral threats. Since “privacy and security matters” are the most concerning issues in this regard, then some solutions such as Results “Validation”, “Verification”, “Balanced Score Card Assessment” and “Biometrics Support” have been prescribed. In future studies, it is recommended to deal with various fields of Medicine affected by AR and propose some cures for other kinds of AR concerns such as “cost” and “physical protocols”. The authors declare no conflict of interest.


Transl Med UniSa. 2018 Mar 31;17:25–33, reports a mistake in the affiliation list. The correct affiliation for dott Albino Carrizzo is: IRCCS Neuromed, Pozzilli (IS), 86077, Italy and for prof Vecchione is Department of Medicine and Surgery, Scuola Medica Salernitana, University of Salerno, 84081, Baronissi (SA), Italy, and IRCCS Neuromed, Pozzilli (IS), 86077, Italy.The manuscript “siRNA Delivery for Control of Cyclin D1 and E2F1 Expression in Crohn’s Disease” published in


Rhodobacter sphaeroides, which forms an intracytoplasmic membrane, can be used for long-chain FFA production using phospholipase.Long-chain free fatty acids (FFAs) are a type of backbone molecule that can react with alcohol to produce biodiesels. Various microorganisms have become potent producers of FFAs. Efforts have focused on increasing metabolic flux to the synthesis of either neutral fat or fatty acyl intermediates attached to acyl carrier protein (ACP), which are the source of FFAs. Membrane lipids are also a source of FFAs. As an alternative way of producing FFAs, exogenous phospholipase may be used after heterologous production and localization in the periplasmic space. In this work, we examined whether R. sphaeroides strain Rs-A2, which heterologously produces Arabidopsis thaliana phospholipase A2 (PLA2) in the periplasm, excretes FFAs during growth. FFA productivity under photoheterotrophic conditions is higher than that observed under aerobic or semiaerobic conditions. When the biosynthetic enzymes for FA  and phosphatidate  were overproduced in Rs-A2, the FFA productivity of the resulting strain Rs-HCA2 was elevated, and the FFAs produced mainly consisted of long-chain FAs of cis-vaccenate, stearate, and palmitate in an approximately equimolar ratio. The high-cell-density culture of Rs-HCA2 with DMSO in two-phase culture with dodecane resulted in an increase of overall carbon substrate consumption, which subsequently leads to a large increase in FFA productivity of up to 2.0 g L−1 day−1. Overexpression of the genes encoding phosphate acyltransferase (PlsX) and glycerol-3-phosphate acyltransferase (PlsY), which catalyze the biosynthetic steps immediately upstream from PlsC, in Rs-HCA2 generated Rs-HXYCA2, which grew faster than Rs-HCA2 and showed an FFA productivity of 2.8 g L−1 day−1 with an FFA titer of 8.5 g L−1.The recombinant R. sphaeroides heterologously producing PLA2 in the periplasm. The FFA productivity was greatly increased by high-cell-density culture in two-phase culture with dodecane. This approach provides highly competitive productivity of long-chain FFAs by R. sphaeroides compared with other bacteria. This method may be applied to FFA production by other photosynthetic bacteria with similar differentiated membrane systems.We showed that long-chain FFAs can be produced from metabolically engineered The online version of this article (10.1186/s12934-019-1070-8) contains supplementary material, which is available to authorized users. Given the increasing concern over the past decade regarding the projected depletion of fossil-fuel reserves and the concomitant emissions of greenhouse gases, the exploration of renewable and sustainable alternative biofuels is imperative. Much attention has been given lately to the microbial production of biofuels –3, incluEscherichia coli engineered for enhanced metabolic flow to ethanol provides significantly increased ethanol yield and productivity  were obtained from A. thaliana cDNA. The cDNA sequence of A. thaliana was obtained from http://www.arabidopsis.org/index.jsp, and cDNA was synthesized as follows. Total RNA was extracted from 2-week-old Arabidopsis plants using a Plant RNA Kit . DNase I  was added to the total RNA to remove genomic DNA. Using the total RNA as templates, first-strand cDNA was synthesized by PrimeScript reverse transcriptase  according to the manufacturer’s protocol. Briefly, total RNA (5 μg) was mixed with oligo dT primer (5 μM) and dNTP (2 mM) in 10 μL of H2O and incubated at 65 °C for 5 min, followed by mixing with 20 U RNase inhibitor and 100 U reverse transcriptase in PrimeScript buffer (Takara). The reaction proceeded at 42 °C for 60 min, and the reverse transcriptase was heat-inactivated at 70 °C for 5 min to stop the reaction.All DNA fragments containing genes encoding enzymes involved in the metabolism of FAs and PLs were PCR-amplified from SmaI/StuI transcription and translation stop Ω [streptomycin/spectinomycin-resistant (Smr/Spr)] DNA was inserted into the SmaI site of the kanamycin-resistant (Kmr) gene of pIND4 ) for 2 h with shaking at room temperature. The chloroform layer was evaporated under a nitrogen stream, and the FFAs were determined as described previously [CFAs of eviously . Standareviously . When ceFFA productivity was determined from the FFA level in culture supernatant (and in the dodecane in dodecane-overlaid culture) harvested at several time points from exponential phase to the beginning part of the stationary phase. The FFA productivity was derived from the FFA levels at a given sampling point divided by the time at that sampling point, which had elapsed after inoculation. The maximal FFA productivities at exponential growth phase, which remained unchanged to the beginning part of the stationary phase, were regarded as a representative FFA productivity. In contrast, FFA titer was determined from the maximal level of FFAs in culture supernatant (and in the dodecane in dodecane-overlaid culture) during the stationary phase.cis-vaccenic acid  was dissolved in 10 mL of alcoholic KOH (40 g L−1), followed by boiling for 1 h. The solution was cooled to room temperature, neutralized with 0.5 N HCl, and then completely dried at 65 °C and used as potassium cis-vaccenate.One gram of Aliquots of cell culture were centrifuged to obtain the supernatant, which was stored at 4 °C for further analysis. The glucose concentration was examined using a Glucose Assay Kit (Sigma-Aldrich). A Free Glycerol Colorimetric/Fluorometric Assay Kit  was used to determine glycerol levels, and a Succinate (Succinic Acid) Colorimetric Assay Kit (BioVision) was used to examine the succinate levels in the culture supernatant.R. sphaeroides KD131 grown under photoheterotrophic and semiaerobic conditions is approximately twofold higher than that of cells grown aerobically  of the periplasmic protein cytochrome c2 (CycA) of R. sphaeroides to generate the plasmid pINDA′-PLA1  to E. coli TolC, to excrete long-chain FFAs into the culture medium [R. sphaeroides TolC homolog (Rsp_1576), which shows approximately 41–43% similarity (23–24% identity) to the TolCs of E. coli and Salmonella, was interrupted to yield the Rs-tol strain  or the initial condensation to form acetoacetyl-ACP  in Rs-CA2. FFA productivities of the resulting recombinant strains Rs-DCA2, Rs-AccCA2, and Rs-HCA2 were not less than Rs-CA2 Fig. a. UnsatuR. sphaeroides overexpressing plsC alone or plsC with either fabD, accABCD, or fabH did not differ from those of WT cells  yeast extracts). The maximal turbidity of cells grown in SisH medium was almost twice that of cells grown in Sis minimal medium  stimulates PL biosynthesis in yeast cells . The CFA25% Fig. a without25% Fig. b. AccordR. sphaeroides was strongly affected by the presence of cis-vaccenate  resulted in the complete inhibition of cell growth  of cis-vaccenate had a strong effect (Additional file FFAs produced by PLA2 in the periplasmic space may cross either the outer membrane for secretion or the inner membrane for reutilization by the cell. FFAs in the culture broth may also be utilized again after uptake by cells. Moreover, some unsaturated FAs, such as palmitoleic acid, oleic acid, linolenic acid, and arachidonic acid, affect bacterial growth by inhibiting enoyl-ACP reductase . Likewis−1 day−1, at 30% dodecane (Fig. Rs-HCA2 grew faster in the two-phase culture system as dodecane levels increased up to 30% Fig. b. The maane Fig. a. More tane Fig. a, and thcis-vaccenate, stearate, and palmitate in an approximately equimolar ratio. As in the FFAs produced by Rs-A2 (Fig. cis-vaccenate among the FFAs indicates its importance in the membrane for the viability and growth of R. sphaeroides. The proportion of cis-vaccenate in the CFAs of Rs-HCA2 is approximately 60% (Additional file The FFAs produced by Rs-HCA2 (Fig. -A2 Fig. , the lowfabH and plsC in Rs-HCA2 were examined by RT-qPCR and shown as the mean ratio to the expression of the corresponding gene in WT cells (Table fabH and plsC were overexpressed in Rs-HCA2 compared with WT cells. Interestingly, plsX and plsY of Rs-HCA2, which encode phosphate acyltransferase and glycerol-3-phosphate acyltransferase, respectively, catalyzing the two consecutive metabolic steps immediately upstream of PlsC (Fig. plsX, plsY, and plsC in the presence of extra copies of pla2 remains to be defined, but the overexpression of plsC in Rs-HCA2 may result in a higher demand for acyl-ACP, which is also a substrate of PlsX (Fig. plsX and plsY (Fig. The expression levels of lsC Fig. , were exlsX Fig. . As a relsY Fig. .Table 2EplsX and plsY, both genes were overexpressed in Rs-HCA2, generating the strain Rs-HXYCA2 (Table plsX and plsY in Rs-HXYCA2 compared with the corresponding expression levels in Rs-HCA2 (Table pla2 remained unchanged in the same comparison (Table plsX and plsY in Rs-HCA2 led to the efficient synthesis of phosphatidate as a precursor of PL and subsequently to accelerated cell growth. The FFA productivity of Rs-HXYCA2 was approximately 40% higher than that of Rs-HCA2 (Fig. To elevate the low expression of on Table b. The CFCA2 Fig. a, and thCA2 Fig. a.−1 day−1 with a maximal FFA titer of 6.8 g (Fig. We then examined the FFA productivity of Rs-HXYCA2 grown in SisH-D medium in a two-phase culture system with dodecane Fig. a2, b2. R8 g Fig. . When Rs8 g Fig. .Fig. 8FF−1 day−1 with a maximal FFA titer of approximately 8.5 g L−1 (Fig. Rs-HXYCA2 grown in SisH-D medium in a two-phase culture system with dodecane showed higher FFA productivity of 2.8 g LL−1 Fig. . The FFAL−1 Fig. . Rs-HXYCplsX and plsY in Rs-HCA2 together with the sequestration of FFAs in the dodecane layer had a positive effect on the carbon-to-lipid conversion yield, the increase of FFA productivity in the two-phase system is due to an increase in overall carbon substrate consumption rather than due to an increased efficiency of carbon substrate conversion to FFA (Table The residual carbons in the culture broth were determined (Additional file R. sphaeroides can be used as an ideal oleaginous host source for the production of long-chain FFAs based on its intrinsic high lipid contents. Because R. sphaeroides is capable of using various carbon and nitrogen sources as substrates to grow in a wide variety of conditions, additional genetic modification can also be applied to enhance the potential of this bacterium for the production of FFAs.In summary, the photosynthetic bacteria Additional file 1. Additional figures and tables.


The aging population increasingly needs assistive technologies, such as rollators, to function and live less dependently. Rollators are designed to decrease the risk of falls by improving the gait mechanics of their users. However, data on the biomechanics of rollator assisted gait of older adults are limited, or mostly derived from experiments with younger adults.This review summarises the data from 18 independent studies on the kinematic and kinetic gait parameters of assisted gait of older persons. All of these studies evaluated spatio-temporal parameters, but not joint angles or moments.Due to the limited research on rollator supported gait in older adults, the number of parameters that could be analysed in this systematic review was restricted. Further research in the analysis of spatio-temporal parameters and a higher standardisation in clinical research will be necessary. Due to the aging society there is an increasing need for appropriate technical devices for less dependent living . WalkingFalls are a major issue in older adults. About one third of the people aged older than 65 years fall once a year and half of those aged 80 years and older fall every year . The risSome observational studies have been conducted to analyse the influence of rollator use on gait biomechanics and to get in-depth information on the immanent risk of falls. In an attempt to analyse the biomechanics of walking with a rollator, research was conducted with healthy young adults to compare unsupported versus rollator-assisted gait . HoweverThe aim of this review is to investigate the influence of a rollator on the walking biomechanics in older persons and to gain more insight into the gait parameters evaluated during rollator supported gait. We hypothesise that the biomechanics – kinematic, kinetic and spatio-temporal features – of rollator supported gait differ from unsupported gait in older persons. The further understanding of rollator supported gait is especially relevant due to the increasing development of so called ‘smart’ rollators –19.A systematic literature search was conducted to find related works to the hypothesis stated. The review process was divided into four phases as shown in.Figure In the second phase, titles and abstracts were screened and publications, which did not meet the aforementioned criteria, were excluded. In the third phase, the full texts of the remaining publications were assessed and those that were ineligible, for not covering the set criteria, were excluded. In the fourth phase, all remaining publications were evaluated and the references checked for further publications, which could be included in this review.This review was based on scientific journal papers and conference proceedings analysing gait biomechanics of older rollator users. Book chapters and review papers were excluded.Two independent researchers performed the data extraction and the results were compared afterwards. Disagreements were discussed and solved. In exceptional cases where they disagreed, a third researcher was consulted. Considering the methodological quality of the studies, the two reviewers focused on the following topics: number of participants; study description; type of measurement system; type of walking aid; gait parameters evaluated.Due to the inhomogeneous objectives of the studies included, the quality assessment of the different studies was performed using an adapted questionnaire based on the Critical Appraisal Skills Program (CASP) specifically developed for this review. The questionnaire comprised five questions that could be answered by: “Yes”, “No” and “Partly”, in case there was not enough information. These three answers were scored as: “Yes” = 1.0, “Partly” = 0.5, and “No” = 0.0. As this review combines studies related to medicine and engineering, the quality assessment tool was not used as an exclusion criterion, but as an instrument to objectively compare different publications. The questionnaire used is presented in Table This section was divided into two parts. The first subsection deals with the results from the quality assessment. The second subsection provides a detailed study description summarising the tested population, gait parameters evaluated, measurement systems used and results of the different studies.The literature search yielded 18 papers that met the inclusion criteria  and first time users (FTUs) were summarised. In the second part, the outcomes of spatio-temporal gait parameters in the same population with and without the use of a rollator are presented. Although the absolute values and the magnitude of changes between FUs and FTUs differed, the trend towards improvement appeared similar . TherefoThree studies , 24, 31 Eight studies analysed the influence of the use of a rollator on the spatio-temporal gait parameters. Two studies compared the gait parameters of FUs only , 21, two− 1, cane: 0.94 ± 0.05 ms− 1) [In five studies other assistive devices than rollators were used , 26, 30.5 ms− 1) . Both as5 ms− 1) , 23. The5 ms− 1) .The use of two crutches led to an unsymmetrical gait whereas the use of a rollator maintained the symmetry patterns of the stride length, step length, stance and swing duration, leg speed, double support duration and step time of natural gait . AdditioWalkers without wheels induced asymmetric gait patterns similar to those of crutches, because they have to be moved before each step . TherebyThe two-wheeled walker also needed to be lifted before moving which led to a lower gait velocity and shorter stride length , 25. TheThere were different studies of one research group analysing the use of a rollator during different tasks of daily living –7 and anCostamagna et al.  used an Lindemann et al. analysed gait speed, stride length, cadence and walk-ratio (step length/cadence) during different inclines with and without using a rollator . During In another study, Lindemann et al. analysed one common problem in rollator use: walking through a door . They evWang et al. analysed straight walking as well as turns of 90° and 180° using an instrumented walker in younger and older adults . They diIn this paper, we aimed to review systematically those studies analysing biomechanical gait parameters of rollator supported gait in persons aged 65 years and older with the underlying hypothesis whether the rollator supported gait differs from unsupported gait in older persons. Regarding the spatio-temporal parameters, the hypothesis could be accepted.The studies included in this review were very heterogeneous regarding their research question, assistive devices and study design. Therefore, the quality assessment results were only used to guide the interpretation of review findings and to indicate the strength of inferences. Three studies had different objectives than that proposed for this review: one covers the validation of a new measurement system , anotherThe number of studies analysing rollator supported gait conducted with older persons was restricted and did not consider the investigation of joint angles or joint moments. Therefore, mainly spatio-temporal parameters could be considered in this study. In some cases, the studies included in this review reveal contradictory findings (cf. Tables The use of a rollator caused higher cognitive demands than free walking . This miThe quality of gait was analysed in few studies only. First time users showed a worse quality of gait (cf. Table The analysis of activities of daily living highlighted the necessity of training these activities with the rollator user in detail to avoid difficulties and an increased risk of falls –7, 17. TAlthough the hypothesis of this review could be accepted regarding the spatio-temporal parameters, further research will be necessary to expand these findings to the analysis of joint angles and moments to get further insight in the gait mechanics of rollator assisted gait.Due to the limited research on rollator supported gait in older persons, the number of parameters that could be analysed in this systematic review were restricted. Further research in the analysis of spatio-temporal parameters and a higher standardisation in clinical research will be necessary. Additionally, there were no information in the literature regarding the joint kinematics or kinetics of rollator supported gait in older persons. Although the use of a rollator may be the best option to walk safely, the high rate of falls in rollator users is still a major concern that still needs to be addressed. Additionally, the rollator as such needs further improvements for a better handling.


NR2E1), which is upregulated in prostate cancer, plays an oncogenic role in prostate carcinogenesis by suppressing oncogene-induced senescence. In the present study, we further established that TLX exhibited an increased expression in metastatic CRPC. Further analyses showed that overexpression of TLX could confer resistance to androgen deprivation and anti-androgen in androgen-dependent prostate cancer cells in vitro and in vivo, whereas knockdown of endogenous TLX could potentiate the sensitivity to androgen deprivation and anti-androgen in prostate cancer cells. Our study revealed that the TLX-induced resistance to androgen deprivation and anti-androgen was mediated through its direct suppression of AR gene transcription and signaling in both androgen-stimulated and -unstimulated prostate cancer cells. We also characterized that TLX could bind directly to AR promoter and repress AR transcription by recruitment of histone modifiers, including HDAC1, HDAC3, and LSD1. Together, our present study shows, for the first time, that TLX can contribute to androgen insensitivity in CRPC via repression of AR gene transcription and signaling, and also implicates that targeting the druggable TLX may have a potential therapeutic significance in CRPC management, particularly in NEPC and PCSCs.The metastatic castration-resistant prostate cancer (CRPC) is a lethal form of prostate cancer, in which the expression of androgen receptor (AR) is highly heterogeneous. Indeed, lower AR expression and attenuated AR signature activity is shown in CRPC tissues, especially in the subset of neuroendocrine prostate cancer (NEPC) and prostate cancer stem-like cells (PCSCs). However, the significance of AR downregulation in androgen insensitivity and de-differentiation of tumor cells in CRPC is poorly understood and much neglected. Our previous study shows that the orphan nuclear receptor TLX ( The initial and advanced growth of prostate cancer is critically dependent on androgens. Hormone or androgen-deprivation therapy (ADT), which acts to suppress the androgen receptor (AR) signaling by androgen depletion or AR antagonists, is still the principal treatment option for locally advanced and metastatic prostate cancers. However, after initial favorable responses to hormone therapy, most patients inevitably develop resistance to treatment and relapse with a more aggressive form of castration-resistant prostate cancer (CRPC) within 2–3 years. Most studies on CRPC suggest that the advanced disease progression involves multiple and interrelating AR-dependent mechanisms, including 1) overexpression of AR and its co-regulators, (2) AR point mutations, (3) AR activation by growth factors-mediated signal transduction pathways, (4) AR-mediated activation of oncogenic fusion genes, (5) constitutively active AR splice variants, and (6) intratumoral production of androgens by either conversion from adrenal androgens or de novo androgen biosynthesis from cholesterol via overexpressed steroidogenic enzymes, that leading to persistent and reactivated AR signaling and altered androgen metabolism [ overexprAR gene has been found in 30% CPRC and even higher in 50% metastatic CRPC (mCRPC) [AR signaling pathway is commonly altered and remains persistent in CRPC. Genomic amplification of  (mCRPC) . However (mCRPC) –13. Quan (mCRPC) . Decreas (mCRPC) , 15. A s (mCRPC) , 16–19.  (mCRPC) . HoweverNR2E1) is an orphan nuclear receptor belonging to the nuclear receptor superfamily. Studies in past decades indicate that TLX plays important roles in brain and retina development, maintenance of stemness, and self-renewal of embryonic and adult neural stem cells (NSCs) via its direct transcriptional control of genes involved in DNA replication, cell cycle, adhesion, and migration, Wnt/α-catenin, and mitogen-activated protein kinase (MAPK) signaling [OCT4 gene [CDKN1A and SIRT1 [TLX  mice . Express cohorts , 38 in aSince TLX exhibited an increased expression in VCaP-CRPC xenograft model and mCRPC tissues, we hypothesize that TLX might perform a growth promoting role in CRPC. To elucidate the functional significance of TLX in prostate cancer growth upon androgen-deprivation stress, we then generated stable TLX-transduced clones in AR-positive prostate cancer cell lines  for in vitro and in vivo growth phenotype studies Fig. . In vitrAR and AR-target genes  were significantly reduced in LNCaP, VCaP, and LAPC-4 TLX-overexpressing stable cells as compared to their vector-infectant counterparts  and NCAM1 , we next examined the possible association of TLX in NEPC progression in LNCaP-TLX cells. Expression analyses showed that the mRNA and protein levels of two NEPC markers ENO2  and CHGA (chromogranin A) exhibited significant higher expressions in LNCaP-TLX cells, but lower expressions in LNCaP-shTLX cells  or bicalutamide, LNCaP-TLX cells expressed lower levels of AR and PSA as compared to empty vector LNCaP-pPWI cells. DHT treatment induced significant increases of AR and PSA in LNCaP-pWPI cells, but only slight increase of AR and no change of PSA in LNCaP-TLX cells. Bicalutamide treatment, with or without DHT, attenuated expressions of both AR and PSA in LNCaP-pWPI cells, and further suppressed AR and PSA levels in LNCaP-TLX cells Fig. . These rAR gene expression or indirectly via other TLX-controlled downstream signaling pathways. Chromatin immunoprecipitation (ChIP) analysis performed in TLX-transfected HEK293 cells identified two TLX-binding sites, located at 819–658 bp (designated as P1) at the 5′-UTR and −1135 to −952 bp (P2) upstream of the ATG start site , suggesting that maximum repression of AR gene expression would require TLX with intact DBD and LBD  gene promoter as shown previously [AR gene transcription via its direct binding to consensus TLX-binding sequences present at the 5′-UTR and promoter of AR gene.We next sought to determine whether the TLX-induced downregulation of AR expression in prostate cancer cells could be mediated by its direct transrepression of ite Fig. . In ordeLuc Fig. . These r AR Fig. . Based o AR Fig. , in ordeLBD Fig. . Our resLBD Fig. . These reviously . TogetheAR gene, we performed the ChIP assay in LNCaP cells infected with lentiviral vector pWPI-TLX. Sonicated chromatin fragments were immunoprecipitated with antibodies against FLAG, HDACs, and LSD1. Results of ChIP-PCR assay showed that DNA fragments flanking either the P1 or P2 sites could be immunoprecipitated by HDAC1, HDAC3, and LSD1 antibodies but not HDAC5, and PCR-amplified  pull-down assay was then performed to further validate whether TLX could directly interact with HDACs and LSD1 so as to execute its transrepression function. Results of immunoblot analysis showed that HDAC1, HDAC3, and LSD1 could be immunodetected in the GST-TLX protein complex, but these chromatin modifiers were much less accumulated in the GST-TLXΔLBD complex, indicating that interaction between TLX and chromatin modifiers would require TLX with intact LBD  and LSD1 (pargyline). Results showed that treatments with HDAC and LSD1 inhibitors could dose-dependently reverse and restore the repressed AR-Luc reporter activity mediated by the transfected TLX in HEK293 cells  and lysine-specific demethylase (LSD1) , 40. In ied Fig. . In vitrLBD Fig. . To valiLBD Fig. . Togethells Fig. . Moreovells Fig. . TogetheThe current view on the persistent and reactivated AR signaling in CRPC, that forms the basis of targeting the AR-axis signaling in ADT, is largely based on the facts of positive AR expression detected in clinical CRPC tumor tissues , 41, perAR gene transcription and suppression of AR transcriptional activity in prostate cancer cells via a mechanism of recruitment of chromatin modifiers HDACs and LSD1 to the TLX-binding motifs at the AR gene promoter. We also observed that the expressions of at least two NED markers (ENO2 and CHGA) were significantly upregulated in TLX infectants. Our newly published results show that TLX exhibits an upregulation in PCSCs enriched by three-dimensional cultures [CDKN1A and SIRT1 [CDKN1A and SIRT1. However, the specific role of TLX in NEPC progression and stemness of advanced prostate cancer need further investigation.In the present study, we demonstrated that the orphan nuclear receptor TLX, which displayed an upregulation expression in both clinical mCRPC and xenograft models, could confer androgen insensitivity in AR-positive prostate cancer cells in vitro and in vivo. Our functional analyses further revealed that the TLX-induced androgen insensitivity was mediated through its direct repression of cultures . Our prend SIRT1 . Therefo−/low/PSAhigh and ARlow/ARhigh populations can be distinguished among prostate cancer patients [high/PSAhigh cell populations in castration-relapse CRPC tumors. Our present findings show that TLX can directly target and repress the AR gene promoter, and also suppress the ligand-activated transcriptional activity of AR in prostate cancer cells, and through which it could enhance the NED progression and stemness of PCSCs in subpopulations of CRPC. We also showed that histone modifiers HDACs and LSD1, whose overexrepression are implicated in CRPC progression [AR transcription. Indeed, TLX can interact with multiple co-regulators to mediate its transcriptional activity in target cells [Prostate cancer is a heterogeneous disease and exhibits different clinical behaviors in patients. Indeed, subsets of PSApatients , 54. Ourpatients , which egression , 56, canet cells . HoweverAR transcription via recruitment of histone modifiers HDACs and LSD1 , bicalutamide, pargyline hydrochloride, sodium butyrate (NaBut), trichostatin A (TSA), and valproic acid (VPA) were purchased from Sigma-Aldrich . The rabbit polyclonal TLX-antibody was immunoblot-validated as described previously . Other aHuman prostate cancer cell lines  and their sublines  were used in this study. LNCaP, LAPC-4, HEK293, and PA317 cell lines were obtained from ATCC . VCaP cells were kindly provided by Dr. Kenneth Pienta (University of Michigan); LNCaP-104-R1 cells from Dr. Shutsung Liao (University of Chicago); LNCaP-abl cells from Dr. Helmet Klocker (University of Innsbruck). LNCaP-abl cells were maintained in RPMI1640 supplemented with 10% CS-FBS and LNCaP-104R1 cells were cultured in DMEM with 10% CS-FBS. LNCaP-BC and VCaP-BC cells were established as described previously [Human prostate cancer tissue microarray was provided by Department of Defense Prostate Cancer Research Program, Prostate Cancer Biorepository Network (PCBN), NYU. Peroxidase immunohistochemistry was performed on paraffin sections of formaldehyde-fixed prostatic tissues as described previously .Escherichia coli. (b) Reporter plasmids: ARE-Luc was kindly provided by Dr. J.M. Vanacker  [(a) Expression plasmids pBABE-TLX, pWPI-TLX, pcDNA3.1-TLX, and truncated mutant pcDNA3.1-TLXΔZF1 and pcDNA3.1-TLXΔLBD-AF2 were generated as described previously . Full-le France) . pGL3-ARAAGTCA to AGATCA [from Dr. Angelo Poletti . pGL3-ARo AGATCA .The production of retrovirus and lentivirus, and generation of stable TLX-overexpressed cells, AR-positive prostate cancer cells  was performed as described previously , 63.Procedures on the generation of stable TLX-knockdown prostate cancer cells by shRNA were described previously .In vitro cell growth of TLX- or shTLX-transduced prostate cancer cells were evaluated by MTT assay as described previously .Procedures on AR immunofluorescence were described previously .Detailed procedures on PCR and immunoblotting are described as previously  and prim3 or larger. Host mice were then orchidectomized and allowed to grow for another 6–7 weeks. Tumor sizes were measured weekly. The VCaP-CRPC xenograft model was established previously [LNCaP-TLX and vector-control cells were subcutaneously inoculated into the flank region of intact male SCID mice and allowed to grow for 11 weeks when tumors reached sizes of 1 cmeviously . All aniRenilla-firefly dual-luciferase assay as described previously [For ARE-Luc and AR-Luc reporter assay performed in HEK 293 cells, plasmids were transduced into cells by Lipofectamine 2000 . For ARE-Luc reporter assay performed in LNCaP and LNCaP-TLX cells, cells were transduced with pGL3-ARE-Luc and pRL-SV40 by electroporation with an optimized exponential pulse of 230 V and 950 μF . After 24 h post transfection, cells were treated with hormone (DHT) or epigenetic modifiers  or vehicles  as control, and incubated for another 24 h. Cells were lysed for luciferase luminescence measurement using the eviously .AR gene promoter was performed in HEK293 cells transfected with pcDNA3.1-TLX/pcDNA3.1 or TLX-transduced LNCaP cells, following procedure as described previously [AR gene promoter .ChIP assay on eviously . GenomicProcedures on co-immunoprecipitation (Co-IP) assay were performed as previously descripted .E. coli cells were transformed with pGEX-TLX or pGEX-TLXΔLBD plasmids to express the GST-fusion recombinant proteins GST-TLX1–385 and GST-TLXΔLBD1–340. After protein induction with isopropyl-β-d-thiogalactopyranoside (IPTG), bacterial cells were sonicated in TIF lysis buffer  and the GST-fusions were affinity-purified with glutathione-sepharose 4B resin . For pull-down of overexpressed TLX, cell lysates of pWPI-TLX- and pWPI-TLXΔLBD-transduced LNCaP cells were incubated with the GST-fusion protein-bound beads overnight with rotation at 4 °C. After washing the beads with TIF buffer, the protein complexes were eluted with Laemmli-SDS sample buffer, separated by SDS-PAGE, and visualized by immunoblotting.BL2 (DE3) competent t test and differences were considered significant where P < 0.05.All results were expressed as mean ± SD. Statistical analysis of data was performed using two-tailed Student’s Supplementary figure S1-S3 and figure legends(PDF 808 kb)Supplementrary Table 1(DOCX 12 kb)


In luminal androgen receptor (AR) tumours, FOXA1 may direct AR to sites occupied by ER in luminal tumours, thus stimulating proliferation.PIK3CA mutations, PTEN defects and BRCA1 promoter methylation were assessed.AR and FOXA1 expression were evaluated by immunohistochemistry in 333 non-metastatic triple-negative breast cancers (TNBC). Positivity threshold was set at ≥ 1% staining. Lymphocytic infiltration, PD-L1expression, PIK3CA mutations; exhibited less frequently BRCA1 promoter methylation, defects of PTEN and PD-L1 expression than others. Recurrence-free and overall survivals were significantly lower for AR + /FOXA1 + TNBC (median follow-up: 7.8 years).AR + /FOXA1 + tumours (42.4%) were more frequently: found in older patients, lobular, of lower nuclear grade, with more frequently PIK3CA mutations, suggesting a role for PI3K inhibitors in this subgroup.AR + /FOXA1 + expression defines a luminal-like TNBC subgroup affected with a worse outcome compared to other TNBC and a higher risk of late recurrences. This subgroup appears enriched in  LAR cell lines are sensitive to AR antagonists.1 Using immunohistochemistry (IHC), AR is expressed in 8–53% of TNBC2 and its prognostic value is controversial.4Triple negative breast cancers (TNBCs) represent 15% of all breast cancer (BC) and are defined by the lack of oestrogen receptor (ER), progesterone receptor (PR) and HER2 expression/amplification. This subgroup of BC is extremely heterogeneous: Lehmann et al. distinguished seven TNBC subtypes displaying unique gene expression profiles, including the luminal androgen receptor (LAR) subtype.PIK3CA activating mutations and PTEN loss of expression may contribute to BC therapeutic resistance. In the study of Lehmann et al., PIK3CA mutations were more frequent in AR + TNBC than in AR- TNBC.5The phosphatidylinositol 3-kinase (PI3K) signalling pathway is crucial for cell growth and survival. 6 TNBCs are thought to be more immunogenic than other BC and AR + TNBC show a higher frequency of PD-L1 expression.7Programmed cell death (PD-1) is an immune checkpoint receptor. Its ligand, PD-L1, is expressed by immune cells, BC cells, and tumour-infiltrating lymphocytes (TILs). PD-1 binding to PD-L1 specifically inhibits T-cell activation and represents one mechanism of immune tumour escape.8 Our team has shown that AR + /FOXA1 + TNBC even tend to behave like luminal tumours.9 These two biomarkers could be useful to identify a particular subgroup of TNBC.In LAR tumours, AR functionality is dependent on FOXA1: FOXA1 is required for AR binding chromatin, AR transcriptional activity and cell growth, directing AR to sites normally occupied by ER in luminal tumours, inducing an oestrogen-like programme stimulating proliferation.PIK3CA status.This study aimed to evaluate in a large series of non-metastatic TNBC with a long follow-up both the profiles and the prognostic value of AR/FOXA1 co-expression and its correlation with other biomarkers like PD-L1 and This study included 349 patients with unifocal, unilateral, untreated, non-metastatic TNBC operated in our institution between 2002 and 2012. ER and PR negativity was defined as < 10% by IHC and HER2 negativity was defined as IHC 0/1 + or 2 + and negative fluorescent/chromogenic hybridisation in situ.BRCA1 promoter hypermethylation and is associated with basal markers, we also assessed BRCA1 promoter methylation status. AR and FOXA1 positivity cut-off was ≥ 1% (nuclear staining) , with a more frequent nodal involvement  compared to AR- tumours. They exhibited tumours with significantly lower grades , more frequent lobular histology  and PIK3CA mutations , less basal-like phenotype , BRCA1 promoter methylation  and defects in PTEN . There was no significant difference for TILs density, neither for PD-L1 expression   were significantly older (p = 0.003) than others. They exhibited tumours with significantly lower grades , a more frequent lobular histology  and PIK3CA mutations , a lower frequency of basal-like phenotype , BRCA1 promoter methylation , PTEN defects (p = 0.026) and PD-L1 expression [for both tumour cell membrane (p = 0.009) or TIL staining (p = 0.015)]. There was no significant difference regarding TILs density. AR + /FOXA1- and AR- tumours more frequently exhibited a staining of > 50% of TILs, compared to AR + /FOXA1 + tumours (10–50% of stained TILs more frequent)  with FOXA1 + tumour. The concordance rate between the two cores was 89.8%. Supplemental table After a 7.8 year median follow-up [0.6-14.7], 77 relapses  and 89 deaths  were reported  , nodal involvement (p < 0.001), adjuvant chemotherapy (p = 0.005), AR status (p = 0.034), AR/FOXA1 co-expression (p = 0.020), TILs density (p = 0.002) and PD-L1 expression by TILs (p = 0.018)  Fig. . Univari p = 0.03, AR/FOXAp = 0.024) , tumour size (p < 0.001), nodal involvement (p < 0.001), adjuvant chemotherapy (p < 0.001), AR status (p = 0.046), AR/FOXA1 co-expression (p = 0.024) and TILs density (p = 0.023)  Fig. . In univ p = 0.02 (SupplemN = 145), RFS (p = 0.012) and OS (p = 0.002) were shorter in case of AR/FOXA1 co-expression , our results are in accordance with the literature.11 Lehmann et al showed that PIK3CA mutations were significantly enriched among LAR TNBCs (46.2%) compared to all other TNBC subtypes (4.5%), with a predominance of exon 20 mutations that encode the catalytic domain of PI3K.5 We observed similar results with 27.7% of PIK3CA mutations in AR + TNBC (16.1% on exon 20) compared to 3.3% in AR- tumours . PTEN inactivation leads to constitutive AKT activation, promoting cell growth, proliferation, survival, and migration. Millis et al reported 58% of PIK3CA or PTEN mutation/protein loss in AR + TNBC,11 which is concordant with our results (40.0% PIK3CA mutation/PTEN aberration). Subgroup analysis showed a significantly higher PIK3CA mutation rate in the AR + /FOXA1 + subgroup (31.8% vs 16.7% in AR + /FOXA1- and 3.5% in AR-). Ongoing clinical trials are currently evaluating the association of anti-androgen therapy and PIK3 inhibitor. FOXA1 will allow the identification of a TNBC subgroup that could retrieve more benefit from this therapeutic strategy.Regarding the Stromal TILs constitute a robust and an independent prognostic marker in TNBC treated with chemotherapy. In our series, TILs density was also a strong and independent prognostic factor for both RFS and OS. To the best of our knowledge, no study has yet evaluated the correlation between TILs and AR expression. In our study, there was no difference between AR + and AR- tumours on this point, including in the subgroup analyses according to FOXA1 status.7 reporting a 2.6-fold higher PD-L1 rate in their AR + TNBC population.7 A higher rate of PD-L1 expression was seen in the AR + /FOXA1- subgroup (76.7% vs 49.6% in AR + /FOXA1 + and 55.2% in AR-). Among patients with a PD-L1 + tumour, we found significantly poorer RFS and OS in case of AR/FOXA1 co-expression. It could be interesting to specifically evaluate the benefit of anti-PD1 or PD-L1 targeted therapies in association with an anti-androgen in this subgroup.Cancer cell could escape from immune surveillance by upregulating PD-L1 expression. The rate of PD-L1 expression in TNBC is extremely variable across studies, due to the lack of standard assay and its prognostic value remains controversial. In our study, 56.1% of TNBC expressed PD-L1 and it was not an independent prognostic marker in multivariate analysis. The 1% threshold for positivity was selected based on data demonstrating a clinical response to PD-L1 inhibition at this expression level in some cancers. There was no difference regarding PD-L1 expression and AR status in our series, contrary to the results of Tung et al.PIK3CA mutations, advocating for PIK3 inhibitors evaluation, alone or in association with anti-androgens, in this specific subgroup. All these data suggest the need for a concomitant evaluation of AR/FOXA1 to identify a specific subgroup of patients with TNBC who could benefit from targeted therapies.In this large homogeneous series with a long follow-up, 42% of non-metastatic TNBC presented an AR/FOXA1 co-expression. AR + /FOXA1 + expression defines a luminal-like TNBC subgroup with a worse outcome compared to other TNBC and a higher risk of late recurrences mimicking luminal tumours behaviour and suggesting a putative role for anti-androgen therapies. This subgroup appears enriched in Supplemental Figure 1Supplemental Figure 2Supplemental Figure 3ASupplemental Figure 3BSupplemental Table 1Supplemental Table 2Supplemental Table 3Supplemental Table 4Supplemental Table 5Supplemental data 1


We conducted a national population-based cohort study by obtaining patient data from the National Health Insurance Research Database of Taiwan for the 2008–2013 period. PM2.5 concentration data were obtained from the ambient air quality monitoring network established by the Environmental Protection Administration of Taiwan. Monthly PM2.5 exposure levels were categorized into quartiles from Q1–Q4. The Cox proportional hazards analysis, after adjusting for age, sex, low income, and urbanization level, revealed that patients with AR had an elevated risk of developing AD (hazard ratio (HR): 2.008). In addition, the cumulative incidence of AD in the AR group was significantly higher than in the comparison group. The PM2.5 levels at Q2–Q4  were stratified on the basis of the PM2.5 exposure group and revealed that AR patients exposed to PM2.5 are significantly prone to develop AD. In addition, the logistic regression analyses, after adjustment, demonstrated that an increase in the PM2.5 exposure level at Q2–Q4 (adjusted odds ratio (OR): 2.656–5.604) increased the risk of AR in AD patients. In conclusion, an increased PM2.5 exposure level could be correlated with AR, which could in turn cause AD. AR increased the risk of AD, in which exposure to PM2.5 increases the higher probability of AD.Alzheimer’s disease (AD) is an irreversible neurodegenerative disease that leads to dementia, health impairment, and high economic cost. Allergic rhinitis (AR) is a chronic inflammatory and allergic disease of the respiratory system that leads to health problems and has major effects on the daily lives of patients and their caregivers. Particulate matter (PM) refers to air pollutants 2.5 μm or less in diameter that are a source of concern because of their role in numerous diseases, including AR and other neurodegenerative diseases. To date, no study has demonstrated how PM Alzheimer’s disease (AD) is an irreversible and progressive neurodegenerative and neuroinflammatory disease that leads to the impairment of memory, cognition, and behavior ,2. The mAllergic rhinitis (AR), an IgE-mediated inflammatory and allergic disease of the respiratory system, is characterized by symptoms such as nasal congestion, anterior nasal leakage, airflow obstruction, posterior rhinorrhea, olfactory dysfunction, and sneezing . Althoug2.5, referring to air pollutants or particulate matter with a size of 2.5 μm in diameter or less, is a concern because of its potential negative health effects. Indeed, PM2.5 is highly correlated with AR and influences its occurrence in China and Germany [2.5 exposure is a major risk factor for neurological disorders, such as AD, stroke, dementia, autism spectrum disorder, and Parkinson’s disease [2.5. The present study investigated the relationship between AR and AD at various levels of PM2.5 exposure.Epidemiological studies have revealed a rapid increase in the prevalence of AR in the past decades . The inc Germany ,13. In a disease . Inflamm disease . To dateIn the present study, the patient data were sourced from the Longitudinal Health Insurance Database (LHID) of the National Health Insurance Database (NHIRD), which is the compulsory insurance database used primarily for reimbursement purposes in Taiwan. The NHIRD provides de-recognized files that contain information concerning healthcare services rendered to more than 99% of Taiwan’s 23 million residents. Data regarding inpatient and outpatient visits, admissions, and discharges in the NHIRD records are coded by physicians according to the International Classification of Disease, 9th Revision, Clinical Modification (ICD-9).2.5 concentrations in the atmosphere were measured using a tapered element oscillating microbalance . The measured values were recorded every hour. The protocol of study was approved by the Ethics Review Committee of Chung Shan Medical University Hospital (CS215106). Since the time unit used during follow-up period was the month, this study used the monthly average cumulative exposure as a comparison of patient exposure. The patient exposure was based on the exposure of the station where the patient is located. If there is no station at the location of the patient, it was based on the nearest station. The monthly average cumulative exposure of the patient was observed from 2008 to the end point. The cumulative exposure per hour was multiplied by 24 as the basis for daily exposure, which was excluded if there were more than 8 h of observed omissions. The average daily exposure is multiplied by the number of days in the month is the monthly average exposure, which is excluded if there are more than 10 days of observed omissions. The monthly average PM2.5 concentration was estimated and considered as the population exposure at the county level using data from AQMN in Taiwan. We refer to the study using quartiles as the basis for grouping exposure concentrations [2.5 were categorized into the following quartiles: <25th percentile (Q1), <646 μg/mm3; 25–50th percentile (Q2) 646–1253 μg/mm3; 50–75th percentile (Q3), 1253–2056 μg/mm3; and >75th percentile (Q4), >2056 μg/mm3.The Environmental Protection Administration of Taiwan (TEPA) set up the ambient air quality monitoring network (AQMN) in Taiwan to monitor general air quality . The PM2trations  To corro2.5 undetected from AQMN. From 2008–2013, 3803 patients were diagnosed with AD. All enrolled cases were divided into AR and non-AR (comparison) groups. In the AR group, the date of the first AR diagnosis was the index date, and then the patients visited doctors for AR treatment at least two times. In the comparison group, the index date was 1 January 2008. The date of AD diagnosis was considered the end point. We excluded patients with an end point before the index date.Datasets for the years 2008–2013 from the LHID and AQMN were obtained for the present study. As illustrated in The basic characteristics of the subjects included sex, age, low income, and urbanization levels. The age divided into young group (aged 30–44 years), middle-aged group (aged 45–59 years), young-old group (aged 60–74 years), and middle-old group (aged 75-years). Exemption of income tax represents family monthly income less than 20,000 NTD (New Taiwan Dollar) per month in Taiwan   and 95% CI. Multivariable models were adjusted for AD-related co-morbidities, gender, age, low-income, and urbanization level. Kaplan–Meier Curves estimating cumulative incidence of AD between AR and non-AR patients. Conditional logistic regression was used to estimate the patients with AD odds ratios (ORs) and 95% confidence intervals for the risk factors of AR. Potential risk factors were sex, age, low income, other operations, and comorbidities. Statistical analyses were performed using SAS 9.3 software , and p < 0.05 was considered statistically significant.The χp < 0.0001, p < 0.001; p < 0.05) and low income  patients were the risk factor for AD. Patients lived in remote township  was a risk factor for AD. However, patients with comorbidities such as hypertension , hyperlipidemia , and extrapyramidal signs  were at a reduced risk compared with those with none.During the follow-up period, the cumulative incidence of AD in the AR group was significantly higher than that in the comparison group . In the PM2.5 exposure level in Q2–Q4 level, patients with AR were at a significantly higher risk for AD , suggesting that the higher the cumulative exposure to PM2.5 for AR patient is, the higher the risk of AD is.2.5 and the AR in AD patients [2.5 exposure at Q1 level as controls in the analysis of case-cohort studies. This trick similar as pervious study [2.5 exposure level and risk of AR in AD patients was analyzed by logistic regression better than probit regression, COX regression, and Prentice’s model. Logistic regression analyses were used to calculate the odds ratios (ORs) and CIs for the association between the cumulative level of PM2.5 exposure and AR in AD patients. The adjusted OR (CI) for cumulative levels of PM2.5 at Q2, Q3, and Q4 were 2.656 (1.666–4.234), 4.805 (2.606–6.401), and 5.604 (3.607–8.706). The results indicate that PM2.5 is a risk factor for AR in patients with AD . However, the concentration-dependent effects of PM2.5 on the exacerbation of AR in animal models and human trials have been reported globally [2.5 exposure level is a major risk factor for AR [2.5 exposure and AR in patients with AD. As shown in 2.5 at Q2, Q3, and Q4 were 0.327 (0.096–0.557), 0.474 (0.249–0.699), and 0.622 (0.402–0.843), respectively. Similar to the logistic regression model, elevation of the PM2.5 exposure level caused the risk of AR. All the aforementioned evidence indicates that PM2.5 could be the risk factor for AD by increasing the risk of AR. On the basis of adjusted HRs and ORs in our study, we determined that higher PM2.5 exposure levels increase the risk of AR and in turn AD.The present study entailed a systematic review and meta-analysis and observed a strong association between PM disease . To dateglobally ,31,32. Tr for AR . Olfactor for AR . Olfactor for AR . Patientr for AR ,37. On t2.5 exposure levels in the patients with AD, data analysis was based on their registered addresses, which were obtained from personal IDs in the NHIRD rather than the actual residences of the patients.The merits of the present study consist of its use of population-based data, which are highly representative of the general population. However, several potential limitations of the present study should be considered. First, the NHIRD does not include data on the behavior and lifestyles of patients; for example, smoking, secondhand smoking, eating habits, and psychological stress. Among these factors, smoking, secondhand smoking, depression, anxiety, and eating habits have been reported to influence the risk for AR and AD. Second, with regard to the PM2.5 is a risk factor for AR in patients with AD, after the adjustment for PM2.5, age, occupational category, urbanization level, and comorbidities. The present study demonstrates that with an increase in PM2.5 concentration, the risk of patients with AD having AR will also rise. Our study is the first national population-based cohort study to suggest that PM2.5 exposure level is a major risk factor for AR and the further development of AD.According to the results of the present study, we could purposed that AR is a risk factor for AD, and PM2.5 are significantly prone to develop AD. The logistic regression analyses demonstrated that an increase in the PM2.5 exposure level at Q2–Q4 increased the risk of AR in AD patients. Our study is the first national population-based cohort study to suggest that PM2.5 exposure level is a major risk factor for AR and the further development of AD.AD is the irreversible and progressive neurodegenerative and neuroinflammatory disease. AR is an inflammatory and allergic disease of the respiratory system. The Cox proportional hazards analysis purposed that patients with AR had an elevated risk of developing AD. More, AR patients exposed to PM


Inpatient rehabilitation is an expensive option following total hip arthroplasty (THA). We aimed to determine if THA patients who receive inpatient rehabilitation report better hip and quality of life scores post-surgery compared to those discharged directly home.Prospective, propensity score matched cohort involving 12 private hospitals across five Australian States. Patients undergoing THA secondary to osteoarthritis were included. Those receiving inpatient rehabilitation for reasons other than choice or who experienced significant health events within 90-days post-surgery were excluded. Comparisons were made between those who did and did not receive inpatient rehabilitation for patient-reported hip pain and function  and ‘today’ health rating . Rehabilitation provider charges were also estimated and compared.P = 0.60; 0 (− 1 to 1), P = 0.91, at 90 and 365-days, respectively; EuroQol scale median difference 0 , P = 0.24; 0 , P = 0.49; 5 , P = 0.09, at 35-, 90- and 365-days, respectively]. Median rehabilitation provider charges were 10-fold higher for those who received inpatient rehabilitation . Sensitivity analyses corroborated the results of the primary analyses.Two hundred forty-six patients  yr., 66% female) were matched on 19 covariates for their propensity to receive inpatient rehabilitation. No statistically nor clinically significant between-group differences were observed [OHS median difference (IQR): 0 , Utilization of inpatient rehabilitation pathways following THA appears to be low value healthcare. Sustainability of inpatient rehabilitation models may be enhanced if inpatient rehabilitation is reserved for those most impaired or who have limited social supports.NCT01899443.ClinicalTrials.gov Identifier: The online version of this article (10.1186/s12891-018-2134-3) contains supplementary material, which is available to authorized users. Total hip arthroplasty (THA) has been heralded as the ‘operation of the Century’ . Large iFollowing surgery, physiotherapy-led exercise-based rehabilitation is often prescribed . EvidencOnly one randomized controlled trial (RCT) has been published aimed at determining the efficacy of inpatient therapy over a non-inpatient alternative following THA . EighteeRandomized trials are difficult to undertake in general, but they are particularly difficult to perform in the private healthcare sector where consumer and provider preferences are strong drivers of care delivery , 27. ThiIn light of the difficulty in performing an RCT, this study, using a propensity score (PS) matched cohort, aimed to determine whether privately insured THA patients who received inpatient rehabilitation, compared to those who did not, had better patient-reported joint and health scores across the first 12 months post-surgery. Informed by the high- and low-level evidence in this area, we hypothesized that the inpatient pathway would not procure superior patient-reported recovery to a level that was clinically meaningful over the alternative.ClinicalTrials.gov Identifier: NCT01899443). We have previously reported the results of a related PS matched cohort aimed at determining the effectiveness of a rehabilitation pathway involving inpatient rehabilitation compared to one not involving inpatient rehabilitation following TKA .In the unmatched cohort, a PS was estimable for 403 patients. The mean (SD) propensity score for the sample was 0.34 (0.18). Assessment of the overlap of the PSs across the unmatched groups revealed sufficient common support between the two treatment groups [Inpatient Group, In the unmatched cohort, the inpatient rehabilitation group was older, had more males, had higher levels of comorbidity, and worse baseline OHSs Table . Unadjus35- and 90-days: Table 365-days: The Inpatient Group did not have superior outcomes at 365 days; the median OHS in both groups was the maximum score possible (48). Sensitivity analyses for the 365-day outcomes involving 114 pairs, yielded the same results  of privately insured patients may require inpatient rehabilitation based on these three conditions  Additional file 2:Sensitivity analysis 1. Sensitivity analysis for 365 day outcomes. (DOCX 19 kb)Additional file 3:Sensitivity analysis 2. Sensitivity analysis to determine effect of ‘hospital’ and ‘surgeon’. (DOCX 39 kb)Additional file 4:Sensitivity analysis 3. Sensitivity analysis to determine effect of the unmeasured confounders. (DOCX 21 kb)