The demographic transition towards an ageing population and the epidemiological transition from communicable to noncommunicable diseases have increased the demand for rehabilitation services globally. The aims of this paper were to describe the integration of rehabilitation into the Japanese health system and to illustrate how health information systems containing real-world data can be used to improve rehabilitation services, especially for the ageing population of Japan. In addition, there is an overview of how evidence-informed rehabilitation policy is guided by the analysis of large Japanese health databases, such as: (i) the National Database of Health Insurance Claims and Specific Health Checkups; (ii) the long-term care insurance comprehensive database; and (iii) the Long-Term Care Information System for Evidence database. Especially since the 1990s, the integration of rehabilitation into the Japanese health system has been driven by the country’s ageing population and rehabilitation is today provided widely to an increasing number of older adults. General medical insurance in Japan covers acute and post-acute (or recovery) intensive rehabilitation. Long-term care insurance covers rehabilitation at long-term care institutions and community facilities for older adults with the goal of helping to maintain independence in an ageing population. The analysis of large health databases can be used to improve the management of rehabilitation care services and increase scientific knowledge as well as guide rehabilitation policy and practice. In particular, such analyses could help solve the current challenges of overtreatment and undertreatment by identifying strict criteria for determining who should receive long-term rehabilitation services. Member States of the United Nations are committed to sustainable development goals,We describe how rehabilitation services were integrated into the Japanese health system and discuss the potential of new health information systems based on real-world data for developing evidence-informed rehabilitation policies and practices that will strengthen services in the country.,–Historically, the Japanese government began to train rehabilitation professionals under the guidance of WHO. The first school of rehabilitation – the Professional School of Rehabilitation at the National Sanatoria Tokyo Hospital – was established in 1963 , the Phy,,Japan achieved universal health coverage through the establishment of a national health insurance system in 1961.A unit-based payment system for rehabilitation was introduced in 2002 under which a fee is charged for each 20-minute unit of rehabilitation. In 2006, a new payment system was introduced that stipulated time-limits on intensive rehabilitation for different disease groups.Many high-income countries use a bundled payment system based on diagnosis-related groups to pay for rehabilitation services, whereas Japan employs a fee-for-service approach within the health insurance system.The long-term care insurance system established in 2000, which is based on the principle of supporting independent living, enables services such as nursing, long-term care and rehabilitation to be provided in both people’s homes and long-term care facilities.,In 2011, a community-based integrated care system was introduced following a revision of the Long-Term Care Insurance Law.Strict criteria need to be established for determining who should be covered by rehabilitation services because everyone’s health and well-being could potentially benefit from rehabilitation. After the intensive rehabilitation system was introduced in Japan in 2006, the maximum monthly limit on rehabilitation services was removed. Instead, the duration of intensive rehabilitation was determined for individual disease groups, which had the effect of counterbalancing supplier-induced demand for overtreatment to a certain extent. In addition, intensive rehabilitation was reserved for those diseases and clinical disease phases for which there was evidence that interventions were cost-effective and had substantial benefits for patients.Long-term care insurance differs from medical insurance in having no clear criteria for determining which individuals who require long-term care can have access to rehabilitation. In extreme cases, patients may be permitted to undergo rehabilitation if they demand it, even if there is no real prospect of recovery. Another concern is overtreatment by providers but, on the other hand, there is also the possibility of undertreatment. For people who require long-term care, it might not be appropriate to set an initial limit to their rehabilitation based on disease duration or type because many other factors can contribute to functional decline and the resultant need for rehabilitation. In Japan, efforts have recently been made to improve the management of, for example, short-term intensive rehabilitation immediately after hospital discharge. Overall, it is vital that an effective system is established for providing long-term rehabilitation, especially for an ageing population.,,Globally, an increasing number of studies are making use of health-care databases.,,The Japanese National Database of Health Insurance Claims and Specific Health Checkups is a comprehensive database covering insurance claims for medical service fees under Japan’s National Health Insurance system .22 In 20Although insurance claims data are particularly useful for descriptive epidemiological research and large-scale follow-up surveys, they are limited: the databases lack information on disease severity, on the socioeconomic characteristics of patients and their families, on the patients’ educational level and on laboratory test results, which are key outcome measures. This lack of information can confound study results, which therefore need to be interpreted with caution.Details of rehabilitation services provided under the medical insurance system are stored in the National Database of Health Insurance Claims and Specific Health Checkups, and the long-term care insurance comprehensive database contains information on rehabilitation provided both in the community and in long-term care facilities .Previously the National Database was employed primarily to study the usage of rehabilitation services. For example, a recent study investigated cardiac rehabilitation for patients who underwent a percutaneous coronary intervention or coronary artery bypass grafting between April 2017 and March 2018.Other potential applications of the National Database in Japan include analysing the quality and utilization of rehabilitation services by geographical region . By using these large data sets, researchers can estimate future demand for rehabilitation in each geographical region, thereby guiding the expansion of rehabilitation services in a way that minimizes regional gaps.,One example of the application of these large data sets was our analysis of the impact of the coronavirus disease 2019 (COVID-19) pandemic on rehabilitation services. We used data from the National Database of Health Insurance Claims and Specific Health Checkups and long-term care insurance claims data to compare rehabilitation service utilization before the pandemic in 2019 with that during the pandemic in 2020.,–In early 2022, with the appearance of the omicron variants of severe acute respiratory syndrome coronavirus 2, there was no sign of the pandemic ending and, by 13 January 2022, Japan had reported a total of 1.79 million cases and 18 412 deaths.The collection of good-quality evidence is essential for providing effective and efficient rehabilitation in a range of contexts, such as during the COVID-19 pandemic. However, there is a lack of evidence on the effectiveness of long-term rehabilitation.The quality of long-term care has recently been recognized as important for dealing with issues that arise from population ageing. Consequently, there is a growing interest in Japan in developing evidence-based care on the same principles as evidence-based medicine.The LIFE database currently contains data submitted voluntarily by service providers on service users and on the services provided. In contrast, the National Database of Health Insurance Claims and Specific Health Checkups and the long-term care insurance comprehensive database cover the services provided by all agencies throughout the country. Data are submitted to the LIFE database when a reimbursement claim for long-term care is made, with each reimbursement claim corresponding to one long-term care service user. According to the August 2021 monthly report, 1275 million claims, which included information on users’ conditions, were submitted that month to the LIFE database from long-term care service providers.Recently, the government has started to use the LIFE database to help service providers improve the management of their businesses and service performance. Based on its analyses, the government gives providers feedback on each service user’s condition and the services performed so they can compare themselves against the national average and improve their operations if necessary. In addition, service providers are expected to enter details of changes in service users’ conditions into the LIFE database, which will also help improve the quality of services.–In addition to its use for improving the business management of care services, the analysis of LIFE data is expected to help guide policy and increase scientific knowledge. The LIFE database contains a wealth of information on individuals and their conditions and on rehabilitation interventions and their outcomes , includiBox 1Confidence; visuospatial perception; language; mental functioning in sequencing complex movements; hearing; pain; voice; respiration; exercise tolerance functions; ingestion functions; joint mobility; muscle power; muscle tone; muscle endurance functions; and movement functions.Basic learning; learning to read; learning to write; learning to calculate; solving problems; making decisions; carrying out daily routine; handling stress and other psychological demands; changing basic body position; maintaining body position; transferring oneself; carrying, moving and handling objects; walking and moving; using transportation; washing oneself; caring for body parts; toileting; dressing; eating and drinking; looking after one’s health; acquisition of goods and services; preparation of meals; washing and drying clothes and garments; cleaning cooking area and utensils; cleaning living area; household tasks, other specified and unspecified; maintaining dwelling and furnishings; maintaining domestic appliances; taking care of plants; taking care of animals; general interpersonal interactions; remunerative employment; recreation and leisure; and products and technology.ICF: International Classification of Functioning, Disability and Health; LIFE: Long-Term Care Information System for Evidence.Notes: Body functions, body structures, activities and participation are domains defined in ICF. Whenever rehabilitation or functional training is provided, information on the intervention is recorded in the LIFE database using the same categories as the ICF with the exception of two categories that are included in the LIFE database only: “giving information” and “teaching how to care.”Today, it is common practice in Japan for care policy and practice to be guided by the evidence through knowledge translation. For instance, recently a long-term care prevention programme using a population approach was developed and adopted as national policy on the basis of the scientific evidence.We have summarized how rehabilitation was integrated into the Japanese health system and how large data sets can be used to develop evidence-informed rehabilitation policy and practice. Since the 1990s, in particular, the integration of rehabilitation has been driven by Japan’s ageing population and, today, a growing number of older adults are able to maintain their independence with the help of rehabilitation. The analysis of large data sets could also help solve current issues, such as overtreatment, by identifying strict criteria for determining who should receive long-term rehabilitation services.


Virtual reality (VR) and augmented reality (AR) are aspiring, new technologies with increasing use in critical care medicine. While VR fully immerses the user into a virtual three-dimensional space, AR adds overlaid virtual elements into a real-world environment. VR and AR offer great potential to improve critical care medicine for patients, relatives and health care providers. VR may help to ameliorate anxiety, stress, fear, and pain for the patient. It may assist patients in mobilisation and rehabilitation and can improve communication between all those involved in the patient’s care. AR can be an effective tool to support continuous education of intensive care medicine providers, and may complement traditional learning methods to acquire key practical competences such as central venous line placement, cardiopulmonary resuscitation, extracorporeal membrane oxygenation device management or endotracheal intubation. Currently, technical, human, and ethical challenges remain. The adaptation and integration of VR/AR modalities into useful clinical applications that can be used routinely on the ICU is challenging. Users may experience unwanted side effects  during VR/AR sessions, which may limit its applicability. Furthermore, critically ill patients are one of the most vulnerable patient groups and warrant special ethical considerations if new technologies are to be introduced into their daily care. To date, most studies involving AR/VR in critical care medicine provide only a low level of evidence due to their research design. Here we summarise background information, current developments, and key considerations that should be taken into account for future scientific investigations in this field. Both, virtual reality (VR) and augmented reality (AR) are technological breakthroughs which facilitate entertainment and communication worldwide . VR immePatients often experience the ICU as a “hostile” environment due to a number of factors including: excessive noise, loss of self-autonomy and a lack of information . This isRousseaux et al. randomised 100 cardiac surgery patients into four arms . Every patient underwent one of the techniques for 20 min the day before and the day after surgery. , 10. HowIn the subgroup of paediatric critically ill patients, VR applications have been shown to have a positive effect on stress, anxiety, and delirium. Badke et al. conducted a cross-sectional, single-arm pilot study with 32 paediatric ICU patients who were provided with simple VR headsets and smartphone videos from a widely available multimedia source for distraction . In thisIn conclusion, many studies suggest a positive effect of VR on stress, anxiety, and delirium in critically ill patients. To date, the largest, prospective, randomised-controlled trials in this area have shown neutral  or positAlong with anxiety and stress, pain is one of the most common, and burdensome symptoms in critical care patients. The concept of using VR to distract patients during painful procedures emerged in the late nineteen nineties Fig. : There i“Intensive care unit acquired weakness” during an extended ICU stay is a common phenomenon and has a negative impact on short- and long-term outcomes . VR applUp to 60% of ICU survivors suffer from significant long-term neurocognitive impairment . Turon eFollowing ICU treatment, many patients suffer from Post Intensive Care Syndrome (PICS), which consists of mental health issues, cognitive dysfunction, and problems with mobility . It was Admission to a paediatric intensive care unit poses significant stress and uncertainty on relatives—especially the parents. During the COVID-19 pandemic, parents had limited ability to participate in clinical rounds. As a countermeasure, Tallent et al. developed a VR-based virtual visit to the ICU. The VR-visit did not increase the duration of the ward. . In thisVR can be used as a tool to train staff how to manage different clinical scenarios and perform clinical skills. , 4. VR hn = 30) received a VR simulation for 15 min, and the control group regular text-based training. VR increased self-efficacy, including familiarity and confidence, and reduced anxiety about tracheostomy-related knowledge and skills compared to the control group. This effect persisted until three to four weeks after the intervention [Multiple studies have been conducted to test the ability of VR to support learning and training of health care providers. In an ICU setting, Chiang et al. evaluated the success of VR-based learning on tracheostomy care in a prospective, controlled, 2:1 randomised pre–post-study. The interventional group  on intubating an infant manikin, in a controlled trial. The primary endpoint (the performance accuracy measured by a checklist) did not differ between groups . Over 20Stress affects ICU health care providers, potentially resulting in burnout and decreased productivity . Nijlandp = 0.003) [AR can assist health care providers in critical care procedures, such as intubation or central line placement. Alismail et al. conducted a controlled trial with 32 ICU trainees. The AR group (15 participants) used head-mounted AR glasses during endotracheal intubation of a training doll. The AR display repeated the essential, practical steps. The interventional group needed more time to intubate and ventilate, but had a higher adherence to evidence-based intubation practice . Airway = 0.003) . Heo et = 0.003) .AR can also be used to assess the mental and physical status of patients more accurately and may improve the recognition of deteriorating vital signs. In a trial by Zackoff et al., ICU teams completed two critical care scenarios: first, traditional training using a manikin, then AR-enhanced training using a manikin. AR improved the ability to assess the patient's mental status, respiratory status, and perfusion status, as well as recognition of hypoxemia, shock, apnoea and decompensation, but not the recognition of cardiac arrest.Central line placement and endotracheal intubation are standard ICU procedures but can be associated with severe complications. Percutaneous dilatational tracheostomy is a frequently performed intervention on the ICU. In this context, Gan et al. used AR in six patients undergoing the aforementioned procedure with “good success and excellent user feedback” . The useThere are a number of promising indications for AR/VR use in critical care medicine, which could be integrated into daily practice. VR could be part of a multimodal strategy, used to reduce analgesic requirements. Likewise, VR may help to support cognitive stimulation and physical activity. However, AR/VR applications are not designed to, and will not be able to, replace personal communication. Patients and their relatives welcome VR-assisted information about ICU procedures . A similVR can cause side effects such as headache, nausea and vomiting—so-called “cybersickness”—which can be related to motion sickness . CybersiIf there is a choice, a human-to-human interaction should be preferred  over human-to-machine interaction .VR technology should centre around “critical human values,” including dignity and autonomy .VR systems should be patient centred, not focusing on the need of professional customers (“patient-centered design”).In vulnerable patient groups, such as critically ill patients, there are some ethical concerns regarding the use of VR/AR. For this purpose, Kellermeyer et al. established three core principles :If thereFrom our point of view, these principles are of pivotal importance. VR/AR should always enhance the real-world provider—patient-relationship and should not be a tool to replace it. Some researchers proposed the creation of a new medical specialty, the “virtualist”, who undergoes extensive technical and medical training, but also has a deep understanding of the ethical implications of VR/AR technologies . We beliLtd or Healthy Mind®). Most studies are "proof-of-principle" approaches focusing on the feasibility and safety of a specific VR/AR application.There are a number of difficulties surrounding clinical studies using VR/AR applications. Namely, due to the extensive range of VR/AR glasses (hardware) and software it is extremely difficult to make a direct comparison. In fact, both components are often tested simultaneously in one trial, which may lead to interaction and a lack of clarity in the interpretation of results. . In futuAnother problem is that VR hardware is rapidly evolving: head-mounted displays are generating ever-higher graphics resolution, easier interactivity, and, thus, greater immersion. Therefore, studies using the latest VR hardware demonstrate greater utility than older devices.Unfortunately, the degree of immersion and occurrence of cybersickness are rarely measured or reported, although the effect of VR crucially depends on it . ComplexCurrently, there is a lack of prospectively randomised controlled trials in this area of research. In addition, none of the studies were blinded. Theoretically, the intervention group could be compared with a control group, in which “sham VR applications” are used. “Sham VR applications” could consist of using VR glasses with no specific digital content. It is often difficult to distinguish between the relative benefits of immersive VR compared with established non-pharmacological distraction methods such as relaxation techniques or music therapy. At a minimum, investigators should be blinded to reduce bias.Methodical separation of software and hardware.A detailed statement of the software development and validation process.Prospective trial design with a randomised-controlled recruitment.If possible, double blinding, but at least single blinding should be ensured.Degree of immersion measurement.Structured recording of "cybersickness" using validated scores.Descriptive measures of “usual care” in the control group.In summary, future studies should consider the following aspects:With the ongoing COVID-19 pandemic, innovative VR and AR applications offer new solutions for many aspects of daily critical care medicine. With advancing data transfer speeds; additional applications are emerging, such as remote distance treatment and care. Currently, remote treatments using robotic devices are under development . This mi


The concentration of exhaled NO and CO is considered as a candidate marker of respiratory inflammatory disease. This report discusses the exhaled NO and CO in the auxiliary diagnosis and evaluation of allergic rhinitis (AR).  60 AR patients from October 2017 to March 2019, compared with 30 healthy controls. The severity of AR disease was distinguished by symptom score. Both groups were tested for exhaled nitric oxide through the nose or mouth and exhale carbon monoxide through the mouth. AR patients received glucocorticoid nasal spray for 1 month and were tested again for nNO, eNO, eCO, and symptom score.  Before treatment, all the nNO, eNO, and eCO of the AR group were higher than the control group. There were differences in the severe and moderate subgroup: severe > moderate > mild. eCO was not significantly different between the mild and control groups. The nNO, eNO, and eCO levels were positively correlated with symptom score. After treatment, nNO decreased significantly in the three subgroups; eNO and eCO in the severe AR group decreased significantly. Drawing the ROC curve, the area under curve (AUC) of nNO is 0.978. The AUC of eNO and eCO was 0.786 and 0.577, respectively.  The nNO, eNO, and eCO in the AR group are higher than healthy people, which positively correlated with the severity of AR symptoms. The detection of nNO, eNO, and eCO can monitor the changes of AR. The detection of nNO level as an indicator of AR auxiliary diagnosis has high accuracy. The increasing incidence of allergic rhinitis (AR) in recent years severely affects the patients' quality of life. In clinical work, we mainly diagnose AR by asking patients about their allergy history, clinical manifestations, and the results of invasive allergen testing. But the severity of AR mainly depends on the symptom score subjectively, and the accuracy of the evaluation results is poor due to the different tolerance of patients , 2. AlonNitric oxide (NO) is the first gas molecule found to be in the diagnosis of the disease. In 2005, the American Thoracic Society and European Respiratory Society (ATS/ERS) issued the exhaled oxide (eNO) measurement standard and reference range for people aged 4 to 17, and in 2011, eNO level test has been widely used in the diagnosis and efficacy evaluation of asthma . Carbon In order to further investigate the correlation between the levels of nNO, eNO, and eCO in nasal exhalation and the severity of AR, we measured the levels of nNO, eNO, and eCO in nasal exhalation. We also conducted data analysis to explore the role of the levels of nNO, eNO, and eCO in the auxiliary diagnosis and status monitoring of AR. Through the analysis of the relationship between the AR and the upper and lower airway exhaled endogenous CO and NO levels, we explore the auxiliary diagnosis and condition monitoring of AR by testing expired endogenous NO and CO.From October 2017 to March 2019, according to the Guidelines for Diagnosis and Treatment of Allergic Rhinitis , patients who were diagnosed as allergic rhinitis in our outpatient department were selected. We set inclusion criteria and exclusion criteria and then set up the AR group and healthy control group. The AR group, according to the symptom score, was divided into three subgroups: mild, moderate, and severe. Both groups are nonsmoking. The study protocol was approved by the Ethics Committee of our hospital. All the research objects in this experiment participate voluntarily and sign the informed consent.More than 2 (including 2) symptoms such as sneezing, water-like nasal discharge, nasal congestion and nasal itching, and last or accumulate for more than 0.5-1.0 hour every day, which can be accompanied by eye itching, conjunctival congestion, and other eye symptomsSkin prick test and/or serum specific IgE (SIgE) positiveSymptoms ≥ 4 days/weekInflammatory changes of nasal mucosa: pallor, edema, and nasal watery secretionObjects can actively cooperate with relevant examination and treatmentPatients with asthma, nasal polyps, sinusitis, or other inflammatory diseases of the upper and lower airwaysPatients with a history of nasal sinus surgery, markedly deviation of the septum leading to prolonged nasal congestion or significant abnormalities of the nasal anatomical structurePatients with abnormal cardiopulmonary functions or long-term medicationSmokers, respiratory infections, and systemic or local use of glucocorticoid drugs within the last 4 weeksPatients with allergic rhinitis were treated with systemic or local drugs such as antihistamine in the last 4 weeksSymptom intensity is scored by the four-point method: 0 points: asymptomatic; 1-3 points: mild symptoms (mild and tolerable); 4-6 points: moderate symptoms ; and 7-10: severe symptoms (enough to interfere with daily activities or sleep at night). According to the result of the symptom score and disease severity, the AR group was divided into three subgroups: mild, moderate, and severe. The scores 0 and 3 were classified as the mild subgroup, 4 as the moderate subgroup, and 7 as the severe subgroup.The Nakoulam respiratory analyzer SUNVOU-CA2122 (product No. SVP003170802024) was manufactured by Wuxi Shangwo Medical Electronics Co., Ltd. Strictly follow the instructions.Empty the nitric oxide in the instrument, and then place the olive-shaped nose probe on one of the participants' front nostrils to connect the nasal catheter with the nose probe. Then, click the device to start, the instrument inhales gas continuously in the nasal cavity of the participant through the connecting tube (the speed is 10 ml/s), and then instructs the participant to continue whistling, at this time, the soft palate is closed, blocking the airway gas mixed with the nasal cavity until the end of the nasal cavity measurement display time. The unit is ppb.2O, the soft palate is closed, blocking the nasal gas into the lower airway until the displayed time reaches the end. Unit is the ppb.Empty nitric oxide in instrument, let the participants sit, plug the filter and breathe into the filter until the inspection mark down to the lowest, then exhale, and guide the objects in the course of the breath as far as possible to keep the indicator in the designated areas. While the expiratory flow is50 ± 5 ml/s and expiratory pressure is 5-20 cm HEmpty carbon monoxide in instrument, let the participants sit, plug the filter, begin to breathe through the mouth, make the air without carbon monoxide into the lungs until totally, hold breath for 5 seconds, the pulmonary circulation takes away inhaled CO in the air, then begin to exhale, and guide the objects breath as far as possible to keep the indicator in the designated areas, while the soft palate is closed at this time, blocking the nasal gas into the lower airway until the displayed time reaches the end. Unit is the ppm.Clean the nasal cavity before using general glucocorticoid nasal spray, and shake the liquid well Tilt your head slightly forward, press the other nostril by hand , and then squeeze the bottle with your thumb steadily and rapidly to spray the liquid in a fog into one side of the nasal cavitySpray twice on each side of the nasal cavity every morning and evening for one monthAt the end of glucocorticoid treatment, determine the nNO, eNO, eCO, and symptom scores again as describedIn patients with AR, we use glucocorticoid nasal spray, mometasone furoate nasal spray, for treatment without taking other drugs:x ± s). The t-test is used to perform statistical tests on the general data and the level of test indicators; p < 0.05 was considered statistically significant; the Pearson correlation is used for correlation analysis, and p < 0.05 was considered statistically significant. The receiver operating characteristic (ROC) curve is used to evaluate the recognition ability of the nNO, eNO, and eCO for AR. The greater the area under curve (AUC) value is, the higher the accuracy of the auxiliary diagnosis of the corresponding indicators will be.SPSS24.0 and Excel software are used for statistical processing of the data; the data were presented in the form of mean ± standard deviation (x ± s), and p values are all greater than 0.05 obtained by t-test, which means no statistically significant differences in the baseline data  of the AR group and control group are used for descriptive statistics using mean ± standard deviation , eNO and eCO , and eNO and nNO  have a certain correlation , the eNO level was positively correlated with the symptom score in AR group , and the eCO level was positively correlated with the symptom score in AR group  . When the boundary value of the nNO measurement has taken 516 ppb, the sensitivity and specificity are both high , while the specificity was 96.7%. The ROC curve was plotted alike using eNO and eCO values as diagnostic indicators of AR   . As an iAR, as the most common type of rhinitis, is a type I allergic disease mediated by IgE. The clinical diagnosis of AR is mainly based on the patient's typical history of allergy, present symptoms, and invasive allergen test results , 10, butNoninvasive airway inflammation has gained increasing attention with the introduction of the concept of “inflammometry.” More and more researchers are involved in the field. In addition, NO is synthesized from L-arginine catalyzed by nitric oxide synthase with high lipid solubility and active properties. Endogenous NO can play a physiological role in vascular tension and homeostasis, such as NO produced in the upper and lower airways that can inhibit the growth of bacteria, viruses, fungi, and tumor cells; therefore, it can protect the upper and lower airways . Endogenp < 0.05), so did the correlation analysis showing that the nNO level was positively correlated with the severity of the symptoms of AR patients . But Lee et al. and Baraldi et al. study the nNO level by comparing different severity of patients with AR and found that the nNO level of patients with severe AR is below than that of moderate AR patients, while the conclusion was that there was no significant correlation between the level of nNO and the severity of the symptoms in AR patients [The results of this study showed that the nNO level of AR group was higher than that of the control group, and the difference was statistically significant. At the same time, the nNO level of patients with mild AR was also higher than that of the control group, which was consistent with the conclusions of other studies. The increase of nNO level in AR has a variety of pathophysiological effects, including vasodilation and changes of sensory nerve endings, so it aggravated nasal congestion, nasal leakage, and sneezing. In other words, the higher the nNO level, the more severe the symptoms would be. As shown in the results of this study, the nNO level of the severe AR subgroup was higher than that of the moderate and mild AR subgroups , and eNO level in severe AR subgroup was higher than those in patients with moderate or mild AR (p < 0.05), and eNO level was positively correlated with the severity of the symptoms  [The eNO level in AR group was higher than those in the normal control group ( < 0.05) , 16. Lee < 0.05) . Baraldi < 0.05) .There was no significant difference in the level of eCO between the mild and moderate AR patients and the control group, which was consistent with the study of Shaoqing et al. . It may p < 0.001) and 0.577 (p = 0.445), respectively. Compared with the nNO, the accuracy of eNO and eCO for AR diagnosis was relatively low. In the study of Lee et al., the nNO and eNO levels were detected to assist the diagnosis of AR, and ROC curve was drawn with AUC of 0.8527 and 0.6463, respectively [In this study, the detection of nNO level is used as an indicator for AR auxiliary diagnosis, and ROC curve is drawn. The area under the curve reached 0.978. When the threshold value is 516 ppm, the sensitivity and specificity were both high, 91.7% and 96.7%, respectively. Using the detection of eNO and eCO as auxiliary diagnostic indicators of AR, ROC curve is drawn, the area under the curve was 0.786 (ectively , consistWe believe that AR patients may have chronic lower airway inflammation without clinical symptoms, and the higher the degree of inflammation in AR patients and the higher the eNO in AR patients, it is speculated that the greater the possibility of AR patients complicated with chronic lower airway inflammatory disease. Takeno et al. and Olin et al. research the correlation between the eNO level and occurrence of wheezing in the general population reported. The elevated NO level in the lower and middle airways of objects with no respiratory symptoms as a sign of subclinical airway inflammation, heralding the small airway inflammation exists, will be a risk factor for the development of asthma , 18. In


Although community psychiatric rehabilitation plays an important role in returning persons with schizophrenia to the society, many patients in China stay in rehabilitation centers for longer periods of time and subsequently fail to integrate. This study is aimed to explore the underlying causes of this trend and identify possible solutions.This study used a qualitative descriptive design to examine the persons with schizophrenia who stay in rehabilitation centers for longer periods of time. The researchers conducted semi-structured telephone interviews with the patients recruited through purposeful sampling. The audio-recorded interviews were transcribed in transcripts in Chinese. Thematic analysis was performed using Colaizzi's 7-step method.Most patients believe that they have gained knowledge, improved skills, friendship and social circles through community mental rehabilitation, with the sense of belonging and enriched life strongly attracting them to the rehabilitation centers. They felt that the difficulty of further integration into society is mainly because of social prejudice and rejection. In addition, the activities of community mental rehabilitation meet the needs of social communication, which also hinder patients from further entering the society.Persons with schizophrenia with long-term stay in community mental rehabilitation centers meet their friendship, sense of belonging and social needs by participating in rehabilitation activities. Providing special social opportunity for these patients can get them out of the rehabilitation center. Overall, it is possible for patients to gradually return to society in a collective form. Schizophrenia, a serious chronic mental illness that affects more than 20 million people in the world  seriouslPsychiatric rehabilitation in China started decades later than that in developed countries, while community-based rehabilitation has only developed in the past ten years. In the capital, Beijing, resources for rehabilitation are quite short, due to various reasons such as lack of experience, limited space, and shortage of staff, among others. At the same time, many patients who have been rehabilitated for several years and have improved social functions, still participate in rehabilitation activities every week. Notably, these patients use the available resources making it difficult for those with poor social function and who urgently need rehabilitation to join. Ensuring that patients with improved social functions leave rehabilitation centers is imperative to enable those in urgent need access the limited rehabilitation resources. Numerous studies have focused on community psychiatric rehabilitation, owing to its importance for patients. The most applied rehabilitation measures across communities include health education (disease knowledge and prevention of recurrence), physical exercises, group discussions, and trainings for cognitive, life, vocational and social –15. The To ensure that the limited resources in rehabilitation benefit more patients, it is necessary to solve the problem associated with long-term stays in rehabilitation by some patients. Understanding reasons why these patients stay for longer periods is imperative to designing accurate exit strategies for them and identification of alternative activities that satisfy them. In the present study, we interviewed persons with schizophrenia who have stayed in rehabilitation centers for many years with the aim of identifying the reasons why they have not integrated into the society. Our findings are expected to provide valuable insights to guide effective and applicable rehabilitation policies, which will in turn ensure that the limited rehabilitation resources can play a greater role in patient integration back to the society.We adopted a qualitative study design, based on semi-structured telephone interviews, to understand participants' personal experiences and feelings under rehabilitation. All interviews were conducted between April and June 2021. The interview guide was developed by the research team based on the study aims and available literature. Then it was adjusted according to pilot study and expert opinion. The main interview questions were as follows: (1) How do you think the community psychiatric-health rehabilitation helped you? (2) What has changed in your life after joining in rehabilitation? (3) What rehabilitation is your favorite and why? (4) What attract you in this group? (5) How long do you plan to take part in rehabilitation? (6) Do you join other social group? If yes, what? If no, why? (7) What difficulties have you met in further social activities?Purposeful sampling was used to recruit persons with schizophrenia in the study. Eligible participants, across 6 community psychiatric rehabilitation centers of Beijing Haidian district, were referred by psychiatrists. All participants were diagnosed with schizophrenia, which was confirmed by psychiatrists at the mental hospitals. Criteria for inclusion and exclusion of patients in the study are summarized in Table . The interviews were based on open-ended questions, with many examples and details collected to clarify the information. All the interviews were audio recorded, with each one taking between 25 and 43 min.This was an initial phase of a doctoral study titled "Effect of group cognitive behavior therapy on rehabilitation of patients with severe mental disorders". Ethical approval for the study was obtained from the Ethics Committee of Capital Medical University. The purpose and procedures of the study were explicitly explained to the participants, who then voluntarily signed a written consent prior to the interview. Since confidentiality was an important part of the research, we used numbers instead of names to ensure participant anonymity. Psychiatrists across the 6 community psychiatric rehabilitation centers provided demographic information for the recruited participants and obtained their consents. Subsequently, the first author (PhD candidate) arranged the interview time, and conducted all individual interviews via the telephone. All the participants were native speakers of Chinese, so the interviews were conducted in ChineseThe audio-recorded interviews with the patients were transcribed verbatim into word documents by the first author in Chinese. The documents were then checked for accuracy by two people who were not associated with the study. The data were extracted inductively from the interview transcripts. Summaries of codes and themes are presented in Table A total of 32 patients were invited to participate in this study. However, 2 declined the invitation for no reason while another 2 failed to complete the invitation. Finally, 28 patients across 6 community rehabilitation centers were interviewed. The participants’ ages ranged from 35 to 67 (with a mean of approximately 50.5) years. Mean duration of illness of the schizophrenia was 22.71 years (SD = 6.72), and mean period of community rehabilitation was 9.43 years (SD = 1.83). All participants in this study lived at home, 22 (78.57%) were living with their families, 2 (7.14%) were living with relatives and 4 (14.29%) were living alone. They were receiving treatment with oral antipsychotic medication, with most patients being administered two or more drugs. A summary of their characteristics is outlined in Table The generated data were stratified into three main themes, namely effect of community rehabilitation, attractiveness, and difficulties in social communication.1. Effect of community rehabilitationHere, three main dimensions that focus on the effect of community rehabilitation, namely knowledgeable of disease and adherence to treatment, improvement in life ability as well as stable friendship and social interaction, were analyzed.1.1 Knowledge of the disease and adherence to treatmentThe doctor told me that I was not crazy, but sick. I couldn't control the performance of the illness. That was not my fault. I would be fine if I could take the medicine regularly. It is a chronic disease just like hypertension. (No.6).I didn't know what the disease was at the beginning. I have learned more (from community rehabilitation) about it. (No.12)I just can't sleep and think more about everything sometimes, now I know that’s also a symptom of my disease. (No.20)In the past, I always stopped taking the drugs as soon as the symptoms improved. Now I know that I must take the medicine consistently to prevent a recurrence. I will never stop the medicine in the future. (No.24)Among the 28 respondents, 16 stated that they had understood disease characteristics and the importance of adhering to medication more explicit because of various health educations. From the responses, all patients adhered to medication, although some said they had done well before joining rehabilitation. Knowledge from rehabilitation activities strengthened their belief, while more patients accepted the reality of their illness and the side effects associated with medicine rather than fear or avoidance. Some of their responses are as follows:1.2 Improvements of deficits in daily living abilityI used to respond very slowly. I needed to redial several times when I made a call, but now I do everything much faster. (No.9)I used to be timid and hardly to go out. Now I go for a walk every day and I can help my family with shopping. (No.7)In the past, I always felt that others were talking about me behind and thought that the loud voice from others was aimed at me. It's better now. I understand it has nothing to do with me whatever others say or do. (No.28)In the past, I was very nervous and angry when I heard somebody talking about my illness. Now, I know that although I can't stop their talking, I can control my response. My emotions should not be influenced by others. (No.27)A total of 14 correspondents mentioned effect of rehabilitation on improved living or coping ability. This was manifested across many aspects, such as taking care of oneself in life, taking care of family members, emotional processing, and social interaction. Some of their responses were as follows:1.3 Stable friendship and social interactionWe have been together (in the community psychiatric rehabilitation centers) for many years. Some of them (patients) are my friends. I missed them very much when the rehabilitation activities stopped because of the Covid-19 last year. (No.5)Everyone here is in the same situation . No one laughs at me. I am willing to tell them something (that happened in my life). They will encourage me and give me some useful advice. (No.19)At first, I thought that rehabilitation activities were just playing. Everyone treated me very well, and I learned new skills from the interesting activities. In short, I feel very happy here. Recently, I find that I can comfort and help others sometimes, which give me a sense of accomplishment. (No.11)Apart from coming here (to participate in rehabilitation activities), I don't have any other activities with others. (No.25)24 out of the 28 respondents stated that they had forged friendships in rehabilitation, while 19 of them indicated that rehabilitation was the most important social activity of their current lives. Some of their responses were as follows:2 AttractivenessParticipants had been under rehabilitation for so many years that they wanted to continue until the rehabilitation center was not allowed due to age or health reasons. The main reason for rehabilitation attractiveness was due to a sense of belonging, and the associated enriched and interesting lives.2.1 Sense of belongingI had no friend since I got sick. I made friends again when I came here. It's not easy (to make these friends) for me, so I cherish (these friendships) very much. (No.2)All my best friends are here. It's wonderful that we can talk and play together every week. Here (community psychiatric rehabilitation center) is another big family for me. (No.17)I don't have any friends in my life. It's great being accepted by the (rehabilitation) center where I can open my minds to others, which is necessary for me. (No.26)24 of the enrolled participants alluded to friendship, support and being supported, an equal and safe social environment, and a family-like group, as some of the reasons they felt a sense of belonging at their rehabilitation center. Some of their responses were as follows:We are all suffering from this disease . We have a lot of common topics due to the similar experiences and feelings. Nobody looks down up on others. (No.1)The doctors, nurses and teachers here  are very nice. If we could not understand or catch up, they would explain again and again with more patient than our family members. (No.23)It's okay to make a joke here, since we understand each other. Joking is unimaginable in other social lives. (No.15)I feel pretty good as long as we are together, no matter what rehabilitation activities to do. (No.4)Moreover, 18 correspondents indicated that they had experienced respect and equality in their rehabilitation group. In fact, they found it easy to speak more freely because there was no discrimination. Some of their responses included:2.2 Enriched and interesting livesI come here (to participate in rehabilitation activities) every week, otherwise I am watching TV or mobile phone at home, which is very boring. (No.22)The rehabilitation activities include making handicrafts, paintings, planting, arranging flowers, and picking fruits among others, nearly all of which can’t be done in the family. That's why I like to be here. (No.14)I like singing. The rehabilitation center often organizes rehearsal programs to participate in performances during festivals. I am always the lead singer in the chorus show, which give me a sense of accomplishment. (No.3)Those of us who have recovered have the opportunity to travel nearby. It's great to spend a day in the scenic spot and have lunch in a restaurant. This makes our relationship closer. (No.26)Respondents with mental illness indicated that their daily lives were mostly monotonous and repetitive due to lack of work and social interaction. Specifically, 25 patients out of the 28 enrolled participants indicated that various activities organized by the rehabilitation centers made their lives rich and interesting. Some of their responses were:3. Difficulties in social communicationParticipant responses revealed existence of 3 difficulties under rehabilitation, namely not being accepted by society, self-stigma and low self-confidence, and lack of motivation and interest.3.1 Not being accepted by the societyAfter all, we are different from the normal persons. It’s better to stay away from them rather than they avoid and laugh at me. (No.21).Even my family members don't like me, let alone strangers. (No.19)I know other people have looked down on me and call me a lunatic. (No.13)Nobody wants to hire people like us (persons with schizophrenia). Some shopkeepers even prevent me to enter the store, for fear of affecting their business. (No.8)Nearly all respondents strongly believed that they were excluded from society and had experienced social rejections. Specific shows include discrimination and prejudice, sarcasm and ridicule, social isolation and lack of job opportunities.3.2 Self-stigma and low self-confidenceI go out every day to exercise, all by myself, and try to keep away from the crowd. (No.11).This disease (schizophrenia) is rather special, no one is willing to socialize with people with this disease. So, I'd rather stay alone, lest others disgust me. (No.14)I have a job in the sub-district, mainly responsible for cleaning. I was willing to take on more works, but I didn't mention, for fear that I would lose this job. (No.16)There are also some group activities in my community, I never try to participate in because I am sure that they must mind (that I have schizophrenia). (No.3)I never quarrel with people outside. I am always the first one to make a concession, even though I am right. What I fear mostly is (the sentence) 'he is sick/crazy' and (this phrase) nearly can be heard every day. (No.10)Patients' self-stigma and low self-confidence were mainly displayed in self-isolation during daily life. Notably, the correspondents felt they didn't strive for themselves even during interactions with others. Specifically, 12 correspondents avoided communicating with others when outside, 4 had jobs in supportive employment where they obeyed the arrangement and never asked for any needs, while 15 selected concessions when faced with conflicts with others in public. Some of their responses included:3.3 Lack of motivation and interestThe society is too complicated for me. The community rehabilitation brings me happiness and hope. (No.18)Anyway, as long as I have time, I will continue to participate in the (rehabilitation) activity here. I don't want to participate any other groups. (No.2)Friends and activities here are enough, I don't need any more. (No.23)It's enough to participate in activities here every week, and more activities will make me too tired. (No.17)Almost all patients indicated that rehabilitation was one of their most important social activities, with more than 20 participants indicating that rehabilitation was their only external social activity as well as the only means of communication with relatives. Some of the responses included:The present survey reveals the perceptions of persons with schizophrenia who have spent long periods of time under rehabilitation. From the collected information, three main information subthemes, namely reasons why the patients were willing to join rehabilitation, benefits of engaging in the activities, and the obstacles they face during transition from the rehabilitation centers to the real society, emerged. Specifically, the respondents indicated that rehabilitation activities had markedly improved their medication compliance, life skills and coping ability. Interestingly, the patients believed that friendship, a sense of personal belonging and value gained under rehabilitation were more important than the aforementioned gains. Various rehabilitation activities had enriched the patient's daily life. However, they hindered them from further integration into society to some extent. These results, which are based on patients' experience, can help us to comprehensively understand the current status of rehabilitation for this group of patients. These findings are expected to guide future designs into effective approaches for seamless integration of these patients into society.The findings of this study indicated that rehabilitation enhances patients' ability to learn more about the disease, improves their medication adherence, boosts their skills such as living ability, social interaction and problem solving. Information regarding the signs and symptoms of schizophrenia, as well as the reasons for relapse is important for patients. This is because once they not only understand that the disease causes many problems, but they are also gain deeper insights into drug efficacy, phenomena that consequently promote their adherence to medication as previously reported , 30. ApaPatient responses indicated that friendship and fixed social activities are very important benefits of rehabilitation. Specifically, most patients believe that friendship and social interaction have changed their lives, from boring to interesting, and from monotonous to diverse. In fact, the positive energy they have gained gives them full hope for the future. Moreover, they also indicated that community psychiatric rehabilitation centers have given them a sense of belonging. Previous studies have shown that having hope and feeling a sense of belonging are important aspects for improving quality of life , 35. TheThis study found that some patients who had recovered for many years no longer benefited from rehabilitation activities, but they still actively participated in rehabilitation and didn't want to leave the rehabilitation group. The most important reason was that they valued the friendships of their group members and were unwilling to lose them. Persons with schizophrenia always isolate themselves and limit their scope of activities due to strong stigma. They lack friends and have a strong sense of loneliness . HoweverThe study also found that rehabilitation activities enriched the quality of life for patients. Daily entertainment for patients is relatively simple at home, where they watch TV, use their mobile phones or go out to exercise alone. On the contrary, rehabilitation activities are diverse and interesting, introducing new experiences to the life of patients. The satisfaction and happiness gained from rehabilitation activities are often greater than those in daily life. Patients are full of expectations for the ongoing rehabilitation activities. To some extent, the expectation has become one of the goals of life for the patients, making it easier for them to cope with daily life.The main obstacles for patients to participate in general social activities are social prejudice and non-acceptance. There have been many previous studies on this subject . The neeBased on an analysis of the basic data of patients who have been in rehabilitation for a long time, we discovered that these patients have a longer duration and a fixed income. Most of them live with their families, which means that they have strong family support. According to Maslow's needs theory, these patients have met the two levels of physiology and safety, so the next goals are the needs for belonging and respect. Because most patients have a sense of family belonging, the need for friendship and social belonging is more urgent and the rehabilitation center simply meets their demand. Previous investigations on the friendships of schizophrenia patients had shown that although the friendship network of the patients was small, the quality of friendship was mostly positive, and patients attached great importance to friendship . ReciproAlthough extensive publicity and education has been done, the general public still knows little about mental illness, and the persons with schizophrenia also subject to high rate of stigmatisation and discrimination . In suchUnderstand how patients evaluate rehabilitation and why they stay in the rehabilitation centers can help rehabilitation managers to find solutions to the problem of patients overstaying in the rehabilitation centers. Because psychiatric rehabilitation is a developing field in China, the professional psychiatric rehabilitation providers are not enough. In this study, staff from the Beijing Disabled Persons' Federation and community psychiatrists or nurses collaborated to provide rehabilitation. In addition to rehabilitation work, the community psychiatrists or nurses have many daily management responsibilities, which limits the amount of time available for psychiatric rehabilitation. Every new patient who enters a rehabilitation group needs a series assessment of disease conditions and safety, which require more time from psychiatrists or nurses. Patients continue to participate in community psychiatric rehabilitation, reducing not only the workload of psychiatrists, but also the risk during rehabilitation activities. In the past, this state was suitable because many patients refused to participate in rehabilitation because the benefits of rehabilitation were not well-known, resulting in an oversupply of psychiatric rehabilitation. Recently, the abilities of the patients who joined rehabilitation gradually improved, and they approved the rehabilitation effect and were willing to continue rehabilitation. Because of the good curative effect, an increasing number of patients have been asked to participate in rehabilitation. However, due to staff and space constraints, the rehabilitation centers are unable to meet the rehabilitation needs of patients. Therefore, it is necessary to find suitable outlets for patients who are still stranded in rehabilitation centers after their life and social abilities have improved in order to provide rehabilitation opportunities to more patients with severely damaged social functioning. Rehabilitation is a long-term course that is required at every step from inpatient to outpatient and from returning to family to returning to society. Patients should be classified according to their remnant abilities, and treated with different rehabilitation measures, which requires a significant increase in the number of mental rehabilitation practitioners. Patients who are stranded in the rehabilitation centers have completed the rehabilitation course, and rehabilitation activities are important to meeting the needs of social interactions, the sense of belonging, and value. Development of other social groups and group activities that differ from rehabilitation centers in order to meet their needs maybe a feasible measure. Social workers or volunteers should organize cultural, artist, sports, or other entertainment regularly for the patients only, who can participate in any activity according to their interests. If possible, the government can also provide jobs in the community for well-functioning mental patients. The patients integrate into society gradually as a small group just like in the community rehabilitation centers.This study used purposive and convenience sampling because it was concerned with long-term schizophrenia patients who wanted to participate in rehabilitation. Despite being sampled from multiple communities, all patients belonged to the same area, making it difficult to avoid selective migration. Respondents were voluntary patients, suggesting that they represent patients with the best social function rather than all patients who joined in the long-term rehabilitation. Furthermore, because the interviewer was a psychiatrist, power differentials may have affected negative information expression from the patient, resulting in information bias. Because telephone interviews may lose implicit information in facial expressions, we increased the sample size by 30% after reaching information saturation.This is the first study in China on schizophrenia patients who continue to participate in community psychiatric rehabilitation after their life and social abilities have improved. According to the results, community psychiatric rehabilitation improves life skills and social skills, but the patients believe that friendship, personal belonging, and a sense of self-worth are more important and attractive to them. Various types of rehabilitation activities enrich daily life and meet the social and entertainment needs of the patients. However, it has become an obstacle for patients to further integrate into society. Therefore, we can try to organize other group activities specifically who have recovered from mental illness and have good social functioning. These activities should not be aimed at functional recovery, but rather at meeting the social and belonging needs of the patients. Moreover, the government may provide these patients with collective jobs in order for them to gradually integrate into the society as a unit, which may be easier than as individuals.


AR gene on chromosome X, often reported with shorter survival and higher prevalence of GBM among males. Copy number (CN) and mRNA expression of AR were tested with droplet digital PCR in 91 fresh‐frozen GBM samples and 170 formalin‐fixed, paraffin‐embedded samples collected at Linköping University Hospital. The fresh‐frozen cohort was also subjected to pyrosequencing methylation analysis of 17 CpG sites in the AR promoter. Additionally, the gene expression of AR was analysed in the fresh‐frozen cohort and The Cancer Genome Atlas (TCGA) cohort of isocitrate dehydrogenase wild‐type primary GBM . The association of AR expression and overall survival (OS) was tested with Kaplan–Meier log rank analysis after dichotomisation by maximally selected rank statistics. We found that AR CN alterations were more common in female GBM. AR gene expression correlated with methylation levels of different CpG sites in males and females but there was no difference in expression between sexes. Survival analysis of TCGA cohort revealed the opposite effect of AR overexpression on OS of males and females, with high AR expression correlating with shorter OS in females and longer OS in males. Additional gene set enrichment analysis showed that AR expression correlated with DNA repair response, especially in the male group. In summary, we found that high AR gene expression in GBM exhibits sex‐dependent effects on patient survival, which, for males, is linked to DNA repair response.We sought to analyse the androgen receptor (AR) in glioblastoma (GBM) due to the location of the  Glioblastoma (GBM) is more common among males; however, the reason for sex differences remains largely unknown. Through molecular analyses of androgen receptor (AR) in GBM samples, we found that AR is commonly expressed in tumours of both sexes, but copy number alterations of the gene coding for AR are more frequent in females. Additionally, high AR expression correlates with worse survival among females but better survival among males. Aktprotein kinase BARandrogen receptorATRXalpha thalassemia/mental retardation syndrome X‐LinkedCNcopy numberDDX3XDEAD‐box helicase 3 X‐linkedDHTdihydrotestosteroneEGFRepithelial growth factor receptorFDRfalse discovery rateFFPEformalin‐fixed, paraffin‐embeddedGBMglioblastomaGSEAgene set enrichment analysisIDHisocitrate dehydrogenaseMGMTO‐6‐methylguanine‐DNA methyltransferasemiRmicroRNAmTORmechanistic target of rapamycin kinaseOSoverall survivalPI3Kphosphoinositide 3‐kinaseSVZsubventricular zoneTCGAThe Cancer Genome AtlasTCPAThe Cancer Proteome AtlasTGFβtransforming growth factor β1Glioblastoma (GBM) remains a nearly incurable brain tumour with a poor prognosis  . GBM belSex chromosomes are often purposefully omitted in analyses, due to the challenges they present. The gene coding for the androgen receptor (AR) is located on chromosome X, Xq12. The AR is a ligand‐dependent nuclear transcription factor and a member of a superfamily of steroid hormone nuclear receptors. Androgens, testosterone and dihydrotestosterone (DHT), mediate their effects via AR, and when bound to cytoplasmic AR cause the release of heat shock proteins . The ligin vitro, e.g., enzalutamide, led to inhibition of proliferation of GBM cells [A recent pan‐cancer study revealed that AR is overexpressed in GBM , and fewBM cells , 12, 13.BM cells . Hence, There are a limited number of studies exploring AR antagonists as possible treatment for GBM, and not much is known about AR genetic and epigenetic characteristics in GBM, which could influence the receptor's activity. Mutation frequency in AR in GBM is very low, only about 1%, as found in cBioPortal v3.7.5 based on The Cancer Genome Atlas (TCGA) data , 16. Hen22.1All patients included in this study underwent surgery at Linköping University Hospital, were at least 18 years old, and provided written informed consent. The study was conducted according to the guidelines of the Declaration of Helsinki and approved by the Regional Ethics Committee of Linköping University, Sweden . All patient samples, as well as control samples were collected in South‐East Sweden. Table The second cohort consisted of 91 fresh‐frozen samples, partially overlapping with the FFPE cohort  and aligned using blast to confirm correct amplification and enable counting of CAG repeats. Eight samples with a different number of repeats were selected and used as controls and markers in the following fragment analysis. DNA extracted from blood of 799 healthy controls and 167 GBM patients was amplified using the same set of primers as for sequencing but with the forward primer labelled with FAM fluorochrome at the 5′ end. Samples were then diluted 1 : 12 with water, and 1 μL was mixed with 0.3 μL of GeneScan 600 LIZ dye Size Standard (Applied Biosystems) and 15 μL of Hi‐Di Formamide , and separated in the 3500 Genetic Analyzer. Fragments were analysed with the genemapper v.4.1 (Applied Biosystems) and the number of CAG repeats was determined by comparison of fragment sizes to control samples included in every run.For all samples included in the CAG repeat analysis, DNA was extracted from blood using Maxwell 16 Blood DNA Purification Kit  on the Maxwell 16 Instrument (Promega). A fragment encompassing the variable region was amplified with primers: forward‐ACCGAGGAGCTTTCCAGAAT, reverse‐ GCTGCCTGGGGCTAGTCTCTT, and sequenced for 20 healthy males from the control cohort. Amplification of exon 1 of AR was done with MyTaq DNA Polymerase , and a touchdown protocol was applied. The first three cycles were performed with annealing temperature 63 °C, followed by three cycles with annealing temperature 62 °C and 29 cycles with annealing temperature 61 °C. Sequencing was performed according to the BigDye Terminator v3.1  protocol with fragment separation on 3500 Genetic Analyzer . Electropheograms were visualised in the 2.3psq assay design 2.0.1.15 (Qiagen), are given in the Table pyroq‐cpg 1.0.9 software .Methylation analysis of 17 CpG sites spanning 750 bp of the promoter region of AR in 91 fresh‐frozen tumour samples  was done by pyrosequencing. EZ DNA Methylation Kit  was used for bisulfite conversion of 350 ng of DNA, out of which 20 ng was used for each of the subsequent amplification reactions done with the HotStarTaq Master Mix Kit (Qiagen). The promoter region was divided into seven amplicons and all used primers adapted from Hornig et al. [2.4quantasoft v1.7.4 (BioRad).The AR CN analysis was performed on 91 fresh‐frozen GBM and 83 IDH‐mutated gliomas, as well as 170 FFPE GBM samples using droplet digital PCR. The same technique was used for assessment of mRNA expression, both for total AR as well as the AR‐V7 variant. In all instances, droplet generation was done using the Automated Droplet Generator , and after PCR, droplet reading was performed on the QX200 Droplet Reader (BioRad). The results were analysed using the For CN analysis, DNA from fresh‐frozen tissue was subjected to enzymatic digestion . This step was omitted for DNA from FFPE tissue due to its pre‐existing fragmentation. Then, 20 ng of DNA was mixed with probes and ddPCR Supermix for Probes (no dUTP) (BioRad), and amplified according to the manufacturer's protocol with annealing temperature of 60 °C. The FAM‐labelled probe targeting AR  was used together with the reference HEX‐labelled probe AP3B1 . Deletion was reported for CN values below or equal to 1.7 for females and 0.7 for males, amplification for females was reported for CN values above 2.3 and 1.3 for males.Reverse transcription of 500 ng–1 mg RNA for expression analysis was done with Maxima First Strand cDNA Synthesis Kit for RT‐qPCR (ThermoFischer Scientific). We used primers and probes for AR gene expression, as reported by Ma et al.  and GUSB2.5gsea 4.1.0 software [gsea software default settings, high and low AR expressions were treated as categorical values, and phenotype labels for the two groups were created based on the survival analysis results. In the second analysis, the AR expression values were treated as continuous data, allowing us to look for enrichment of gene sets associated with the increasing AR expression within each sex group, without the influence of survival data. Here, the Euclidean distance as a metric for ranking genes was used. We also investigated the enrichment of microRNA (miR) targets gene sets associated with AR expression due to the involvement of AR in miR regulation. In all analyses, only gene sets with false discovery rate (FDR) < 25% and P < 0.01 were considered significant.The gene expression data from TCGA GBM samples were used in the gene set enrichment analysis (GSEA), keeping the analysis separate for males and females. The analyses included hallmark gene sets version 7.4 and was performed on software , 27. In 2.6P < 0.05. All statistical analyses were done in spss v.26  unless stated otherwise, and maximally selected rank statistics was done in rstudio v.1.4  with r version 4.0.3 using packages maxstat and survminer. Normality of distribution of CAG repeats, AR gene expression and methylation data were tested with the Shapiro–Wilk test before other tests were performed. The Kruskal–Wallis test with Bonferroni correction for multiple pairwise comparisons was used to compare AR gene expression from TCGA data and between fresh‐frozen GBM and IDH‐mutated gliomas, whilst the Mann–Whitney U test was used for 2‐group AR mRNA expression between females and males. The Pearson coefficient was used for correlation analysis between AR CN and gene expression. The CAG repeats were compared with Mann–Whitney U test. In females, two alleles were separated  before statistical analysis, but we also compared the biallelic mean values. Additionally, we dichotomised data based on the median value from the control group  and divided into a group with lower and equal or higher number of CAG repeats [2 test.Differences in OS were analysed with the Kaplan–Meier log rank method complemented by maximally selected rank statistics  used for repeats . Such gr33.1First, we analysed CN changes in FFPE and fresh‐frozen GBM samples, and detected amplifications and deletions of the gene. In both cohorts, combined CN alterations were more frequent in females than in males Table . More frP = 0.099) . In female GBM, no such relationship was found , however, in IDH‐mutated gliomas the correlation was the opposite, found in females but not in males (Table P = 2 × 10−8) and mesenchymal (P = 1 × 10−6) subtypes. Additionally, we divided samples by sex, and multiple pairwise comparison revealed significant differences between several subtypes and across sexes, but no differences were found between females and males within the same subtypes   Fig. . Correlaes Table . Howeverpes Fig. . Protein65) Fig. . Interes65) Fig. .P = 0.258)  Fig. .3.2We further investigated the influence of AR CN and gene expression on OS. First, we analysed the cohort of FFPE samples, with the advantage of all patients following an equal treatment regimen, and we compared survival between patients with AR amplification, deletion and normal CN with the log rank Kaplan–Meier analysis. Males and females were analysed in combination and separately, but no significant differences were found. There were also no survival differences in the analyses of amplification vs. remaining samples, in the sex‐combined and sex‐separated setting Fig. .2) cut‐off value estimated with maximally selected rank statistics ensuring the best separation of survival curves and allocation of at least 20% of samples in each group. In females, the cut‐off value was 4.8303log2, and in males it was estimated at 4.9594log2. Surprisingly, we recorded the opposite effect of AR expression on survival with high AR mRNA expression associating with better survival among males    Fig. , and wor35) Fig. . No sign35) Fig. .3.3Pyrosequencing allows for semi‐quantitative evaluation of methylation at specific CpG sites. We analysed the promoter region of AR, with the first CpG site located 750 bases upstream from the transcription start site Fig.  in the c3.4We performed GSEA for TCGA cohort, trying to resolve cellular mechanisms that are responsible for the sex difference linking AR expression with survival, however, no gene sets were identified. We then repeated GSEA, but instead of dividing samples into two groups based on their survival, we looked for gene sets associated with AR expression (AR‐positive samples). Surprisingly, only one set of genes, namely DNA repair genes, was associated with AR expression in males Fig. . In fema3.52, P = 0.075). We did not observe any significant differences between the CAG length distributions in either sex, even after treating data as binary qualitative and dividing samples based on the median CAG repeat value in the control group , and among control males 21.9 (±2.8), whereas for the female patients it was 20.1 (±2.2) for the shorter allele and 23.4 ±2.6) for the longer allele, and in female controls 20.4 (±2.3) and 23.6 (±2.4), respectively. The number of repeats ranged from 14 to 35 in males and from 10 to 31 in females. Among the samples tested, we found 62 (15.5%) homozygous females in the control group and 15 (24.6%) in the GBM group but the difference between groups was not significant  acts as a transcription factor and the main controller of cell cycle in response to DNA damage [O‐6‐methylguanine‐DNA methyltransferase (MGMT) [The results presented in this study complement the current knowledge about AR and its involvement in GBM, also indicating a sex‐specific influence of AR on patients' survival. The abundance of AR expression in GBM is encouraging as it may constitute a novel therapeutic target. In fact, enzalutamide, an oral AR antagonist used for prostate cancer treatment , was shoA damage . It has A damage . AdditioA damage . As repoA damage . In otheA damage , 39, 40.e (MGMT) . Silencie (MGMT) , 43. TheGlioblastoma presents to be a tumour dependent on other sex hormone receptors as well. Intriguingly, oestrogen receptor beta was shown to act as a tumour suppressor in GBM by downregulating DNA damage response , which cWe also report on the frequency of AR CN changes, which affect females more often than males but without a clear direction towards amplifications or deletions. In the previously published work by Zalcman et al. , AR amplAs reviewed by Bramble et al. , neural High AR expression in GBM has been previously reported by several groups , 31, 58.In the methylation analysis, we found a sex difference in the CpG sites, where methylation inversely correlated with AR expression. Two CpG sites were identified for males and three different for females. Hornig et al. , showed To our knowledge, this is the first study exploring CAG‐length polymorphism in AR in GBM patients. A decreasing number of CAG repeats encoding polyglutamine was shown to be associated with an increased risk of prostate cancer , and lon5In summary, sex differences are observed in the association of AR expression and survival as well as in the frequencies of AR CN alterations, but no association was found between CAG repeat number and GBM development. AR is commonly expressed in GBM of both sexes and the negligeable presence of the AR‐V7 transcript suggests the need for the ligand to trigger downstream signalling, which is more strongly linked to DNA damage response in males than in females. Hence, further research focusing on both mechanistic studies and discriminating sex differences associated with AR and other sex hormone receptors might translate into sex‐dependent treatment of GBM in the future.The authors declare no conflict of interest.MŁ and AM conceptualised the study, administered the project and performed data curation. MŁ designed the methodology, investigated and visualised the study, and wrote and prepared the original draft. MŁ and MT performed the formal analysis. MM, CB, MS, PM, MH and AM provided resources. MŁ, MT, MM, CB, MS, PM, MH and AM wrote, reviewed and edited the manuscript. AM supervised the study and acquired funding. All authors have read and agreed to the published version of the manuscript.Fig. S1. Relative expression of AR in the fresh‐frozen tumours collected in South‐East Sweden.Fig. S2. Analysis of AR CN changes influence on overall survival in the FFPE Linköping cohort (Kaplan‐Meier log‐rank method).Fig. S3. Survival analysis of IDH‐mutated tumours from TCGA.Table S1. Primers used for the methylation analysis of the promoter region of AR and amplicon specific annealing temperatures.Table S2. Mean methylation values for each analysed CpG site within the AR promoter region from the fresh‐frozen cohort.Table S3. Results of Spearman correlation analysis between methylation of 17 CpGs in the promoter of AR and AR gene expression.Table S4. Spearman's correlation of AR protein expression and 9 selected proteins; TCGA cohort .Click here for additional data file.


Early mobilization decreases the likelihood of negative outcomes for acute-phase inpatients. Adverse events occurring during intensive care unit rehabilitation have previously been reported; however, no study has reported the incidence rates for adverse events during the acute rehabilitation phase. This study aimed to investigate the incidence of severe adverse events during acute-phase rehabilitation and evaluate them in detail.Reports of adverse events occurring during acute-phase rehabilitation in a university hospital from April 1, 2011 to March 31, 2018 were retrospectively assessed.Nine severe adverse events occurred during this period , comprising 2 cardiopulmonary arrests, 2 pulseless electrical activity events, 2 deterioration in consciousness events, 1 deterioration in consciousness event due to cerebral infarction, 1 fracture due to a fall, and 1 event involving removal of a ventricular drain. Pulmonary thromboembolism was implicated in 1 adverse event involving pulseless electrical activity and 1 deterioration in consciousness event. The causes for the 6 other adverse events could not be identified. The mean days from admission and the onset of rehabilitation to adverse event occurrence were 22.0 ± 18.2 and 17.9 ± 13.5 days (mean ± standard deviation), respectively. Four of 9 patients died, and 5 patients were discharged home or transferred to other stepdown facilities. When assessed retrospectively, there were no conflicts between patient conditions and the cancellation criteria of rehabilitation by the Japanese Association of Rehabilitation Medicine.The occurrences of severe adverse event may not be related to early mobilization (or onset time of rehabilitation) and compliance status of cancellation criteria. In the United States, medical malpractice in hospitals is a serious issue,–12 with one or more adverse events (AEs) due to hospital care having been reported to occur in 3% to 17% of inpatients in acute-phase hospitals in the United States and Europe, regardless of rehabilitation. Risk management strategies for early mobilization should be considered.The effects of early mobilization from intensive care units (ICUs) on inpatients has been previously demonstrated.,15 However, these studies did not specify the target patient populations, nor were the medical safety measures described, and these results should be interpreted with caution. No studies concerning inpatients in acute-phase hospitals have reported SAEs during early mobilization.Severe adverse events (SAEs) may prolong a hospital stay, and may have medical sequelae along with the possibility of litigation, resulting in increasing medical cost burdens. Two studies reported that adverse events occurring during rehabilitation in ICUs mostly involved no additional treatment, cost, and/or extension of hospitalization.,6 At our hospital, we have experienced several SAEs during rehabilitation. In this study, we retrospectively assessed our department's reports of SAEs. This study aimed to evaluate the SAE incidence rate and obtain detailed information for future improvement to our risk management strategy.Our medical hospital is an acute care and tertiary emergency medical facility. Rehabilitation therapies are provided by a specialized team comprised of physiatrists and registered therapists operating rehabilitation, depending on the condition of each patient under medical management.22.1,6Our hospital has 760 general beds (including ten ICU beds) and 40 psychiatric beds, serving 27 clinical departments and 22 central medical treatment sections. Physiatrists examine inpatients prior to starting rehabilitation and evaluate their diagnosis, disease state, and physical condition. Registered and skilled therapists then commence exercise therapy. A team meeting is held in the evening of the patient referral day to identify challenges and consider solutions, with the aim of improving rehabilitation safety and efficacy. Patient status is assessed every morning for all patients participating in rehabilitation sessions. Therapists measure vital signs pre- and postrehabilitation. Rehabilitation therapies are performed based on a thorough clinical examination and in accordance with each patient's condition.2.2In this retrospective cohort study, we analyzed SAE reports that had been submitted to the Medical Safety Promotion Department at our hospital from the Department of Rehabilitation Medicine between April 2011 and March 2018, during which time 1 author (T.K.) worked as the department's patient safety manager.2.3: Category A (no error); categories B to D (error but no harm); categories E to H (error and harm), and category I (error and death). For adverse events that occur in categories A to D, no additional treatment is required. For adverse events that occur in category E, minor treatment is required. For adverse events that occur in category F, intensive treatments are required and/or extension of hospital stay is needed. If permanent disability and sequelae with no significant or with significant functional or cosmetic problems develop, SAEs are defined as G or H, respectively; thus, SAEs are defined as categories F to I in reference to the above index.At our hospital, all staff are required to report an AE to their relevant risk manager each time an AE occurs. A decision is made concerning the AE level by the Medical Safety Promotion Department at our hospital. According to the National Coordination Council for Medication Error Reporting and Prevention index, AEs are categorized into nine levels, as followsRehabilitation period was defined as the period when a therapist provided rehabilitation in a patient's bedroom, corridor, training room (or outdoors). Specific definitions of the period include durations1.from when a therapist enters patient's room until leaving,2.from when a patient enters a training room until leaving, or3.if a surveillance and/or assistance patient was moved with a transfer staff, duration was defined as from when a therapist received a patient to when a patient was passed over to a transfer staff member.We investigated the numbers of hospitalized patients, patients (inpatients and outpatients) referred to our department, deaths, discharge, length of admission, days until the onset of rehabilitation, and total numbers of AEs, namely, non-SAEs or SAEs that occurred in our hospital during the study period, and the total number of patients who underwent rehabilitation annually during the study period. , the department that had mainly treated the patients with SAEs, the primary disease, and comorbidities were obtained from the SAE reports. We also obtained data concerning contents and causes, the place of SAE occurrence, occurrence status, whether a stat call was made, the number of days from admission to starting rehabilitation to SAE occurrence and to discharge, days from surgery to SAE occurrence, discharge status , predictability determined by the Medical Safety Promotion Department, and therapist experience years. For all patients with SAEs, we retrospectively verified whether a patient's status conformed with Guidelines for Safety Management and Promotion cancellation criteria for rehabilitation, which had been edited by the Clinical Practice Guidelines Committee of the Japanese Association of Rehabilitation Medicine in Japan Table .2.4The values of the variables are given as numbers, %, mean ± standard deviation (SD), or median (min-max) where applicable.2.5This study was conducted in accordance with the Declaration of Helsinki and its protocol was approved by the relevant ethics review committee (No. 2677). In this retrospective study, there were no additional risks to patients during the data collection and analysis. All information related to the patients was protected. Information concerning this study was posted on the university website and patients or their families and relatives were given the opportunity to opt-out. The ethics review committee waived the requirement for written informed patient consent due to the study's retrospective design.3The average annual number of inpatients during the study period was 16231.9 ± 646.4, and the average length of admission was 14.6 ± 0.6 days  for the seven-year period. Two cardiopulmonary arrests and 2 pulseless electrical activities were involved.This study is the first to evaluate SAEs occurring during acute-phase rehabilitation. At our hospital, a specialized team of rehabilitation physiatrists and registered therapists provide rehabilitation,6,18,19 In our study, the period from admission  or from the onset of rehabilitation to the occurrence of an SAE  was approximately 20 days, which indicated that early onset of rehabilitation was unlikely to be related to SAE occurrence. Furthermore, only in Case A did an SAE occur on the day when the exercise load was increased. In the other 8 cases, the rehabilitation program at the time of SAE occurrence had begun being performed from at least the day before . Therefore, it appears unlikely that SAE occurrences were related to increased exercise loads.Previous studies have reported that, in patients with stroke and in patients in ICU, early rehabilitation intervention did not increase the number of deaths, which supports our results. However, as the years of experience among the responsible therapist in charge of each patient was approximately 8 years (1–22 years) in the 9 cases presented in this study, with considerable variation, it would appear that the number of years of experience was not associated with the occurrences of SAEs.A previous report investigating the occurrence of AEs during rehabilitation among acute-phase hospital, rehabilitation hospital, and nursing home inpatients reported a negative correlation between SAEs occurrences and therapist years of experience. Furthermore, 57% of acute pulmonary thromboembolic events have been reported to occur during standing or walking and 22% to 53% have occurred during defecation or urination. Most emboli were derived from venous thrombi in the lower limbs and pelvis, and muscle contraction of the lower limbs when standing, walking, or during defecation increases venous return to the heart due to the action of the muscle pump, at which time a thrombus can be released and an acute pulmonary thromboembolism may occur. However, 1 meta-analysis reported that early gait training was not associated with an increased incidence of new pulmonary thromboembolisms, deep vein thrombosis (DVT) progression, or DVT-related mortality when compared with patients not undertaking gait training.,26 Moreover, Japanese guidelines recommend early walking for patients with DVT.All the SAEs in this study accorded with established cancellation criteria, which mainly comprise an evaluation of vital signs and chest symptoms used in early detection of status changes in patients. There is a need to be aware of the risk of thrombus formation during rehabilitation, especially in an acute phase. In a previous study of 11,786,489 surgeries from 6530 hospitals during a ten-year period from 2002 to 2012, pulmonary thromboembolism was reported in 3667 perioperative patients with an incidence rate of 0.031%.Of the 2 episodes of pulmonary thromboembolism in our study, 1 patient had started to get out of bed more than 1 month earlier and had continued standing training and started walking training prior to the day of the SAE (Case A). In another case, rehabilitation had been performed preoperatively, and walking training recommenced the day after surgery, with the pulmonary thromboembolism occurring when the walking distance was extended from the second postoperative day (Case D). Rehabilitation medical care may not increase the risk of the occurrence of pulmonary thromboembolism; however, it is necessary to prepare for its possible occurrence at any time during rehabilitation.This study was limited in that it was a single-center, retrospective cohort study; therefore, information concerning a non-adverse event group was not available. Furthermore, due to the small sample size, statistical analyses other than in relation to descriptive statistics were not possible.5Nine SAEs occurred during acute-phase rehabilitation over a seven-year study period, and rehabilitation did not increase the occurrence of SAEs in our hospital. SAEs were not found to be related to early mobilization (or onset time of rehabilitation), an increased exercise load, or therapists’ years of experience. In clinical acute rehabilitation medicine, SAEs that require intensive care might occur regardless of whether they accord with Japanese Association of Rehabilitation Medicine cancellation criteria. Rehabilitation should be performed depending on each patient's status under medical management as undertaken by physiatrists.The authors thank Mrs. Yuta Minoshima, Yuri Matsuura, Daichi Shima, Shinji Kawasaki, and Shinnosuke Hori for their excellent assistance with data collection. We also thank Dr. Sven P. Hoekstra for kindly editing of the manuscript. This work was supported by the Nachikatsuura Research Foundation [grant numbers 1221].Conceptualization: Tokio Kinoshita, Yoshi-Ichiro Kamijo, Yukihide Nishimura.Data curation: Makoto Kawanishi, Takahiro Ogawa, Tokio Kinoshita, Yasunori Umemoto, Yoshinori Yasuoka.Formal analysis: Makoto Kawanishi, Yoshinori Yasuoka.Investigation: Yoshi-Ichiro Kamijo.Methodology: Takahiro Ogawa, Yoshi-Ichiro Kamijo.Project administration: Fumihiro Tajima.Supervision: Fumihiro Tajima, Yukihide Nishimura.Validation: Ken Kouda.Writing – original draft: Tokio Kinoshita, Yoshi-Ichiro Kamijo.Writing – review & editing: Fumihiro Tajima, Ken Kouda, Yasunori Umemoto, Yoshi-Ichiro Kamijo, Yukihide Nishimura, Yukio Mikami.