The COVID-19 pandemic has largely affected people’s mental health and psychological well-being. Specifically, individuals with a pre-existing mental health disorder seem more impaired by lockdown measures posing as major stress factors. Medical rehabilitation treatment can help people cope with these stressors. The internet and digital apps provide a platform to contribute to regular treatment and to conduct research on this topic.Making use of internet-based assessments, this study investigated individuals from the general population and patients from medical, psychosomatic rehabilitation clinics. Levels of depression, anxiety, loneliness, and perceived stress during the COVID-19 pandemic, common COVID-19–related worries, and the intention to use digital apps were compared. Furthermore, we investigated whether participating in internet-delivered digital trainings prior to and during patients’ rehabilitation stay, as well as the perceived usefulness of digital trainings, were associated with improved mental health after rehabilitation.A large-scale, online, cross-sectional study was conducted among a study sample taken from the general population (N=1812) in Germany from May 2020 to April 2021. Further, a longitudinal study was conducted making use of the internet among a second study sample of psychosomatic rehabilitation patients at two measurement time points—before (N=1719) and after (n=738) rehabilitation—between July 2020 and April 2021. Validated questionnaires and adapted items were used to assess mental health and COVID-19–related worries. Digital trainings were evaluated. Propensity score matching, multivariate analyses of covariance, an exploratory factor analysis, and hierarchical regression analyses were performed.F4,2028=183.74, P<.001, 2pη=0.27) compared to the general population. Patients perceived greater satisfaction in communication with health care professionals , had lower financial worries , but had higher household-related worries  compared to the general population. Symptoms of depression, anxiety, loneliness, and perceived stress were lower postrehabilitation  than prior to rehabilitation. Psychosomatic patients reported a higher intention to use common apps and digital trainings  than the general population. With regard to digital trainings offered prior to and during the rehabilitation stay, the perceived usefulness of digital trainings on rehabilitation goals was associated with decreased symptoms of depression , anxiety , loneliness , and stress postrehabilitation . Participation in digital group therapy for depression was associated with an overall change in depression  and anxiety  from pre- to postrehabilitation.Patients from the psychosomatic rehabilitation clinics reported increased symptoms with regard to depression, anxiety, loneliness, and stress (This study validated the increased mental health constraints of psychosomatic rehabilitation patients in comparison to the general population and the effects of rehabilitation treatment. Digital rehabilitation components are promising tools that could prepare patients for their rehabilitation stay, could integrate well with face-to-face therapy during rehabilitation treatment, and could support aftercare.ClinicalTrials.gov NCT04453475; https://clinicaltrials.gov/ct2/show/NCT04453475 and ClinicalTrials.gov NCT03855735; https://clinicaltrials.gov/ct2/show/NCT03855735 The COVID-19 pandemic has led to rapid changes in the lives of people all over the world, thus affecting both physical health as well as mental health and well-being ,3. In caA study by Wang et al asked respondents to assess the psychological impact of the COVID-19 pandemic on their mental health. Results highlighted that 54% of the respondents rated the psychological impact of the COVID-19 pandemic as moderate to severe. Further, 29% estimated their own anxiety symptoms to be between moderate and severe, and 17% estimated symptoms of depression as moderate to severe . Recent The conjectured decrease in mental health worldwide may be explained by two developments associated with the ongoing course of the COVID-19 pandemic. On the one hand, the ramifications associated with the COVID-19 pandemic, such as uncertainties, unemployment, short-term employment, or social isolation, may pose a mental health threat. A cross-national comparison of Norway, the United Kingdom, the United States, and Australia found that secure employment status was associated with lower levels of loneliness and mental health distress as well as higher levels of well-being and quality of life during the early social distancing requirements of the pandemic .On the other hand, the way most people live, work, study, socialize, or travel has been abruptly disrupted or shifted online. The associated containment measures, such as quarantining and physical distancing, restrict people in their freedom, but are necessary to control the disease's spread. Literature has shown that quarantining or physically distancing oneself from others may lead to problems associated with a decreased mental health status . It can The World Health Organization (WHO) has also expressed concerns with regard to the mental health and psychological well-being of individuals due to containment measures. According to the WHO, restrictions may interfere with people's daily activities and routines and may consequently lead to an increased perception of loneliness, depression and anxiety, insomnia, substance misuse, self-harm, or even suicidal behavior . It has Literature on the impact of the 2003 severe acute respiratory syndrome (SARS) outbreak and the COVID-19 pandemic underlined more negative feelings associated with worry ,15. WorrFor patients with a pre-existing mental health disorder or a decreased perception of well-being, lockdown measures are major stress factors affecting daily routine and social rhythms. A study by van Rheenen et al examined the mental health status of individuals with a mood disorder during the COVID-19 pandemic in an Australian sample as compared to individuals without a prior mood disorder. Their results underlined that distress in response to the COVID-19 pandemic is highlighted in individuals with a mood disorder . PatientA population that has been especially concerned by the COVID-19 pandemic because of pre-existing mental health problems comprises psychosomatic patients in medical rehabilitation. They may be afraid of visiting a doctor and receiving inpatient treatment in a hospital; on the other hand, they report worsening physical and mental well-being . This deDue to the pandemic and, accordingly, its restrictions, resources had to be re-allocated and therapies had to be paused, which caused a decrease in the availability of on-site services . ParticuDigital interventions and trainings allow for adherence to hygiene measures as well as allow for therapeutic services to be offered on a large-scale basis. In addition, patients may be offered digital treatment options if they refrain from entering a rehabilitation stay due to worries and fears associated with the current COVID-19 pandemic, such as their own health and well-being or worries associated with losing their work placement . SeveralDrawing on the Health Action Process Approach (HAPA) ,34, whicBased on the described background, we posed a number of research questions in order to understand worries and associated consequences regarding the COVID-19 pandemic in different populations, especially medical, psychosomatic rehabilitation patients, by means of internet technology:What differences are there in reported psychological variables such as depression, anxiety, loneliness, and perceived stress between the general population and patients assigned to medical, psychosomatic rehabilitation clinics? The patients were diagnosed with a mental illness and were, thus, hypothesized to be at a higher risk for an exaggeration of their illness due to the pandemic, as shown above.Which worries are associated with the current COVID-19 pandemic and are there differences in the perception between the two groups? We hypothesized that individuals from the psychosomatic rehabilitation group experienced more worries with regard to the pandemic.Is medical, psychosomatic rehabilitation treatment effective in terms of a decrease in symptomatology for depressive symptoms, symptoms of anxiety, loneliness, and perceived stress?Do the general population and patient groups intend to make use of internet-delivered treatment components?Is there a relationship between the usage, as well as perceived usefulness, of digital trainings that are offered before as well as during the rehabilitation stay in association with the intensity of mental health symptoms  of patients after their medical rehabilitation?By testing these research questions, we aimed to close the research gap of evaluating mental health and COVID-19–related worries between the general population and psychosomatic rehabilitation. Furthermore, this study assessed the usefulness of internet-delivered trainings and their association with the mental health status of psychosomatic rehabilitation patients in Germany. To our knowledge, this has not been done before systematically. It is warranted to implement not only innovative but also effective internet-delivered interventions into the provision of medical services.The study was conducted as part of the project “Anhand-COVID19 – Offer to achieve treatment and rehabilitation goals in compliance with hygiene and social-distancing rules” , which is supported by the Dr Becker clinic group. In addition, data collection and analyses on the general population was part of the research project “TeamBaby – Safe, digitally supported communication in obstetrics and gynecology” , which is funded by the German Innovation Fund (Project No. 01VSF18023) of The Federal Joint Committee (G-BA).Data were collected anonymously through a nationwide recruitment campaign, press releases, social media posts, and the study home page of the TeamBaby project. No market research company or public sample was involved; however, the sample might have been selective. For data collection purposes, the software tool Unipark was used. The nationwide cross-sectional survey aimed to examine worries and coping mechanisms during the COVID-19 pandemic. All participants were informed about the purpose of the survey beforehand and provided online informed consent. Participants from the general population were not offered any form of compensation for participation. Data collection from the general population took place between May 2020 and April 2021. Time to complete the survey took, on average, 15.18 minutes (SD 11.50). Ethical approval for the online survey for the general population was given by the Ethics Committee at Jacobs University Bremen on September 17, 2019.The second group of participants were recruited through four psychosomatic clinics from the Dr Becker clinic group and attended regular treatment at the recruiting clinics, consisting of psychological and physical interventions  as part of the incoming process for their rehabilitation stay. The German rehabilitation system focuses not on curation but on reintegration and social participation. “Interventions in rehabilitation include psychoeducation, physical training, psychotherapy, and the training of skills particularly with regard to working ability” (page 81 in Scheidt ). ParticThe online survey at the psychosomatic clinics was administered between July 2020 and April 2021. Data collection at the rehabilitation clinics was longitudinal and took place at two time points: 6 weeks before the start until the first day of rehabilitation (T1) and after their rehabilitation stay (T2). Four medical, psychosomatic rehabilitation clinics took part in this study and supported the recruitment of participants as well as provided psychosomatic rehabilitation between measurement points T1 and T2. For the recruitment process and data collection process, see Digital trainings were provided via the internet prior to patients’ rehabilitation stay to optimally prepare them for their medical rehabilitation treatment and to make good use of the treatment components, including psychoeducation, physical training, psychotherapy, and the training of skills, particularly with regard to working ability in the clinic. Such trainings could address rehabilitation goals.The digital training on rehabilitation goals was offered to the patients in a digital PowerPoint (Microsoft) presentation training without face-to-face elements. Participants were able to participate in the digital training before their rehabilitation stay with a computer, laptop, tablet, or smartphone. The training included exercises on formulating precise plans for the rehabilitation stay. After the training, the patients were encouraged to make use of a digital exercise booklet containing exercises on formulating plans as well as for writing journal entries. Participation was on a voluntary basis. In addition, participants from two out of four psychosomatic rehabilitation clinics with a diagnosis of depression took part in group therapy for depression in the form of a flipped classroom as part of the rehabilitation treatment program .The digital group training for depression was a combination of digital and face-to-face components. The training was divided into six sessions, each consisting of a 5-minute digital training followed by a 45-minute analog group session. The digital training, including input from a therapist with flip chart accompaniment, was either viewed independently or was watched as a group at the beginning of the analog group session. Participation for patients with a diagnosed depressive disorder was mandatory. The digital group training for depression was based on cognitive behavioral therapy (CBT) and contained evidence-based components of eCBT and internet-delivered CBT interventions, based on the current state of the art -39. ContItems assessing worries related to the COVID-19 pandemic were derived from a study that measured frequently reported burdens and worries due to the COVID-19 pandemic . Consequρ=0.75) and the GAD-2 (Spearman ρ=0.74) indicated a probable case of depression and anxiety [For both subsamples, symptoms of depression and anxiety were measured with the 4-item Patient Health Questionnaire (PHQ-4), which is the composite measure of the 2-item Patient Health Questionnaire (PHQ-2)  and the  anxiety ,44. The α of .79.The Perceived Stress Scale (PSS)  is a gloρ=0.85). The items were rated on a 4-point Likert scale from 1  to 4 . Both items were presented to the general population and to the psychosomatic rehabilitation patients.Loneliness was assessed with two items: “How often do you feel lonely?” stemming from the Center for Epidemiologic Studies–Depression scale , and “HoIntention to use apps or digital trainings as supportive means during the COVID-19 pandemic was assessed by rating three items on a 5-point Likert scale from 1  to 5 . These items were adapted based on the stages of change as part of the HAPA, which suggests that individuals typically progress through stages of behavior change independently of any time frame ,50.Based on the different digital trainings that psychosomatic rehabilitation patients took part in, the perceived usefulness of the offered digital trainings was measured by rating two items on a 5-point Likert scale from 1  to 5 (completely useful): one item for the digital training on rehabilitation goals and one item for the digital, flipped classroom, group therapy for depression. Both items were adopted and modified based on the Technology Acceptance Model, which was originally designed to evaluate patients’ responses to health information technology .Additional data on sociodemographic information included participants' age, sex, and educational status. Age was categorized into five groups: ≤29 years, 30-39 years, 40-49 years, 50-59 years, and ≥60 years. Sex was categorized into three groups: male, female, and diverse. The highest obtained educational status was categorized into four groups: 10 or 11 years of schooling, 12 or more years of schooling, vocational training, and university degree. All variables were measured as categorical variables.Literature has shown that propensity score matching (PSM) has been able to effectively reduce biases of treatment selection in nonrandomized studies . ThroughAfter PSM, 2054 participants were included for further analyses, and data from the general population and the psychosomatic clinics were examined for differences. To assess whether individuals recruited from the general population and individuals from the psychosomatic clinics differed in their expression concerning psychological symptoms of depression, anxiety, loneliness, and perceived stress, a multivariate analysis of covariance was performed, controlling for gender, age, and educational level. Afterward, an exploratory factor analysis (EFA) was carried out to determine factors within the worries related to the COVID-19 pandemic based on items' factor loadings. Regarding the EFA, meaningful factors to retain for further analysis were based on the scree plot as well as the percentage of common variance explained by a given factor with an eigenvalue above 1. Meaningful factors were retained for varimax rotation. Items with a factor loading above 0.40 were used for interpretation purposes. Hence, out of 17 items primarily used to analyze worries related to the COVID-19 pandemic, one item was eliminated due to a low item loading. After EFA, significant differences between the data from the general population and the psychosomatic clinics, regarding the defined factors measuring worries related to the COVID-19 pandemic, were examined by a multivariate analysis of covariance controlling for gender, age, educational status, perceived stress, loneliness, depressive symptoms, and symptoms of anxiety.In addition, a repeated-measures analysis of covariance was performed, controlling for gender and age on 738 psychosomatic rehabilitation patients to examine whether individuals from the psychosomatic clinics showed a change in psychological symptoms on the variables of depression, anxiety, loneliness, and perceived stress prior to and after their rehabilitation stay. To evaluate whether taking part in digital trainings  was associated with a significant change in symptom intensity with regard to depression, anxiety, loneliness, and perceived stress, a repeated-measures analysis of covariance was performed, controlling for age and gender.To examine the intention to use common digital apps and trainings with a focus on health that were not offered during the rehabilitation stay with regard to the general population and patients from the psychosomatic rehabilitation clinics, an analysis of covariance was performed controlling for age, gender, and educational status. Finally, to evaluate the perceived usefulness of internet trainings offered during the rehabilitation stay and the association with patients' mental health status after their rehabilitation stay, a hierarchical regression analysis was performed. All data analyses were carried out using SPSS, version 27 (IBM Corp).The amount of missing data was below 5% for all items and 1.3% on average. Participants with missing data on the social-cognitive variables were included for further analysis if they had at least one nonmissing data point under the assumption of missing completely at random. However, no missing data points were imputed due to the overall low percentage of missing data points.Overall, 3531 participants completed the online questionnaire. With regard to the general population, 1812 participants participated in the data collection. Out of these participants, 1267 (69.9%) were female and 16 (0.9%) did not respond. Age ranged from 18 to over 60 years. Out of 1812 participants, 193 (10.7%) had 10 or 11 years of schooling, 421 (23.2%) had 12 or more years of schooling, 507 (28.0%) had completed vocational training, and 690 (38.1%) had a university degree; there was 1 (0.1%) missing data point.Concerning participants from the psychosomatic rehabilitation clinics, 1719 participants participated in the survey before their rehabilitation stay. Of these participants, 1104 (64.2%) were female and there were 13 (0.8%) missing data points. Age ranged from 18 to over 60 years. Out of 1719 participants, 398 (23.2%) had 10 or 11 years of schooling, 241 (14.0%) had 12 or more years of schooling, 791 (46.0%) had completed vocational training, and 266 (15.5%) had a university degree; there were 23 (1.3%) missing data points. After the rehabilitation stay, 738 participants participated in the survey.With regard to the general population of 1027 participants, 684 (66.6%) were female, their age ranged from 18 to over 60 years, 163 (15.9%) had 10 or 11 years of schooling, 173 (16.8%) had 12 or more years of schooling, 409 (39.8%) had completed vocational training, and 282 (27.5%) had a university degree.With regard to the 1027 participants from the psychosomatic rehabilitation clinics, 659 (64.2%) were female, their age ranged from 18 to over 60 years, 167 (16.3%) had 10 or 11 years of schooling, 194 (18.9%) had 12 or more years of schooling, 404 (39.3%) had completed vocational training, and 262 (25.5%) had a university degree.F4,2028=183.74, P<.001, 2pη=0.27), with age, gender, and education being significant covariates. Individuals from the psychosomatic clinics displayed significantly higher scores on all four psychological variables compared to individuals recruited from the general population: depression , anxiety , loneliness , and perceived stress   .α=.90), health-related worries , financial worries , and household-related worries . With regard to household measures, one item was assessed on a 4-point Likert scale from 1  to 4 (completely). The second item was assessed on a 6-point Likert scale from 1 (never or less than once per month) to 6 . Hence, the Likert scale of the second item was transformed to a 4-point Likert scale. For all factors, composite mean scores were computed.After varimax rotation, 16 items were retained in the analysis with factor loadings of ≥0.40 with the respective factor . Four faThe same factor structure was found in both samples. A total of 70.32% of the variance could be explained in the general population and 64.33% of the variance could be explained in the sample of psychosomatic rehabilitation patients.Summarizing the results from the factor analysis, the factor structure of the evaluated worries associated with the current COVID-19 pandemic was equal across samples. Hence, the overall EFA across samples revealed four factors associated with the COVID-19 pandemic: satisfaction with communication, health-related worries, financial worries, and household-related worries.F4,835=17.17, P<.001, 2pη=0.08) concerning worries related to the COVID-19 pandemic , household-related worries , and financial worries . Age, gender, perceived stress, loneliness, depressive symptoms, and symptoms of anxiety were significant covariates. Hence, patients recruited from the psychosomatic clinics perceived a significantly greater satisfaction with communication, increased household-related worries, but significantly lower financial worries before their rehabilitation stay .Patients reported being unemployed more frequently prior to their rehabilitation stay  compared to the general population . Taking a closer look at individual test variables, results revealed a significant reduction in depression , anxiety , perceived stress , and loneliness  in psychosomatic patients after their rehabilitation . Patients appeared more inclined to use common apps and digital trainings offered outside of their rehabilitation stay supporting them in their communication with health care professionals  as well as COVID-19–related health care apps .Results of the multivariate analysis of variance revealed an overall significant difference between individuals from the general population and individuals from the medical, psychosomatic rehabilitation clinics  and anxiety .We examined whether taking part in the digital training on rehabilitation goals  and digital group therapy for depression  were associated with a decrease in symptom intensity after the rehabilitation stay compared to before. The results highlighted the following significant differences: taking part in the digital group therapy for depression was associated with a significant decrease in symptom intensity after the rehabilitation stay with regard to depression (The data that support the findings of this study are available from the corresponding author (SL) upon reasonable request.In this study, differences between a sample of 1027 individuals from the general population and 1027 patients from medical, psychosomatic rehabilitation clinics in depression, anxiety, loneliness, and perceived stress during the COVID-19 pandemic were examined by means of the internet after PSM. The expression of symptoms and worries related to the COVID-19 pandemic were psychometrically assessed and tested for differences between the two samples (research questions 1 and 2). As a third research question, a potential decrease in symptom intensity on the test variables was examined for psychosomatic rehabilitation patients before starting and after their rehabilitation stay. Moreover, this paper evaluated the differences in intention to use digital apps and trainings during the COVID-19 pandemic between individuals from the general population and individuals from the psychosomatic rehabilitation clinics (research question 4). With regard to the potential decrease in symptoms, research question 5 evaluated the association between participation in digital trainings addressing rehabilitation goals and digital depression group therapy. Furthermore, the perceived usefulness of digital trainings before  and during  the rehabilitation stay was evaluated with regard to the symptom intensity of depression, anxiety, loneliness, and perceived stress after the rehabilitation stay.The findings from this study confirm that individuals felt affected by the COVID-19 pandemic in terms of their mental health and well-being. For individuals from the psychosomatic medical rehabilitation, symptoms of depression, anxiety, loneliness, and perceived stress were elevated compared to the general population. Thus, we can answer the research question 1 by showing that individuals assigned to medical, psychosomatic rehabilitation clinics perceive and express more mental health symptoms, which is in line with our hypothesis. In prior research, individuals with a pre-existing mental health disorder reported poorer access to support services since the beginning of the pandemic, had earlier discharges from psychiatric units, or had discontinuation of psychotherapy treatments -55. The Surprisingly, psychosomatic patients perceived significantly greater satisfaction in communication with health care professionals and had significantly lower financial worries but higher household-related worries, even after statistically controlling for confounding variables. However, no significant difference between the groups was found with regard to health-related worries, which is contrary to the hypothesis that they would experience more worries (research question 2). The fact that psychosomatic rehabilitation patients perceived greater satisfaction with communication before their rehabilitation stay may be due to previous information obtained digitally  from the clinic as well as participating in surveys and tasks before their stay. Furthermore, contact with the rehabilitation clinics might have been perceived as an emerging support system by the rehabilitation patients, offering the hope that their situation would soon improve and that they would receive help during the pandemic. Literature has shown that effective communication with patients may prove empowering for patients .The results concerning financial worries are partly in line with van Rheenen et al . Their sPsychosomatic rehabilitation patients indicated greater worries associated with their household, which includes conflicts within the family or dissatisfaction with household dynamics before their rehabilitation stay, as compared to individuals from the general population. As the COVID-19 pandemic is characterized by strict travel restrictions, an increase in working from home and homeschooling, short-term employment, or unemployment, people tend to either spend more time with immediate family at home, leading to an increase in family conflicts, or experience isolation while quarantining. The results by Guo et al support the results of this study. They highlight that a risk factor associated with reduced mental health status during the COVID-19 pandemic is living alone . NeverthMoreover, individuals with and without mood disorders reported a similar frequency of worries related to health, such as worries about loved ones falling sick with COVID-19 as well as implications for one's own health and well-being. This is in line with results by van Rheenen et al highlighting equal concerns about the health and well-being of the social environment for individuals with mood disorders  and those without a mental health disorder. Furthermore, individuals with and without a mental health disorder indicated almost equal concerns regarding their own health and well-being during the COVID-19 pandemic . This shIn addition, results indicated that for psychosomatic patients, symptoms of depression and anxiety as well as of perceived stress and loneliness decreased significantly between pre- and postrehabilitation, thus answering in favor of the third research question. This underlines the importance and necessity of medical rehabilitation treatment for patients with chronic mental disorders ; in partInterestingly, compared to individuals from the general population, psychosomatic rehabilitation patients reported a greater intention to use common apps and digital trainings focusing on health and that are not offered during rehabilitation. This offers important insights into research question 4. First of all, patients who have applied for a rehabilitation stay may already be more open to medical and lifestyle interventions. Hence, pre-existing motivation to change may foster intentions to pursue a change. Furthermore, patients with an affective disorder may be more prone to excessive reassurance-seeking, which may be defined as the repeated need for safety-related information ,68. TherNext to the increased intentions of psychosomatic rehabilitation patients to use digital trainings, those who evaluated the perceived usefulness of the digital training on rehabilitation goals as increasingly useful and helpful postrehabilitation stay also displayed lower symptoms regarding depression, anxiety, loneliness, and perceived stress compared to the general population. This finding clearly supports a positive association that was examined in the final research question. One might postulate that useful and helpful preparation for the rehabilitation stay provides the basis for effective digital training, such as digital group therapy for depression. Feeling well prepared, informed, and being offered additional material prior to the rehabilitation stay may motivate the patients to be an active agent and engage effectively in the subsequent digital treatment programs. Moreover, the result can be explained by the assumptions of the HAPA . During With the support of the digital group therapy addressing depression, the desired behavior of achieving a better mental health status may be facilitated by means of developing coping strategies, learning new skills, and activating resources. Initial approaches in offering psychosomatic rehabilitation patients digital therapy tools for aftercare have been made by Schmädeke et al and have proven to be effective . Hence, Overall, psychosomatic rehabilitation is an effective treatment, especially during the pandemic, and should be offered to all people who either suffer from a pre-existing chronic mental disorder or who developed mental disorders due to the pandemic and its restrictions. In addition, digital trainings should be integrated with the rehabilitation process for patients with an affective mood disorder. As the COVID-19 pandemic poses several barriers toward the uptake of a psychosomatic treatment , it mustThis study highlights the need to offer individuals support to maintain sufficient mental health, especially in times of a pandemic and its aftermath. This can be achieved in multiple, low-threshold ways that meet different needs and preferences. It may include offering individuals—not only limited to individuals with a prior mental health diagnosis to ensure prevention—facilitated access to video and telephone consultation hours, digital preventive programs, or psychosomatic rehabilitation stays. Facing a substantial lack of medical doctors, therapists, and other health care workers and the need to reduce physical contact, it is necessary to develop and establish internet-based programs and trainings as one component of therapy as well as digital support systems and platforms.Internet-delivered treatment components offer different advantages that need to be planned more systematically. For instance, physicians or general practitioners should briefly screen all patients perceived to be at risk for stress, anxiety, or depression due to the pandemic  and then recommend further online services -72 or hySeveral limitations need to be considered while interpreting the findings of this study. First of all, the data evaluated from the general population are cross-sectional. Also, any changes due to the COVID-19 pandemic  could not have been controlled for significant events such as lockdown measures in Germany.Furthermore, the items assessing worries related to the COVID-19 pandemic were nonvalidated items based on research found in the literature so far. Hence, for future studies, the analyzed items should be examined with respect to validity, while this study provides the first results regarding reliability. Another critical point to highlight is that mental health, in the form of symptoms of depression, anxiety, loneliness, and stress, was self-reported. In addition, the questionnaires that were used  only gave an indication about the symptom intensity but were not used as diagnostic tools.Furthermore, we had no indication of symptoms or clinical mental health diagnoses before the start of the COVID-19 pandemic. Hence, we cannot be certain that the levels of psychological symptoms reported by participants were subject to the COVID-19 pandemic. However, it has been suggested that symptoms of anxiety and depression increased as a result of the COVID-19 pandemic compared to historical normative data .In addition, the digital training on rehabilitation goals and group therapy for depression were not tested with regard to their effectiveness beforehand. Furthermore, with regard to the data collected with the psychosomatic clinics, it remains to be evaluated in future research whether somatic aspects, including a potential COVID-19 infection, are a confounding factor for the expression of symptoms of depression, anxiety, loneliness, and perceived stress.This study provides insights into the mental health status and perceived well-being of psychosomatic rehabilitation patients compared to the general population during the COVID-19 pandemic. In addition, this study was able to evaluate COVID-19–related worries between the general population and psychosomatic rehabilitation patients. Further, the usefulness of internet-delivered trainings and their association with the mental health status of psychosomatic rehabilitation patients in Germany was assessed. The results suggest that psychosomatic rehabilitation patients perceived greater symptoms of depression, anxiety, loneliness, and stress compared to the general population before their rehabilitation stay, which validates their status as assigned to rehabilitation. Future studies should replicate these findings in other countries and with individuals from a different cultural background. In particular, the question remains as to whether different health care systems and rehabilitation treatments  would result in the same outcomes. It is also imperative to disentangle which components of the internet-delivered interventions were especially effective in which patients.The general population perceived greater financial worries, whereas patients before their rehabilitation stay perceived greater worries associated with their health and household. In addition, our results underline that in comparison to before their medical rehabilitation stay, patients’ symptoms of depression, anxiety, and perceived stress were significantly lower after their rehabilitation stay. This stresses the value and necessity of psychosomatic rehabilitation treatments, concerning the psychotherapy of chronic mood disorder, and their relevance during the COVID-19 pandemic, especially among individuals with elevated symptoms and needs.Internet-delivered medical rehabilitation components integrated into face-to-face therapy have the option to accelerate mental health improvements due to rehabilitation, which is especially important in times of limited treatment capacities and the need to reduce the transmission of viruses . Internet-delivered medical treatment can bridge the gap and can also help patients to cope with a potential aftermath of the COVID-19 pandemic in terms of more patients in need of care than available resources at the patients’ residence.


Various rehabilitation services and return-to-work programs have been developed in order to reduce sickness absence and increase sustainable return-to-work. To ensure that people with a high risk of not returning to work can participate in working life, the model of work-related medical rehabilitation was developed in Germany. The efficacy of these programs in patients with mental disorders has been tested in only a few trials with very specific intervention approaches. To date, there is no clear evidence of the effectiveness of work-related medical rehabilitation implemented in real-care practice.Our randomized controlled trial will be conducted in six rehabilitation centers across Germany. Within 15 months, 1800 patients with mental disorders (300 per rehabilitation center) will be recruited and assigned one-to-one either to a work-related medical rehabilitation program or to a conventional psychosomatic rehabilitation program. Participants will be aged 18–60 years. The control group will receive a conventional psychosomatic rehabilitation program without additional work-related components. The intervention group will receive a work-related medical rehabilitation program that contains at least 11 h of work-related treatment modules. Follow-up data will be assessed at the end of the rehabilitation and 3 and 12 months after completing the rehabilitation program. The primary outcome is a stable return to work. Secondary outcomes cover several dimensions of health, functioning and coping strategies. Focus groups and individual interviews supplement our study with qualitative data.This study will determine the relative effectiveness of a complex and newly implemented work-related rehabilitation strategy for patients with mental disorders.DRKS00023175, September 29 2020).German Clinical Trials Register (The online version contains supplementary material available at 10.1186/s12888-021-03181-7. The 12-month prevalence of mental disorders in the German general population is about 30%. Contrary to public perception, this prevalence rate has been remarkably stable since the 1970s , health-In many countries, rehabilitation services are available to support patients with chronic diseases in order to enable work participation . In GermDue to the adverse consequences of mental illness for work participation, researchers have increasingly used work participation outcomes to appraise the effects of rehabilitation programs in recent years. In a randomized controlled trial, Hillert and colleagues have investigated the effects of a work-related medical rehabilitation (WMR) approach in a sample of patients with long-term sickness absence and unemployed patients. Participants in the intervention group were exposed to real work environments by completing part-time internships outside the rehabilitation center over a period of 4 weeks. This work exposure was accompanied by behavioral therapy in the rehabilitation department. One year after the rehabilitation program, participants in the intervention group returned to work significantly more often and reported more positive job-related attitudes . A studyRehabilitative services provided by the German Pension Insurance aim at work participation and the avoidance of disability pensions. The increasingly stronger orientation towards these goals is reflected in the dissemination of WMR programs. For the implementation of such programs, pension insurances have developed joint recommendations concerning target group, content and scope. These recommendations are summarized in the WMR guidelines –17. WMR We hypothesize that WMR improves stable return to work 12 months after rehabilitation (primary outcome) compared with conventional psychosomatic rehabilitation (CPR). Moreover, we expect more favorable secondary outcomes in patients treated with WMR.The study is a randomized controlled trial with two parallel groups. Participants are randomly assigned to a WMR or CPR group in a one-to-one ratio. Focus groups and individual interviews supplement our study with qualitative data.Participants will receive either a WMR or CPR program in one of six rehabilitation centers located in Germany . The rehabilitation programs will be provided as inpatient programs. Participation was approved either by the Federal German Pension Insurance or a regional pension insurance agency. In both programs, interventions will be performed by rehabilitation physicians, psychologists, physiotherapists, sports therapists, social workers, occupational therapists and other health professionals.The duration of the rehabilitation program is initially determined by the pension insurance agency . The rehabilitation center and the patient can agree on an extension of the program. By request, the patient may stop the rehabilitation program ahead of schedule.Patients are aged 18–60 years and have chronic mental disorders. Only patients with a need for WMR (i.e. with severe restrictions in work ability and a higher risk of not returning to work) will be included in the study. Patients have requested rehabilitation due to mental disorders interfering with work ability. Need for rehabilitation was acknowledged by a registered doctor and approved by the pension insurance agency. After approval, the pension agencies assign patients to the participating rehabilitation centers. The need for WMR is identified in the participating rehabilitation center by the SIMBO-C, a standardized screening instrument –24. PatiParticipants of the control group will receive a CPR program according to current treatment standards and guidelines for the rehabilitation of mental disorders. CPR programs last approximately 5 weeks. The duration of daily therapy amounts to 3 or 4 h. Following a multimodal approach, CPR programs include psychotherapy, psychoeducation, relaxation training, sports and exercise therapy, health education, expressive arts therapy, occupational therapy, social counseling and initiation of follow-up care. CPR programs address past and present mental health problems and aim to prevent a relapse. Patients are supported in recognizing and changing dysfunctional patterns of behavior and relationships and in developing behavioral alternatives. In contrast to WMR programs, they do not integrate an explicit focus on work, work ability and return to work in the diagnostics and therapy. Rehabilitation follows the recommendations of the guidelines for inpatient rehabilitation centers concerning the medical rehabilitation of adults with psychosomatic and mental disorders , 26.Participants of the intervention group will receive a WMR program according to the guidelines for WMR , 27 as wThis study will assess one primary outcome as well as secondary outcomes and moderator variables. Outcomes and other measures will be assessed with patient questionnaires or extracted from the rehabilitation discharge letters. A complete list of all measured constructs, measurement points and expected scaling is shown in Table The primary outcome of this study is stable return to work 12 months after rehabilitation. Return to work will also be assessed at the three-month follow-up. Stable return to work has been defined in accordance with Kuijer and colleagues  as a minSecondary outcomes cover several dimensions of health, functioning and coping strategies (see below) and will be measured at all four measurement points. At the first follow-up after completing the rehabilitation program, participants will also appraise how the rehabilitation programs dealt with work-related issues and how satisfied they were with the treatment.To cover participation in working life, the employment status (employed vs. unemployed) is noted. We record the professional position and economic sector. Moreover, we will assess if patients are on sick leave and how long they have been on sick leave. To assess the duration of sick leave, participants will be asked to report the number of weeks they have been off work for health reasons since discharge from the rehabilitation center. At baseline, this question is related to the last 12 months.Work ability will be assessed by the Work Ability Score (WAS), which is the first item of the Work Ability Index (WAI)  and compThe 36-Item Short-Form Health Survey (SF-36) will be used to assess the health-related quality of life . The SF-Psychosocial health will be measured by three modules of the German survey “HEALTH-49”  . The firA short 13-item form of the Job Anxiety Scale , 40 willIn order to assess attitudes and beliefs about coping with stressful events, a 20-item German questionnaire  will be used . Ten iteTo assess the fidelity of our intervention according to the patients treated, we will employ a slightly modified version of a previously used set of items from a study that investigated the nationwide implementation of the WMR guidelines in patients with musculoskeletal disorders . ParticiTreatment satisfaction will be assessed using the German version of the Client Satisfaction Questionnaire (CSQ-8) . This quAdditional measures will be assessed as potential effect modifiers and to conduct a health economic analysis.Therapeutic interventions will be extracted from the standardized rehabilitation discharge letters . The docCapacity for the most recent occupational activity and the general labor market, as well as recommendations for subsequent benefits, is assessed by the rehabilitation center. We take the information from the rehabilitation discharge letters .We will ask participants for socio-demographic data .For our health economic evaluation we use the German Questionnaire for Health-Related Resource Use in an Elderly Population  . We willParticipants fill in the baseline questionnaire at the beginning of rehabilitation. At the end of rehabilitation the participants fill in the first follow-up questionnaire at the rehabilitation center. At the 3- and 12-month follow-ups, participants who completed the baseline questionnaire will receive follow-up questionnaires from the University of Lübeck. Focus groups with some of the participants will be conducted during the intervention as well as three and 12 months after rehabilitation , an analysis sample of 194 persons (i.e. 97 persons per intervention arm) is necessary. Although we will use multiple imputations to perform an intention-to-treat analysis, we increase the sample size to compensate for the potential loss of participants during our follow-up assessments. This ensures sufficient power even if only complete cases are analyzed. Assuming a response rate of 65% after 1 year, we will recruit 300 patients per rehabilitation center. In a total sample of 1800 patients, a minimal difference of seven points can be detected. In a total sample of 1164 patients (response rate of 65%), a minimal difference of eight points can be detected  and that allocation to the two groups will be randomized.No one will be blinded before, during or after the trial as the realized rehabilitation program will be recognizable for all stakeholders.Outcomes and other measures will be assessed with patient questionnaires or will be extracted from the rehabilitation discharge letters  and the work-related treatment dose delivered. To reduce the number of subgroup analyses, the mean differences between WMR and CPR for dose delivered and dose received are used to categorize the subgroups (high distinguishability vs. low distinguishability). We assume that greater distinguishability of both interventions based on treatment dose delivered and received is associated with higher effects. Further characteristics of the rehabilitation centers for subgroup analyses may derive from the focus groups. Gender, age, migration background and education are examined as possible moderating patient characteristics. Multiple imputations will be used to fill in missing data and to perform an intention-to-treat analysis.An incremental cost–utility analysis is performed . Costs aTwo central aspects will be examined in the qualitative part. On the one hand, we will identify personal and environmental facilitators and barriers , which iFor these two interview areas, two research questions are guiding. First, which characteristics of the patient and which environmental factors influence a successful return to working life after psychosomatic WMR? Second, which characteristics influence a successful implementation and realization of WMR?The study will be conducted as a qualitative longitudinal study. Data will be collected using guided interviews . The intA maximum of eight patients (each intervention group and control group) from the six participating rehabilitation facilities will be interviewed three times. Patients already participating in the quantitative study will be eligible for participation. The first interview will be conducted in the clinics as a focus group. We will start with discussing personal and environmental factors, then we will address the implementation of WMR and its core components. The second and third interview will each be conducted by telephone or video conference 3 months and 12 months after the end of rehabilitation. We will include three patients from each focus group for these follow-up interviews. The guidelines of the follow-up interviews are similar to the initial guidelines, but their content is adapted to the home situation to be able to explore the individual course after rehabilitation.In addition, one team per rehabilitation facility, all team leaders and the medical directors are interviewed. Two interviews are planned with these participants. The first appointment will be conducted in person in the rehabilitation facility. The second interview, 6 months later, will be held by telephone or video conference. All interviews with teams and team leaders are conducted as focus groups. The interviews of the teams, team leaders and medical directors broach the same broad two areas as those of the patients. However, the patients’ situation will be assessed from a professional perspective. In addition, the working conditions of the therapeutic staff in the rehabilitation facilities will be addressed in these interviews.The follow-up interviews are done to be able to capture changes and progress. A pretest is planned to clarify the feasibility and appropriateness of our interview questions. We will adapt our final guide accordingly. All interviews are transcribed  and analA data and safety monitoring board accompanies the study. The committee consists of four statisticians and psychologists who attend the advisory board meetings, have insight into the statistical methods and provide advice to the university researchers. The committee provides feedback on the current status of the study and on already available results. The feedback is given orally at the advisory board meetings or in writing when milestones are reached. Members of the data and safety monitoring board are independent of the sponsor and have no competing interests.The study assistants in the rehabilitation centers, who were recruited and trained specifically for the study, provide the universities with feedback on spontaneously reported adverse events and other unintended effects of trial interventions or trial conduct. The universities then document this information.www.mbor-psychosomatik.de. The findings of this study will be published in peer-reviewed journal articles and conference presentations.This study is intended to provide evidence of the relative effectiveness of a complex, newly implemented work-related rehabilitation strategy for patients with mental disorders. We will provide a detailed description of the programs on our website: The study protocol has been prepared according to the SPIRIT checklist  .Additional file 1. Participant information letter.


Regular outpatient rehabilitation is prescribed for many patients with chronic neurological disorders, such as Parkinson’s disease or multiple sclerosis, to constantly support patients and their proxies in disease management. Due to the coronavirus disease 2019 pandemic, federal institutions and governments worldwide have directed local or nationwide lockdowns. During these times, the provision of regular outpatient rehabilitation service is drastically limited, making it actually impossible for community-dwelling patients with neurological disorders to receive prescribed rehabilitation interventions.A 67-year-old White Swiss man with two chronic neurological diseases, Parkinson’s disease and multiple sclerosis, underwent a 4-week inpatient rehabilitation in our hospital. The main rehabilitation goals were related to improvements of mobility and a decrease in the risk of falls. The patient gained significant functional improvements that he maintained over the following months, supported by the continuation of physiotherapy in the domestic environment. Due to a coronavirus disease 2019 pandemic-related interruption of the regular ambulatory rehabilitation for several weeks during the first coronavirus disease 2019 wave in Switzerland, the patient’s functional abilities decreased significantly. Thus, the patient was again referred to our hospital for intensive inpatient rehabilitation to regain his physical functioning and mobility capacity. At hospital discharge, the patient improved most of his physical functioning to a prepandemic level.The interruption of a rehabilitation service due to a pandemic-related lockdown can significantly impact the functional abilities of patients with chronic neurological diseases. This case report supports the claim for continuous access to rehabilitation services for all people with rehabilitation needs. Neurorehabilitation targets neurological disease manifestations to help patients maintain greater and longer-lasting independence . EspeciaPD is a common chronic neurodegenerative disorder, resulting in both motor and non-motor symptoms that significantly reduce quality of life. According to clinical guidelines, neurorehabilitation is an important non-pharmaceutical intervention to manage symptoms such as freezing of gait, balance impairment, and also non-motor symptoms . MS is aPeople with chronic neurological disorders are often referred to regular ambulatory rehabilitation interventions, such as physiotherapy, speech and language therapy, exercise training, or occupational therapy, and for temporary, multimodal, intensive hospital-based rehabilitation .Regular ambulatory rehabilitation is prescribed for many patients with PD or MS, especially those in the later stage of the disease, to constantly support patients and their proxies in disease management. This approach is, however, controversial, since the optimal duration, frequency, intensity, and form of outpatient rehabilitation in people with PD and MS is still unclear , 5, 7, 8Temporary, hospital-based rehabilitation, including intensive and high-frequency therapies to “boost” functional capacities, is usually considered for patients with chronic neurological diseases in specific situations or for specific reasons. Common reasons are (progressive) deterioration of symptoms or isolated attacks (such as relapsing forms of MS), significant worsening of symptoms after a “trigger event” , or escalation of medical therapy (such as after deep brain stimulation ). There Our hospital, the Rehaklinik Zihlschlacht in Switzerland, offers neurological rehabilitation for people with various symptoms of subacute or chronic neurological diseases that impact their functioning in daily life, participation in life roles, and/or quality of life. Many of those patients with chronic neurological disorders who are referred to our hospital for temporary (short-term) inpatient rehabilitation participate in regular outpatient rehabilitation interventions, such as physiotherapy in a private practice or in outpatient clinics. At discharge, most patients are motivated and, if needed, referred to initiation or continuation of (regular) ambulatory rehabilitation interventions.Since December 2019, the world has been faced with the coronavirus disease 2019 (COVID-19) pandemic, a still ongoing global pandemic of COVID‑19, which is caused by severe acute respiratory syndrome coronavirus 2 (SARS‑CoV‑2) –12. In SAccording to the Global Rehabilitation Alliance, more scientific studies related to COVID-19 and rehabilitation are needed . This caThis case report describes the course of a 67-year-old White Swiss male patient diagnosed with PD and MS who visited our rehabilitation hospital for intensive neurorehabilitation two times within 1 year.The patient lives with his wife in a flat. He worked as a consultant in a private company before his disease symptoms, especially fatigue and muscle weakness (tetraparesis due to MS), forced him to retire 21 years ago (in 1999). The patient was a recreational musician, but stopped his activities because of the disease-related impairments, including manual dexterity. Currently, he likes listening to audiobooks and he enjoys doing administrative work for his family and neighbors. He used to attend a support group for people with MS, but quit some years ago. The patient reports no other structured social activities except for close contact to his family, friends, and neighbors.Parkinson’s disease of the akinetic–rigid subtype and with left-sided predominance. Disease severity as rated with the Hoehn and Yahr scale was 4 out of 5 . The firRelapsing–remitting multiple sclerosis with a secondary progressive course. First MS-specific medication in 1988, confirmed diagnosis in 1992. The last relapse took place in June 2016.Diabetes mellitus type 2.Arterial hypertension.Urinary retention and incomplete bladder emptying.State after right-sided L3 pain syndrome due to a foraminal/extraforaminal disc hernia at lumbar vertebrae 3/4. Microsurgical herniotomy L3 on the right side in September 2011.The following diagnoses have been confirmed at hospital admission in October 2019 and in May 2020:The main symptoms of the patient were related to PD, MS, and his low back pain syndrome. Clinical examination revealed bradykinesia of the limbs, while no significant rigidity or rest tremor were observed. The patient reported motor fluctuations including off-periods and dyskinesia. He featured a complex gait disorder with hypokinetic and spastic–ataxic elements. Besides, he suffered from postural instability and freezing of gait episodes. The main physical MS-specific symptoms were tetraparesis, fatigue, and trouble with sensation and coordination. The main activity limitations were related to mobility .The patient received a combination therapy consisting of levodopa/benserazide , levodopa/carbidopa/entacapone  and pramipexole (Sifrol ER) for treatment of PD. During the first reported stay in our hospital, the daily dosage of levodopa was reduced by 150 mg. During the second stay, daily dosage of levodopa was increased by 150 mg and that of pramipexole by 0.75 mg. Motor fluctuations improved by the adjustments of the pharmacological therapy. The MS-specific medication consisted of 44 μg interferon beta-1a (Rebif) three times per week and has been unchanged for several years.Since the patient was diagnosed with PD in 2015, he had visited our clinic already several times for intensive inpatient rehabilitation, as prescribed by his general practitioner.The complete timeline of the patient is illustrated in Fig. On 4 September 2019, the patient fell and fractured three ribs on the right side. The fractures were treated conservatively, but within the following weeks, the patient experienced significant deterioration in physical functioning, mobility, and functional independence. Thus, he presented to his general practitioner who referred him for intensive inpatient rehabilitation to our neurological rehabilitation hospital. The patient visited the hospital for 4 weeks, starting 13 October 2019 until 9 November 2019. He was discharged home and referred to regular outpatient physiotherapy two times per week.From 10 November 2019 on, the patient lived in his home and participated in the prescribed regular outpatient rehabilitation. On 16 March 2020, a lockdown was federally directed in Switzerland owing to the COVID-19 pandemic, including severe restrictions on outpatient rehabilitation services. Physiotherapy practices were only allowed to offer very limited outpatient services during the lockdown. Physiotherapy interventions for chronic neurological conditions were not considered “urgent” and usually not allowed during the lockdown. Thus, the patient paused his outpatient rehabilitation for 6 weeks. Over this period of time, the patient experienced significant deteriorations in physical functioning and functional independence.On 27 April 2020, outpatient physiotherapy services and practices were allowed to reopen, and on 5 May 2020, the patient had his first physiotherapy session after the start of the lockdown. He had two physiotherapy sessions per week, but failed to regain his functional abilities that he lost during the COVID-19-related interruption of his rehabilitation process.The patient reattended our hospital for intensive inpatient rehabilitation, starting 25 May 2020 and ending 19 June 2020 (4 weeks). After discharge, the patient received outpatient physiotherapy services two times a week. We did not follow up the patient after discharge.At hospital admission, the patient was assessed with a broad set of generic and disease-specific measures of physical functioning and mobility as part of the physiotherapy treatment. All assessments were performed during the on-state. The clinical outcome assessments are described in the following section.The first inpatient rehabilitation stay (4 weeks) was prescribed to improve the patient’s mobility, walking distance, and physical functioning; to reduce fall risk and fear of falling; to improve disease-related symptoms and activity limitations such as MS-related fatigue and PD-related start hesitations; to learn cuing strategies to deal with freezing of gait episodes; to increase quality of life; and to improve functional independence in the activities of daily living.In the rehabilitation hospital, the patient received multimodal, interprofessional, and intensive rehabilitation, according to clinical practice guidelines , 5 and aRegular outpatient physiotherapy was performed two times a week (30-minute session each) to maintain and improve physical functioning, mobility, balance, quality of life, and functional independence in the activities of daily life. The reduction of the patient’s low back pain was a further objective of the prescribed physiotherapy. The main treatment modalities were exercise and resistance training for the lower limbs and the trunk, balance training, massages, manual therapy interventions for the back and shoulders, and gait training, as reported by the outpatient physiotherapists. The selection of modalities was subject to the participant’s current needs and abilities. In addition, the patient performed regular gait training with his wife.During the lockdown, the patient did not receive any professional rehabilitation interventions, but continued gait training with his wife frequently.The second inpatient rehabilitation stay 4 weeks) was prescribed to improve the patient’s safe ambulation, mobility capacity, balance, and functional independence, and to regain the functional level that he had prior to the COVID-19-related therapy break. Similar to the first hospital stay, the patient received multimodal, interprofessional, and intensive rehabilitation, according to clinical practice guidelines  weeks wa. The extWithin the regular hospital physiotherapy care, a set of functional outcome assessments was performed with the patient on admission and discharge. During the second inpatient stay, some outcome assessments were repeated weekly to better describe the rehabilitation course. The physical outcome assessments and the patient’s assessment scores are listed in Table Mobility capacity was assessed with the de Morton Mobility Index  of the patient over time are illustrated in Fig. In addition, we conducted some disease-specific assessments that were not part of standard clinical routine. To assess the level of fatigue, we conducted the Fatigue Severity Scale, a patient-reported outcome assessment . HoweverWe do not have sufficient information or objective measures of the patient’s physical functioning or assessment scores prior to hospital admission in October 2019 or from the outpatient physiotherapy. We do not report any assessment scores from other rehabilitation disciplines, such as speech and language therapy or nutritional therapy.At hospital discharge in November 2019, the patient was able to walk independently with a rollator within his domestic environment, and he was able to ambulate with two crutches when guided by his wife or another person. The maximum walking distance with two crutches was 605 m, which he was able to complete continually within 23 minutes.Intermediate goal: After 2 weeks of rehabilitation, the patient walks independently with a rollator in the hospital (FAC score of 4).Discharge goal 1: At hospital discharge, the patient walks independently with a rollator in the hospital (FAC score of 4) and the patient is able to walk with two crutches under stand-by assistance (FAC score of 3).Discharge goal 2: At hospital discharge, the patient can walk up to 600 m continually with two crutches (no limitation of time defined).The rehabilitation goals for the second inpatient stay were directed by the patient, who aimed for independent ambulation within his house with a walking aid. In addition, the patient enjoys walking with crutches and he reported to aim at “a better gait stability and a long walking distance with crutches.” Since the patient explicitly wished to “regain his pre-pandemic functional abilities,” the mobility-related rehabilitation goals were subjected to the patient’s functional abilities prior to the pandemic and defined as:The patient failed to reach the intermediate rehabilitation goal. Two weeks after hospital admission, he still needed stand-by assistance when he walked with a rollator within the hospital. Concerning discharge goal 1, the patient was able to walk for 200 m with two crutches and stand-by assistance or for 300 m with a rollator independently . He failed, however, to reach the discharge goal 2 since he did not reach the maximal walking distance of 600 m with two crutches.The present case demonstrates how a pandemic-related lockdown and interruption of a regular outpatient rehabilitation can impact the functional abilities of a patient with chronic neurological disorders. The observed functional decline developed immediately and drastically, and could not be improved by just restarting ambulatory physiotherapy. The patient was referred to intensive inpatient neurorehabilitation, where he significantly improved his mobility capacity and ambulation. However, the patient did not regain his prepandemic maximum walking distance, and after 4 weeks of rehabilitation, we did not observe any clinically relevant change of fatigue, MS-specific disability (EDSS score), or quality of life.Continuous rehabilitation for patients with chronic neurological diseases is one key to address the progressive developments of diseases such as PD and MS and to delay or prevent functional impairments and disability. For example, for individuals with PD, clinical guidelines recommend a continuum of care that is focused on self-management support since supervised physiotherapy intervention cannot and does not need to be ongoing . AccordiA strength of the management of this case is that the patient’s physical functioning was monitored with a broad set of valid and reliable clinical outcome assessments over a long period of time, covering an immediate interruption of his regular ambulatory rehabilitation process surrounded by two inpatient rehabilitation stays. We provide objective and patient-reported data on the functional course of the patient assessed at several time points, which allow a detailed analysis of his functional development during the different rehabilitation interventions. The patient received intensive, multimodal inpatient rehabilitation according to clinical guidelines , 5.The patient’s functional abilities and rehabilitation needs differed for each inpatient rehabilitation stay. Since rehabilitation procedure were individually tailored, the prescribed multimodal therapies differed for each inpatient rehabilitation stay with respect to their kind, number, duration, and frequency. Medication was also altered during the first and the second inpatient rehabilitation.One limitation of the management of this patient may be the lack of a home-based exercise program provided to the patient during the prepandemic inpatient or outpatient rehabilitation. If the patient had been provided with such an exercise program and strategies for adherence and motivation, he would have been able to perform physical exercises during the COVID-19-related lockdown to stop or slow down his functional decline. Several structured home-based exercise programs for people with PD or MS have been developed , 33. TheWe can draw several conclusions from this case report, which have, however, limited generalizability but may be important for neurological patients, rehabilitation professionals, and health care providers. These conclusions may be particularly important with respect to ongoing lockdowns, future lockdowns due to following waves of COVID-19 infections  or otherIf a regular inpatient or outpatient rehabilitation intervention is interrupted for a longer period of time, this lack of therapeutic interventions and support can significantly impact the functional abilities of patients with chronic neurological conditions, as observed in the present case . RegainiOne of the most important lessons that can be drawn from this case report is that, in the time of a pandemic, rehabilitation teams need to continue to follow evidence-based care for patients with neurological conditions, including PD and MS. This is in line with the statement of the Global Rehabilitation Alliance, which claims that it must be ensured that all persons with rehabilitation needs have access to rehabilitation services during the current COVID-19 pandemic . HoweverA report from Italy evaluated the needs of patients with PD during the COVID-19 pandemic . Among oA further conclusion that can be drawn from the present case is the importance of frequent monitoring of functional abilities with patient-centered, reliable, valid, responsive, and informative outcome assessments. This approach can inform healthcare professionals and patients about significant changes of functioning. Such changes may indicate significant deteriorations and can be used as a warning sign, leading to alterations in the therapy regime or management of the patient.The patient has regularly visited ambulatory rehabilitation services, such as physiotherapy, for many years. He reported enjoying this service, but feeling that he would lose some of his functional abilities more quickly if he did not participate in this service and perform “his exercises.” Concerning the pandemic-related interruption of his regular ambulatory rehabilitation, the patient reported significant regret and disappointment when he was informed that he could not visit the ambulatory physiotherapy any longer. He tried to exercise with his wife but felt how he “got worse and worse,” and failed to stop the deteriorations in physical functioning . The worsening of physical abilities “developed strikingly fast,” and the patient was “very concerned” about his functional independence.The patient reported high motivation for each hospital-based rehabilitation stay, and during the second inpatient rehabilitation, he experienced a subjective improvement in his gait stability, fall risk, and mobility capacity, with respect to hospital admission. However, he was also disappointed that he could not reach his goal of walking 600 m with two crutches. He confirms continuing walking exercises and regular ambulatory physiotherapy to regain his prepandemic functional abilities.


Maintaining 26S proteasome activity under diverse physiological conditions is a fundamental requirement in order to maintain cellular proteostasis. Several quantitative and qualitative mechanisms have evolved to ensure that ubiquitin–proteasome system (UPS) substrates do not accumulate and lead to promiscuous protein–protein interactions that, in turn, lead to cellular malfunction. In this report, we demonstrate that Arsenite Inducible Regulatory Particle-Associate Protein (AIRAP), previously reported as a proteasomal adaptor required for maintaining proteasomal flux during arsenite exposure, can directly bind arsenite molecules. We further show that arsenite inhibits Psmd14/Rpn11 metalloprotease deubiquitination activity by substituting zinc binding to the MPN/JAMM domain. The proteasomal adaptor AIRAP is able to directly relieve PSMD14/Rpn11 inhibition. A possible metal relay between arsenylated PSMD14/Rpn11 and AIRAP may serve as a cellular mechanism that senses proteasomal inhibition to restore Psmd14/Rpn11 activity. Maintaining proteome functionality is a major challenge that the cell must resolve in order to survive the diverse conditions that it encounters. Changes in biophysical conditions and post-translational modifications all impact the correct folding of proteins, and cellular machineries have evolved to maintain proteome integrity. Promiscuous interactions of misfolded proteins are highly toxic to the cell and manifest in various pathologies ; therefoOriginally identified as an arsenite inducible gene , AIRAP/Z2, 1 mM DTT and protease inhibitors). Lysates were centrifuged at 17,000× g, 4 °C, for 10 min and supernatants were used for further analysis. In 26S proteasome purifications, ATP (4 mM) was added to the TNH buffer in order to preserve the proteasome complex. In AIRAP proteasome purifications, hexokinase (135 µg/mL) with glucose (20 mM) was added to the TNH buffer in order to deplete ATP required for AIRAP–proteasome integrity [HEK293 and MEF cell lines were cultured in complete medium . Cell lysis was performed in TNH buffer , S5a peptide  or a GST-S5a protein (150 μg/mL), 850 RPM, for 1 h, R.T.Then, 26S proteasome purifications from lysate were performed by immunoprecipitation, as previously described using PSMA1 Mab 2–17 hybridoma . Where aFor evaluation of Psmd14 MPN/JAMM motif requirement for PAO binding, cells were transfected with mammalian expression vectors expressing YFP-tagged PSMD14, Flag-Psmd14 Mut (pCDNA3.1) and Flag-tag GFP, used as a specificity control. Nucleotide mutations for Flag-Psmd14 (His113/115 Ala) were performed using Quick Change Site-Directed Mutagenesis (Stratagene). All constructs were verified by sequencing. Transient transfections were performed using the calcium phosphate precipitation method and cell lysates were evaluated 36–48 h post-transfection.2, 0.5% NP40, 1 mM DTT and protease inhibitors). S5a purified proteasomes were then washed with high-salt buffer , twice for 10 min. After incubation, proteasomes were restored back to low-salt buffer. Proteasomal deubiquitination was performed by incubating the purified 19SΔUU in the presence of polyubiquitinated Sic1 and samples were withdrawn into Laemmli buffer at the indicated time points. Proteasomes were untreated or arsenite-treated (4 uM) with or without recombinant AIRAP as indicated. Then, 26S vs. 19SΔUU DUB content was evaluated by Psmd14, Uch37 and Usp14 immunoblots. AIRAP, Psmd14 and Sic1 content was evaluated by immunoblot.Proteasomes containing only Psmd14 and not Uch37 or Usp14 DUBs were prepared as previously described . Briefly2) for 2 h at RT. The reaction was resuspended in 500 μL PBS buffer and T7 tagged Sic1 WT was Ni-NTA affinity purified and imidazole eluted. Sic1 content was revealed by T7 immunoblots.For the in vitro ubiquitination of Sic1, the following proteins were produced: E1 was produced as previously described , the UBCAntisera to AIRAP has been previously described . PolycloAIRAP cDNA was subcloned into pET30a  to yield a C-terminus His tag. Overnight auto-induction in BL21 bacteria  was perfPAO beads were purchased from Toronto research chemicals , dissolved in methanol and conjugated to affigel  by mixing at R.T. for 2 h. Aminoethanol was thereafter added to block any remaining active sites, and the sample was extensively washed with methanol followed by PBS washes. Control beads (assigned as control in the relevant figures) were prepared by aminoethanol blocked beads. Recombinant AIRAP in the presence or absence of the indicated compounds  was mixeFor ICP-OES measurements, samples of Ni-NTA bound recombinant AIRAP (25 μM) were prepared with arsenite and zinc pre-wash at the indicated concentrations (0.1–10 mM) at R.T. for 10 min. Samples were washed with HN buffer, eluted with 400 μL elution buffer  and diluted with 4 mL DDW and 3% nitric acid. Zinc and arsenite content were measured by Optima 3000  calibrated with Merck standards. For MST measurements, recombinant AIRAP (1 μM) was incubated with a series of 16 dilutions of arsenite (range 0.6 nM–20 μM). AIRAP samples gave a significantly higher intrinsic tryptophane fluorescence signal than the HNT buffer (HN buffer with 1 μM Tween-20). Samples were loaded into glass capillaries and measured by Monolith LabelFree .Arsenite-induced protein misfolding occurs through binding to vicinal cysteine residues . AIRAP iN-ethylmaleamide (NEM) or the reducing agent THP. Finally, a trivalent arsenite (As3+) and a bivalent form of arsenite were used to evaluate their ability to outcompete the immobilized PAO binding to AIRAP. As evident from the results in 3+ and Fe3+ reduced AIRAP’s binding to the PAO matrix . These results coincided with the indicated increase in AIRAP binding to the PAO matrix upon zinc incubation , AIRAP could not be detected on the PAO matrix from total lysate  lane 4, After establishing the ability of AIRAP to bind arsenite, we sought to understand the extent to which arsenite-binding proteins bind the proteasome and how this function may relieve UPS impairment upon arsenite exposure. We reasoned that the 26S proteasome has one metal-binding protein, Psmd14/Rpn11, that functions as a proteasomal deubiquitination enzyme ,36. PossPsmd14 is a zinc-binding protein that contains an N-terminal MPN/JAMM motif, with two reactive histidines and one aspartic acid, which coordinate a zinc ion and catalyze deubiquitination ,36,38. IPrevious reports demonstrated arsenite-dependent induction in the cellular content of polyubiquitinated proteins ,26. AIRAPSMD14 D126A knock-in cells is a desirable perspective for such investigations that would enable us to address the AIRAP–PSMD14 relation in the context of an intact 19S particle. In addition to the above, the selective effect of metal substitution on deubiquitination activity [Direct perturbation of proteasome activity gives rise to polyubiquitin accumulation, attesting to the continuous degradation of proteins in the cell by the proteasome. However, protein misfolding conditions that increase UPS substrate levels cause only minor changes in polyubiquitin levels in the cell , Figure  therein.activity  further -/- cells upon acute exposure to arsenite and to the elevated polyubiquitin found in proteasomes acquired from AIRAP-/- cells [The AIRAP gene induction program is tuned to proteasomal dysfunction via the NRF and HSF pathways ,25 and n/- cells . Establi


BPIFB2 as a potential diagnostic biomarker and therapeutic target for AR. Functional enrichment analyses showed that YJD significantly inhibited cytokine secretion pathways in AR model guinea pigs. These findings demonstrate that YJD protects against OVA-induced AR in guinea pigs by suppressing inflammation in the nasal mucosa, restoring Th1/Th2 balance, and improving cellular metabolism.We investigated the mechanisms underlying the therapeutic effects of Yiqi Jiemin decoction (YJD), a traditional Chinese medicine (TCM), in the ovalbumin (OVA)-induced allergic rhinitis (AR) model in guinea pigs. YJD significantly decreased infiltration of mast cells and eosinophils into the nasal mucosa of AR model guinea pigs. YJD also increased expression of TGF-β in the nasal mucosa, restored the balance of Th1/Th2 immune cell responses, and decreased serum levels of various pro-inflammatory mediators, including histamine (HA), neuropeptide Y (NPY), acetylcholine (ACH), norepinephrine and immunoglobulin E (IgE). Metabolic analyses using liquid chromatography coupled with high-resolution mass spectrometry revealed that YJD improved cellular metabolism in AR model guinea pigs and increased serum levels of glycocholic acid while decreasing levels 1-palmitoyl lysophosphatidic acid. RNA-sequencing analysis identified  Allergic rhinitis (AR) is an IgE-mediated inflammatory disease of the nasal mucosa in response to allergen exposure, with symptoms such as airflow obstruction, nasal itching, rhinorrhoea, and sneezing . The worin vivo skin prick tests (SPTs) and in vitro estimation of serum allergen-specific IgE levels [Th1/Th2 cytokine imbalance is a key feature of AR . During E levels –13. SecoE levels . In mostE levels . TherefoTraditional Chinese medicine (TCM) has been widely accepted and practiced in China for more than two thousand years , 17. PreWe used the clinical nasal symptom scoring system to determine the effects of YJD on the AR model guinea pigs. In addition, dexamethasone is a glucocorticoid steroid used to treat many diseases including allergic rhinitis, which used as a positive control , 22. TheMast cells (MC) play an essential role in AR pathogenesis . TherefoNext, we measured the serum levels of pro-inflammatory mediators such as HA, NP-γ, ACH, NADR, and IgE by ELISA. The serum levels of HA, NP-γ, ACH, NADR, and IgE were significantly upregulated in the AR model group compared to the control group, but were significantly reduced in the YJD and dexamethasone treatment groups –3E. FurtWe then used liquid chromatography coupled to high resolution mass spectrometry (LC-HRMS) to investigate YJD-induced metabolic changes and identified alterations in the levels of 57 metabolites. The levels of 9 metabolites were significantly higher and the levels of 13 metabolites were significantly reduced in the AR model group compared to the control group –4D. In cKEGG pathway enrichment analysis of the differentially expressed metabolites showed that metabolic pathway was enriched in the AR and YJD groups compared to the control group , 5B. MorWe then performed RNA-seq analyses to determine genome-wide transcriptome changes in the nasal mucosal tissues among the four groups of guinea pigs.We used two-fold cut-off criterion to identify differentially expressed genes (DEGs) and identified 98 upregulated and 150 downregulated genes in the AR group compared to the control group . We alsoNext, we performed gene ontology (GO) analysis and showed that DEGs in the AR model group were highly enriched in transcription regulation (MF), centriole functions (CC), and fata cell regulation (BP) . DEGs inKEGG pathway enrichment analysis demonstrated that the top 20 significant pathways in the AR, YJD, and dexamethasone groups were involved in cytokine interactions, cytokine binding, and cytokine production –8D. DEGsTraditional Chinese Medicines (TCMs) have been used for many centuries to treat multi-factorial diseases including AR. YJD is a widely used TCM regime to treat inflammatory diseases in China , 19, 24.The nasal symptoms of AR are mediated by histamine and other inflammatory mediators, which are secreted by activated MC, eosinophils and basophils . EpithelTranscriptomic approaches have been extensively used to identify mechanisms of several drugs . Liquid In this study, we found that YJD could suppress inflammation in a guinea pig model via inactivating NF-kappaB pathway. However, the mechanism by which YJD alleviated allergic rhinitis remains largely unclear. It has been shown that inhibition of Wnt/β-catenin and JAK1/STAT3 signalings could suppress the development of allergic rhinitis , 38. Thuin vivo guinea pig model by suppressing inflammation and improving cellular metabolism. We also demonstrated that BPIFB2 was a potential diagnostic biomarker and therapeutic target in AR patients.In conclusion, integrated metabolomic and transcriptomic analysis demonstrated that YJD alleviated AR in the We purchased 8-week-old guinea pigs (body weight: 400 ±20 g) from Wuhan Wanqianjiaxing Biotechnology Company . They were housed under standard conditions  with free access to standard food and water. All animal protocols were approved by the Ethics Committee of Dongzhimen Hospital, The First Affiliated Hospital of Beijing University of Chinese Medicine , and were carried out according to the National Institute of Health (NIH) guidelines for the care and use of animals.Astragalus (30 g), bran-fried Atractylodes rhizoma (10 g), Radix saposhnikoviae (10 g), Ephedrae (10 g), cinnamon sticks (10 g), peony root (12 g), dried ginger (10 g), Schisandra (10 g), Asarum (3 g), Magnoliae flos (10 g), Radix bupleuri (10 g), Periostracum cicada (10 g), and Radix glycyrrhizae preparata (10 g) in water (1:12 weight/volume ratio) for 50 min. Subsequently, the mixture was boiled for 60 min and filtered. The dregs were then added to water, and the above steps were repeated [YJD was prepared by soaking a powdered mixture of repeated .3 solution prepared in 10 mL physiological saline. Then, the sensitized guinea pigs were administered daily with 1% w/v OVA in physiological saline into their nasal cavities from days 15 to 21. After the last OVA treatment, the AR symptoms were evaluated for 30 min using the scoring criteria, which included estimating the frequency of sneezing, nose-rubbing, and the extent of rhinorrhea. The guinea pigs with more than 5 points according to the scoring criteria were considered as AR models.The AR model guinea pigs were established as described previously with minor modifications , 19. In Guinea pigs administered with physiological saline for 2 weeks were used as the control group (n=8). The AR model guinea pigs were then randomly divided into three groups (n=8/group): (1) AR model group , (2) AR model plus YJD group , and (3) AR model plus dexamethasone group . Dexamethasone was purchased from Shanghai Yuanye Bio-Technology Company. After 2 weeks, the guinea pigs were sacrificed. The nasal tissues were harvested and tested for various parameters.The guinea pigs were euthanized using isoflurane and decapitated for blood collection. The nasal tissues were harvested, fixed in 4% paraformaldehyde  for 2 days, gradually dehydrated with graded series of alcohol, and embedded in paraffin. Then, 4-6 μm serial sections of the paraffin-embedded nasal tissue samples were cut and mounted onto 3-ammonia propyl-3-ethoxy silane (APES)-treated slides. After deparaffinization, the sections were stained with hematoxylin and eosin  for general histology, toluidine blue stain  for estimating mast cells, and Wright’s-Giemsa stain  for estimating eosinophils. The stained sections were examined and photographed under a light microscope.The nasal mucosal tissue sections were deparaffinized and rehydrated with graded series of ethanol. Then, antigen retrieval was performed. The sections were then blocked for 1h with 3% bovine serum albumin  followed by overnight incubation with anti-TGF-β primary antibody  at 4° C in a humidified chamber. The sections were then incubated with a secondary antibody. The sections were then developed with diaminobenzidine, counterstained by hematoxylin, washed 3 times with PBS, and photographed under a light microscope. TGF-β expression was quantified using the Image Pro Plus 6.0 analysis system . Briefly, 10 digital images were captured at 1360×1024 pixel resolution and 400× magnification. Then, the size of TGF-β-positive area and the integrated optical density (IOD) in each area was evaluated. Finally, average optical density (AOD = IOD/Area) was calculated to determine TGF-β expression values for each sample.http://www.uscnk.com), whereas, those used for estimating NADR (cat. no. E03N0013) and IgE (cat. no. E05I0037) were purchased from Bluegene (China). Glycocholic acid and 1-Palmitoyl lysophosphatidic acid levels in the blood serum samples were analyzed using the corresponding ELISA kits purchased from Buya-TFK (USA). All experiments were performed according to the manufacturer's instructions.We centrifuged blood serum samples at 300 rpm for 10 min at 4° C and used the supernatants to measure IL-6, TNF-α, IL-1β, NP-γ, HA, ACHI, IL4, IFNγ, NADR, and IgE levels. ELISA assay kits for estimating NP-γ (cat. no. CEA879Gu), HA (cat. no. CEA927Ge), ACH (cat. no. CEA912Ge), IL4 (cat. no. SEA077Gu), IFNγ (cat. no. SEA049Gu), IL-6 (cat. no. SEA079Gu), TNF-α (cat. no. SEA133Gu) and IL-1β (cat. no. SEA563Gu) were purchased from USCN Life Science Inc. . CDNA synthesis was performed using total RNA (1μg) samples with the Verso cDNA Kit . Then, q-PCR was performed to quantify the relative expression levels of BPIFB2. The temperature conditions were as follows: 95° C for 3 min, followed by 40 cycles at 95° C for 10 sec, 58° C for 30 sec and 72° C for 30 sec. GAPDH was used as the internal control. The q-PCR primers were: BPIFB2-F: 5’-CAGCACCTGTTTGACTGTGC-3’; BPIFB2-R: 5’-GCTGCACCTTGAGTACCAGT-3’; GAPDH-F: 5’-TTCTACCCACGGCAAGTTCC-3’; GAPDH-R: 5’-CCAGCATCACCCCACTTGAT-3’. The relative expression of BPIFB2 was calculated using the 2Flow cytometry assay was carried out as described by Ren et al. . After iWe performed paired-end RNA sequencing (RNA-seq) using 2 μg of total RNA from the nasal mucosal tissues. The quality and quantity of the RNA samples was determined using the Agilent 2100 bioanalyzer. The RNA sequencing library was prepared using the UltraTM RNA Library Prep Kit  according to the manufacturer’s instructions and sequenced with the Illumina Hiseq 4000 machine. The sequencing reads were processed and aligned to the human genome assembly (hg19) using TopHat (version 2.0) and Bowtie2.We obtained 2 mL of femoral artery blood from all guinea pigs after the last treatment and incubated them at room temperature for 30 min. The samples were then centrifuged at 3000 rpm for 10 min and obtained the supernatant. The supernatant was incubated with 500 μL methanol solution  at 4° C for 5 min, centrifuged at 3000 rpm for 10 min at 4° C, diluted with ultrapure water to obtain a final methanol concentration of 60%, and filtered through a 0.22 μm filter. The samples were analyzed by LC-HRMA/MS using a Dionex UltiMate 3000 chromatographic system  coupled to a TF Q-Exactive mass spectrometer equipped with a heated electrospray ionization (HESI)-II source.Functional enrichment analysis was performed to determine gene ontology (GO) terms and KEGG pathways associated with the differentially expressed genes (DEGs). Gene ontology (GO) analysis was performed using the GOseq R package. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis was performed using the clusterprofile software.The protein lysates were separated by SDS-PAGE and then transferred onto polyvinylidene difluoride (PVDF) membranes. Later on, the membranes were incubated with primary antibodies at 4° C overnight, and then incubated with the corresponding secondary antibodies for 1 h. After that, the membrane was visualized with enhanced chemiluminescence reagent (Thermo Fisher Scientific). Rabbit polyclonal p-NF-κB p65 , NF-κB p65  and β-actin  were used at a dilution of 1:1,000.All statistical data was expressed as means ± SD of three independent experiments. SPSS 13.0 software was used for statistical analyses. The differences between groups were estimated using one-way analysis of variance (ANOVA) followed by Dunnett’s test and LSD analysis of variance. All comparisons were made relative to the corresponding controls. P < 0.05 was considered statistically significant.Supplementary Figures