Patients with severe FFA showed a higher FFA-QLI (19.72) score compared to those with a mild disease (14.11) (p = 0.002), and the area under the curve for identifying severe disease was greater in the FFA-QLI than in the DLQI. The cut-off points were used to select patients with mild, moderate, and severe impairment in QoL. A score < 21 in the FFA-QLI corresponded to a low impact on QoL; values > 35 matched with greater QoL impairment; and values ranging from 21 to 35 corresponded to moderate QoL alteration. To conclude, a validated disease-specific questionnaire to assess QoL in FFA patients is here presented, with a greater power to discriminate severe cases of FFA than the DLQI.Quality of life (QoL) can be affected in patients with alopecia. The few studies that evaluate QoL in FFA use unspecific questionnaires. The aim of this report was to design and validate a specific questionnaire to assess the impairment of QoL in FFA patients. A specific questionnaire, called the Frontal Fibrosing Alopecia Quality of Life Index (FFA-QLI), was designed and validated using the Dermatology Life Quality Index (DLQI). One-hundred and one women with FFA were included. Cronbach’s alpha value was 0.865, and the intraclass correlation coefficient between all the items in the questionnaire was 0.870. The FFA-QLI correlated positively with the DLQI (r = 0.729,  The prevalence of frontal fibrosing alopecia (FFA) has been increasing progressively since its first description , becominAs hair is an important element of identity and self-image, alopecia can impact negatively on quality of life (QoL). QoL is generally assessed by unspecific self-reporting questionnaires. It has been demonstrated that alopecia may have substantial psychological consequences, especially in women . FeelingMost studies regarding QoL and alopecia are about alopecia areata and AGA ,9. HowevThe main objective of this study was to design and validate a new disease-specific questionnaire for FFA, the Frontal Fibrosing Alopecia Quality of Life Index (FFA-QLI), for QoL measurement in patients with FFA.A cross-sectional study, including women with FFA and a control group, was performed at the Dermatology Departments of the University Hospital San Cecilio and Virgen de las Nieves, both situated in Granada, Spain. Inclusion criteria for FFA patients were the presence of frontal and/or temporoparietal hairline recession, leading to a scarring band without follicular openings, with or without perifollicular erythema and follicular hyperkeratosis. Inclusion criteria for the control group were as follows: women aged between 45 and 95 years, without any hair disease. Control individuals were people who had consulted the Dermatology Department for other reasons . The exclusion criterion for both groups was the male sex. All patients and control subjects signed an informed consent, and the project was approved by the local ethics committee.Demographic and general information was recorded for both patients and control subjects. In patients, data regarding the alopecia were obtained, such as age of onset, presence of perifollicular erythema and follicular hyperkeratosis, presence of itchiness or trichodynia, eyebrow and eyelash alopecia, and the existence of facial papules and other types of alopecia. The severity grade was assessed following the V-grade classification described by Vañó et al. and grouped into mild (I-II) or severe (III-V) FFA .Three types of questionnaires were administered to both patients and control subjects: the DLQI, the HADS, and the newly designed FFA-QLI. A translated English version of the questionnaire is provided , althougThe FFA-QLI consisted of 20 questions divided into three parts: Items 1 to 7 are questions related to emotions; Items 8 to 14 are questions about their social life; and Items 15 to 20 are questions about functional changes. The responses were scored from 0  to 3 (highly affected). The results of the FFA-QLI are presented on a scale varying between 0 (best QoL) and 60 (worst QoL). The questions were developed by dermatologists working in the trichology area. They were selected on the basis of the main clinical signs and symptoms of FFA, focusing on different areas of life in which patients can feel ashamed or worried and also on behaviors that could be modified because of the alopecia. The questionnaire was refined after interviewing 25 patients, and the questions were modified to improve the patients’ understanding of them, as a result of the feedback from the first impressions of the interviewed patients; after that, the final questionnaire was used for all the participants.The psychometric validation of the FFA-QLI was based on the DLQI and the HADS. Reliability was evaluated using internal consistency analysis with the Cronbach α (acceptable if > 0.7) and reproducibility analysis with the intraclass correlation coefficient (ICC) (adequate if > 0.7). To determine the test–retest reliability, the ICC for the global value of the questionnaire and Cohen’s kappa (acceptable strength of agreement if kappa > 0.5) of the items were calculated from the original FFA-QLI.Convergent validity, examining the degree to which two measures of the constructs are related, was assessed by calculating the extent of correlation between raw scores from the FFA-QLI and the DLQI using the Pearson correlation coefficient. The cut-off points to select patients with mild, moderate, and severe QoL impairment were calculated using receiver operating characteristic (ROC) curve analysis and comparison with the DLQI categories.t-test was applied to compare the mean values of the quantitative variables. Qualitative variables were analyzed with the χ2 test. Statistical significance was defined by a two-tailed p < 0.05. SPSS Version 24.0  was used for the statistical analyses.Continuous data are presented as the mean (standard deviation) and categorical data as the relative (absolute) frequency. Continuous data were tested for normality using the Kolmogorov–Smirnov test. Student’s Regarding the sample size, at least four participants per variable would be necessary to validate a questionnaire . As the p = 0.824) and sex. Additional data about patients are listed in A total of 101 women with FFA and 40 healthy women were included. Case and control groups were comparable regarding age . The mean DLQI score in patients was 3.42 (SD 3.65), compared to 0.50 (SD 0.99) in control individuals (p < 0.001). The mean HADS-A score in patients was 7.91 (SD 4.02), while in control participants, it was 5.65 (SD 3.37) (p = 0.002). Finally, the mean HADS-D score in patients was 4.6 (SD 3.39), compared to 4.25 (SD 3.24) in control individuals (p = 0.57).The mean FFA-QLI score in patients was 17.11 (SD 9.37) (ranging from 3 to 44), whereas in control subjects, it was 0.98 (SD 1.31) (ranging from 0 to 5) (p < 0.001) and HADS  in patients with FFA.Cronbach’s α value was 0.911 in the overall cohort, 0.865 in patients with FFA, and 0.324 in healthy individuals. The ICC between all the items in the questionnaire was 0.912 in the overall cohort, 0.870 in patients with FFA, and 0.324 in healthy individuals. Regarding convergent validity, the FFA-QLI was positively correlated with the DLQI  and DLQI , without differences in the HADS scores. Moreover, it was observed that the FFA-QLI had a higher discriminative power to select severe FFA patients (area under the curve (AUC) = 0.704, p < 0.001) than the DLQI   had a mild disease and 53.5% (54/101) had a severe disease. Patients with a severe disease showed higher values in the FFA-QLI  .p < 0.001) (p = 0.002) (p < 0.001)  a. To sel= 0.002) b. The se< 0.001) c.p = 0.022) and hair loss , using a different hairstyle to cover the alopecia , capacity to forget the alopecia , use of eyebrow make-up or having the eyebrows micropigmented , and use of wigs or any type of hair system .The distribution of the scores of all the questionnaires in FFA patients is presented in p < 0.001) between each item in the first and second questionnaire, showing at least an acceptable strength of agreement.The test–retest reliability was tested in 30 patients with FFA. The mean FFA-QLI was similar in the first and the second test (17.48 vs. 16.86). The time between the test and retest was 30 days. The test–retest reliability was high (ICC = 0.989). The correlation between items in the two tests was also high. Moreover, Cohen’s kappa was > 0.5 (p = 0.052). Patients with a long-lasting alopecia (> 36 months) had higher FFA-QLI scores ; the FFA-QLI had a higher discriminative power to select patients with long-lasting alopecia  compared to the DLQI  (p = 0.04), although the FFA-QLI did not have enough power to select patients with facial papules , nor did the DLQI   compared to those with a later age of onset (> 58 years)  a. With r= 0.468) b.p < 0.001); the FFA-QLI had a higher discriminative power to select patients with eyebrow alopecia  compared to DLQI  (p = 0.165) or in relation to the presence of other types of alopecia . No differences were noted in the FFA-QLI scores regarding the occupational status (active vs. inactive), civil status , and having children (yes vs. no).Patients with eyebrow alopecia had higher FFA-QLI scores  c. No sigIn this study, a specific and validated questionnaire to assess QoL in patients with FFA is proposed, called the FFA-QLI. It has demonstrated a higher capacity than the DLQI to select patients with severe FFA and also with long-lasting FFA and eyebrow alopecia, features that were related to a worse FFA-QLI score in FFA patients.Around a third of patients with FFA showed at least a moderate impairment of their QoL after evaluation with the FFA-QLI. Women’s QoL is usually more affected than men’s , and thiOnly three reports regarding the assessment of QoL in specifically FFA patients have been published. Saceda-Corralo et al.’s study included 82 FFA female patients and used the DLQI, the HADS, and the Revised Illness Perception Questionnaire . They foAll the questionnaires used in these studies were unspecific, as the DLQI is used for different types of skin conditions and the HADS is even more general. FFA has very characteristic features, such as eyebrow alopecia, facial papules, and the typical scarring alopecic band, which may specifically affect the QoL of patients. Therefore, to obtain an accurate assessment of QoL impairment in patients with FFA, a specific questionnaire is necessary. The proposed FFA-QLI showed a close correlation with the DLQI and a poor correlation with the HADS, meaning that the FFA-QLI is more valuable in assessing the global impairment in QoL than evaluating anxiety or depression.Most of our patients had mild alteration in their QoL, similar to previous reports . HoweverLimitations to the present study include possible cultural bias related to the monocultural development of the questionnaire. Nevertheless, this is a potential limitation inherent in most questionnaire development processes. FFA is, by far, more common in women, whose QoL is usually more impaired than the QoL in male patients with alopecia. In this article, the FFA-QLI has been validated only in women with FFA.In conclusion, a specific validated questionnaire for FFA is proposed, called the FFA-QLI. It also shows a higher power to discriminate patients with a more severe disease than the DLQI. The impact of FFA on QoL could be higher than that which was previously reported using only unspecific questionnaires. This questionnaire may help dermatologists identify patients with a greater impairment in their QoL and seek help for the patients who need it.Validated questionnaire registered in safeCreative, with the number 2205301246067.


Allergic rhinitis (AR) is the most frequent inflammatory disorder in the nasal mucosa that remains unclear etiology. Mounting studies suggested that genetic instability could trigger and worsen the inflammatory response. The nucleotide excision repair (NER) system is an important pathway in maintaining the stability of the genome. Therefore, the genetic variations in NER pathway genes may have potential effects on AR risk.  We evaluated the correlation between 19 candidate single nucleotide polymorphisms (SNPs) in NER pathway genes and AR susceptibility by a case-control study in a Chinese population, which contains 508 AR cases and 526 controls. ERCC1 rs2298881 C > A (recessive model: adjusted odds ratios (OR) = 0.30, 95%confidence interval (CI) = 0.18–0.50, P < 0.0001), ERCC1 rs11615 G > A , and XPC rs2228001 A > C . Stratified analysis showed that ERCC1 rs2298881 AA genotype was correlated with a lower risk of AR among all the subgroups compared with rs2298881 CC/CA genotype. XPC rs2228001 AC/CC genotype reduced AR risk among the following subgroups: age > 60 months, clinical stage I and III.  Three independent SNPs were identified as significantly associated with AR susceptibility, including ERCC1 and XPC may affect the risk of AR, which will provide new insights into the genetics of AR from the perspective of DNA damage repair. Our finding showed that genetic variations in NER pathway genes:  Allergic rhinitis (AR) is defined as an immunoglobulin E- (IgE-) mediated nasal inflammatory disease and is characterized by allergic symptoms . It affeThe occurrence and development of AR were attributed to the aberration of regulatory T (Treg) cells, the imbalance between Th1 and Th2 immune response, the excessive secretion of proinflammatory cytokines, and the selective accumulation in the nasal mucosa of various immune cells , 6. CurrIL4 IL4 [IL6 L6 [IL13 , IL18 [213 [IL18 , and IL318 [IL33  have beeNFκB, a crucial transcription factor that contributes to inflammatory response greatly through facilitating transcription of proinflammatory genes [ERCC1, XPA, XPC, XPD, XPF, and XPG. Mutations and abnormal expression of these core genes may affect the NER activity and the DNA repair efficiency thus increasing genetic instability and eventually leading to cancers or inflammatory disorders. Previous studies have shown that SNPs in NER pathway genes are significantly associated with the risks of various cancers [Numerous studies suggested that there is a complex relationship between genomic instability and inflammation. The DNA damage events can activate the proinflammatory signals and then exacerbate the inflammatory response. The inflammation also contributes to DNA damage by producing nitrogen species (RNS) and reactive oxygen species (ROS). This positive feedback loop was finely regulated through a complex network of transcription factors, cellular signals, and DNA damage repair pathways . DNA damry genes . Additiory genes , 24. The cancers . For ins cancers . The ass cancers .However, no study reports the associations between genetic variations in NER pathway genes and AR risk. Hence, we performed this current case-control study to assess this association and identified AR risk-associated genetic markers from the NER pathway, which may help to screen the individuals with a high risk of AR and make early interventions to prevent the occurrence and development of AR.In this present case-control study, 508 AR cases and 526 healthy controls were included. All the subjects are of Chinese origin and recruited from Guangzhou Women and Children's Medical Center . The diagnostic criteria were followed the Allergic Rhinitis and Impact on Asthma (ARIA) guideline criteria .In brief, AR cases were recruited and diagnosed by ENT doctors according to classic nasal symptoms and positive allergens test confirmed by skin prick test or specific IgE measurement. Patients with other comorbid diseases  and other systematic diseases were excluded. The severity of AR was classified according to the degree of influence level of sleep, daily activities, and work and/or school performance . The informed consent forms were signed by the guardian of all participants before the research. The study protocol was authorized by the hospital institutional review board.μL for each well in 384-well reaction plate) into the instrument. Finally, we loaded the reaction plate, then start the run. To ensure the reliability and authenticity of the results, a second-time genotyping was conducted in randomly selected 10% DNA samples. Two sets of results were 100% consistent.Potential functional SNPs among the NER core genes were selected via the dbSNP database and SNP info as described by previous research . A totalThe eQTL is a kind of specific genetic maker that spread over genomes, which may affect gene expressions. The public databases from GTEx (Genotype-Tissue Expression) platform are usually used to analyze the correlation between genetic variants and gene expressions. Here, we performed the eQTL analysis to evaluate the bioeffect of associated SNPs on gene expression by applying the released data from GTEx Portal. The details of GTEx and analysis were reported in the previous publications .χ2 test was used to evaluate whether the 19 candidate SNPs were in Hardy-Weinberg equilibrium (HWE) among control subjects. Differences in allele frequencies of selected SNPs between cases and controls were assessed using Pearson's chi-square test. The odds ratios (ORs) and 95% confidence intervals (CIs) were calculated to assess the association between 19 candidate SNPs and AR susceptibility. And the unconditional multivariate logistic regression analysis that adjusted for age and sex was conducted to calculate adjusted ORs and corresponding 95% CIs. Additionally, stratification analysis was performed in terms of age, gender, and clinical stage of subjects. The statistical analyses were performed in the SAS statistical software . The result would be regarded as statistically significant when P value < 0.05.The goodness-of-fit P ≥ 0.05). We discovered that ERCC1 rs2298881 C > A was associated with decreased AR susceptibility, and carriers with rs2298881 AA genotype had significantly reduced AR risk when compared to subjects with CC/CA genotype . However, another SNP in ERCC1: rs11615 G > A was found to be related to increased risk of AR, and subjects with GA/AA genotype have higher AR risk compared to those with GG genotype . In addition, we also identified XPC rs2228001 A > C was correlated with reduced AR susceptibility, and individuals with AC/CC genotype have a lower risk of AR compared to those with AA genotype . For the rest of the SNPs, no significant effect was found in AR risk (P ≥ 0.05).In this present case-control study, 508 AR cases and 526 healthy controls were included for analyzing the correlations between 19 candidate SNPs and AR susceptibility. As displayed in P = 0.007), age > 60 , females , males , clinical I , clinical II , and clinical III . However, the significant risk effect of rs11615 G > A in AR was not found among all subgroups . And XPC rs2228001 AC/CC genotype decreased the AR risk among following subgroups: age > 60 , clinical I , and clinical III .To eliminate potential effect of age, gender, and clinical stages on AR risk, we further performed the stratified analysis through adjusting these confounding factors. As displayed in ERCC1 in the cell-cultured fibroblasts and whole blood  in the XPC gene were significantly associated with AR risk. To the best of our knowledge, this research is the first study that systematically evaluated the relationship between multiple functional SNPs in NER pathway genes and AR susceptibility. Our findings may help screen the high-risk groups and make early interventions of AR, which will greatly reduce its morbidity.To explore the effects of SNP in NER pathway genes on AR susceptibility, we performed this current case-control research in the Chinese population which comprehensively assessed the association between 19 functional SNPs in 6 NER core genes and AR risk. Our results showed that two SNPs (rs2298881 C > A and rs11615 G > A) in the IL4 and IL13 are known for their key role in the pathogenesis of AR. One SNP rs2243250 C > T located in the promoter region of IL4 was shown associated with an increased risk of AR. The further study uncovered that this SNP can upregulate the expression of IL4 and increase the plasma IgE subsequently, which will exacerbate the symptoms of AR eventually [IL13 was demonstrated increasing the risk of AR in Asian populations significantly [IL13. It was reported that rs20541 A allele was related to higher serum IL13 and IgE levels, which contributed to an increase of eosinophil counts and increased risk of AR [Although being subject of extensive study, the pathogenesis of AR is still poorly understood, which might attribute to its intricate etiology that involves the complex interactions of genetic and environmental factors , 32. Howentually . Furtherficantly . Functiosk of AR , 35HMGB1 and NFκB, which caused and aggravate inflammatory responses by augmenting the expression of downstream proinflammatory cytokines [Despite it being widely believed that DNA damage was one of the most common events in cancer, however, growing studies showed that genomic instability also triggers inflammatory responses. Previous researches have shown that some crucial transcription factors were activated during inflammation, such as ytokines , 37. In ytokines , 39. TheERCC-1 and XPF encode 5′ endonucleases, XPA, and XPC function as damage recognition, XPD gene encodes the helicase and the XPG for 3′ endonuclease. The abnormity of these NER core genes may affect the DNA repair efficiency and increase the probability of genome instability, therefore, increasing the risk of inflammation. One study conducted by Gungor et al. suggested that the reduced NER activity contributed to the LPS-induced acute pulmonary inflammation [XPA-deficient mice developed stronger and longer-lasting acute inflammation than wild-type mice after irradiation with UVB [XPC knock-out mice compared with wild-type mice [The NER pathway is the primary repair mechanism for DNA damage, which plays an important role in maintaining genomic stability and preventing the occurrence of diseases, such as various cancers and inflammations. The NER process is completed collaboratively by the NER machinery that is composed of several crucial enzymes: ammation . Horio ewith UVB . A more ype mice . Howeverype mice , 43, 44.ERCC1 rs2298881 C > A, ERCC1 rs11615 G > A, and XPC rs2228001 A > C were significantly associated with AR susceptibility. Detailed ERCC1 rs2298881 AA genotype decreased AR risk significantly when compared with CC/CA genotype. However, ERCC1 rs11615 GA/AA genotype was found to increase AR risk compared with the GG genotype. And XPC rs2228001 AC/CC genotype also reduced the risk of AR compared with those with AA genotype. The stratification analysis further showed that the protective effect of ERCC1 rs2298881 AA genotype was observed among all subgroups: age ≤ 60 months, age > 60, females, males, clinical I, clinical II, and clinical III. But the risk effect of ERCC1 rs11615 GA/AA genotype was disappeared among all subgroups. Maybe these confounding factors  have certain potential effects on AR risk, or it is just a chance finding attributed to the relatively small sample size in the stratified analysis. And carriers with XPC rs2228001 AC/CC genotype had a lower risk of AR compared with those with AA genotype in the following subgroups: age > 60, clinical I, and clinical III. The proteins of ERCC1 and XPC play an essential role during the NER process because of their excision and damage recognition ability. The ERCC1 protein can form a heterodimer with the XPF, and the complex that catalyzes the incision of 5′ phosphodiester backbone around the DNA damage sites was an indispensable component in the NER. And the protein of XPC can also form the XPC–HR23B complex by binding to the HR23B tightly, which plays a key role in the early DNA damage recognition and the recruitment of the transcription factor IIH to the sites of DNA lesions during the NER. Polymorphisms in the ERCC1 and XPC genes may influence the genomic stability then modify the disease risk, especially cancers. For example, He et al. showed that the rs2298881 C allele and rs11615 A allele increased the susceptibility of gastric cancer [XPC, then contribute to the breast cancer risk [ERCC1 (rs2298881 C > A and rs11615 G > A) and XPC (rs2228001 A > C) genes modify the risk of AR.In this current study, we as a vanguard to first comprehensively assessed the association between 19 SNPs in 6 NER core genes and AR susceptibility. Here, we identified three SNPs: c cancer . And Malcer risk . HoweverHow these associated SNP modify the AR susceptibility? Interestingly, a recent study has introduced compelling evidence about shorter telomere lengths (TLs) among patients with AR. TLs as biomarkers of aging are prompted shortening by raised inflammation . As a DNERCC1 in the cell-cultured fibroblasts and whole blood, and rs11615 G allele was found to reduce the mRNA level of CD3EAP. Regarding rs2228001, the T allele was related to decreased expression of CHCHD4 and XPC. Maybe these SNP-base expression changes of neighboring genes contribute to the modification of genotype-base AR risk. However, further study is still needed to illuminate the exact underlining mechanisms. Although in the initial stage, our study provides new insights into the modification of AR risk by the NER pathway gene variants.To further explore the functional effects of these significant SNPs on the expression of adjacent genes, then dope out the possible mechanisms by which the associated SNPs affect the AR risk, the eQTL analysis was carried out. Our results showed that rs2298881 A allele was significantly associated with lower mRNA expression of There are several concomitant limitations in this study. First, the present case-control study is hospital-based, so the selection bias is ineluctable. Second, the sample size enrolled in this study remained moderate, however, it was relatively small for stratified analysis, which may whittle the statistical power and reduce the reliability of the conclusions. Third, although we have made a comprehensive assessment on 19 SNP of NER pathway genes, other potentially functional SNP should be assessed. Fourth, environmental factors should be considered, as the etiology of AR involves complex interactions between multiple genetic and environmental factors. Fifth, the conclusions from this research may not apply to any ethnic group other than the Chinese, because of the Chinese origin of all participants. Sixth, mechanism studies should be included, which will further elucidate the underlying mechanism by which genetic variations in NER pathway genes modify the AR risk. Seventh, most of AR cases in this study were perennial and caused by indoor allergen, especially house dust mite (>90%). Therefore, despite that there may be significant differences in pathogenesis between perennial and seasonal rhinitis, we believe that there may be less effect on our study. However, further study on seasonal rhinitis was also needed.ERCC1 and XPC genes influence AR susceptibility significantly. Well-designed studies with a large sample size involving different ethnicities should be performed to verify our conclusions in the future. Further, the potentially exact mechanisms that ERCC1 and XPC genetic variants modify AR susceptibility should be revealed by further functional studies.In summary, this current research was the first case-control study to systematically evaluate the effects of SNPs in NER-associated genes on AR risk. Our findings showed that in Chinese children, genetic variations in


During the last ten years the use of robotic-assisted rehabilitation has increased significantly. Compared with traditional care, robotic rehabilitation has several potential advantages. Platform-based robotic rehabilitation can help patients recover from musculoskeletal and neurological conditions. Evidence on how platform-based robotic technologies can positively impact on disability recovery is still lacking, and it is unclear which intervention is most effective in individual cases. This systematic review aims to evaluate the effectiveness of platform-based robotic rehabilitation for individuals with musculoskeletal or neurological injuries. Thirty-eight studies met the inclusion criteria and evaluated the efficacy of platform-based rehabilitation robots. Our findings showed that rehabilitation with platform-based robots produced some encouraging results. Among the platform-based robots studied, the VR-based Rutgers Ankle and the Hunova were found to be the most effective robots for the rehabilitation of patients with neurological conditions  and various musculoskeletal ankle injuries. Our results were drawn mainly from studies with low-level evidence, and we think that our conclusions should be taken with caution to some extent and that further studies are needed to better evaluate the effectiveness of platform-based robotic rehabilitation devices. In the last several years, the use of robotic-assisted rehabilitation has increased significantly ,2. CompaTwo major types of robotic rehabilitation devices are available. The first one consists of wearable devices: robotic orthoses  and exosRecently, systematic reviews (SRs) have examined the effectiveness of wearable robotic technologies: exoskeletons and orthoses for upper limbs ; exoskelThis systematic review was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) checklist .A literature search was performed in the following electronic databases: PubMed, Excerpta Medical Database (EMBASE), Cochrane Database of Systematic Reviews (CDSR), and Scopus. The medical subject headings (MeSH) used were ”robotics” and ”rehabilitation”, “robotics” and “rehabilitate*” or “treat*” and “effectiveness of robotics.” In addition, we performed a free search on Google Scholar by using keywords (such as ”platform-based robotics” and “robotic rehabilitation effectiveness”) and reviewed key references in relevant publications to make our search as systematic and complete as possible. We also used a snowball search strategy, which means the reference lists of selected and published systematic review articles were manually searched to identify other possible eligible studies. The snowball search was limited to articles published between January 2016 and August 2021. The Movendo technology website was also searched for the clinical trials .We included all the studies that examined the clinical outcomes of platform-based robotic rehabilitation training. Both male and female participants  were included to allow for the generalization of the results. We considered studies with at least one ill subject in the intervention group rehabilitated with a platform-based robot and articles in English and Italian published (as of August 2021) in peer-reviewed journals or as conference papers , abstracts, or as gray literature. Studies that included only healthy subjects and/or evaluated outcomes with another type of robotic rehabilitation technology were excluded.Based on the titles, a screening of the articles was performed by two independent reviewers (M.R. and R.R.) to identify relevant studies. One reviewer (M.R.) evaluated all article abstracts for eligibility after the screening of titles was completed. Abstracts that met the inclusion criteria were included in the full review. Otherwise, they were excluded. Studies which one reviewer (M.R.) was unsure whether to include were discussed by two reviewers . Disagreements between the two reviewers were resolved by the inclusion of the third reviewer (A.B.P.) and discussion between these three reviewers. The full texts of the included articles were examined for the typology of platform-based technological rehabilitation robot studied, and the duration of training in the intervention group.The quality of all included studies was evaluated by two independent reviewers  by using the Joanna Briggs Institute (JBI) critical appraisal tool . The JBIA data extraction sheet was developed to collect data of interest. Three reviewers  read all included articles. One author (A.B.P.) extracted the data from the articles, and later they were double-checked by two other authors . The following information was extracted from each study: title, study design, clinical area, patient characteristics , intervention group, outcome measures, and study conclusions. A qualitative synthesis was conducted for the included studies.We found 1085 entries in Medline (PubMed), Scopus, Cochrane Library, and EMBASE, and 20 additional entries came from Google Scholar and the Movendo technology website . After rRegarding the outcomes, as they are shown in We found the following types of platform-based robotic rehabilitation systems, and their effectiveness is described as follows.This robotic system has multiple DOF. It operates based on a parallel mechanism (PM) driven by linear actuators, and it is used specifically for ankle rehabilitation in cases of limited mobility . Ten stuThe Virtual Reality System (VR) Rutgers Ankle robot has been investigated in five studies ,52,53,56Two studies investigated the effectiveness of the Rutgers ankle robot in patients with cerebral palsy (CP) ,57. BothTwo studies evaluated the effectiveness of the Rutgers ankle haptic interface in patients with musculoskeletal ankle injuries ,27. One This type of robotic rehabilitation system usually consists of a single DOF and is usually driven by a rotating motor for a specific application . Robotic ankle-stretching devices have been used for rehabilitation in four studies.Two studies ,55 invesRobotic passive stretching and active training  for ankle rehabilitation has been studied in post-stroke individuals  and loweHomma et al. developed a training robot for ankle dorsiflexion/plantarflexion with a passive mechanical joint. Its effectiveness was evaluated based on pressure distribution on the footplate in a hemiplegic patient. It was unclear in the study whether pressure distribution could be used as an indicator of recovery. Therefore, the study concluded that its relationship to biological data should be further investigated .Cordo et al. tested the efficacy of Assisted Movement with Enhanced Sensation (AMES) by using a robotic ankle device as a treatment for hemiplegia by using strength and joint alignment tests and motor function in post-stroke patients. Results showed improvements in most functional tests within six months .Zhou et al. validated the treatment strategy of proprioceptive neuromuscular facilitation (PNF) with a robotic ankle–foot system in post-stroke patients over six weeks. Results showed improvements in ankle spasticity and/or contracture at the end of the study .ARBOT is a robotic prototype for ankle rehabilitation. The effectiveness of ARBOT was evaluated on 32 subjects (with ankle and/or hindfoot fractures) comparing conventional and ARBOT-assisted ankle rehabilitation. After a 4-week rehabilitation program, the experimental group showed a significant improvement in the proprioceptive test compared to the control group .Hunova is a “platform-based” end-effector robot consisting of two electromechanical platforms with 2 DOF: one is located under the feet and the other under the seat. It is possible to perform exercises both sitting and standing. It allows passive (mobilization), active (with elastic or fluid resistance), proprioceptive, and assistive therapy . The device can work in both static and dynamic modes. It is used for rehabilitation and evaluation of the sensory-motor function of the lower limbs and torso as well as balance . Twenty Geriatric rehabilitationTwo studies focused on the assessment of balance parameters with Hunova in 96 elderly subjects ,34. One ii.NeurorehabilitationSix studies investigated the effectiveness of robotic rehabilitation  in patients with Parkinson’s disease ,36,37, sFour studies investigated the effectiveness of robotic assessment and training  in individuals with spinal cord injuries (SCI) ,41,42 aniii.Orthopedic rehabilitationThree studies investigated Hunova as an aid in rehabilitation, in patients with knee arthroplasty , post-trThe main results showed improvements in orthostatic stability, postural passages  , left anThe purpose of our systematic review was to determine the evidence-based effectiveness of platform-based rehabilitation robots for patients with musculoskeletal or neurological disabilities. As a major finding, our study showed that patients with neurological impairments and musculoskeletal injuries can be effectively treated with platform-based robotic rehabilitation devices after their health status is stabilized. With the higher repetitions that robotic devices provide, patients can exercise more, which stimulates neural plasticity in neurological patients in the early stages of their recovery. Once patients can walk better, they can transition to conventional walking to further practice walking on different terrain, improve balance, and correct abnormal gait patterns.Therefore, we think that platform-based robotic training should be routinely adopted in rehab clinics next to traditional physical therapy. In fact, physiotherapists can use robotic equipment as a multiplier to train more patients. Instead of traditional one-to-one practice, therapists can use robotic devices to treat more patients at the same time. This frees up valuable time for therapists to either train severe patients individually or practice more function-based tasks that require the integration of multiple motor skills. By spending their time on this higher value training activities and letting the robotic devices take over the “heavy” routine tasks, therapists can provide an appropriate level of personalized treatment to their patients and increase their efficiency.Even though in our study we identified seven types of platform-based robotic rehabilitation systems and reported on their effectiveness ,31,32,54According to our observations and included studies, researchers have studied platform-based robotic rehabilitation in different phases  and at different time points in patients after injuries. Saglia et al. , have suBessler et al. reported about 17 adverse events, including tissue-related, musculoskeletal, and physiological adverse events (adverse blood pressure changes) with the use of stationary gait robots (exoskeletons and end-effector) ,60. HoweRobotic rehabilitation was positively evaluated by physiotherapists and occupational therapists. They reported that patients like to use robotic devices for rehabilitation and that they increase accessibility, autonomy, and comfort, and reduce costs ,64,65,66Our study showed that rehabilitation by using platform-based robots had some encouraging results. The use of robotic rehabilitation allows efficient planning of the rehabilitation process in terms of the duration of sessions, required tools, and availability of a therapist. Therefore, compared to traditional rehabilitation that require combined and intensive efforts of therapists and patients, robotic-assisted rehabilitation should reduce costs because of a shorter hospital stay and greater autonomy at discharge. This highlights the importance of novel rehabilitation techniques that allow therapists to deliver effective treatment interventions while reducing the burden on staff and resources, and related costs. Robotic technology has the potential to transform rehabilitation clinics from labor-intensive to technology-enabled workflows, providing a rich stream of data to help diagnose patients, adjust therapy, and maintain patient records (in a clinic and at home).Based on our findings, we believe that further studies able to provide results with a higher level of evidence are needed to confirm the effectiveness of platform-based robotic rehabilitation devices. This should primarily include the execution of large sample-size RCTs. These studies should be based on rigorous comparison among the available devices (interventions) and usual care ), and should necessarily adopt standardized outcomes to better compare the different models of platform-based rehabilitation robots and to effectively generalize the eventual findings. Therefore, new outcome research is also needed to define universally accepted evaluation criteria able to standardize the devices’ outcomes evaluation. To this end, we also think that wider outcomes should be evaluated, including assessment of comfort, safety, and training performance for the end user.Despite most studies’ claims that platform-based robots would increase rehabilitation intensity, they allow complex and specialized spatial movements, and the architectures give the robotic device high stiffness, balanced force distribution, and better adaptability to the mechanical properties of human ankles. We believe that this robotic technology can be effectively used by the physiotherapists in the rehabilitation units.Moreover, in the era of big data and artificial intelligence (AI), computer models can be developed to understand recovery mechanisms, predict the use of different motor control strategies, and ultimately tailor treatment to the patient. We would also like to emphasize that platform-based robotic rehabilitation can only be effective if it would be considered an added value by the patient. Indeed, it is important to consider the perspective of the end user when developing a particular platform-based robotic device to support a specific dysfunction. Such a synergistic effort will certainly lead to effective treatment.In addition, future research should also focus on the structured and complete recording and dissemination of adverse events related to platform-based robotic rehabilitation to increase knowledge about risks. With this information, appropriate risk mitigation strategies can and should be developed and implemented in platform-based robotic devices to enhance their safety.https://www.movendo.technology/en/) (accessed on 1 August 2021). Therefore, we assume that it has undergone several safety validations before its market launch. In some studies that investigated the Hunova robot, end users also gave positive feedback on training performance and reported that they felt comfortable using the robot for rehabilitation.Finally, among the platform-based robots studied, the Hunova robot by Movendo technology is commercialized and already available on the market (


Numerous functional factors may interactively contribute to the course of self-report functional abilities after anterior cruciate ligament  (ACL)-reconstruction. This study purposes to identify these predictors using exploratory moderation-mediation models in a cohort study design. Adults with post unilateral ACL reconstruction (hamstring graft) status and who were aiming to return to their pre-injury type and level of sport were included. Our dependent variables were self-reported function, as assessed by the the KOOS subscales sport (SPORT), and activities of daily living (ADL). The independent variables assessed were the KOOS subscale pain and the time since reconstruction [days]. All other variables , and the presence or absence of COVID-19-associated restrictions) were further considered as moderators, mediators, or co-variates. Data from 203 participants  were finally modelled. Total variance explanation was 59% (KOOS-SPORT) and 47% (KOOS-ADL). In the initial rehabilitation phase (< 2 weeks after reconstruction), pain was the strongest contributor to self-report function . In the early phase (2–6 weeks after reconstruction), time since reconstruction [days] was the major contributor . Starting with the mid-phases of the rehabilitation, self-report function was no longer explicitly impacted by one or more contributors. The amount of rehabilitation [minutes] is affected by COVID-19-associated restrictions  and by the pre-injury activity scale . Other hypothesised contributors such as sex/gender or age were not found to mediate the time or pain, rehabilitation dose and self-report function triangle. When self-report function is rated after an ACL reconstruction, the rehabilitation phases , the potentially COVID-19-associated rehabilitation limitations, and pain intensity should also be considered. As, for example, pain is the strongest contributor to function in the early rehabilitation phase, focussing on the value of the self-report function only may, consequently, not be sufficient to rate bias-free function. Following ACL-reconstruction, affected athletes display a high risk for subsequent issues. Graft failure, contralateral ACL-injury3, or the development of osteoarthritis4 are often named in this context. These severe potential consequences highlight the importance of a rehabilitation process targeting a decrease in the risk for secondary health problems.A rupture of the anterior cruciate ligament (ACL) is a serious hazard for health and career advancement in sports5. The Knee Injury and Osteoarthritis Outcome Score (KOOS) is a valid possibility to measure long and short-term patient-reported confidence in their knee-related function. Highlighted in a systematic review5, the KOOS possesses a re-injury-predictive value, in both isolation6 and as part of a testing battery9. Restoring functional abilities such as conidence in knee function following ACL-reconstruction may consequently lead to a decrease in the re-injury risk10. Monitoring self-report function as a potential surrogate of both functional abilities and self-confidence may be helpful in re-injury or osteoarthritis preventive measures and therapy settings.Beyond psychosocial readiness and morphological graft healing, particularly important targets of the rehabilitation process are the restoration of neuromuscular and motor knee-related function11. Although it is not possible to define fixed time points at which a certain goal or functional ability is reached, time is, nevertheless, an important factor to consider12.Based on the individual courses of wound healing, functional abilities and psychological readiness, the time until rehabilitation completion and return to sports is variable13. Therapy measures are dependent on the individual functional status13. The current functional status, in turn, has been found to be dependent on the pre-injury activity and pre-surgery functional status13. Another, contemporary contributor to the possibility to utilise exercises and trainings is the Coronavirus disease 2019 (COVID-19)-associated restrictions14. Herewith associated confinements cannot be neglected when therapy-associated function is rated.The individual wound healing progress, functional abilities, and psychological readiness do not only affect the time until rehabilitation completion, but also on the rehabilitation measures themselves. A sufficient training stimulus to reach functional progress and the risk for, inter alia, a graft failure must be weighted16, pain intensity/perception during performance18, time passed between injury and reconstruction19 and kinesiophobia20 must also be taken into account when the function after ACL reconstruction is rated. Many of these numerous contributors are nested predictors of functional outcomes after anterior cruciate ligament reconstruction21.Beyond the contributors highlighted so far, age, sex/genderFrom a theoretical point of view, a mediating effect of the amount of rehabilitation measures on how time since reconstruction affects functional abilities is possible. It is likely that this interaction differs further in the various post-reconstruction wound healing phases; the importance of pain, for example, decreases with increasing time. The different stages are, thus, of potential relevance as moderators of the interactions sketched above.21 are known in a study sample, a multitude of individual and spatiotemporal factors interact during the rehabilitation, return to sports and re-injury prevention processes following ACL reconstruction. We, thus, performed an exploratory moderation-mediation model to consider these known potential associations and theoretical interactions. We hypothesised that (1) rehabilitation dose mediates the direct effect of the regressors time and pain on the dependent variable function, (2) the direct effect of time and pain on function is moderated by the post-reconstruction period, the effect of pain and time differs in dependence of the different wound healing stages and (3) numerous co-variates, such as pandemic-associated restrictions and pre-injury activity status, contribute to the rehabilitation dose and post-reconstruction functional status.Conclusively, when the contribution of graft type or concomitant injuries22. Ethical approval has been provided by the Ethics Committee of the Hessen Regional Medical Council , and, subsequently, by each centre’s responsible ethics committee. Informed consent was obtained by each participant prior to study enrolment.The present data were assessed directly after the inclusion into a multicentre, single-blind, randomised-controlled, superiority two-arm-trial23. All methods were performed in accordance with this guideline and in accordance with the declaration of Helsinki.When reporting our results, we followed the AGReMA Statement guideline for items to be reported in mediation analysesAdults (age at inclusion from 18 to 35 years) after an acute unilateral ACL rupture and having being passed (< 9 months ago) or scheduled for an arthroscopically assisted, anatomic reconstruction (semitendinosus tendon or semitendinosus-gracilis tendon graft) were included. Only participants engaged in sport  prior to the injury and with the aim to return to their previous sporting activity were included.Exclusion criteria were (1) meniscus lesion > 2 cm, (2) cartilage lesion > ICRS II°, (3) previous musculoskeletal surgery of the uninvolved  leg, (4) leg mal-alignment > 5°, (5) multi-ligament injury pattern, (6) post-operative re-injury, (7) acute or chronic inflammation of the musculoskeletal system or muscle soreness and (8) pregnancy.Potential participants were addressed by personal communication from one of the centre's heads (physicians) during or after a scheduled visit. Screening and recruitment followed a structured informed consent schedule.24 and their pre-injury type(s) of sport and training amount. The athletic level was categorised as either recreational/low-level competitive, semi-professional25, or professional.After the inclusion, a structured telephone interview was conducted. The type of work  and sociodemographic values, such as age, height and weight (body mass index), were asked. The participants, likewise, reported the injury mechanism  and all (rehabilitation) measures taken between injury and reconstruction13. Basically, after the diminishing of joint swelling and pain reduction, restoring the knee range of motion was followed by a function-based progression to strengthening and neuromuscular motor control training. Due to local and health-assurance differences, minor between-participant differences regarding the exact design and structuring of the rehabilitation measures may exist.Further surgery-specific outcomes were retrieved from the previously pseudonymised surgery report: graft type (semitendinosus or semitendinosus-gracilis), tendon folding (from three times up to eight times), tendon diameter [mm] and date of the surgery. From the time between surgery and questionnaire completion, the potential phases  were calculated: initial: 0–2 weeks, early: 2 up to 6 weeks, mid-1: up to 12 weeks, mid-2: up to 26 weeks, late: > 6 months. The wound healing phases acted as moderators. The individual medically prescribed rehabilitation followed a stepwise function-based periodisation and progressionwww.soscisurvey.de, using the participants’ pseudonym only. The validated German versions of the questionnaires were used.All questionnaires were completed online at The survey consisted of the following outcomes (measured by the respective questionnaires): activity level , knee function and symptoms , injury history (free text) and kinesiophobia . The latter two acted as variables to describe the sample.26.The Tegner activity scale was included into the model as a co-variate. It contains a 0–10 point Likert scale to assess a participant’s activity level, scaled from low-level daily living activity to high-level competitive sports: scoring is from 0 (= low level activity regarding knee loading), up to and including 10 (= highest possible level of activity regarding knee loading). The KOOS’ subscales are three of the five KOOS subdomains, each item and must be scored from 0 to 4. The PAIN sum score, included as independent variable is calculated based on 9 single items, ADL on 17 and SPORT on 5. The ADL and SPORT subscales were our dependent variables. The TSK uses 11 items across the domain “fear of movement/(re-)injury”: it is scored using a 4-point Likert scale. Internal consistency and structural validity were found to be sufficientThe training protocol consisted of: therapy type, therapy frequency [times per week], rehabilitation dose [minutes per week], total dose since reconstruction [minutes] and mean perceived exhaustion  [points]. The rehabilitation dose acted as mediator.The time since reconstruction [days] and the presence or absence of COVID-19-associated restrictions (Co-variate), dichotomised as pre-restriction or during restriction, were calculated based on the date the online survey was filled in.The temporal structure of the variables assessment was: surgery report outcomes were followed by the structured interviews at inclusion, which, in turn, were followed by the questionnaires.The reconstruction-specific outcomes were retrospectively retrieved from the surgery report, while the structured interview was performed to assess the sociodemographic  as well as the injury mechanisms and pre-injury training amounts and levels.The independent variables were the time since surgery and the pain intensity at the questionnaire completion. The mediator was the rehabilitation training volume. The dependent variables were the KOOS SPORT sum score (model 1) and the KOOS ADL sum score (model 2). Co-variates were age, sex/gender, body mass index, time between injury and reconstruction, kinesiophobia, pre- or during COVID-associated restrictions and the pre-injury Tegner activity scale. As moderators, the potential phases  were included in the models.Temporarily, the independent variable and mediator were assessed retrospectively, while the dependent variable was assessed as the current status; all three were assessed at questionnaire completion. The co-variates were collected retrospectively. The time and pandemic-associated restrictions were retrieved calendrically. Thus, the order of the assessment does comply with the hypothesised order of the mediated moderation model.27). The outcome variables were the KOOS scores, the independent variable was time since reconstruction, the suggested mediator (m) variable was the amount of rehabilitation measures and the (categorised) time-dependent rehabilitation phases were the moderators.Data were subsequently analysed by mediated moderation regression analyses. We used a macro developed and provided by Hayes  and conditionally direct (moderated) effects were calculated for each dependent variable. Sobel testing and 95% confidence interval bias corrected bootstrapping  were conducted for indirect effect determination. To build (forward/inclusion) the models, RAll statistical calculations were conducted using SPSS 25 . Statistical procedures were executed after the examination of the underlying assumptions , linearity by visual examination of the scatter plots, homoscedasticity, auto-correlation and negligible multicollinearity). The a priori level of significance was set at 5% for all statistical analyses.Ethical approval has been provided by the Ethics Committee of the Hessen Regional Medical Council , and, subsequently, by each centre’s responsible ethics committee.Yes. Each participant signed informed consent prior to study enrolment.In total, 222 persons were recruited and included. During the study conduction, 9 withdrew their consent . Missing values of the dependent variable occurred in 10 participants; these participants were excluded from the present analysis. Data from 203 participants were finally modelled.The sociodemographic, sport-, injury-, surgery- and pandemic-specific characteristics of the study sample are displayed in Tables The final models, one for the dependent variable sum score for KOOS SPORT and one for the corresponding KOOS ADL-sum-score, are displayed in Figs. The self-report function after autologous hamstring graft ACL-reconstruction is influenced by several factors. Rehabilitation had no significant mediator role in the way how time since reconstruction or pain intensity influence self-reported function. In the initial rehabilitation stage, pain was the strongest regressor of the dependent variable to self-report function. In the following early stage, time since reconstruction becomes a further major regressor to the self-report function. Starting with the afterwards commencing mid-phases of the rehabilitation, the self–report function is not explicitly impacted by one or more independent variables or mediators any more. The amount of rehabilitation training itself is strongly affected by COVID-19-associated restrictions and by the pre-injury activity scale. Other hypothesised co-variates, such as sex/gender or age, were not found to be moderators or mediators in the time or pain, rehabilitation dose and self-report function triangle. Our hypothesis (1), suggesting that the rehabilitation dose mediates the direct effect of the regressors time and pain on the dependent variable function, must, thus, be rejected because the rehabilitation dose did not mediate the effect of time on function. Hypothesis (2), suggesting that the effect of pain and time differs in dependence of the different wound healing stages was verified since the contributors to function are not unique in the different wound healing stages/rehabilitation phases. The same is true for hypothesis (3), that numerous secondary co-variates, such as pandemic-associated restrictions and pre-injury activity status, would contribute to the rehabilitation dose and post-reconstruction functional status: we found a few secondary contributors to the rehabilitation measures and port-reconstruction functional status.16. The time passed since reconstruction was only a relevant predictor of function during the early rehabilitation phase. This provides another hint that performing one single assessment at the hypothetical end of the RTS process is not goal achieving28. Multiple repetitive measurements, aimed to monitor and verify the course of the RTS process, are more promising28. Such a repetitive measurement approach over time considers both time and  status factors and was found to be feasible  in an athletic RTS setting29.The association of function and pain intensity during performance is in accordance with current comparable evidence13. Initially, restoring the passive knee extension range of motion is aimed for (after the diminishing of joint swelling and pain reduction); this seems to be in accordance with our finding of  the major contributor pain (to function). The next rehabilitation phase (the early phase), usually 2–4 weeks post-surgery, includes a function-based progression to strengthening and neuromuscular control training. Here, the inter-individual contributors (i.e. time since reconstruction) increase, not only pain seems to be decisive for self-report function, any more. Starting with the progressive strengthening/neuromuscular control phase, the contribution of time, again, decreases. The contribution of pain is, lastly, not present any more in the last (advanced activity) phase.During the different rehabilitation stages, different factors are of interacting relevance10. Such functional abilities also includes those measured at a low-threshold self-report questionnaire level (such as the KOOS). The KOOS-SPORT-sub-score may be re-injury-predictive6, thus, improving factors (functions), which are mirrored by this outcome, may consequently be helpful in re-injury prevention after ACL-reconstruction.Knowing the contributors to functional abilities (estimate/coefficient) and their interactions is helpful for the function-based/deficit-oriented rating and management of rehabilitation and RTS strategies. Improving or even restoring functional abilities and, thus, decreasing the identified deficit, may consequently lead to a decrease in the subsequent injury risk32, were, thus, not included. The present sample is, consequently, representative for a young and physically active sample after hamstring graft reconstruction.We only included participants after an isolated ACL rupture with a subsequent reconstruction using a hamstring graft. Potential contributors (or even confounding variables) to function, such as concomitant injuries and other graft types16 is not surprising, but this must also be considered when function should be rated more holistically, i.e. in dependence of the rehabilitation/wound healing phase. Here, the interactive description of the various factors must be considered as a strength of this analysis. However, we only reported associations and no experimentally derived effects, therefore, this must be considered as a major limitation of this analysis. Although statistically sufficiently powered, the relatively small sample size might lead to a certain overfitting and, thus, be a source of bias for the transferability to the underlying population.The association of function and pain intensity during performance34. In the present sample, the dose of rehabilitation measures was impacted by the pre-injury Tegner activity scale and COVID-19-associated restrictions. Participants with a higher Tegner activity scale may be more compliant than those with a lower scale. Concerning the outcome, the KOOS may not be sensitive enough in the later stages when compared to the more late-stage-associated functional scores, such as the ACL Return to Sports Injury Scale (RSI-ACL) or even objective functional outcomes. In contrast, the KOOS can, unlike objective functional tests, be applied very early after the reconstruction and may, thus, be able to mirror function during the most phases after the reconstruction. Among the most selected self-reported functional outcomes accessible at an early stage, the KOOS outperformed the International Knee Documentation Committee Subjective Knee Form (IKDC)35. Another potential consequence of only applying a self-reported outcome has recently been elegantly shown in a re-injury predictive analysis: patients at RTS who passed a battery of functional tests and showed low knee-related confidence were at lower risk for a re-injury than those who were both confident and met all RTS criteria36. A certain overrating of one's own knee-related abilities can, thus, also be re-injury-risk enhancing rather than preventing. Including further potential contributors to self-reported function such as residual laxity might have provided further variance explanation. The time categories we set followed potential wound healing phases but are, of course, somewhat arbitrary and could also be set differently.When considering all potential contributors and their interactions, we found no clear mediating contribution of the rehabilitation dose. Although a clear dose–response relationship has not been described in the literature (on rehabilitation after ACL reconstruction), higher scheduled rehabilitation adherence/compliance may lead to better functional outcomes37 and rehabilitation measures. The contact restrictions lead to an increase in the importance of (supervised and controlled) home-based and/or telemedicine measures, as well as in the (late stages of the) rehabilitation. This is one of the advantages of the trial of which the inclusion visit data are presented here22.The finding of the pandemic-restrictions effect on rehabilitation measures provides another hint on the relevance of considering pre-versus during  COVID-19-associated restrictions (or even the specific measures) as a categorising variable. In orthopaedic settings, this may impact both surgery15. Whether this is attributable to the somewhat  homogeneous sample, or if these contributors are not significantly relevant in the underlying sample when all relevant interacting factors are considered, can only be speculated.When known potential contributors and confounders, such as in the present analyses, are considered, gender/sex and age were not significant contributors to the self-report function. This is somewhat in contrast with major parts of the literatureAs highlighted in the limitations, we only calculated cross-sectional associations and no longitudinal effects. To prove (or disprove) our findings, the associations found should be reproduced in a longitudinal setting in future study.Numerous factors, such as pain, the time since reconstruction, different wound healing stages and rehabilitation phases, contribute to the course of self-reported functional abilities after ACL-reconstruction. The amount of rehabilitation measures required is further impacted by the participant’s pre-injury activity and COVID-19-associated restrictions. Knowing these factors and also knowing their nested contribution value is helpful for the management of deficit-oriented function-based rehabilitation and individualised RTS strategies. When self-report function is rated, the rehabilitation phases , the potentially COVID-19-associated rehabilitation limitations, and pain intensity should be considered in decision-making. Focussing on the value of the self-report function only may, consequently, not be sufficient to rate bias-free function.