Correct positioning of the endoscope is crucial for successful hip arthroscopy. Only with adequate alignment can the anatomical target area be visualized and the procedure be successfully performed. Conventionally, surgeons rely on anatomical landmarks such as bone structure, and on intraoperative X-ray imaging, to correctly place the surgical trocar and insert the endoscope to gain access to the surgical site. One factor complicating the placement is deformable soft tissue, as it can obscure important anatomical landmarks. In addition, the commonly used endoscopes with an angled camera complicate hand–eye coordination and, thus, navigation to the target area. Adjusting for an incorrectly positioned endoscope prolongs surgery time, requires a further incision and increases the radiation exposure as well as the risk of infection. In this work, we propose an augmented reality system to support endoscope placement during arthroscopy. Our method comprises the augmentation of a tracked endoscope with a virtual augmented frustum to indicate the reachable working volume. This is further combined with an in situ visualization of the patient anatomy to improve perception of the target area. For this purpose, we highlight the anatomy that is visible in the endoscopic camera frustum and use an automatic colorization method to improve spatial perception. Our system was implemented and visualized on a head-mounted display. The results of our user study indicate the benefit of the proposed system compared to baseline positioning without additional support, such as an increased alignment speed, improved positioning error and reduced mental effort. The proposed approach might aid in the positioning of an angled endoscope, and may result in better access to the surgical area, reduced surgery time, less patient trauma, and less X-ray exposure during surgery. Arthroscopy is a mostly outpatient procedure used to diagnose or treat abnormalities and disorders in growing joints. It can enable the diagnosis and treatment of a broad variety of non-inflammatory, inflammatory, and infectious types of arthritis, as well as various injuries within the joint. To perform an arthroscopic procedure, orthopedic surgeons insert an arthroscope, a tube-like viewing instrument, through a small incision. The incision size depends on the size of the examined joint, but can typically be approximated by the size of a buttonhole. The arthroscope includes a small tube that contains optical fibers and lenses, which is connected to a video camera. In a typical setup, the camera view visualizing the interior of the examined joint is displayed on an external monitor.Minimal access techniques through surgical trocars seek to perform surgical procedures while avoiding the morbidity associated with conventional surgical wounds . AlthougIn this work, we propose an augmented reality (AR) system to support endoscope positioning for arthroscopy. Tracking the endoscopic instrument as well as the patient’s anatomy facilitates the augmentation of the angled endoscope frustum and in situ visualization of patient anatomy from pre-operative CT data. To evaluate the effectiveness of our system, we conduct a user study with a phantom setup, comparing the performance of our AR system to baseline insertions without additional support. Finally, we report and discuss our results, confirming the effectiveness of our AR system.To date, there are only a few works that integrate components related to our proposed system. To overcome the challenges of portal placement, Traub et al.  introducIn recent years, AR became more accessible with the useo f commercially available head-mounted displays (HMD). The applications for the use of AR include robotics, manufacturing, product assembly, medical training, and image-guided procedures ,6,7,8. SFurthermore, Qian et al.  proposedTo visualize anatomical structures inside the body in an in situ AR visualization, Bichlmeier et al.  proposedIn this paper, we propose a method that combines several state-of-the-art AR techniques to enhance hip arthroscopy and try to overcome the challenges presented in the current endoscope positioning procedure. To the best of our knowledge, this is the first time that an HMD-based AR prototype has been introduced for hip arthroscopy optimal endoscope positioning.This section describes the components of the proposed AR system. Those include the calibration of the endoscopic instrument, described in Since the marker is rigidly attached to the endoscope, the calibration problem can be formulated as a pivot calibration. This system of equations can be solved if we rotate the endoscope around a fixed point and collect the tracking poses of the marker. For every tracked pose, the homogeneous rigid body transformation Therefore, for all transformations, we have the following formulation:pTCS1orRipTCS−pWFinally, to approximate the best solution, we adopted the least-squares minimization using Moore–Penrose inverse .Due to the limitations of image-based tracking accuracy and tracking volume on HMD, an outside-in tracking system was employed. However, the introduction of an external tracking system brought a new coordinate frame to the setup. Therefore, a calibration procedure to register the HMD to the tracking system needed to be performed, as shown in Algorithm 1 Tracking Space to HMD Space Calibration procedurepoint sets registration(M pairs)         ▹ M = 5           for N = 1 to M do                       end for                    end procedure To visualize the anatomy that is located along the view of the angled endoscope, we attached a virtual camera angled at 30 degrees to the tracked endoscope model. The camera view frustum was visualized based on the the standard 11 DoF camera parameters. The 6-DoF extrinsic parameters was calculated using the tracking information, and the 5-DoF intrinsic parameters were derived from the simulated virtual camera. We configured the virtual camera to only render the patient anatomy of the registered pre-operative data. To aid navigation of the endoscope, we augmented the camera frustum on the HMD, while the virtual camera’s view was projected onto its far clipping plane. This setup is illustrated in In order to provide a better spatial perception of the anatomical structures in the endoscope field of view, we augmented the part of the registered pre-operative anatomical bone model in the field of view of the endoscope. In an effort to reduce visual clutter in AR, the peripheral anatomy was rendered transparent, where transparency increased with increased distance to the focus area. To highlight the focused area containing the endoscopic camera frustum, we integrated an outline, adapted from the virtual window technique , for in In the following sections, we describe the user study setup , the exphttps://www.z-anatomy.com/ (accessed on 5 October 2022)), and designed the marker attachment to the bone for localization. To evaluate if our proposed system provides adequate guidance and could improve the placement of an angled endoscope for hip arthroscopy, we developed a solution using Unity3D , which was deployed to an optical see-through HMD (OST-HMD), the Microsoft HoloLens 2 . To evaluate the effectiveness of our system, we conducted a user study in which participants were asked to navigate an angled endoscope to predefined target locations for hip arthroscopy. For this reason, we designed a study setup consisting of a hip phantom model, an angled endoscope and an external monitor, illustrated in For our physical phantom setup, we segmented the hip and femur bones from the open-source 3D human anatomy model: z-anatomy  .Our principal assumption is that the use of our AR system would benefit the overall alignment accuracy without significantly affecting the time required to complete the alignment task. Thus, we present the following hypotheses:Hypothese 1.Participants can achieve significantly better alignment scores when using AR visualization.Hypothese 2.Participants can complete the alignment task with significantly less time when using AR visualization.Hypothese 3.Participants can complete the alignment task with significantly less mental effort when using AR visualization.A total of seven users were recruited using mailing lists and campus announcements. The participants were aged between 25 and 29, with a mean age of The participants were informed about the study procedure and were provided with a consent form. Upon completion of this form, participants were asked to perform a set of visual tests, including the Ishihara, Landolt, and stereo tests, to ensure correct or corrected-to-normal vision. Our exclusion criteria included color vision deficiency, impaired stereopsis  and orientation (p = 0.2056) had no statistical significance with our AR system in the conducted study.Comparing the poses of the endoscope after performing the positioning task to the respective ground-truth endoscope poses, we individually evaluated the positional error of the endoscope tip and the rotational error. As shown in p = 0.3466).As shown in p = 0.0156), physical demand (p = 0.0156), temporal demand (p = 0.0156), the effort level (p = 0.0078) and the frustration (p = 0.0078) were significantly reduced, while the performance significantly increased (p = 0.0078).We used NASA-TLX to subjectively evaluate the task load of the alignment task with and without AR visualization, and the results are shown in Results from a user study comparing these interactive schemes using AR HMDs shows that the AR-guided solution has advantages in terms of usability, related to a decrease in physical demand, mental effort and frustration. Overall, participants achieved lower distance and orientation errors when using the proposed AR solution compared to the Baseline. However, the statistical significance could not be shown to support our hypothesis H1. We noticed that there are a few large orientation errors centered around 180 degrees, while the translational errors associated with the data are small in both cases. This shows that it is still very challenging for users to find the correct orientation with an angled endoscope, even with the help of AR, which might be related to the steep learning curve associated with the alignment of an angled endoscope. Nevertheless, on average, participants in the study took less time to complete the alignment tasks using an AR-aided endoscope positioning compared to the baseline. However, similar to the pose error, statistical significance could not be proven; thus, hypothesis H2 could not be supported. While we believe this trend could become more significant with the addition of more users, further studies need to be conducted in this regard. In terms of the subjective measures, the scores reported by the participants show significant differences in every category between the baseline and our proposed AR solution. This implies that the usability of our system significantly improves the Baseline method, supporting the hypothesis H3. This finding further suggests that, compared to the Baseline method, the cognitive load used while positioning an angled endoscope could be reduced when using our AR system.Despite the proposed AR solution achieving significantly better results in a qualitative evaluation, with similar quantitative results to the baseline method, there are still a few limitations. The setup for the tracking system and calibration before the procedure is complicated and time-consuming compared to the baseline method. While we tried to mitigate potential third-variable biases that could have impacted the user study outcome, some limitations are inherent to the study design. First, the tracking space to HMD space calibration is subject to calibration errors, and thus can affect the user alignment. Recent works have explored the possibility of accurately tracking IR makers using sensors on HMD ,23. MartIn this work, we proposed a novel method for AR assistance during the positioning of an angled endoscope for hip arthroscopy. An HMD-based application was developed and evaluated with a mock 3D-printed setup. Our system integrates features of frustum visualization, augmentation of the anatomical focus area and distance-based colorization. We conducted a user study, in which we compared the endoscope positioning with our AR system to baseline positioning without additional support. The results from our user study suggest that the average endoscope positioning accuracy could be improved using our AR system. Furthermore, the speed at which endoscope positioning was performed could be increased. In addition, statistical significance was demonstrated in terms of usability, indicating a lower cognitive load when aligning an angled endoscope with our AR system compared to baseline positioning. We believe that such a method could improve the overall operation quality, decrease the cognitive effort of aligning an angled endoscope, and might reduce the required X-ray dose during surgery.


Backgroundand Objective. Poststroke dysphagia is one of the most common stroke complications with high morbidity and long course, while acupuncture treatment is easily accepted by patients due to its reliability, feasibility, simple operation, low price, and quick effect. Our objective was to evaluate the efficacy of manual acupuncture in poststroke dysphagia patients. Methods. Databases including Medline, Web of Science, PubMed, Cochrane Library databases, EMBASE, CNKI , WanFang (WanFang Database), and VIP (Chongqing VIP) were searched from inception until Aug 19, 2022. Data were analyzed using Revman 5.3, Stata 14.0, and TSA 0.9.5.10 Beta software. Evidence quality evaluation was performed by using GRADE profiler 3.6. Results. A total of 33 randomized control trials (RCTs) enrolled 2680 patients. Meta-analysis results revealed that compared to rehabilitation, acupuncture decreased water swallow test (WST) and standard swallowing assessment (SSA) scores. Meanwhile, in contrast to rehabilitation alone, integration of acupuncture with rehabilitation effectively decreased WST and SSA scores; improved swallowing scores of videofluoroscopic swallowing study (VFSS), swallowing scores of Fujishima Ichiro, Barthel index (BI), and swallowing quality of life questionnaire (SWAL-QOL); reduced the aspiration rates as well as aspiration pneumonia; and shortened the duration of empty swallowing and the duration of 5 mL water swallowing. Pooled analysis did not reveal any significant differences in dysphagia outcome severity scores (DOSS) (p=0.15 > 0.05p) between the acupuncture group combined with rehabilitation group and the rehabilitation group alone. After the risk-of-bias assessment, these studies were not of low quality, except in terms of allocation concealment and blindness. Evidence quality evaluation showed that allocation concealment and blindness led to a downgrade and primary outcomes' evaluation of acupuncture combined with rehabilitation were ranked as moderate-quality evidence while acupuncture alone was ranked as low-quality. Conclusion. This meta-analysis provided positive pieces of evidences that acupuncture and acupuncture combined with rehabilitation were better than using rehabilitation alone in the treatment of poststroke dysphagia. Dysphagia, whose typical clinical manifestations include sialorrhea, bradymasesis, coughing, and choking when drinking water or eating, is prevalent among stroke patients . A cohorThe current professional rehabilitation therapies include exercises that improve the coordination of muscle movements in the mouth and throat. Besides, applications of nasogastric tubes remain a priority for severe dysphagia patients with high aspiration risks . Long peHowever, the existing systematic reviews in some aspects should be improved. For instance, the included studies are of low quality, the level of clinical evidence cannot be established, and acupuncture methods, as well as acupoints in different studies, significantly vary. A recent review on swallowing therapy  from theCRD42021258346.We conducted a protocol of systematic review and meta-analysis following preferred reporting items for systematic reviews and meta-analyses protocol (PRISMA-P). Meanwhile, the study was registered on the PROSPERO  on July 8, 2021, and the registration number is ∗ OR Poststroke OR Cerebrovascular OR CVA ∗ OR Apoplexy OR Vascular Accident ∗ OR brain OR Cerebral ∗) and (Point ∗ OR Acupuncture OR Acupoint ∗) and  and (Randomized OR RCT OR Randomly) and . The search strategy is listed in Two independent reviewers (Jiang. HL and Zhang. Q) searched databases including Medline, Web of Science, PubMed, Cochrane Library databases, EMBASE, CNKI , WanFang (WanFang Database), and VIP (Chongqing VIP) from inception until Aug 19, 2022, and found no language restriction. Based on the characteristics of each database to develop the corresponding retrieval strategy, the following English keywords were used|: (stroke The inclusion criteria for the selected literature were as follows: (i) patients with dysphagia after stroke; (ii) clinical randomized controlled trials comparing manual acupuncture with rehabilitation therapy for the treatment of poststroke dysphagia; the manual acupuncture study group included acupuncture alone or acupuncture coupled with rehabilitation therapy to treat dysphagia; the control group was treated with rehabilitation therapy; (iii) in duplicated published articles, the one with more complete data was included; and (iv) literature that included acupoints located around the nape, neck, or throat.Note: the diagnostic criteria for poststroke dysphagia refers to “Diagnostic Criteria of Cerebrovascular Diseases in China (version 2019) ” and “EuRehabilitation therapy for swallowing disorders includes indirect training and direct training . Direct The exclusion criteria were as follows: (i) articles whose full literature was unavailable and (ii) if the quality of the article, as evaluated by the modified Jadad scale, was rated as low quality (Jadad ＜ 4), then it was excluded.  Water swallow test (WST)  Video fluoroscopic swallowing study (VFSS)The primary outcomes were as follows:  Standard swallowing assessment (SSA) scores  Swallowing scores of Fujishima Ichiro  The rates of aspiration  The rates of aspiration pneumonia  The dysphagia outcome severity score (DOSS)  Barthel index (BI)  Swallowing quality of life questionnaire (SWAL-QOL)  Duration of empty swallowing  Duration of 5 mL water swallowingThe secondary outcomes were as follows:Two independent reviewers (Jiang. HL and Zhang. Q) searched and screened the works of the literature and then extracted the general information of the included trials, involving the name of the first author, year of publication, source of diagnosis, sample size, age of participants, RCTs districts, types of stroke, duration of dysphagia after stroke, intervention measures, the course of the intervention, outcome indicators, and the information about acupuncture treatment . If any inconsistency is being raised up, then the decision would be made through discussion, and if the discrepancies still persisted, then the third reviewer (Zhao Q) would make the final decision.Each study was classified as “low,” “high,” or “unclear risk of bias” at the following items: ①random sequence generation (selection bias), ②allocation concealment (selection bias), ③ blinding of participants and personnel (performance bias), ④blinding of outcome assessment (detection bias), ⑤ incomplete outcome data (attrition bias), ⑥ selective reporting (reporting bias), and ⑦ Other bias. Two independent reviewers (Jiang. HL and Zhang. Q) evaluated the methodological quality and the risk of bias of the included RCTs separately and discussed on resolving the disagreements, based on the Cochrane risk-of-bias criteria . If two I2 or Chi-square test pp was used to quantitatively determine heterogeneity. When I2 < 50% or chi-square test p ≥ 0.1p, heterogeneity was considered unapparent, and the fixed-effects model was applied. However, significant heterogeneity was present when I2 ≥ 50% or chi-square test p < 0.1p, and the random-effect model was applied. Then, sensitivity or subgroup analyses were performed to determine heterogeneity sources. Egger's test was performed to test for publication bias, and p > 0.05p implied the absence of publication bias. The prespecified pp value threshold for one primary outcome was set at p=0.05p, and for the other, it was set at p=0.033p [p < 0.05p were considered significant.Data synthesis was performed using the Review Manager software 5.4  and Stata 14.0 (developed by the USA's StataCorp LLC). Relative risks (RR) were used as the effect analysis statistics for dichotomous variables, while the weighted mean difference (WMD) and a 95% confidence interval (CI) were calculated for continuous variables. The chi-square test was used to establish statistical heterogeneity between data of included trials; besides, p=0.033p . SecondaTrial sequence analysis (TSA) was performed using TSA 0.9.5.10 Beta . TSA parameter setting: I error probability of 5% and II error probability of 20% [X-axis represents the sample size; the Y-axis represents the statistics on the Z-value; the symmetrical green horizontal dashed lines represent the conventional boundary value ); the symmetrical solid red lines represent the TSA boundary value; the vertical red line represents the required information size (RIS), and the blue curve represents the cumulative Z-value.The In case the blue curve did not intersect with any red line, then the sample size was considered insufficient; consequently, a series of similar trials should be performed. The current sample size was considered enough if the blue curve intersected with any of the red lines.The GRADE profiler 3.6  was used to evaluate the quality of evidence for the primary outcome, based on the grading of recommendations, assessment, development, and evaluation (GRADE) approach . Two indThis study included 33 trials –55 invol  ① Random sequence generation (selection bias): All the trials reported specific randomization methods, except Xie's study , thus on  ② Allocation concealment (selection bias): A total of nine , 52, 54   ③ Blinding of participants and personnel (performance bias) and blinding of outcome assessment (detection bias): Five , 52, 54   ④ Incomplete outcome data (attrition bias): All of the studies provided the causes and numbers of lost patients at follow-up. A total of 100 patients in 16 trials were excluded after they were lost to follow-up and ITT analysis was not used; they were considered to have an “unclear risk” attrition of bias since the lost follow-up rate was less than 15%.  ⑤ Selective reporting (reporting bias): Only one trial  conducte  ⑥Other bias: Any other bias source was not detected, therefore, all the trials were considered to have a “low risk” of bias.The modified Jadad score for all these studies was ≥4.Overall, the quality of these trials was not low, especially in terms of allocation concealment, and blindness is low. The blindness of manual acupuncture is a prevalent problem in clinical acupuncture trials, therefore, additional mechanisms are necessary to overcome it. The bias risk assessment is presented in Characteristics of manual acupuncture are summarized in 3.4.1.p < 0.05p) and SSA .The results of the meta-analysis showed that the swallowing scores of WST of the acupuncture + rehabilitation group were lower than that of the rehabilitation group ). In this analysis, there was no significant between-study heterogeneity . The index of one study [p > 0.05p), while after excluding it, heterogeneity remained apparent (I2 = 80% ⟶ I2 = 66%); meanwhile, no significant methodological heterogeneity was noted in Jing's study [I2 = 89.3%). The subgroup with treatment of twice/week ) had better outcomes than that of once/d ). The result of the subgroup analysis revealed a tendency for WMD of SSA to increase with increasing frequencies of acupuncture treatment. However, further research is still needed due to the small number of included studies.The results of the meta-analysis showed that the SSA score of the acupuncture group was lower than that of the rehabilitation group ), and the heterogeneity of the SSA score was high , SSA, swallowing scores of Fujishima Ichiro, aspiration rates, aspiration pneumonia rates, BI, SWAL-QOL, duration of empty swallowing, and duration of 5 mL water swallowing (p < 0.05p) as shown in Figures 6Compared to rehabilitation, we found eleven indicators of the meta-analysis on acupuncture combined with rehabilitation. Pooled analysis revealed significant differences in ten indicators, including swallowing scores of WST, swallowing scores of VFSS (3.5.1.I2 = 87%). Subgroup analysis was based on categories of stimulation therapies in rehabilitation , which illustrated that the mode of stimulation was a significant effect factor. The rehabilitation without stimulation therapy ) had better outcomes than the rehabilitation with ice stimulation therapy ) and electrical stimulation therapy ). Subgroup analysis 2.1 indicated a tendency for WMD of WST to decrease when removing stimulation therapy in rehabilitation treatment.The results of the meta-analysis showed that the WST score of the acupuncture + rehabilitation group was lower than that of the rehabilitation group ), and swallowing scores of heterogeneity WST were high . It illustrated that the total number of treatments which was greater than 20 times in subgroup ) had better outcomes than less than 20 times' subgroup ). Subgroup 2.2 analysis indicated a tendency for WMD of WST to decrease when the total number of acupuncture treatments was increased.3.5.2.I2 = 77%). All indices were on the right of the invalid line, without significant methodological heterogeneity. Using a one-by-one exclusion method, Wang's study [I2's variation. According to subgroup analysis 2.3 based on disease duration , it illustrated that disease duration may be a significant effect factor. The subgroup with disease duration of more than 3 years ) had better outcomes than the less than 6 months' subgroup ). Subgroup analysis 2.3 suggested a tendency for WMD of VFSS to increase with a prolonged disease course.The results of the meta-analysis showed that the VFSS score of the acupuncture + rehabilitation group was higher than that of the rehabilitation group ), and swallowing scores of VFSS's heterogeneity were high (9 RCTs and 's study  exhibiteI2 = 92.8% and tag 2.4). The subgroup with treatment of 10 times/week ) had better outcomes than that of 67 times/week ) and 5 times/week ). The result of the subgroup analysis revealed a tendency for WMD of VFSS to increase with increasing frequency of treatment.Additionally, subgroup analysis 2.4 was performed based on the treatment frequency , indicating that heterogeneity was derived from the treatment frequency, showing that treatment frequency may be a significant effect factor, and heterogeneity was significant among the three subgroups . All indices were on the left of the invalid line without significant methodological heterogeneity. Subgroup analysis was conducted based on categories of stimulation therapies in rehabilitation , and it illustrated that the mode of stimulation may influence the SSA score, as the rehabilitation without stimulation therapy ) had better outcomes than the rehabilitation with sensory stimulation therapy ) and electrical stimulation therapy ). However, no indication was found with regard to whether heterogeneity was derived from stimulation (tag 2.5), and there was no significant heterogeneity among the three subgroups (I2 = 0%). Subgroup analysis indicated a tendency for WMD of SSA to decrease when removing stimulation therapy during rehabilitation treatment.The results of the meta-analysis showed that the SSA score of the acupuncture + rehabilitation group was lower than that of the rehabilitation group ), and the heterogeneity of SSA score was high (12 RCTs and 3.5.4.I2 = 57%). The index of Song's study [p > 0.05p), and after excluding it, the variation in heterogeneity was remarkable (I2 = 57% ⟶ I2 = 0%). Subgroup analysis was performed based on the number of acupoints (single point and acupoint combination) and it illustrated that the acupuncture prescription contained acupoint combination ) and had better outcomes than single acupoint ).The results of the meta-analysis showed that the swallowing scores of Fujishima Ichirowas of the acupuncture + rehabilitation group were higher than that of the rehabilitation group ), and the heterogeneity was high (4 RCTs and 3.5.5.I2 = 12%) was observed.The results of the meta-analysis showed that the rates of aspiration of the acupuncture + rehabilitation group were lower than that of the rehabilitation group ). In this analysis, no significant between-study heterogeneity (2 RCTs and 3.5.6.I2 = 0%), and subgroup analysis was not performed.The results of the meta-analysis showed that the rates of aspiration pneumonia of the acupuncture + rehabilitation group were lower than that of the rehabilitation group ). In this analysis, there was no significant between-study heterogeneity (4 RCTs and 3.5.7.p=0.15 > 0.05p) between the groups. In this analysis, there was a significant between-study heterogeneity (2 RCTs and I2 = 96%).Pooled analysis did not reveal significant differences in DOSS , 3.5.8.I2 = 34%).The results of the meta-analysis showed that the BI score of the acupuncture + rehabilitation group was lower than that of the rehabilitation group ). In this analysis, there was no significant between-study heterogeneity (2 RCTs and 3.5.9.I2 = 91%).The pooled results of the meta-analysis presented that the SWAL-QOL score of the acupuncture + rehabilitation group was higher than that of the rehabilitation group ). In this analysis, there was a significant between-study heterogeneity , WMD2 = −0.28, 95% CI (−0.45–0.12)). In this analysis, a significant between-study heterogeneity  was observed.The pooled results of meta-analysis presented that the duration of empty swallowing of the acupuncture + rehabilitation group took less time than that of the rehabilitation group , WMD2 = −0.24, 95% CI (−0.36–0.12)). In this analysis, there was significant between study heterogeneity .The pooled results of meta-analysis presented that the duration of 5 mL water swallowing of the acupuncture + rehabilitation group took less time than that of the rehabilitation group ) and RIS (162 cases) when the third study [The TSA of acupuncture alone (WST) revealed that the cumulative Z-curve crossed the TSA boundary value when the second trial  was comprd study  was compZ = 1.96, p=0.05p (two-sided)) when the first study [The TSA of acupuncture combined with rehabilitation (WST) revealed that the cumulative Z-curve crossed the conventional boundary value ) when the third study [The TSA of acupuncture combined with rehabilitation (VFSS) revealed that the cumulative st study  was compst study  was comprd study  was compThirty-three randomized controlled trials were included in this study, twelve of which reported the loss at follow-up; however, this loss at follow-up was insignificantly related to experimental research. The reasons for loss at follow-up were mostly factors, including poor patient compliance and family reasons. Furthermore, one trial  reported3.8.p=0.018p, p=0.082p, p=0.316p, Egger's test was performed to investigate the publication bias of the primary outcome. Five studies were evaluated for the WST of acupuncture alone . Study limitations  led to a downgrade, one outcome was ranked as low-quality evidence and two were ranked as moderate-quality evidence and the results are shown in Compared to the rehabilitation group, the acupuncture group and acupuncture combined with the rehabilitation group demonstrated better effects in the treatment of poststroke dysphagia.All included studies contained acupoints in the nape, neck, or throat areas, thereby reducing clinical heterogeneity. Besides, they were closely associated with the stimulation of neck muscles and nerves in dysphagia treatment. Acupuncture at Fengchi (GB20) point increases the amplitude of submental muscles and subhyoid muscles, indicating that acupuncture increases average muscle amplitude and muscle strength ; acupuncIn the acupuncture combined with the rehabilitation group, subgroup analyses of WST and SSA , tag 2.5In the review, there was one high-quality study  of acupuSubgroup analysis of VFFS revealed that acupuncture combined with rehabilitation exhibits a good curative effect on the long course of the disease and a high frequency of treatment  were selected as the primary outcomes of this study. Chen's study  used WSTThis review has various limitations: (i) although most of the included articles used clinical success rate as an outcome indicator, there is no uniform international standard for the definition of success rate. Therefore, we did not consider clinical response rate as one of the outcome indicators, which may have caused a loss of evidence; (ii) poststroke dysphagia is one of the most prevalent stroke complications with high morbidity and a long disease course. The shortest course of treatment in the included studies is 10 days, while the longest is 8 weeks; and only one study  had a 3-This meta-analysis provided positive evidence that acupuncture or acupuncture combined with rehabilitation were better than using rehabilitation alone in the treatment of poststroke dysphagia. Meanwhile, multicenter RCTs with a large sample and a rigorous design are needed to explore whether acupuncture could replace other stimulative therapies in rehabilitation training. Moreover, acupoint combination, frequency, and the total number of treatments may be important factors that could influence therapeutic effect, which can provide guidance for subsequent similar RCTs.


Mutations in simple sequence repeat loci underlie many inherited disorders in humans, and are increasingly recognized as important determinants of natural phenotypic variation. In eukaryotes, mutations in these sequences are primarily repaired by the MutSβ mismatch repair complex. To better understand the role of this complex in mismatch repair and the determinants of simple sequence repeat mutation predisposition, we performed mutation accumulation in yeast strains with abrogated MutSβ function. We demonstrate that mutations in simple sequence repeat loci in the absence of mismatch repair are primarily deletions. We also show that mutations accumulate at drastically different rates in short (<8 bp) and longer repeat loci. These data lend support to a model in which the mismatch repair complex is responsible for repair primarily in longer simple sequence repeats. Simple sequence repeats (SSRs) are consecutive repeats of short nucleotide sequences found throughout genomes. Their arrangement makes SSRs particularly susceptible to mutation  mechanism . In eukaitutions . NaturalC. elegans  or non-SSR indels. We also find that in strains with an msh3 deletion (msh3Δ), per-base pair (bp) mutation rate is much higher in long SSRs. Finally, we confirm the predominance of SSR deletion mutations in msh3Δ MA strains.To better understand the role of MutSβ in repair of mutations in SSR loci, we performed a MA experiment in ade2, lys2-801, his3-Δ200, leu2–3.112, ura3–52, ho. A single colony derived from this ancestor founded strain s.EP049, which is the +MSH3 ancestral strain used in this study.The parent strain of the MA experiments is a haploid line derived from a single spore of the MA ancestor described in msh3Δ ancestor, s.EP049 was transformed with a linear construct containing homology upstream and downstream of the MSH3 gene flanking a hygromycin/5-fluorodeoxyuridine positive/negative selection cassette  was petite in both the primary and secondary transfer near the last generation, and was removed from further analysis; one additional line (A10) was removed due to potential contamination during final MA generations. After each transfer, a mixture of many yeast colonies from the transfer plate was also frozen in 50% YPD, 15% glycerol. Transfers were halted for ∼3 months after the first 6 transfers (∼120 generations) due to an interruption in lab activities caused by the COVID-19 pandemic; MA was resumed by streaking frozen whole colonies. A total of 10 transfers (∼200 generations of MA) were performed.To perform MA, single YPD-grown colonies of Cultures derived from single frozen colonies from the final MA transfer, as well as from ancestral MA strains, were grown in SC media and DNA extraction was performed as in All sequences were deposited in SRA under project PRJNA871948, with run numbers listed in https://github.com/Siegallab/ssr_mutation_rate_pipeline. In short, reads were aligned using bwa mem (v0.7.17)   to a refified in , and aliified in .To identify SSR loci, we first ran tandem repeat finder (TRF)  v4.09 wimin_mapping_quality was set to 1; any calls with a QUAL value > 1 were used in downstream analysis. This created a list of calls at sites, including SSRs, where at least one strain was mutated relative to the reference. In order to get call likelihood values for non-mutant SSR loci, any loci called as mutant were removed from the full list of SSRs. The SSR list was then converted to a vcf, with the alternate allele at each locus listed as a missing value. FreeBayes was then re-run with the vcf of non-mutant SSR loci provided as –variant-input, and with the –only-use-input-alleles, –min-alternate-count 0, –min-alternate-fraction 0, and –min-coverage 0 options. In this mode , FreeBayes evaluated the likelihood of each unmutated SSR locus as compared to a version of the locus one motif repeat shorter than the original. The resulting calls and likelihood values were joined with the list of calls from the initial round of FreeBayes analysis.We initially ran FreeBayes (v1.3.4)  with theResults.In order to filter out spurious mutation calls, we removed any calls identified within 100 bp of a telomere, centromere, or LTR transposon ; we also+MSH3 and msh3Δ strains separately, specifying s.EP049 and s.EP060.3 as the ancestor strain, respectively. We filtered muver's results to exclude mutations called in low mappability regions of the genome, including centromeric and telomeric regions and LTRs. Mutations occurring on mitochondrial DNA were also filtered out. Among the +MSH3 strains, only C3 had 3 mutations compared to the ancestor, whereas muver identified 117 mutations across the 34 msh3Δ strains. Ninety-one of the called mutations fall into loci that we classified in our analysis as SSRs leaving 26 non-SSR loci mutated in the msh3Δ strains. Of these, 2 mutations were absent in FreeBayes calls; both of these loci were Sanger sequenced and found to be unmutated.In addition to calling SNMs with FreeBayes, we performed SNM calling for all MA strains using muver, a tool specifically designed for the analysis of MA experiment data   . We thenTo model the probability of SSR locus mutation, we modeled the odds of the observed mutation rate as a function of a baseline mutation rate, the locus length in bp, and any coefficients of interest:n is the length of the locus in bp, Obase is a “baseline” per-bp mutation rate, and each iθ is a coefficient by which a given parameter i affects the odds of mutation.where +MSH3 strains, the effects of SSR parameters on mutation rate were modeled using data from msh3Δ strains only . A model including only a Boolean parameter representing long (>7 bp) vs short SSRs (in addition to locus length in bp and baseline mutation rate) was used as a null model for calculating the significance of A/T proportion and motif length on SSR mutation rate; to calculate the significance of long vs short SSRs, this model was compared to a null model in which the odds of mutation are determined only by a baseline mutation rate and the length of the locus in bp. Finally, to calculate the significance and confidence intervals for the effect of the msh3Δ mutation, we ran the model above on the full dataset, including coefficients for long vs short SSRs (which had the only significant effect on SSR mutation rate) and MSH3 mutation status.Modeling was performed with a binomial generalized linear model in R . BecauseAll confidence intervals were calculated using likelihood profiling.MSH3 affected substitution rate, we performed MA for ∼200 generations on wild-type and msh3Δ haploid strains . We filtered all FreeBayes-identified mutations to select mutations sequenced at at least 10 × coverage and outside of SSR regions. All muver-identified mutations outside of SSR regions, except two, were a subset of the filtered mutations identified by FreeBayes; Sanger sequencing revealed that these two mutations were false positives. We therefore performed further analysis using FreeBayes mutation calls.Previous work indicates that Msh3p, and the MutSβ complex it is part of, is a key component of the MMR system for small indels, but not for substitutions . Because all MA lines are independently derived from a single common ancestor, the chance of two or more lines sharing a mutation is very low. An additional 10 substitutions were found a small distance (<50 bp away) from another substitution in a different strain, also highly unlikely to occur by chance considering that across all strains, only 27 unique substitutions were called elsewhere in the genome. We therefore further examined these calls. We first selected single-nucleotide substitution mutations, grouped mutations found within 50-bp of each other, and determined the number of strains that had a mutation within each such locus. This allowed us to identify regions with recurring mutation calls across strains. We found that loci mutated across multiple strains had properties distinct from single-strain substitutions: unlike uniquely mutated loci, all loci with mutations in multiple strains had, in either the MA line or its ancestor, a mix of reads supporting two different alleles, with the proportion of reads supporting the not-called allele being >25% of the total mapped reads. Strains without a called mutation at these loci also had a high proportion of reads supporting alleles other than the called allele; this was not the case for filtration-passing loci at which a single strain was mutated . Togethe+MSH3 strain, and the rest were found among 17 of the 34 sequenced msh3Δ strains. To compute the non-SSR SNM mutation rate across strains, we considered the non-repetitive proportion of the genome sequenced at 10 × or higher. We found no significant difference between the non-SNM mutation rate in +MSH3 and msh3Δ MA strains (P = 0.36); the non-SSR SNM mutation rate across all strains is 0.8 mutations/genome (over the course of ∼200 generations), or 3.5 × 10−10 mutations/bp/generation (95% CI: 2.3–4.9 × 10−10 mutations/bp/generation).The final FreeBayes mutation call-set consisted of 27 SNMs outside SSR regions, sequenced at >10 × coverage and present in a single strain . We checMaterials and methods. However, closer inspection revealed that all of these occurred in SSRs that were not labeled as such by our original algorithm , so that both putatively mutated and wild-type loci are thresholded in the same way.The possible correlation of SSR mutation call confidence with SSR mutation rate means that using a single confidence-based cutoff to filter calls at SSR loci will bias any assessments of factors contributing to SSR mutation rate: the filter will be inherently less stringent for loci less likely to be mutated, resulting in a higher perceived mutation rate in those loci. To avoid this bias, we set up a custom filtration strategy, in which the appropriate filtering thresholds are applied to individual groups of SSR loci with matching properties . We grouWe tested quantile thresholds corresponding to the removal of anywhere from 0% to 95% of all allele calls. Because calls were made at nearly all SSR loci, regardless of whether they were mutated, we can estimate the proportion of mutant loci at each threshold, by merging the calls passing the chosen threshold in each group of SSR loci . BecauseWe also compared the calls that passed filtration in our MA lines to calls made by muver within SSR regions and by MSIsensor, a program for calling SSR mutations in mutated samples relative to a control sample , we detect mutations in a total of 36 SSR loci , with 0–msh3Δ strains. To do this, we modeled the odds of a mutation in an SSR as a per-bp odds of mutation multiplied by the length of the SSR; in turn, the per-bp mutation odds are modeled as the product of coefficients corresponding to various properties of the SSR and the strain's MSH3 status. We do not include the 5 indels identified in unannotated SSR loci in this modeling; because we do not have a complete list of loci with similar properties (e.g. with motif size >4) we are not able to apply the same filtering criteria as for the other SSR mutations, which could lead to incorrect mutation rate estimate.We first sought to characterize the determinants of the SSR mutation rate in msh2 mutant strains . We also do not find a significant effect of motif length  on mutation rate (P = 0.5) (Previous work has shown that the proportion of A/T nucleotides in the SSR influences the SSR mutation rate in  strains . Among tP = 0.5) .P < 0.001)  .msh3Δ strains corresponded to ∼1.8 mutations/strain/200 generations. Although a total of more than 700,000 SSR loci passed filtration in +MSH3 strains, none of these threshold-passing SSRs were mutated in these strains. We therefore do not have enough data to calculate an estimate for the true SSR mutation rate in wild-type yeast, but we can calculate a lower bound on the fold-difference between +MSH3 and msh3Δ mutation rates: the 95% CI bound for the msh3 mutation effect is a 1.8-fold increase in mutation rate in msh3Δ relative to +MSH3.The overall mutation rate in msh3Δ strains. Previous work has shown that SSR mutations display a bias toward deletions in homopolymers . Finally, msh2Δ MA strains. We identified 4 substitutions within filtration-passing SSR regions in msh3Δ MA strains, at an overall rate of ∼1 substitution per 40,000 bp per generation. This is about 1.8 × the non-SSR substitution rate; however, this difference is not statistically significant (P = 0.3).We next looked at the spectrum of mutations accumulated in SSR loci by the rs . Loci consisting of 10 or more repeats are less frequent than expected within genes (Fisher's exact P < 0.001), although this dependency on length is only observable for non-trinucleotide repeats. The observed bias against non-trinucleotide repeats, especially long repeats, within gene bodies indicates the presence of selective pressure against potential frameshift mutations in coding regions, which would be highly deleterious . A similar bias was reported by P < 0.001) but not for trinucleotide mutations (Fisher's exact P = 0.9).Because selection should be minimal during an MA experiment, we expected the proportion of SSR mutations falling within genes to align with the previously described observations, with ∼70% of mutations falling within genes. Instead, we observed that SSR mutations were less likely than expected to occur within gene regions, with only 44% (16/36) falling within genes   insertions, in SSR loci. Finally, we showed that the mutation rate in SSRs at least 8 bp long is dramatically increased in msh3Δ mutants relative to shorter SSRs, lending further support to a model in which indels occurring within a few base pairs of the polymerase active site can be repaired by the polymerase, rather than by MMR machinery . In addition to the issues described above, read length is likely a key determinant of bias in SSR mutation calls, with loci less likely to be called accurately as their length approaches the length of each read. Furthermore, accurate estimation of mutation rates in SSRs likely requires high read depth: in our study, threshold-passing SSR loci were sequenced with a median sequencing depth of 62×. Although the strategy we describe allows for mitigation of biases in SSR mutation rate estimates, it cannot compensate for insufficient read depth or read length. Importantly, the strategy described here also cannot be used directly for calling mutations in diploids, as heterozygous and homozygous calls inherently have different confidence (ΔGL) levels, and most mutations are heterozygous.MSH3 to be ∼1 mutation/haploid genome/110 generations. Every indel observed in this study was in an SSR locus, and nearly every indel removed or inserted a single copy of the repeated SSR motif; the only exceptions to this were two homopolymers in which two and three of the SSR nucleotides were removed, respectively, and a single trinucleotide repeat in which a non-motif triplet was deleted from the middle of the SSR locus in a single strain. These observations are consistent with previous studies of SSR mutation rate  is not as strongly affected by abrogation of MMR as the mutation rate of longer SSR loci is (per-base pair odds of mutation of an SSR locus are ∼30-fold lower in loci shorter than 8 bp long. msh2Δ background, the rate of mutation for these short loci can be increased by abrogating the repair capabilities of DNA polymerase. Our work therefore supports a model in which the probability of an indel-causing mismatch occurring is dependent on the length of an SSR, but such mismatches are efficiently repaired by polymerase in short SSRs; in longer SSRs, MMR requires the MutSβ complex, and deleting members of this complex significantly increases the mutation rate for long SSR loci specifically.Importantly, our work confirms results from MA in an jkac330_Supplementary_DataClick here for additional data file.


Disability and medical expenses caused by musculoskeletal disorders in China had a great impact on the global health and economy. Rehabilitation is essential for dealing with musculoskeletal disorders. However, China's musculoskeletal rehabilitation needs remain unknown. This study aimed to examine the secular trends for musculoskeletal rehabilitation needs in China from 1990 to 2030.Data on musculoskeletal rehabilitation needs were extracted from the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) repository. Estimated annual percentage changes (EAPCs) were calculated to reflect fluctuations in the age-standardized rates. The Bayesian age-period-cohort models were used to project rehabilitation needs.PI) 14,872.6–27,429.3] per 100,000 persons in 2030. Similarly, the YLD counts will increase to 40.1 million, with the age-standardized YLD rate increasing to 1,811.2  per 100,000 persons in 2030.The number of prevalent cases and years lived with disability (YLD) counts in need of musculoskeletal rehabilitation increased greatly in China from 1990 to 2019. There will be 465.9 million Chinese people in need of rehabilitation, with the age-standardized prevalence rate increasing to 21,151.0 [2.5–97.5% predictive interval (95% Increasing trends in musculoskeletal rehabilitation needs were found from 1990 to 2019, which will be anticipated through 2030. Rehabilitation is suggested to be integrated into primary care settings. According to the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2017, musculoskeletal disorders become one of the three leading contributors to years lived with disability (YLDs) in China  is pain referred to the low back which continues for 1 day or longer . Neck paTo our knowledge, only one study has provided an overall view of musculoskeletal rehabilitation needs at the global and regional levels using data from the GBD study 2019 . AlthougThis is a cross-sectional study using secondary data.https://vizhub.healthdata.org/rehabilitation/) (UI) for each estimate was determined by the 25th and 975th draws in the 1,000 ordered draws, respectively. To assess the associations between musculoskeletal rehabilitation needs and societal development in China, we obtained the sociodemographic index from the GBD project. The sociodemographic index is a composite indicator, which incorporates income per head, total fertility rates younger than 25 years, and the average duration of educational attainment in individuals aged above 15 years (https://population.un.org/wpp/Download/Standard/Population/)  . We incl15 years . To projlation/) .CI) were generated to reflect fluctuations in the age-standardized rate  and its 95% confidence interval  Standard population to standardize the prevalence and YLDs in need of rehabilitation . In the accuracy , where nsmallest  among thi in period j, the logarithm of the number of disease cases λij is calculated by:In an APC model, for age group i, βj, and γk refer to the intercept, age, period, and cohort effects, respectively +j. In this study, the BAPC model with integrated nested Laplace approximations was used to predict rehabilitation needs through 2030  in the following year(s), an independent random effect zij ~ N   , 25. TheUI 173.7–199.2) million to 322.1 (95% UI 301.7–343.0) million from 1990 to 2019, with a significant increase in YLD counts from 17.6 (95% UI 12.5–23.3) million to 28.1 (95% UI 19.9–38.5) million during the same period. The age-standardized prevalence rate in China decreased from 17,966.3  per 100,000 persons to 17,225.4  per 100,000 persons, with an EAPC of −0.10% (95% CI −0.13 to −0.07%) annually. Likewise, age-standardized YLD rate in China decreased from 1707.7  per 100,000 persons to 1,496.8 (95% UI 1073.5–2025.7) per 100,000 persons, with an EAPC of −0.34% (95% CI −0.45 to −0.23%) annually , other injuries , osteoarthritis , and rheumatoid arthritis , remained stable for neck pain  and amputation , and decreased for low back pain  , followed by osteoarthritis (26.7%), neck pain (21.1%), fractures (20.3%), other injuries (12.4%), amputation (8.4%), and rheumatoid arthritis (1.0%). The proportions of prevalent cases by category increased in China, from 0.2% for rheumatoid arthritis to 8.8% for osteoarthritis, except a decrease of 12.1% for low back pain between 1990 and 2019 . The EAP −0.71%) .CI 0.12–0.68%), remained stable for neck pain , fractures , and rheumatoid arthritis , and decreased for low back pain , other injuries , and amputation  , osteoarthritis (16.8%), fractures (13.4%), other injuries (3.9%), amputation (2.8%), and rheumatoid arthritis (2.0%) in China. From 1990 to 2019, the proportions of YLD counts by category in China increased by 0.5, 2.5, 3.8, and 6.5% for rheumatoid arthritis, neck pain, fractures, and osteoarthritis, but decreased by 0.6, 0.9, and 11.8% for other injuries, amputation, and low back pain, respectively . The EAP −1.79%) .CI 0.43–0.55%), and other injuries  but increased faster in men for fractures , and decreased faster in men for low back pain  (CI −3.31 to −1.98%), and other injuries , but decreased faster in men for low back pain   . The age −0.62%) .Overall, musculoskeletal rehabilitation needs increased with age. Notably, sharp increasing trends in prevalence rates were found in fractures, other injuries, and amputation in people aged 90 years and over. The prevalence rates peaked at 75 years for neck pain and 75–80 years for rheumatoid arthritis in both sexes . The treWith increasing sociodemographic index, the age-standardized prevalence rate of low back pain decreased curvilinearly, whereas that of neck pain increased curvilinearly, and that of osteoarthritis increased in a zigzag pattern. The age-standardized prevalence rate of fractures, other injuries, and amputation approached the lowest level when the sociodemographic index increased to 0.57 in 2005. However, the age-standardized prevalence rate of rheumatoid arthritis peaked when the sociodemographic index was 0.66 in 2015 –4. The nPI) 17,729.7–19,091.7] per 100,000 persons in 2020 to 21,151.0  per 100,000 persons in 2030, with an EAPC of 1.39% (95% CI 1.26–1.53%). Similarly, the number of YLD counts will increase significantly from 29.7 million in 2020 to 40.1 million in 2030, with the age-standardized YLD rate increasing from 1,595.5  per 100,000 persons in 2020 to 1,811.2  per 100,000 persons in 2030, with an EAPC of 1.27% (95% CI 0.82–1.73%). Between 2020 and 2030, both age-standardized prevalence and YLD rates will increase for low back pain, fractures, and amputation, but will remain stable for neck pain, osteoarthritis, and rheumatoid arthritis (The number of Chinese people in need of musculoskeletal rehabilitation will increase markedly from 342.0 million in 2020 to 465.9 million in 2030, with the age-standardized prevalence rate increasing from 18,410.7 [2.5–97.5%; predictive interval (95% rthritis ; Table 2To our knowledge, this is the first study to present secular trends in musculoskeletal rehabilitation needs from the past to the future in China. Between 1990 and 2019, the number of prevalent cases and YLDs of musculoskeletal disorders that would benefit from rehabilitation increased remarkedly in China. Particularly, in 2019, musculoskeletal disorders contributed to 19.14% of total YLD counts . In addiParticularly, low back pain accounted for ~40% of total YLD counts due to musculoskeletal disorders in 2019. In fact, low back pain was also the primary cause of YLDs in more than 120 countries and the leading contributor to economic burdens globally . For exaIn terms of both age-standardized prevalence and YLD rates of musculoskeletal disorders, China was ranked from lowest to second-lowest among the G20 countries over the full study period. In addition to the largest population, this could be explained by a more remarkable improvement in life expectancy at birth in China than that in other countries. For example, from 1980 to 2019, life expectancy at birth in China increased significantly from 64.4 to 77.6 years, whereas that in the USA only increased slightly from 74.0 to 78.9 years . As suchSex disparities in rehabilitation needs were also observed. In this study, rehabilitation needs due to fractures, other injuries, and amputation were higher in men, whereas those of low back pain, neck pain, osteoarthritis, and rheumatoid arthritis were higher in women. This phenomenon could be partly attributed to complex traumatic, anatomic, and hormonal effects on the progression of musculoskeletal disorders. For example, men report more rehabilitation needs due to fractures, as men often suffer more serious traumas, such as vehicle accidents, vocational excessive bone loading and recreational injuries , althougGenerally, age-standardized prevalence and YLD rates of musculoskeletal orders increased with the sociodemographic index, which was noted in all 19 countries of the G20. Over the last 30 years, rapid development has been observed in the Chinese economy . As repoHigh rehabilitation needs pose a major challenge to Chinese health systems. In China, the primary care settings mainly provide basic clinical treatment and public healthcare . HoweverThere were several limitations in this study. First, there might be an underestimation of trends in rehabilitation needs, as the understanding and diagnostic criteria for musculoskeletal disorders may have been improved overtime. However, this potential bias was adjusted for during the cause list of diseases mapped to ICD codes. Second, only seven health conditions contributing to the largest number of YLDs and necessitating rehabilitation care were included. However, other categories of musculoskeletal disorders, for example, gout, which might also need rehabilitation services, were excluded. Third, we obtained aggregate data at the national level from the GBD repository, in which data at the subnational level were not available. Therefore, we failed to compare rehabilitation needs among different provinces or between urban and rural areas, which facilitated more specific strategies for rehabilitation initiatives, given that disparities existed in medical resource allocation and health service provision across China , 29. FouChina's musculoskeletal rehabilitation needs have increased substantially over the last three decades. There will be continuing increasing trends in musculoskeletal rehabilitation needs from 2020 to 2030. Rehabilitation services are suggested to be integrated into Chinese primary care settings.The original contributions presented in the study are included in the article/Ethical review and approval was not required for the study on human participants in accordance with the local legislation and institutional requirements. Written informed consent from the participants' legal guardian/next of kin was not required to participate in this study in accordance with the national legislation and the institutional requirements.NC, DF, and JW interpreted the results. NC drafted the manuscript. DF and JW supervised the study. All authors contributed to the critical revision of the manuscript for important intellectual content and approved the final manuscript as submitted.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


Since the enactment of the long-term care insurance (LTCI) act in 2000, the number of LTCI users has increased annually. However, evidence regarding what is being carried out as rehabilitation treatment under LTCI is lacking. In this study, a scoping review was performed to bridge this knowledge gap.Articles related to rehabilitation in connection with LTCI published between April 2000 and November 2020 were searched for in PubMed, CINAHL, CENTRAL , Ichushi Web Ver.5, and CiNii and randomized controlled trials (RCTs) of rehabilitation provided under LTCI were examined.Of the 15,572 publications identified, 15 RCTs, including rehabilitation treatment by physiatrists and therapists, met the eligibility criteria of our review and were included. The rehabilitation trials in the 15 RCTs varied and included balance training, exercise therapy, cognitive tasks, and activities such as singing and dancing. The results allowed us to focus on three categories: fall prevention, dementia, and theory and tools interventions related to occupational therapy practice.The focal points of attention in the rehabilitation treatment of LTCI were identified. However, the physical function, quality of life, and activities of daily living (ADL) of those who “need support” vary from person to person. Therefore, the consolidation of evidence on rehabilitation treatment of LTCI must be continued.The online version contains supplementary material available at 10.1186/s13561-022-00407-6. In 2019, Japan’s population was 126.17 million, of which 35.89 million  were between the ages of 65 and 75 years, and 18.49 million  were over 75 years [The basic concepts defining LTCI comprise “self-reliance,” “user-oriented,” and “social insurance systems.” This “self-reliance support” includes rehabilitation as well as nursing care services that substantially support activities of daily living (ADL) and other aspects of life. Older individuals who wish to receive nursing care services, including rehabilitation, must be certified as requiring nursing care . InitialRehabilitation under LTCI is designed to provide older adults with the required support so that they can live as independently as possible. This rehabilitation for the purpose of “self-reliance support” includes rehabilitation treatment by specialists (therapists) under the supervision of rehabilitation physicians (physiatrists), rehabilitation by non-professional staff, and support by family members. Rehabilitation treatment under medical insurance incorporates the concept of disease-specific implementation as a part of treatment. Based on the available evidence, it is further developing in the direction of maintaining and improving the quality of life (QOL) for individuals with diseases and disabilities. In other words, rehabilitation medical care is essentially covered by medical insurance. Medical insurance is a system in which the insurer pays all or part of the medical expenses incurred by visiting a medical institution and is based on the National Health Insurance Act of 1958. However, the number of people requiring severe nursing care as well as older people with dementia, who also have medical needs, is increasing –12. HoweThis lack of evidence is partly because the LTCI act has not been in effect for a long time, as well as because the background of the target population varies considerably . Users often have multiple diseases, and there are various types of facilities, including some that focus on rehabilitation and others that provide only nursing-centered services. These factors are suspected to have led to an increase in the number of case studies examining individual subjects and a decrease in observational and experimental studies. The subjects of rehabilitation treatment for long-term care insurance are not treated to improve a single function, but rather the necessary exercise content is covered and implemented according to various symptoms to maintain and improve ADL. Therefore, the outcomes and treatment contents are not limited, but rather diverse, and rehabilitation treatment encompasses them all. A scoping review was determined to be an effective way to organize this content.Prior research has reported the importance of distinguishing between reversible and irreversible multidimensional functioning of older adults at different levels of certification, to prevent future functional decline and provide efficient and effective care . This stThe results of this study may provide important insights not only for Japan but also for other countries. In the United States, as of 2015, more than 15,600 nursing homes reportedly provided care for older adults . AccordiTherefore, a scoping review was conducted of studies related to rehabilitation treatment in the LTCI field reported in Japan to date. The study aimed to examine the initiative of rehabilitation treatment covered under the current LTCI scheme, by limiting the scope to experimental studies conducted in facilities that actively implement rehabilitation, and to clarify future issues by summarizing the year of the study report, age, and sex ratio of the subjects, as well as the study design, intervention programs, and their effects.Rehabilitation performed in the long-term care insurance domain can be divided into rehabilitation treatment and rehabilitation management. Rehabilitation therapy is carried out by therapists under the supervision of a physiatrist, whereas rehabilitation management is carried out by non-professionals working together. As the eligibility criteria for this study, the facility category that provides rehabilitation treatment was used. Day-care rehabilitation and visiting rehabilitation from hospitals, home visits, nursing homes, and rehabilitation  from special nursing homes are methods of providing rehabilitation in the long-term care insurance area (welfare facilities for older adults). The first three are staffed by physiatrists and therapists who provide rehabilitation treatment. Therefore, the inclusion criteria were studies related to rehabilitation covered by LTCI, with descriptions of evaluation, rehabilitation in long-term care facilities, day-care rehabilitation, and visiting rehabilitation from hospitals. The target clinical trials examined the effects of rehabilitation in the field of LTCI; the study design was a randomized controlled trial (RCT), and the articles were in the English and Japanese languages. Exclusion criteria were studies related to home visits, nursing homes, rehabilitation  from special nursing homes (welfare facilities for older adults), review articles, case reports, conference records on topics other than those concerning rehabilitation fields, and articles written in languages other than English and Japanese. In addition, publications related to dysphagia and swallowing training were excluded.The conduct of this scoping review was based on the framework and principles reported by Arksey and O’Malley , with adArticles related to rehabilitation in the area of LTCI from April 2000 to November 2020 were searched for in PubMed, CINAHL, CENTRAL , Ichushi Web Ver.5, and CiNii. The search formula is presented in Online Resource 1. The selected articles’ bias risk was reviewed by two authors and approved by one. The co-authors also evaluated nonlinearity and publication bias.Figure When the 15 volumes considered were classified by reporting year, there were three volumes in 2005–2010, five volumes in 2011–2015, and seven volumes in 2016–2020. The average age of the subjects in the included articles was 66.5 years at the minimum and 84.4 years at the maximum. Regarding the sex ratio of the subjects, 1 volume was composed of 64.3% men , 11 voluThe article with the shortest intervention period, which reported efficacy in improving balance ability, examined the effect of rehabilitation on trunk function for 4 weeks. They found that two trunk exercises, using machine training, performed two or three times a week at three sets of 10 repetitions each, for 4 weeks, resulted in significant improvement in the evaluation index of dynamic balance ability. However, no improvement was observed in the center of gravity sway in the standing posture . In a stIn the intervention involving reading aloud and singing, 16 participants in the reading-aloud group read short poems, 16 participants in the singing group sang nursery rhymes and songs, and 16 participants in the control group were each given a 20-min program twice a week for 3 months. As a result, the frontal assessment battery (FAB) scores, an evaluation index of frontal lobe function, were significantly higher in both the singing and reading-aloud groups. The mini-mental state examination (MMSE), a measure of cognitive function, and the FAB showed significantly higher scores after the intervention only in the singing group. The reading aloud program was expected to activate the frontal lobe, while the singing program was expected to improve cognitive and frontal lobe function . In a stIn general, electroencephalography of older people with dementia showed a slow-wave pattern with a decrease in the power of the alpha band and an increase in the level of the theta band. Further, salivary amylase activity increased after the first half of the dance therapy intervention but decreased after the second half. These findings suggest that dance therapy may be effective in improving cognitive, brain, and autonomic functions . Tanaka A study on the efficacy of an occupational therapy program using occupational self-assessment (OSA)-II found the importance of goals and values in the report . The stuFurther, one study examined the MTDLP’s ADL application form . The BarAccording to the results of a survey conducted by the Ministry of Health, Labour and Welfare in 2021, falls and fractures accounted for 13.0% of the total causes of older adults needing nursing care, and it was the third largest cause after dementia and cerebrovascular disease . SeveralThere were seven RCT studies on fall prevention under LTCI. This may indicate growing interest in fall prevention. RCT studies on fall prevention under LTCI included training related to physical functions such as balance ability, trunk muscle strength, and toe muscle strength, as well as eye movement, with some even including a multitarget stepping program. A complex program that includes elements other than physical function may be a necessary component of fall prevention. In addition, the frequency of training should be at least twice a week for 1 month, with a long-term intervention period of 3 or 6 months. Other studies involving with older adults’ reports with older adults’ reports include studies in which training was conducted for 12 and 24 months, and the effects of long-term implementation are high , 42. AltThe fall prevention studies selected did not report effect sizes, and the clinical significance of the intervention effect is unclear. Additionally, only one article also presented 95% confidence intervals . Hence, The LTCI act introduced the measure of “intensive rehabilitation for newly admitted persons with dementia” in 2006 . In JanuThere were five RCT studies on dementia under LTCI. These included a wide variety of trainings, rather than one common training. As described above, most RCT studies on LTCI-covered interventions for rehabilitating patients with dementia reported improvements in cognitive function, followed by improvements in BPSD. Interventions that use a variety of recreational activities, such as singing and dancing, have the potential to increase enjoyment and pleasure. The perspective of enjoyment and pleasure, such as the inclusion of songs for group exercises while having fun, is assumed to be a factor that supports its continuation. Reports indicated that health promotion programs including facial expression muscle training improved QOL in LTCI, which may provide evidence for expressing enjoyment and pleasure . Of the Since the 1980s, the advancement of occupational science has led to the development of many theories and tools related to occupational therapy. Typical theoretical models of occupational therapy that are well known in Japan include the Canadian model of occupational performance developed by the Canadian Association of Occupational Therapists  and the The three selected papers have one thing in common: they all used goal-oriented sheets to improve quality of life and ADLs. One study discovered no difference in health-related quality of life or ADL . OSA II,From these viewpoints, theories and tool interventions related to occupational therapy practice are incorporated in LTCI. However, their effectiveness under LTCI needs to be examined in the future.The limitations of this study are as follows. First, this study aimed to provide evidence to guide rehabilitation interventions covered under LTCI for individuals whose level of independence is expected to improve; thus, the study was limited to only those facilities that actively provide rehabilitation programs covered by LTCI. Therefore, the efficacy of rehabilitation for individuals with more severe conditions, such as bedridden individuals, was not covered. Second, as LTCI is a rare system worldwide, it may not be compatible with other countries. However, older individuals worldwide require nursing care, and many need rehabilitation to maintain or improve their independence.Third, this study was not able to examine the issue from the perspective of collaboration among professionals related to rehabilitation. Physical, occupational, and speech therapists are involved in some rehabilitation programs covered by LTCI. Mutual collaboration (liaison) among professionals has been reported to be highly effective in in-home rehabilitation, but this factor was not examined . IdeallyThis scoping review was conducted to examine the available evidence to guide future rehabilitation treatment for persons with low levels of care provided under LTCI. As a result, fall prevention, dementia, ADL, and QOL were determined to be important factors.In this study, the rehabilitation conducted under LTCI was analyzed from three perspectives: “prevention of falls,” “dementia,” and “theories and tool interventions.” Fall prevention was discussed in several papers among those selected. Intervention methods for dementia vary, and presented tasks should include an element of enjoyment. This study also identified interventions with theories and tools related to occupational therapy practice. However, the examination of evaluation sheets and other tasks needs to be continued. In the future, a systematic review of the three points categorized in this study must be conducted. Furthermore, the examination of the concept of rehabilitation treatment under long-term care insurance, which was carried out in this study, must be continued.Additional file 1.Additional file 2.


It affects more than 10% of the global population. disease .Figure 1lnc-CHAF1B-3, lnc-CHAF1B-2, MIR181A2HG, LOC100507487, and LINC01638) were commonly upregulated. Based on lncRNA expression levels and the unknown function of lnc-CHAF1B-3, the authors chose to investigate this lncRNA further.The long-standing assumption that the non-coding regions of RNAs (ncRNAs) are mostly non-functional has been challenged in recent years due to emerging research unveiling their likely ability to act as therapeutic targets or diagnostic biomarkers for a wide variety of human diseases. lncRNAs are a subtype of ncRNAs that are longer than 200 nucleotides. They are increasingly recognized as regulators of gene expression in both physiological and pathological conditions.lnc-CHAF1B-3, Imai and colleagueslnc-CHAF1B-3 using both small interfering RNA (siRNA) and antisense oligos in two types of epithelial cells, HK2 and RPTECs, with or without TGF-β1 stimulation. Results from these experiments revealed robustly suppressed TGF-β1-induced upregulated expression of epithelial-mesenchymal transition (EMT)-related signaling in renal tubular epithelial cells, emphasizing the significance of lnc-CHAF1B-3 in the development of renal fibrosis. From a translational perspective, the authors further investigated the expression levels of lnc-CHAF1B-3 in patients with immunoglobulin A (IgA) nephropathy (chronic kidney disease) in five mild and 13 advanced cases. Intriguingly, RT-PCR analysis of the masked-form fixed paraffin-embedded kidney biopsies from the aforementioned patients revealed significantly elevated lnc-CHAF1B-3 levels in patients with advanced compared with minor glomerular abnormality (MGA) present with preserved renal function and a urinary protein similar to mild cases of IgA nephropathy, which were chosen as controls. Most importantly, Spearman’s correlation analysis revealed a positive correlation among lnc-CHAF1B-3, urinary protein concentrations, and the progression of renal dysfunction in patients with IgA nephropathy. To further determine the localization of lnc-CHAF1B-3, authors performed segment-specific multiplexed fluorescent in situ hybridization (FISH) assays on kidney biopsy samples, where CD10 and epithelial membrane antigen were used to label proximal tubules and distal tubules, respectively. FISH results revealed that lnc-CHAF1B-3 localized only to the cytoplasm of the proximal tubules but not in fibroblasts, irrespective of disease severity. However, further work will also be required to determine if the proximal tubule’s specific inhibition of lnc-CHAF1B-3 inhibits renal fibrosis and renal dysfunction in a suitable in vivo model, such as non-human primates or pigs as the sequence conservation is higher in these large animals compared with rodents. Taken together, these results highlight the potential clinical implications of lnc-CHAF1B-3 in CKD.To understand the physiological role of lnc-CHAF1B-3  according to the latest annotation provided by the Ensembl database, the authors did not discuss which isoform was investigated. Therefore, given that the genomic locus of this lncRNA is complicated with the presence of a novel transcript  and the protein-coding gene, claudin 14 (CLDN14), in the antisense direction, future studies are required to perform a 5/3′ rapid amplification of cDNA ends (RACE) assay to obtain the full-length sequence of each isoform of lnc-CHAF1B-3 to pinpoint the target lncRNA transcript. Furthermore, the authors attempted to decipher the mechanism of action of lnc-CHAF1B-3 by exploring lncRNA-microRNA (miRNA) interactions that drive lnc-CHAF1B-3-mediated EMT signaling, and it was revealed that lnc-CHAF1B-3 does not act as an miRNA sponge. Since lnc-CHAF1B-3 is localized in the cytoplasm of the proximal tubules, future work is warranted to tease out molecular mechanisms and see if lnc-CHAF1B-3 regulates EMT signaling through post-transcriptional modifications. Nevertheless, the current study by Imai and colleagueslnc-CHAF1B-3 in human RIF.It should be noted that although there are two isoforms of