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Keywords | PMC10691016 | |||
Background | impingement) syndrome, shoulder pain, pain, tendinopathy, disability | Rotator cuff related shoulder pain (RCRSP) over-arching term that encompasses a spectrum of shoulder conditions including; subacromial pain (impingement) syndrome, rotator cuff tendinopathy, and symptomatic partial and full thickness rotator cuff tears [Patient expectations are beliefs or attitudes that include pre-treatment thoughts and beliefs regarding the need for, timing, and intensity of specific treatment methods. Brief interventions designed to influence treatment expectations for physical therapy resulted in slight improvements in expectations, kinesiophobia and perceived disability [Our study purpose was to test an innovative intervention to alter expectations about physical therapy that is informed by principles of cognitive-behavioral theory: | PMC10691016 | |
Methods | This randomized controlled trial was approved by the institutional review board of Duke University Health System and was registered with ClinicalTrials.gov (NCT03353272) (27/11/2017). The full trial protocol was previously published in | PMC10691016 | ||
Trial design | Consented participants were randomized to receive either (1) an impairment-based physical therapy (PT) or (2) PT + PEERC group (Fig. Consort flow diagram for enrollment, allocation, and follow up | PMC10691016 | ||
Participants | psychological disorder, radiculopathy, psychosis, pain, depression | RADICULOPATHY, THORACIC OUTLET SYNDROME | Consecutive patients between 2018 and 2022 with RCRSP who were referred to Urbaniak Sports Sciences Institute by primary care physicians, orthopaedic surgeons, and physician assistants for physical therapy were recruited for the trial. Study activities were not initiated until after the patient provided written consent. The institutional review board of Duke University approved the study.Inclusion criteria for this protocol included: ages 18 to 70; a mobile or land-line telephone; the ability to read, write, and speak English; and an RCRSP diagnosis inclusive of both acute and chronic cases. We excluded patients who had received, or were scheduled for, a surgical intervention for their shoulder condition, demonstrated any evidence of cervicogenic pain and/or radiculopathy from cervical origin, or who demonstrated symptoms consistent with thoracic outlet syndrome; all of which were identified during the clinical examinations by the attending physician and physical therapist. We also excluded individuals who were undergoing treatment for a serious psychological disorder (e.g., severe depression, psychosis). | PMC10691016 |
Randomization | Consented participants were randomized to receive either 1) PT alone or 2) PT + PEERC at the time of enrollment prior to PT evaluation. Consecutively numbered, sealed, opaque envelopes containing group allocation were prepared by a researcher with no other involvement in the study. Condition allocation involved randomization within random permuted blocks using the random number function in Excel and was stratified according to treating therapist so that all physical therapists will deliver approximately equal numbers of patients in both conditions to control for therapist variation. | PMC10691016 | ||
PEERC intervention | Patients in the PT + PEERC group received the PT intervention describe above | PMC10691016 | ||
Outcomes | Disability, Pain, shoulder pain, pain | SECONDARY | Outcomes of interest were collected by study personnel at the time of consent, after 6 weeks of intervention, and at 6 months following discharge. Our primary outcome measure was patient report of having had surgery, or being scheduled for surgery, which was captured using a telephone survey at 6 months after discharge from impairment-based PT care. We selected a question framed around the patient’s choice of treatment approaches, and included the question: “Have you had surgery or are you scheduled for surgery for the shoulder problem that you were treated for in physical therapy?” A positive response was coded if the patient reported had already received surgery for their shoulder or was scheduled for surgery. We elected to use this question, because it allowed us to measure if patients had or were scheduled to have surgery in or outside of the study institution—in which case, a scheduled procedure would not be documented in the medical record.Secondary outcome measures included changes in expectations while participating in PT and satisfaction with the PT outcome, as well as pain and function. Expectations and satisfaction with PT outcome were measured with the Musculoskeletal Outcome Data Evaluation Management System Expectations and Satisfaction Surveys (MODEMS-E and MODEMS-S) questionnaires respectively. The MODEMS [Additional secondary outcomes included: shoulder pain intensity assessed through the Shoulder Pain and Disability Index (SPADI) [At baseline, we collected information on age, sex, marital status, education level, work status, prior episodes of PT (for current or different problem), if an injection was received, the Optimal Screening for Prediction of Referral and Outcome (OSPRO-ROS), and the Pain Catastrophizing Scale (PCS), both to describe participant presentation and to identify any post randomization difference between groups. To further describe and characterize participants after the course of treatment, we reported the Single Assessment Numeric Evaluation (SANE) [ | PMC10691016 |
Sample size | We powered the study for proportional between-group differences in patient report of having had surgery, or being scheduled for surgery at a 6-month follow-up. Using projections from previous data, and assuming offset inequity between two independent conditions; we modelled power on several assumptions previously described in the protocol paper [ | PMC10691016 | ||
Statistical analysis | SPADI, Pain, pain | SECONDARY | As previously described in the protocol paper, we evaluated descriptive statistics of the two conditions using appropriate parametric and nonparametric tests for differences, depending on the data (continuous or frequency based). For our primary outcome (patient report of having had surgery, or being scheduled for surgery), we measured condition differences in proportions between the PT only shoulder treatment and the PT + PEERC, using a chi-square analysis (or Fisher Exact). For our secondary outcomes, we used linear mixed effects modelling to compare follow up expectations and satisfaction of PT outcome (MODEMS) between the two conditions, as well as total SPADI scores, pain (SPADI), function (SPADI, TEGNER, GRoC, and SANE), and total visits. Repeated measures linear mixed effects modelling was used for all SPADI measures, pain, and GRoC scores. Pain intensity measures were evaluated using a negative binomial Poisson, which accounts for count variables with significant skew. A chi square analysis was used to calculated between group differences in patient experience ratings and discharge profile.Effect size measures were calculated using Cohen’s d for continuous measures and an effect size index (w) for chi-square tests. We also evaluated partial eta squared (η | PMC10691016 |
Results | SD | Fifty-four (54) individuals were enrolled in the trial. The average age was 51.81; SD = 12.54, and a majority were female (63%). The mean length of chronicity (days from symptom onset to physical therapy) visit was 174.61 days (SD = 179.58) and 20% had received physical therapy for a similar problem in the past. At baseline, the mean PCS score was 8.98; SD = 8.11, SPADI (total score) was 35.48; SD = 2.13, and MODEMS-E was 4.36; SD = 0.68. At baseline and prior to randomization, 70% of individuals either disagreed or strongly disagreed with the statement that they were interested in having surgery for their current condition. Table Baseline comparisons between physical therapy and PEERC versus physical therapy only8 = High School (15%)18 = College (33%)9 = Graduate School-Doctorate (17%)19 = Graduate School-Masters (35%)7 = High School (24%)9 = College (31%)2 = Graduate School-Doctorate (7%)11 = Graduate School-Masters (38%)1 = High School (4%)9 = College (35%)7 = Graduate School-Doctorate (28%)8 = Graduate School-Masters (31%)44 = Married (81%)3 = Divorced (56%)6 = Single (11%)1 = Widowed (2%)24 = Married (83%)2 = Divorced (7%)3 = Single (10%)0 = Widowed (0%)20 = Married (80%)1 = Divorced (4%)3 = Single (12%)1 = Widowed (4%)41 = Full time (76%)5 = Part time (93%)8 = Retired (15%)19 = Full time (65%)4 = Part time (14%)6 = Retired (21%)22 = Full time (88%)1 = Part time (4%)2 = Retired (8%)1 = Strongly agree (2%)15 = Neither agree or disagree (28%)11 = Disagree (20%)27 = Strongly disagree (50%)1 = Strongly agree (3%)10 = Neither agree or disagree (35%)4 = Disagree (14%)14 = Strongly disagree (48%)0 = Strongly agree (0%)5 = Neither agree or disagree (20%)7 = Disagree (28%)13 = Strongly disagree 52%) | PMC10691016 | |
Primary outcome | At six months (Table Surgery rate, SANE, and patient experience rating at six months | PMC10691016 | ||
Secondary outcomes | SPADI disability, pain | In our repeated linear mixed methods analyses, there were no significant differences between groups for pain (Repeated measures comparisons of pain score, SPADI total score, SPADI pain, and SPADI disability scoresAll analyses include baseline controls of the same variable with the exception of the GRoCSix-week and discharge comparisons between physical therapy PLUS PEERC versus physical therapy only10 = Discharge by PT (35%)13 = Self Discharge (45%)1 = Surgery (3%)5 = Other (17%)13 = Discharge by PT (52%)10 = Self Discharge (40%)1 = Surgery (4%)1 = Other (4%) | PMC10691016 | |
Discussion | chronic pain, pain | CHRONIC PAIN, SECONDARY, EVENTS | Our study examined the effect of PEERC, an intervention designed to improve expectations of PT, on patient report of having had surgery, or being scheduled for surgery (primary outcome). In this manner, PEERC is a novel form of psychologically informed physical therapy as it was not designed to directly address pain associated distress. Our secondary aim was to evaluate the impact of PEERC on expectations and satisfaction with PT outcome, pain, and function. We did not find differences between PT only and PT + PEERC in our primary outcome at six months follow up, nor did we identify between group differences for any of the secondary outcomes included in this trial.There are several potential reasons we did not detect differences between PT and PT + PEERC. Firstly, similar to many studies performed in the 2020 to 2022 timeframe [Third, we used an A versus A + B design to measure the effectiveness of the addition of the PEERC intervention. In theory, this design allows the investigators to understand better the true, isolated ‘effect’ of the “add-on” intervention [The hallmark of the PEERC intervention is the targeting of maladaptive cognitions and provision of compensatory pain management strategies for those with ongoing pain in order to improve patient expectations for treatment. Our pain catastrophizing (PCS) baseline measures were low for the PT arm (10.24; SD = 9.44) and even lower in the PT + PEERC arm (7.89; SD = 6.73). It has been suggested that pain catastrophizing scores of 30 or greater are considered clinically relevant level of catastrophizing in populations with chronic pain [Considered as a whole, the baseline characteristics of our study population suggest there may have been a “mismatch” between the patients we recruited and the goals of PEERC. That is, a majority of the study sample (70%) told us at baseline that they were not interested in having surgery and already had reasonably high expectations of PT care delivered by physical therapists. Simply stated, there is chance that the PEERC intervention is potentially beneficial, but the study was conducted with a population who is not as likely to need or benefit from it.We noticed a number of intriguing issues during implementation of the PEERC health coaching. Although PEERC included six visits, over a six-week timeframe, with phone calls serving as the medium, it was clear that in multiple occasions, patients did not participate in the PEERC health visits at the level that we had hoped. Despite requests to dedicate time to the full session (as outlined in the daily fidelity sheets), there were several times in which PEERC calls occurred during inopportune times; 1) while the patient was driving a car, 2) attending or coaching their youth’s sporting events, 3) while at work, 4) while cooking dinner, or 5) during other activities in which they multi-tasked the cognitive behavioral strategies of the PEERC with other daily activities. There were multiple occasions where a lack of preparedness from the patient was evidenced in the PEERC homework activities. This may be related to our selection of a phone to interact with the PEERC group. Although the use of phone allows broader accessibility, in situations such as cognitive behavioral based approaches, where non-verbal cues relationship building between patient and provider are known to enhance treatment, video may be a better alternative [ | PMC10691016 |
Limitations | pain | RECRUITMENT | In addition to the aforementioned sample size and composition issues, the following limitations are worth noting. Patients were participants referred for a physical therapy treatment program for RCRSP; consequently, there is a high risk of selection bias (e.g., the patients expected physical therapy to work and did not feel surgery was necessary), which may also be the reason for the high baseline expectations for treatment. In order to remedy this recruitment issue, future research should be designed to target recruitment to individuals that are most likely to have lower expectations of physical therapy treatment). Another participant related limitation to consider is that the collection of data did not allow for differentiation of sex and gender identity. Depending on the research question, this distinction may be important to make in future research of interventions like PEERC.In this trial we intentionally used an A versus A + B design as it bested addressed our research question. However, this design could be considered a limitation by those interested in the isolated effects of PEERC. Therefore, future research could consider A versus B designs to address this design choice. PEERC was provided by two experienced, PhD-level physical therapists who had undergone formal external (e.g., educational certificate on pain management) and within-study (dedicated training sessions for the study) training. Nonetheless, both individuals were not psychologists and there is the chance that this influenced the overall quality of the interventions, particularly having the background, experience, and skills to optimize its effectiveness. Also, although a fidelity checklist and “daily coaching” sheets were used to maintain treatment fidelity, there is a risk that some therapist drift may have influenced the uniformity of the interventions. Another limitation is that the primary outcome was collected by self-report. Thus, patient reports of having had surgery or being scheduled for surgery were not verified via electronic medical record. This approach was determined to be acceptable for this trial because the trial team had ready access to this patient population and a manageable ( | PMC10691016 |
Conclusions | pain | A novel six-week cognitive behaviorally-based intervention to alter expectations for PT(PEERC) provided no additional benefit when used as a routine adjunct to conventional PT alone for patients with RCRSP. Although planned sample size estimates were not met, post-hoc power analyses suggest that a substantially larger sample size than projected, or substantially larger treatment effects than observed, would be necessary to show benefits of PEERC on our primary outcome (patient reports of having had surgery or being scheduled for surgery). Therefore, it is difficult to advocate for PEERC adding value to PT alone in the management of RCRSP for individuals matching the characteristics of the patients enrolled in this trial (i.e. with high expectations of physical therapy). Future work in patient populations that are screened for high levels of surgical interest, with higher levels of pain associated distress, and/or poor expectations with physical therapy would be necessary to fully evaluate the potential value of PEERC. | PMC10691016 | |
Acknowledgements | The authors wish to Michael Reiman, Zachary Rethorn, Marissa Carvalho, Alessandra Narciso Garcia Trepte, and Lindsay Ballengee for their contributions to the trial. | PMC10691016 | ||
Authors’ contributions | CM | Conception and design: CC, HM, Critical revision for important intellectual content CC, FK, SZG, Drafting the manuscript HM, CC, Authors’ approval of the manuscript. CC, HM, SZG, FK, CM, JK, ADL, Data collection and analysis CC, HM, CM, JK, ADL. | PMC10691016 | |
Funding | This study is externally funded by the Academy of Orthopaedic Physical Therapy. The role of this funding source is solely financial and not influential or contributory to design or interpretation of results. | PMC10691016 | ||
Availability of data and materials | The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request. | PMC10691016 | ||
Declarations | PMC10691016 | |||
Ethics approval and consent to participate | This trial has the approval of the Institutional Review Board of Duke University Health System under protocol identification number Pro00088013. All study activities were conducted ethically in accordance with the Declaration of Helsinki. Informed consent was obtained from all participants enrolled in the study by institutionally-trained research personnel. Study activities were not initiated until after the patient provided written consent. | PMC10691016 | ||
Consent for publication | Not applicable. | PMC10691016 | ||
Competing interests | The authors declare that they have no competing interests. | PMC10691016 | ||
References | PMC10691016 | |||
1. Introduction | pelvic floor muscle, urinary incontinence | URINARY INCONTINENCE, URINARY INCONTINENCE, COMPLICATIONS | Less than half of women with urinary incontinence (UI) receive treatment, despite the high prevalence and negative impact of UI and the evidence supporting the efficacy of pelvic floor muscle training (PFMT). A non-inferiority randomized controlled trial aiming to support healthcare systems in delivering continence care showed that group-based PFMT was non-inferior and more cost-effective than individual PFMT to treat UI in older women. Recently, the COVID-19 pandemic highlighted the importance of providing online treatment options. Therefore, this pilot study aimed to assess the feasibility of an online group-based PFMT program for UI in older women. Thirty-four older women took part in the program. Feasibility was assessed from both participant and clinician perspectives. One woman dropped out. Participants attended 95.2% of all scheduled sessions, and the majority (32/33, 97.0%) completed their home exercises 4 to 5 times per week. Most women (71.9%) were completely satisfied with the program’s effects on their UI symptoms after completion. Only 3 women (9.1%) reported that they would like to receive additional treatment. Physiotherapists reported high acceptability. The fidelity to the original program guidelines was also good. An online group-based PFMT program appears feasible for the treatment of UI in older women, from both participant and clinician perspectives.Urinary incontinence (UI) is one of the most prevalent health concerns in women age 65 and over [However, the COVID-19 pandemic prevented group gatherings, especially for older adults, who were at higher risk of complications. For the past two years, it therefore limited the implementation of in-person group-based interventions, such as the GROUP trial’s program. At the same time, the pandemic also drove an impressive surge in many remotely delivered healthcare services [One promising solution is telerehabilitation, which refers here to the remote delivery of synchronous rehabilitation services using information and communication technology. It has already shown good feasibility and favorable clinical outcomes for the treatment of various orthopedic and neurological conditions [This study thus aimed to assess the feasibility of an online adaptation of the GROUP program (the teleGROUP program) for UI in women age 65 and over, from both participant and clinician perspectives. Feasibility studies are a critical component of the evaluation of study processes. They establish the necessary groundwork to shape the subsequent phases of clinical development and provide insights for successful implementation [ | PMC10218421 |
2. Materials and Methods | PMC10218421 | |||
2.1. Study Design | COMPLICATIONS | This pilot pre-post feasibility study is part of a larger research program aiming to assess the feasibility, acceptability, effects and costs of the teleGROUP program (ClinicalTrials.gov NCT05182632). The present study focused on feasibility. More specifically, the study aimed to determine the feasibility of teleGROUP in terms of attendance, adherence, complications, dropouts, satisfaction and the overall experience data of participating women; acceptability for the evaluating physiotherapists; and conformity with the original program guidelines from the physiotherapist leading the teleGROUP program. This study follows the Consolidated Standards of Reporting Trials (CONSORT) for reporting results. A detailed study protocol was previously published [ | PMC10218421 | |
2.2. Participants | INCONTINENCE | The research team recruited participants through advertisements, a research participant database and referrals from collaborating clinics. Women were eligible if they were age 65 and older; able to walk independently; presented stress or mixed UI, as confirmed by the Questionnaire for Incontinence Diagnosis (QUID) [ | PMC10218421 | |
2.3. Intervention | During an initial individual in-person evaluation session, participant eligibility was confirmed by an experienced local physiotherapist with specialized training in pelvic floor rehabilitation. During this session, the physiotherapist also took the time to teach the participant how to correctly contract her pelvic floor muscles (PFMs) through digital vaginal palpation and verbal cues [Participants who were able to voluntarily contract their pelvic floor muscles following a verbal command by the end of the evaluation session were deemed eligible and then took part in the teleGROUP program [A videoconference connection link, which was unique for each cohort, was sent weekly via email to all participants two to three days before the session. No login was required, and participants could click to join the session directly from the email they received. Each weekly virtual session began with a 1–3 min individual exchange between the physiotherapist and each participating woman in a private breakout room to quantify UI episodes and exercise adherence in the previous week. In the meantime, the rest of the group were invited to socialize in the Zoom meeting’s “main room”. All sessions were then divided into a 10–15 min educational component and a 30–45 min PFMT exercise component. More detail on both the educational and exercise components of the teleGROUP program are available in | PMC10218421 | ||
2.4. Data Collection | The research team pre-screened women for eligibility through a telephone interview. A specialized physiotherapist located in the participant’s region then confirmed their eligibility through an individual in-person evaluation. During this evaluation, the physiotherapist collected sociodemographic and health data, namely, age, height, weight, socioeconomic status, medical history and general health characteristics, including type of UI symptoms, duration of symptoms and cognitive status through the MMSE [To assess feasibility from the participant perspective, the physiotherapist leading the teleGROUP program recorded attendance at weekly sessions [To assess feasibility from the clinician perspective, both the evaluating physiotherapists and the treating physiotherapist were considered. First, the physiotherapists conducting the initial individual in-person evaluation session completed a questionnaire based on the Theoretical Framework of Acceptability (TFA) [Secondly, still within the assessment of feasibility, the physiotherapist leading the teleGROUP program recorded fidelity to the original program guidelines at each session for the full 12 weeks [ | PMC10218421 | ||
2.5. Data Analysis | Data were tabulated and interpreted using descriptive statistics, such as means, medians, standard deviations and interquartile ranges for continuous variables and frequency distributions for categorical and dichotomous variables, as appropriate. | PMC10218421 | ||
4. Discussion | MINOR, CONTRACTION, CONTRACTIONS | This pilot feasibility study is the first to investigate the feasibility of an online group-based PFMT program. The study showed that the teleGROUP program was feasible from the participant perspective, with high attendance at the online classes, high adherence to the home exercises, infrequent and minor side effects resolving quickly, low attrition throughout the 12-week program, high satisfaction with the program and good perceived usability of the online program. In addition, this study showed good feasibility from the clinician perspective, with high acceptability from the evaluating physiotherapists and relatively good fidelity to the original program guidelines from the physiotherapist leading the program, despite time constraints. Compared to the original in-person version of the program, teleGROUP showed a similar attendance rate (95% vs. 95.2% in GROUP and teleGROUP, respectively) and lower attrition throughout the program (7% vs. 3% during the program and 6% for the overall study) [Throughout the program, the clinical expertise of the specialized physiotherapists played a key role in ensuring adequate treatment delivery, regardless of the online or group format. First, during the initial in-person evaluation, the physiotherapists taught participants to contract their PFMs. They were able to guide the participating women so that they could achieve an adequate PFM contraction by overcoming perineal inversion (i.e., straining and depressing the pelvic floor rather than executing the expected inward lift and squeeze), compensations (e.g., contraction of other muscles, such as abdominal muscles, gluteal muscles, adductors, diaphragm) or difficulty relaxing their PFM. These challenges are similar to those observed in other studies, where between 17% and 43% of women initially strained, pushed or used a Valsalva maneuver when attempting to contract their PFMs [Additionally, when facing time constraints during the 12-week program, the physiotherapist leading the teleGROUP sessions made some decisions that were informed by clinical expertise and experience. This clinical decision process was reflected in the fidelity findings: Besides the individual exchange and the educational session, the physiotherapist prioritized the four main PFM exercises constituting the core elements of the program over the other exercises from the program. Comparatively, in the GROUP trial, the per protocol fidelity percentage was higher overall (77.9% of the content for the functional exercise of the dance activity and 79.8% of the content for the transverse abdominal contractions (unpublished data), compared to 31.2% and 12.5%, respectively, in the teleGROUP program). Yet, the disparities between the in-person and online versions of the program tend to disappear when considering the core elements of the program, notably, the four main PFM exercises. Indeed, the fidelity was relatively similar for these 4 PFM exercises, with 90.7%, 96.2%, 100.0% and 98.7% for each exercise (unpublished data), compared to 96.7%, 97.0%, 98.4% and 100.0% in the GROUP and teleGROUP programs, respectively. Moreover, the physiotherapist leading the teleGROUP program limited the position changes during the sessions to avoid multiple camera angle adjustments by both the physiotherapist and the participating women and to reduce the time spent correcting posture. Additional time was still needed to complete the treatment sessions due to the time spent in individual exchanges, particularly when dealing with a high number of participants. As adherence to the PFM exercise program constitutes the cornerstone of successful UI treatment [The findings of the present study represent an important first step in guiding the upcoming research steps towards the implementation of group-based PFMT telerehabilitation programs in various healthcare settings. This format provides a safe UI treatment option during pandemic periods or in any other situation that presents a health risk (e.g., winter storm). An online option could also increase the accessibility of continence care for women living in rural or remote areas, where pelvic floor rehabilitation services are unavailable or scarce. It could also be an additional asset for any woman who cannot attend in-person treatment due to her living situation (i.e., caring for someone at home), transportation difficulties or any other personal reason. This study also presents some limitations. As this was a feasibility study on an innovative treatment approach, a relatively small sample size was included, and the intervention was delivered from a single institution, limiting the generalizability of the findings. However, pilot studies constitute an important part of the research process [ | PMC10218421 | |
5. Conclusions | In conclusion, this study shows that an online group-based PFMT program for older women with UI is feasible from both patient and clinician perspectives. The time constraints due to time spent in individual exchanges emphasized the importance of respecting the program’s pre-established group size of eight women. The study also highlighted the pivotal role of the physiotherapist leading the program in prioritizing the activities according to the clinical objective pursued. Further investigation is needed to determine the clinical effectiveness of the teleGROUP program. | PMC10218421 | ||
Supplementary Materials | The following supporting information can be downloaded at: Click here for additional data file. | PMC10218421 | ||
Author Contributions | Conceptualization, M.L.B., J.F., B.R. and C.D.; methodology, M.L.B., J.F. and C.D.; software, M.L.B.; validation, M.L.B. and C.D.; formal analysis, M.L.B. and C.D.; investigation, M.L.B. and C.D.; resources, M.L.B. and C.D.; data curation, M.L.B.; writing—original draft preparation, M.L.B. and C.D.; writing—review and editing, M.L.B., J.F., B.R. and C.D.; visualization, M.L.B.; supervision, C.D. and J.F.; project administration, M.L.B. and C.D.; funding acquisition, M.L.B., J.F., B.R. and C.D. All authors have read and agreed to the published version of the manuscript. | PMC10218421 | ||
Institutional Review Board Statement | Santé Et De | The study was conducted in accordance with the Declaration of Helsinki and approved by the Ethics Committee Board of the Aging-Neuroimaging Research of the Centre Intégré Universitaire De Santé Et De Services Sociaux Du Centre-Sud-De-L’île-De-Montréal on 6 March 2021 (CER VN 20-21-33). | PMC10218421 | |
Informed Consent Statement | Informed consent was obtained from all participants involved in the study. | PMC10218421 | ||
Data Availability Statement | The data presented in this study are available upon request from the corresponding author. | PMC10218421 | ||
Conflicts of Interest | The authors declare no conflict of interest. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript; or in the decision to publish the results. | PMC10218421 | ||
Subject terms | Various advantages of isobaric bupivacaine, levobupivacaine, and hyperbaric bupivacaine are described. There are no studies reliably determining the benefits of these forms of bupivacaine. The purpose of the study was to compare the efficacy of spinal anesthesia (SA) performed with 0.5% isobaric bupivacaine, 0.5% levobupivacaine, and 0.5% hyperbaric bupivacaine. The clinical study was approved by the ethics committee. The sample size was calculated for a confidence level of 99%. 111 patients were randomly allocated into 3 equal groups for spinal anesthesia in lower limb surgeries. In group 1 (1B) spinal anesthesia was performed with 3 ml of 0.5% isobaric bupivacaine (n = 37); in group 2 (2L)—3 ml of 0.5% levobupivacaine (n = 37), in group 3 (3H)—3 ml of 0.5% hyperbaric bupivacaine (n = 37). The criterion for assessing the effectiveness of anesthesia was the need to switch to another type of anesthesia (criterion-no anesthesia), or the need for additional use of narcotic analgesics or local anesthesia during surgery (criterion-reporting of painful feelings during the operation). In 1B anesthesia efficiency by the criterion of additional intraoperative analgesia was 100% (37 patients; 95% CI [0.88–1.0]); 2L—86.4%; (31 patients; 95% CI [0.68–0.92]); 3H—72.9% (27 patients; 95% CI [0.56–0.84]). There were significant differences between groups 1B and 2L: p < 0.05 (p = 0.0104). There were no significant differences between groups 2L and 3H (p = 0.2587). All patients in group 1B developed complete sensory block (++) within 4 (3; 5) min. In group 2L complete sensory block developed in 34 patients (89.4%) within 9 (5; 14) min, in group 3H sensory block developed in all patients within 3 (2.5; 4). The duration of analgesia period between 1B and 2L did not statistically differ (p = 0.73). In 3H the duration of analgesia was 170 (150; 200) min. The study found 83.7% efficacy of levobupivacaine and 72.9% efficacy of hyperbaric bupivacaine in comparison with isobaric bupivacaine (100%) when administered intrathecally in equal volumes and amounts (by the criterion of additional intraoperative analgesia).Trial registration: NCT05184465 (Initial Release: 12/01/2021; date of first publication—11/01/2022). | PMC9932064 | ||
Introduction | cardiotoxicity | More than a hundred years ago, a short article was published on the anesthesiologist's choice among not only the various local anesthetics for performing spinal anesthesia, but also on the choice between isobaric and hyperbaric forms of local anestheticAbout 15 million spinal anesthesia procedures are performed worldwide each yearThe literature describes such advantages of levobupivacaine as less cardiotoxicity, longer period of analgesia, more pronounced activity against sensory fibers than against motor fibersHowever, in the literature there are different data on clinical efficacy of levobupivacaine in comparison with ropivacaine and levobupivacaine. So during operations on extremities out of 20 patients surgical anesthesia developed in 18 patientsIn their study, Gautier et al. noted significantly lower efficacy of levobupivacaine in caesarean section compared to bupivacaine and ropivacaine for intrathecal use: 80% vs. 90% and 87%, respectivelyAccording to Heng Sia et al. there is no clear evidence of the advantage of hyperbaric bupivacaine over isobaric bupivacaine for spinal anesthesia for cesarean sectionThere is no clear practical guide to help anesthesiologists make informed decisions about the use of some form of intrathecal bupivacaine in non-cesarean surgery. Carefully designed, adequately conducted studies can provide further results that will contribute to sound clinical decision makingGiven the above, the aim of the study is to compare the effectiveness of spinal anesthesia (SA) performed with 0.5% isobaric bupivacaine solution, 0.5% levobupivacaine solution and 0.5% hyperbaric bupivacaine solution in equivalent volumes in lower limb surgeries. | PMC9932064 | |
Materials and methods | —complete sensory block, Pain, liver disease, neurological or neuromuscular diseases, pain, infectious skin lesions, knee joints, allergic reactions | SKIN, ALLERGIC REACTION, RENAL FAILURE, LIVER DISEASE, BLIND, COAGULOPATHY, COMPLICATIONS | The clinical double blind randomized study was approved by the ethics committee of our institution (protocol dated 01/28/2017). All methods were performed in accordance with the relevant guidelines and standards. All experimental protocols were approved by the Ethics Committee of the Mogilev Regional Clinical Hospital. The study is registered on ClinicalTrials.gov—Identifier: NCT05184465 (Initial Release: 12/01/2021; date of first publication—11/01/2022).111 patients who underwent surgical intervention on the hip, thigh, and knee joints were included in the study (Fig. Flow chart on patient distribution.Criteria for inclusion of patients in the study: indications for surgical intervention on the hip, thigh, and knee joints, the need for anesthetic support (spinal anesthesia).Exclusion criteria: patient refusal to use the proposed type of anesthesia, age < 18 years, body mass index not > 39, physical status according to ASA > 3, history of allergic reactions to the drugs used, coagulopathy, infectious skin lesions in the injection area, neurological or neuromuscular diseases, severe liver disease or renal failure, inability to cooperate with the patient.A written informed consent was obtained from all patients or their legal guardians to participate in the clinical trial. And we obtained written informed consent from all patients or their legal guardians about the type of anesthesia and possible complications of regional anesthesia. After obtaining informed consent, patients were randomized into groups using a random number generator (numbers in envelopes). The random assignment sequence was created by an anesthesiologist not involved in the study. Randomization: sealed envelopes with a type of anesthesia.Spinal anesthesia was administered to the patients for anesthetic support of the surgical intervention. Patients were randomly allocated into three groups: in group 1 (1B) spinal anesthesia was performed with 3 ml of 0.5% bupivacaine (n = 37); in group 2 (2L) spinal anesthesia was performed with 3 ml of 0.5% levobupivacaine (n = 37); in group 3 (3H) 3 ml of 0.5% hyperbaric bupivacaine solution (n = 37) was used for subarachnoid injection. The anesthesiologist, who was not involved in the study, prepared the anesthetic solution immediately before the injection.Intrathecal injections were performed with a 24G or 25G «Pencil point» needle in the L3–L4 interval. Spinal puncture was performed while the patient was sitting on the table. Then the patient was placed on his back. The patient was positioned for surgery 30 min later.Solutions for spinal anesthesia were prepared by an anesthesiologist who was not involved in the anesthesia. Spinal anesthesia was performed by an anesthesiologist with many years of experience, who performs 10–15 spinal anesthesias per week.The peripheral vein was catheterized on the operating table before anesthesia. SPOSurgery was allowed to start after 40 min if the upper level of the sensory block reached the Th10 segment.The criterion for assessing the effectiveness of anesthesia was the need to switch to another type of anesthesia (criterion-no anesthesia), or the need for additional use of narcotic analgesics or local anesthesia during surgery (criterion-reporting of painful feelings during the operation). Criteria for the use of additional anesthesia: the patient's complaint of pain in the surgical area.The block was evaluated by an anesthesiologist who was not involved in the study. Sensory block quality was recorded on both sides along the midclavicular line, assessing changes in needle prick sensation. Skin sensitivity was assessed every 2 min for 40 min. The following scale was used to assess sensory block, where: “++”—complete sensory block (anesthesia); “+”—not complete sensory block, the patient could not differentiate the type of stimulus; “−”—skin sensitivity preserved to the full extent.The development of motor block was assessed using the Bromage scale (0–3) for 40 min. End of motor block was defined as the appearance of the first movements in the lower extremities.The duration of postoperative analgesia was assessed by interviewing the patient in the postoperative period. The duration of analgesia was assessed in the postoperative period every 30 min. Pain sensations were assessed by visual analog scale (VAS) from 0 cm (no pain) to 10 cm (unbearable pain). The end of analgesia was considered the moment when the patient noted the onset of pain (1–2 points). If painful sensations appeared in the postoperative wound area (1–2 points), we injected intramuscularly 2%-1 ml of Promedol for postoperative analgesia. The duration of analgesia was assessed by an independent anesthesiologist, who was not involved in the study.For the additional intraoperative analgesia criterion, the null hypothesis implies that the degree of success in the compared groups (for each local anesthetic) is the same (p > 0.05). If the null hypothesis should be rejected after a statistical test (p < 0.05), it is concluded that one of the groups is superior to the others on this indicator. The sample size was calculated for a confidence level of 99% and statistical power of 99% and a type 1 error of 0.01 (taking into account the effectiveness of performing spinal anesthesia with isobaric bupivacaine 0.5% in orthopedics at our institution). Considering previous studies in this area, where the sample size ranged from 29 to 40 patientsStatistical processing of the obtained data was performed using Statistica 7.0 software. The data were presented as median and quartiles (25th% and 75th%) and also as mean and standard deviation. Differences between the groups were considered statistically significant at p < 0.05. The primary endpoint was the need to switch to another type of anesthesia or the need for additional narcotic analgesics or local anesthesia either initially or during surgery. The frequencies of the binary feature in the two unrelated (independent) groups were compared by analysis of a contingency table (2 × 2). Classic Pearson's χSecondary endpoints: time of sensory and motor block development, duration of postoperative analgesia and motor block. The groups were compared using nonparametric Mann–Whitney test. Differences between the groups were considered statistically significant at p < 0.05. | PMC9932064 |
Discussion | postoperative nausea and vomiting | Our data on the need for additional anesthesia during surgery (84.2% efficiency) are comparable to those obtained by Gautier et al. in the subarachnoid use of levobupivacaine in caesarean section, where its efficiency was 80%However, other studies have shown high efficacy of levobupivacaine in subarachnoid useTime of sensory block development in our study was statistically significantly faster in bupivacaine group than in levobupivacaine group (4 (3; 5) min vs. 9 (5; 14) min), which is consistent with the data obtained in other studiesEfficiency of development of complete motor block in levobupivacaine group was 86.8%, and significantly different from bupivacaine group. These data are consistent with previous studiesIn our study we obtained no significant differences in the duration of postoperative analgesia. These results are similar to the results of other studiesThe authors of a major review found little evidence for the need to switch to general anesthesia and adjuvant analgesia between hyperbaric or isobaric bupivacaine groups. This is due to the rarity of these results, variability in doses, use of adjuvant drugs, and differences in regional anesthesia techniques. Any possible, in the authors' opinion, benefits of hyperbaric bupivacaine should be confirmed in larger randomized trials. In future studies, the criteria for switching to general anesthesia should be defined objectively and applied uniformlyAccording to Heng Sia et al. there is no clear evidence of superiority of hyperbaric anesthesia over conventional bupivacaine for spinal anesthesia in cesarean sectionAt the same time, a study published in 1984 showed fewer failures when using hyperbaric solution than isobaric solutionAccording to other authors, levobupivacaine was not inferior to bupivacaine in quality of motor block, but anesthesia duration was longer when bupivacaine was usedIn Huang et al. study, it was noted that when using hyperbaric bupivacaine 0.5% intrathecally, about 70% of sensory block variants can be predicted. And about 30% are incomprehensible variants and they require studyThe limitations of the study are that we did not compare the hemodynamic effects of the three drugs, nor did we evaluate study groups for the development of postoperative nausea and vomiting.In conclusion, our study determined 83.7% efficacy of levobupivacaine and 72.9% efficacy of hyperbaric bupivacaine compared with isobaric bupivacaine (100%) when administered intrathecally in equal volumes and amounts (according to the criteria of additional intraoperative analgesia). The slowest development of sensory and motor block was noted in levobupivacaine. The longest postoperative analgesia was observed for isobaric bupivacaine and levobupivacaine. It should be noted that the data of different authors on the efficacy of levobupivacaine and hyperbaric bupivacaine are contradictory. Further studies with large numbers of patients are needed to determine whether levobupivacaine and hyperbaric bupivacaine can be equal to bupivacaine in efficacy. | PMC9932064 | |
Author contributions | P.V.: The study design, data collection, patient enrollment, perform anesthesia, the analysis of results, writing the first version of the article. L.M.: Data collection, patient enrollment, perform anesthesia, the analysis of results. | PMC9932064 | ||
Data availability | The datasets used and/or analysed during the current study available from the corresponding author on reasonable request. | PMC9932064 | ||
Competing interests | The authors declare no competing interests. | PMC9932064 | ||
References | PMC9932064 | |||
Background | diabetic models, death, pre-diabetic, pre-diabetes | METABOLIC DISEASES, INFLAMMATION, INSULIN RESISTANCE, PRE-DIABETIC, PRE-DIABETES, PATHOLOGY | Edited by: Benoit Pourcet, Université de Lille, FranceReviewed by: Paola Llanos, University of Chile, Chile; Shulin Yang, Institute of Animal Sciences, Chinese Academy of Agricultural Sciences, China†Lead ContactThis article was submitted to Inflammation, a section of the journal Frontiers in ImmunologyDiabetes is one of the most common metabolic diseases and continues to be a leading cause of death worldwide. The NLRP3 inflammasome has been shown to exert detrimental effects on diabetic models. However, evidence linking NLRP3 inflammasome and pre-diabetes has been scarcely explored. Herein, we aimed to determine whether the NLRP3 inflammasome correlates with insulin resistance and liver pathology in a cohort of pre-diabetic subjects. | PMC9929576 |
Methods | pre-diabetic, DEx, Pre-diabetes | PRE-DIABETIC, PRE-DIABETES | 50 pre-diabetic subjects were randomly assigned to a Pre-diabetes Control (DC, n=25) and a Pre-diabetes exercise (DEx, n=25) group. 25 Normal subjects (NC) were selected as controls. The DEx group performed a 6-month combined Yijingjing and resistance training intervention, while DC and NC group remained daily routines. Clinical metabolic parameters were determined with an automatic biochemistry analyzer; inflammatory cytokines were quantified by the ELISA assay; the protein expressions of NLRP3 inflammasome components in PBMCs were evaluated by Western Blot. | PMC9929576 |
Results | liver injury, pre-diabetic | PRE-DIABETIC, INSULIN RESISTANCE, PATHOLOGY, INSULIN SENSITIVITY | The insulin resistance, liver injury and NLRP3 inflammasome activity were higher in pre-diabetic individuals than in normal control group. However, 6-month exercise intervention counteracted this trend, significantly improved insulin sensitivity, reduced liver injury and inhibited the overactivation of NLRP3 inflammasome in pre-diabetic subjects. Moreover, positive correlations between insulin resistance, liver pathology and NLRP3 inflammasome were also found. | PMC9929576 |
Conclusions | liver injury, pre-diabetic | PRE-DIABETIC, INSULIN RESISTANCE | Our study suggests that exercise training is an effective strategy to alleviate insulin resistance and liver injury in elderly pre-diabetic subjects which is probably associated with the inhibition of NLRP3 inflammasome activity. | PMC9929576 |
Introduction | inflammation, diabetes | INFLAMMATION, CHRONIC INFLAMMATION, PRE-DIABETES, PATHOGENESIS, DIABETES | The prevalence of diabetes has increased worldwide, and it is predicted to affect almost 783.2 million people by 2045 (Considerable evidence has demonstrated that chronic low-grade inflammation caused by aberrant activation of the innate immune system plays an essential role in the pathogenesis of diabetes (Over the past decade, it has been widely recognized that alterations in NLRP3 inflammasome activity is implicated in the pathogenesis of diabetes. In mice, ablation of NLRP3 prevented the obesity-induced inflammasome activation in fat depots and liver together with enhanced insulin-signaling (The prevalence of diabetes is increasing rapidly and this is largely due to the alterations of lifestyle, in particular, excess energy intake and lack of physical activity are critical risk factors for diabetes. Therefore, to prevent pre-diabetes from developing into diabetes at an early stage, lifestyle intervention such as enhancing physical activity has been found to be very promising. Indeed, it has been well established that appropriate exercise is an effective strategy against diabetes but its underlying mechanisms remains unclear. Overwhelming studies have confirmed a strong association between physical inactivity and a moderate degree of chronic inflammation ( | PMC9929576 |
Materials and methods | PMC9929576 | |||
Study design and participants | obesity, overweight | OBESITY | The present study was a RCT trial. All participants provided written informed consent prior to the study. The sample size was determined based on similar literature (The inclusion criteria were as follows: (1) men or women aged 50-70 years; (2) fasting blood glucose (FBG)<6.1 mmol/L and normal glucose tolerance for NC group; (3) 6.1≤FBG ≤ 7 mmol/L and overweight or obesity (waist circumference≥85 cm for men, waist circumference≥80 cm for women) for DC and DEx group. The exclusion criteria were as follows: (1) patients with cardiovascular, musculoskeletal or other kinds of diseases; (2) participants have no highly active lifestyle.The daily physical activity and eating habits of all participants are strictly monitored by interviews every week. They were asked to maintain their routines without changing physical activity and eating habits. This study was approved by the Ethics Committee of Shanghai University of Sport (Clinical Trials ChiCTR2100054684). | PMC9929576 |
Exercise training protocol | Individuals in the DEx group performed a 6-month combined Yijingjing and resistance training under the guidance of a professional Yijinjing instructor, five times/week for 6 months, while NC and DC group remained previous daily routines. The exercise intervention was conducted in Gongnong Park of Shanghai Yangpu district which was close to the subjects’ home from April to December, 2021. Yijinjing of Li Wei’s version was used in this study which was promoted by the General Administration of Sports of China with about 13 minutes. The type of resistance training used in this study was elastic bands exercise with about 8 minutes. All elastic bands were purchased from Li-Ning (China) Sports Goods Co., Ltd. The overload of elastic bands was 35 pounds (1500 mm x 1500 mm x 0.5 mm) for men and 25 pounds (1500 mm x 150 mm x 0.4 mm) for women. The exercise intensity was maintained at 60%-70% of the maximum heart rate with polar watches. Each exercise session consisted of a 5 min warm-up, Yijinjing training, elastic bands training and a 5 min cool-down period. The duration of exercise was increased from 47 minutes to 76 minutes per session. Briefly, in the first two month, two sets of Yijinjing training and two sets of elastic bands training were performed, with a total of 47 minutes per session. In the third and fourth month, three sets of Yijinjing training and three sets of elastic bands training were performed, with a total of 68 minutes per session. In the fifth and sixth month, three sets of Yijinjing training and four sets of elastic bands training were performed, with a total of 76 minutes per session. | PMC9929576 | ||
Methods of measurement | PMC9929576 | |||
Anthropometry and physical examinations | behavioral and motivational characteristics | All the measurements were performed at the baseline and 6 months after intervention at Shanghai University of Sport laboratory.Background information regarding lifestyle, behavioral and motivational characteristics as well as medical history was collected. Height was determined using a wall-fixed measuring device, and weight was measured using a calibrated scale. Height and weight were used to calculate body mass index (BMI=weight(kg)/height(m) | PMC9929576 | |
OGTT test and metabolic parameters measurements | The oral glucose tolerance test (OGTT) was performed in according with the standard. Venous blood samples were taken after overnight fasting at 8:00-8:30 by physicians and at 2 h after the intake of glucose. FBG, fasting insulin (FINS), glycated hemoglobin (HbA | PMC9929576 | ||
ELISA | TUMOR NECROSIS | The concentrations of pro-inflammatory cytokines tumor necrosis factor α (TNFα), interleukin-6 (IL-6) and IL-1β in serum were measured by ELISA assay using the human ELISA kits (Biolegend). | PMC9929576 | |
PBMCs isolation | The activity of NLRP3 inflammasome was evaluated by detecting the protein expressions of NLRP3 inflammasome signaling cascade including NLRP3, IL-1β and caspase-1 in peripheral blood mononuclear cells (PBMCs). The PBMCs were isolated as described previously ( | PMC9929576 | ||
Western blot analysis | LYSED, SECONDARY, LYSIS | The activity of NLRP3 inflammaosme was detected by Western Blot analysis with whole-cell lysates and cell supernatants. Cells were washed with 1xPBS buffer and then lysed in RIPA lysis buffer with protease inhibitor (1 μg/ml) and incubated on ice for 20 min. Lysates were then centrifuged at 15,000 rpm for 15 min at 4°C. The concentration of protein supernatant was determined using the BCA protein kit. Total cell lysates were resolved by SDS-PAGE and analyzed for NLRP3, pro-caspase-1 and IL-1β protein levels. To examine secreted IL-1β and caspase-1, culture medium was collected, equal volume of methanol and 1/4 volume of chloroform was added and vortex. The mixtures then were centrifuged at 12000 rpm at 4°C for 10 min, the upper was discarded, the bottom was transferred to a new tube and equal volume of methanol was added and vortex. The mixtures were centrifuged at 12000 rpm at 4°C for 10 min, the supernatant was discarded and the pellet was dried for 5 min. 1xloading buffer was added to the pellet and then boiled at 95°C for 5 min. The cell culture medium lysates were resolved by SDS-PAGE and analyzed for cleaved caspase-1 and cleaved-IL-1β protein levels. 20-40 μg total lysate was separated by SDS-PAGE and transferred onto a PVDF membrane. Membranes were blocked with 5% non-fat milk and then incubated with primary and secondary antibodies respectively. The primary antibodies used in this study were NLRP3 antibody (abclonal A12694, 1:2000), caspase-1 antibody (Proteintech 22915-1-AP, 1:2000), IL-1β (abclonal A1112, 1:2000), and GAPDH antibody (Proteintech 60004-1-Ig, 1:50000). Western HRP Substrate (Millipore) was used for development of protein bands. | PMC9929576 | |
Statistical analysis | ± | The statistical analysis was performed with Graphpad Prism software V.8. The results are expressed as means ± SD. Paired t-test was used for intra-group comparisons before and after the intervention. Comparison among the three groups was performed by one-way ANOVA. The interactions between group and time were evaluated by two-way ANOVA. Correlation analysis was performed with Pearson’s test in the whole post-intervention samples. Statistical significance was set at | PMC9929576 | |
Results | PMC9929576 | |||
Participants and baseline characteristics | An overview of the study is given in Study Profile of trial participants.The baseline characteristics of all groups were summarized in Baseline characteristics of all groups.BMI, body mass index. | PMC9929576 | ||
Exercise training attenuated insulin resistance in pre-diabetic patients | diabetes | PRE-DIABETES, INSULIN RESISTANCE, DIABETES | Previous evidence has shown that the essence of diabetes is insulin resistance, while appropriate exercise is an effective strategy to defeat diabetes. Therefore, we first checked whether the combined Yijinjing and resistance training also have beneficial effects on pre-diabetes. The characteristics of all subjects after exercise intervention were summarized in The characteristics of all subjects after exercise intervention.HOMA-IR, homeostatic model assessment of insulin resistance; HbA | PMC9929576 |
Exercise training alleviated liver injury in pre-diabetes subjects | PATHOLOGY, INSULIN RESISTANCE | The liver plays a central role in the systemic regulation of glucose and lipid metabolism and aberrant hepatic function is thought to be a primary driver of insulin resistance (Change of liver pathology after exercise intervention. The serum levels of ALT | PMC9929576 | |
Exercise training inhibited the overactivation of NLRP3 inflammasome in pre-diabetic patients | T2DM | As discussed above, although exercise was able to inhibit the overactivation of NLRP3 inflammasome in human models of T2DM (Change of NLRP3 inflammasome activity after exercise intervention. However, on the contrary, the protein expression of NLRP3 ( | PMC9929576 | |
The NLRP3 inflammasome is associated with insulin resistance | PRE-DIABETES, INSULIN RESISTANCE, INSULIN SENSITIVITY | Next, to determine whether NLRP3 inflammasome is involved in the regulation of pre-diabetes and exercise on systemic insulin sensitivity, we performed correlation analysis between the protein levels of NLRP3 inflammasome components and the value of HOMA-IR in the whole samples. As shown in Correlations between the NLRP3 inflammasome activity and insulin resistance in the whole study population after 6-month exercise intervention. Pearson correlation tests were performed between the protein expressions of NLRP3 | PMC9929576 | |
The NLRP3 inflammasome is associated with liver pathology | pre-diabetic, liver injury | PRE-DIABETIC, PATHOLOGY | To further verify whether NLRP3 inflammasome is linked to liver pathology in pre-diabetic patients, we assessed the correlation between the protein levels of NLRP3 inflammasome components and liver injury markers ALT, AST, bilirubin, GGT and CRP in the whole samples. As shown in Correlations between NLRP3 inflammasome and liver pathology. Pearson correlation tests were performed between the protein expression of NLRP3 and serum ALT | PMC9929576 |
Discussion | inflammation, liver injury, metabolic diseases, Diabetes, pre-diabetic, diabetes | INFILTRATION, INFLAMMATION, METABOLIC DISEASES, INSULIN RESISTANCE, DIABETES, PRE-DIABETIC, PRE-DIABETES, PATHOLOGY, INSULIN SENSITIVITY, DIABETES | In this study, for the first time according to our knowledge, we found that 6-month combined Yijingjing and resistance training was able to alleviate systemic insulin resistance and liver injury, and inhibit the overactivation of NLRP3 inflammasome in pre-diabetic elderly subjects. More important, the NLRP3 inflammasome was positively correlated with systemic insulin sensitivity and liver injury.Diabetes has long been associated with a chronic low-grade inflammatory state but its precise mechanisms remain unclear. In the past decade, the role of NLRP3 inflammasome in diabetes has been greatly appreciated, as the chronic low-grade inflammatory state accompanied by diabetes is at least partially consequent to the activation of NLRP3 inflammasome (It is well established that physical exercise is an effective way to counteract diabetes but its mechanisms are not clear. Of note, in 2011, Vandanmagsar (Additionally, we also observed significant alleviation of whole body insulin resistance and liver injury after the exercise intervention, however, whether the improvement of insulin sensitivity and liver function by combined Yijinjing and resistance training intervention is associated with the reduced expression of NLRP3 inflammasome remains unknown. Previous studies have shown that the liver is not only a central organ of energy metabolism, but also acts as an immune organ (The potential mechanisms by how exercise alleviates insulin resistance and liver injury through NLRP3 inflammasome.To sum up, we speculated that the combined Yijinjing and resistance training may be an effective strategy to inhibit the robust NLRP3 inflammasome activation, thereby alleviating liver injury and insulin resistance in pre-diabetes. Apart from this mechanism, the combined Yijinjing and resistance training may also alleviate liver injury, reduce the release of harmful DAMPs from injured hepatocytes, thereby inhibiting the overactivation of NLRP3 inflammasome (Apart from liver, the skeletal muscle is another major metabolic organ. Moreover, increasing evidence suggests that inflammation occurs in skeletal muscle is mainly manifested by increased immune cell infiltration and proinflammatory activation. By secreting proinflammatory molecules, the immune cells may induce inflammation and insulin resistance in skeletal muscle (Strengths of our study include the objects of study, intervention protocol. The objects of our study are pre-diabetic populations. Although it is wise to ameliorate diabetes by developing an effective strategy for the pre-diabetes, no RCTs are available to evaluate the effects of Yijinjing in patients with metabolic diseases such as pre-diabetes. Since data from long-term studies that show the effects of combined Yijinjing and resistance training on pre-diabetic are currently lacking, the findings from our study may have significant clinical implications for diabetes because they show that if healthy lifestyle intervention is established at the early stage of diabetes they can prevent diabetes progression.Our studies have some limitations. First, the sample size of this study is relatively small and thus may not be fully representative of the general pre-diabetic elderly population, therefore, randomized controlled studies with larger sample sizes are needed to confirm these findings in the future. In order to obtain accurate information regarding the degree of inflammation and liver pathology, liver biopsies would be needed. However, given the ethical issues, it is hard to obtain biopsies from patients, thus limiting the direct measurement. Additionally, in this manuscript, we combined the data from males and females. For precision medicine, it would be meaningful to study the function of exercise training in males and females separately. Lastly, although we found positive correlations between insulin resistance, liver pathology and NLRP3 inflammasome, however, it should be noted that correlation does not imply causation. Therefore, more research including mouse model is needed to define the role of NLRP3 inflammasome in pre-diabetic populations in the future. | PMC9929576 |
Conclusion | liver injury, diabetes | PRE-DIABETIC, PRE-DIABETES, INSULIN RESISTANCE, DIABETES | Taken together, our findings indicate that combined Yijinjing and resistance training is effective in alleviating insulin resistance and liver injury in elderly pre-diabetes, which is associated with the inhibition of NLRP3 inflammasome activity. The findings of this study have significant clinical implications for pre-diabetic patient since early prediction of diabetes is vital for timely intervention. | PMC9929576 |
Data availability statement | The original contributions presented in the study are included in the article/supplementary material. Further inquiries can be directed to the corresponding authors. | PMC9929576 | ||
Ethics statement | The studies involving human participants were reviewed and approved by Ethics Committee of Shanghai University of Sport. The patients/participants provided their written informed consent to participate in this study. | PMC9929576 | ||
Author contributions | TZ designed the experiment, participated in data collection and analysis and drafted the manuscript. JT was responsible for exercise intervention and participated in data collection. JF participated in data collection. XL and RW designed the experiment and oversaw the implementation of the project. All authors contributed to the article and approved the submission. | PMC9929576 | ||
Conflict of interest | 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. | PMC9929576 | ||
Publisher’s note | 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. | PMC9929576 | ||
References | PMC9929576 | |||
Abstract | PMC10651956 | |||
Objective | PD, Parkinson's disease, gait impairments | PARKINSON'S DISEASE | In this randomized, double‐blind, sham‐controlled trial, we explored the effect of 20 Hz transcutaneous auricular vagus nerve stimulation (taVNS) on gait impairments in Parkinson's disease (PD) patients and investigated the underlying neural mechanism. | PMC10651956 |
Methods | PD | CORTEX | In total, 22 PD patients and 14 healthy controls were enrolled. PD patients were randomized (1:1) to receive active or sham taVNS (same position as active taVNS group but without releasing current) twice a day for 1 week. Meanwhile, all subjects were measured activation in the bilateral frontal and sensorimotor cortex during usual walking by functional near‐infrared spectroscopy. | PMC10651956 |
Results | PD | CORTEX | PD patients showed instable gait with insufficient range of motion during usual walking. Active taVNS improved gait characteristics including step length, stride velocity, stride length, and step length variability compared with sham taVNS after completion of the 7‐day therapy. No difference was found in the Unified Parkinson's Disease Rating Scale III, Timed Up and Go, Tinetti Balance, and Gait scores. Moreover, PD patients had higher relative change of oxyhemoglobin in the left dorsolateral prefrontal cortex, pre‐motor area, supplementary motor area, primary motor cortex, and primary somatosensory cortex than HCs group during usual walking. Hemodynamic responses in the left primary somatosensory cortex were significantly decreased after taVNS therapy. | PMC10651956 |
Conclusion | PD, gait impairments | taVNS can relieve gait impairments and remodel sensorimotor integration in PD patients.The 20 Hz transcutaneous auricular vagus nerve stimulation (taVNS) could relieve gait impairments and remodel sensorimotor integration in PD patients. The results provided insights into the neural mechanism of taVNS and a new neuromodulation method for treating gait impairments in PD patients.
The first two authors contributed equally to this work. | PMC10651956 | |
INTRODUCTION | PD, Parkinson's disease | PARKINSON'S DISEASE, NEURODEGENERATIVE DISEASES, NEUROLOGICAL DISORDERS | Parkinson's disease (PD), one of the most common neurodegenerative diseases, conveys a mounting socioeconomic burden.Vagus nerve stimulation (VNS), performed by a surgically implantable device, has been approved by the Food and Drug Administration as an adjunct neuromodulation therapy for drug‐resistant epilepsyThe clinical efficacy of nVNS wins growing recognition in neurological disorders, while its underlying mechanism remains elusive. Given that taVNS could induce widespread, diffuse cortical effects through nucleus tractus solitarius (NTS) and locus coeruleus (LC), | PMC10651956 |
METHODS | PMC10651956 | |||
Study design and participants | PD, idiopathic PD | MOVEMENT DISORDER | This was a pilot, randomized, double‐blind, and sham‐controlled study (registration no. NCT05561348). Eligible PD patients were recruited and then randomly (1:1) assigned to the taVNS stimulation group or sham stimulation group. A researcher who did not participate in the evaluations and statistical analysis used SPSS v25.0 software (IBM) to get the random number and was responsible for the interventions for two groups of patients. Our study was approved by the ethics committee of the First Affiliated Hospital of Nanjing Medical University (2022‐SR‐535). Written informed consent was signed by all participants prior to the study. Investigators and all PD patients were blinded to the interventions during the study.Right‐handed patients with idiopathic PD, visiting the Neurology Department of the First Affiliated Hospital of Nanjing Medical University were enrolled. The following inclusion criteria should be satisfied: (1) meet the diagnostic criteria of idiopathic PD according to the Movement Disorder Society (MDS) Clinical Diagnostic Criteria for PD | PMC10651956 |
Study procedure and intervention | auricular branch vagus nerve, PD | PARKINSON'S DISEASE, CORTEX | The study flow is shown in Figure Flow diagram. fNIRS, functional near‐infrared spectroscopy; HCs, healthy control; PD, Parkinson's disease; taVNS, transcutaneous auricular vagus nerve stimulation.Specifically, all PD patients were assessed for the severity of motor symptoms by the Unified Parkinson's Disease Rating Scale section III (UPDRS‐III),Subsequently, 26 PD patients were randomly allocated to receive active‐taVNS or sham‐taVNS stimulation in the outpatient department of Neurology (the First Affiliated Hospital of Nanjing Medical University). taVNS was conducted by transcutaneous electrical stimulation therapy instrument (tVNS501, RISHENA). Two modified dot‐like electrodes delivered the stimulation to the cymba conchae of left ear in the vicinity of the auricular branch vagus nerve (Figure (A) Position of the taVNS stimulation (cymba conchae); (B) Schematic illustration of the fNIRS layout (35 channels, 14 sources, and 14 detectors). The nodes represent optical probes. The arrangement covers the bilateral prefrontal cortex, pre‐motor cortex, supplementary motor cortex, primary motor cortex, and primary somatosensory cortex. Details are shown in Table | PMC10651956 |
Gait assessment | A portable Inertial Measurement Unit (IMU) system (GYENNO Science) during a 5‐m timed TUG test was used to access gait feature. IMUs were placed on the chest, back, wrists, thighs, ankles, and insteps of the subjects via Velcro straps in order. Wirelessly transmitted mobility data were stored and analyzed by a laptop that controlled the protocols. The mean value and variability (coefficient of variation, CV) of gait feature including step length, stride velocity, stride length, arm range of motion (ROM) maximum, double support time, gait cycle, turning average duration, and turning average duration velocity were calculated (CV was calculated as standard deviation/mean × 100%). | PMC10651956 | ||
Functional near infrared spectroscopy data acquisition and preprocess | PD, gait impairments | CORTEX | A 35‐channel portable fNIRS device (Nirsmart, Huichuang) was utilized. The sample frequency was 11 Hz, and the wavelengths were 760 and 850 nm. Given that prefrontal and sensorimotor cortex activity was correlated with gait impairments in PD,The experiment conducted in a quiet room with soft light included two phases: (1) participants were instructed to stand quietly, look straight ahead, and think of nothing for 15 s and (2) when hearing the ‘start’ command, participants walked for 65 s at their comfortable pace back and forth over a 5‐m distance, with a 180‐degree turn at each end. Notably, participants were required to stand still for at least 1 min to ensure stable blood pressure before each experiment. An internal software named NirSpark (Huichuang) was used to preprocess the fNIRS data. The steps are as follows | PMC10651956 |
Outcomes | SECONDARY | The primary outcome measure was the effect of taVNS on gait parameters, UPDRS‐III, TUG, Tinetti Balance, and Tinetti Gait scores. The secondary outcomes included determination of effects of taVNS on ΔHbO | PMC10651956 | |
Safety | dizziness, headaches, tinnitus | SKIN TOXICITY, TINNITUS | Safety was evaluated by recording the number of each participant's headaches, dizziness, tinnitus, ear irritation, or skin toxicity. | PMC10651956 |
Statistical analysis | PD, gait impairments | A sample size of at least 13 patients per group was required (calculated by PASS v15 software, factorial analysis of variance using effect size, minimum power: 0.8, type I error: 0.05, numbers of factors: 2, and effect size: 0.4).All data were analyzed using SPSS v25.0 software (IBM) and Shapiro–Wilks test was performed to assessed for normality. For baseline demographic and clinical characteristics, Later, to evaluate the severity of gait impairments in PD patients, two‐sample Finally, to determine the effect of group and stimulation conditions on gait parameters, motor symptoms, and ΔHbO | PMC10651956 | |
RESULTS | PMC10651956 | |||
Demographic and clinical characteristics | Anxiety, Parkinson's Disease Sleep Scale, Parkinson's Disease Rating Scale, PD, Depression, Fatigue | PARKINSON'S DISEASE | Twenty‐two PD patients and 14 HCs who finished the entire procedures were included in this study. Table Demographic and clinical characteristics of participants.
Abbreviations: ESS, Epworth Sleepiness Scale; F, female; FAB, frontal assessment battery; FSS, Fatigue Severity Scale; H&Y stage, Hoehn and Yahr clinical rating scale; HAMA, Hamilton Anxiety Scale; HAMD‐24, Hamilton Depression Scale‐24; HCs, healthy controls; L, left; LEDD, levodopa equivalent daily dose; M, male; MMSE, Mini‐Mental State Examination; NA, not applicable; PD, Parkinson's disease; PDSS, Parkinson's Disease Sleep Scale; R, right; s, second; taVNS, transcutaneous auricular vagus nerve stimulation; TUG, Time Up and Go; UPDRS, Unified Parkinson's Disease Rating Scale; y, year.Kruskal–Wallis.Fisher's exact test.One‐way ANOVA.Two sample Mann–Whitney Chi‐square test. | PMC10651956 |
The difference of gait parameters between PD and HCs groups | PD | The inter‐group comparison showed that PD patients had decreased step length (Comparing the difference of gait parameters in PD and HCs groups. The statistical threshold was set at | PMC10651956 | |
The difference of ΔHbO | PD | PD patients showed increased ΔHbODifference of ΔHbO | PMC10651956 | |
Effect on gait and motor symptoms | INTERACTION | Two‐way ANOVA showed a significant interaction between group and condition effect in gait parameters including step length (Effects of taVNS on gait parameters and motor symptoms. (A) Interaction effect on gait parameters including step length, variability of step length, stride velocity, and stride length. (B) Main effect of group (taVNS stimulation vs. sham stimulation) on gait parameters including gait cycle and double support. (C) Effect on motor symptoms including TUG, UPDRS‐3, Tinetti Balance, and Tinetti Gait scores. A Bonferroni‐corrected threshold was set at No difference was found in the group main effect, condition main effect, or interaction when analyzing the motor symptoms including UPDRS‐III, TUG, Tinetti Balance, and Gait scores ( | PMC10651956 | |
Effect on ΔHbO | INTERACTION, CORTEX | Two‐way ANOVA showed a significant group main effect for ΔHbO(A) Main effect of group (taVNS stimulation vs. sham stimulation). Significant differences obtained from the main effect of group were in the S6‐D11 (corresponding to the left primary somatosensory cortex). (B) Main effect of stimulation condition (pre‐stimulation vs. post‐stimulation). No significant differences were obtained from the main effect of condition. (C) Interaction between group and condition effect. Interaction between group and stimulation effect was found in the S6‐D11 (corresponding to the left primary somatosensory cortex). The color bar indicates | PMC10651956 | |
Safety | ADVERSE EVENTS | taVNS possessed good tolerance since there were no reports of adverse events caused by stimulation. | PMC10651956 | |
DISCUSSION | PD, gait impairments | CORTEX | This study investigated the effect of taVNS on gait impairments and brain activity in PD. First, PD patients had decreased step length, arm ROM maximum, and turning average duration velocity, while increased turning average duration, stride velocity variability, and gait cycle relative to the HCs group. Simultaneously, improvements in gait characteristics, including step length, stride velocity, stride length, step length variability, gait cycle, and double support after 7‐day taVNS therapy, were significant. Second, PD patients had higher ΔHbOAccumulating literature uncovered that PD patients showed impaired pace, step length, and rhythmicity compared with age‐matched healthy adults.Cerebral gait control is mainly accomplished through direct and indirect pathways: the direct pathway from the M1 to the central pattern generators of the spinal cord participates in the automatic control of gait, and the indirect pathway from the PFC and PMA to the basal ganglia, and then to the brainstem motor center can regulate gait based on challenging situations.Apart from small sample size, some limitation should be considered. First, limited detection depth of fNIRS system hindered the detection of activation in subcortical structures. However, the portable fNIRS enabled us to capture functional alterations in the subjects' cerebral cortex during actual walking, which was beneficial for us to understand the neural mechanism of gait impairments in PD better. Second, dopaminergic therapies might modulate cortical function, | PMC10651956 |
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