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Intervention | CDA, COLD | As part of the standard of care, all livers were preserved by static cold storage following classic organ procurement. All liver grafts were flushed with 1 L of Institut Georges Lopez (IGL-1) preservation solution through the portal vein ex situ at the end of the back-table preparation at the recipient center. All transplants were done with caval replacement using venovenous bypass. After completion of caval and portal anastomosis, reperfusion of the liver was initiated. The standard of care further included an immunosuppressive regimen consisting of tacrolimus (trough levels between 5 and 8 μg/L), mycophenolate mofetil (500 mg, 2 times), and steroids (tapered to 3 months).In addition to standard of care, patients in the CDA group received a combination drug regimen that was adapted from the CDA regimen used in the porcine study. | PMC9975910 | |
End Point Measures | postreperfusion syndrome, liver IRI | The primary end point was defined as the difference between the 2 study arms in peak serum aspartate aminotransferase (AST) levels within the first 72 hours after graft reperfusion, an accepted clinical surrogate of liver IRI that correlates with patient and graft survival and postreperfusion liver histological assessment.Secondary end points included the frequencies of postreperfusion syndrome, | PMC9975910 | |
Safety | ADVERSE EVENTS | All adverse events were prospectively collected in both groups, categorized as adverse events or serious adverse events, and adjudicated for a possible causal relationship with the treatment. Treatment-related adverse events were considered within the first 7 days following transplant. | PMC9975910 | |
Statistical Analysis | AKI, postreperfusion syndrome, DCD liver | REGRESSION, SECONDARY, SURGICAL COMPLICATIONS | A sample size of 58 patients was needed to detect a 50% reduction in peak AST, as determined with a 2-sided, 2-sample pooled Results for the primary end point are reported for the full analysis set and a per protocol set. For secondary outcomes, the results for the per protocol set are given.For the primary end point, a linear regression model was used on log-transformed values with treatment group as a factor, yielding a ratio of geometric means with 95% CIs. In a sensitivity analysis, MELD score and CIT were added as confounders. The primary end point analysis was repeated in the full analysis set with exclusion of patients who received a DCD liver. Odds ratios and 95% CIs are given for the comparison of frequencies of EAD, AKI, postreperfusion syndrome, and severe surgical complications. Mann-Whitney U tests with the Hodges-Lehmann estimator as effect size were performed to compare acute cellular rejection Banff | PMC9975910 |
Results | PMC9975910 | |||
Recruitment | Between September 2013 and February 2018, 310 consecutive patients were screened for the trial ( | PMC9975910 | ||
Flow Diagram of Enrollment, Randomization, and Follow-up of Patients | CDA | CDA indicates combined drug approach. | PMC9975910 | |
Donor, Preservation, and Recipient Demographics | Overall, the 2 study arms were balanced with respect to donor and recipient demographics and baseline characteristics ( | PMC9975910 | ||
Baseline Donor and Graft Preservation Characteristics and Recipient Characteristics | HCC,, death, HCV, hepatitis C, ischemia, NASH, hepatocellular carcinoma, End-stage Liver Disease | HEPATITIS B, VIRUS, CIRCULATORY ARREST, ISCHEMIA, BRAIN DEATH, NONALCOHOLIC STEATOHEPATITIS, CEREBROVASCULAR ACCIDENT, CDA, COLD | Abbreviations: CDA, combined drug approach; CIT, cold ischemia time; CVA, cerebrovascular accident; DBD, donation after brain death; DCD, donation after circulatory death; HBV, hepatitis B virus; HCC, hepatocellular carcinoma; HCV, hepatitis C virus; HTK, histidine tryptophan ketoglutarate; ICU, intensive care unit; IGL, Institut Georges Lopez; LOS, length of stay; MELD, Model for End-stage Liver Disease; NASH, nonalcoholic steatohepatitis; UW, University of Wisconsin.Data are presented as number (percentage) of participants unless otherwise indicated.Time from withdrawal of life-sustaining therapy to start of cold aortic perfusion in the donor (applied only to DCD liver transplants).Time from withdrawal of life-sustaining therapy to circulatory arrest (mean arterial pressure <30 mm Hg).Time between the brain death diagnosis and the cold aortic perfusion.Time between the start of aortic cold perfusion and completion of the donor hepatectomy, when the liver was placed in ice water on the back table.Time between the start of cold aortic perfusion and removal of the liver from cold storage before implantation.Possible score range of 4 to 40, with higher scores indicating a higher risk of mortality at 3 months.Time required for graft reperfusion between the liver leaving the ice water and completion of portal vein anastomosis. | PMC9975910 |
Primary End Point | CDA | In the per protocol analysis, the peak AST level within the first 72 hours following reperfusion was not different in the CDA group compared with the control group both without adjustment for CIT and MELD score (geometric mean, 1262.9 U/L [95% CI, 946.3-1685.4 U/L] vs 1451.2 U/L [95% CI, 1087.4-1936.7 U/L]; geometric mean ratio, 0.87 [95% CI, 0.58-1.31]; | PMC9975910 | |
Primary and Secondary End Points | acute kidney injury, ischemia-reperfusion injury | EVENTS, CDA, BRAIN DEATH | Abbreviations: AST, aspartate aminotransferase; CDA, combined drug approach; DBD, donation after brain death; FAS, full analysis set; IRI, ischemia-reperfusion injury; ND, not determined because of an absence of events in 1 group; PPS, per protocol set analysis.SI conversion factor: To convert AST to μkat/L, multiply by 0.0167.Treatment effect is expressed as the geometric mean ratio. Treatment effect is expressed as the unadjusted odds ratio and 95% CI. In cases with less than 5 events in at least 1 group, the exact 95% CI and exact Treatment effect is expressed as an unadjusted hazard ratio from a Fine-Gray model treating mortality as a competing risk. In each group, the percentage at 1 year derived from the cumulative incidence curve is given.Data were missing for 4 in the CDA group and 4 in the control group.An acute kidney injury score of 1 indicates risk; 2, injury; and 3, failure. The ordinal character of the score was kept (ie, the reported odds ratios and The treatment effect is the Hodges-Lehmann estimator and equals the median of all pairwise differences. Data were missing for 7 each in the CDA and control groups. | PMC9975910 |
Secondary End Points | AKI, postreperfusion syndrome | SURGICAL COMPLICATIONS | There was no difference in the IRI score or frequencies of postreperfusion syndrome, EAD, severe surgical complications, IC, AKI, and acute cellular rejection between arms ( | PMC9975910 |
One-year Cumulative Patient Mortality and Graft Loss in the Combined Drug Approach (CDA) and Control Groups | PMC9975910 | |||
Safety and Adverse Events | CDA, ADVERSE EVENT | A significant difference in the proportion of patients with at least 1 serious adverse event was not observed between groups (10 of 36 [27.8%] in the CDA group and 8 of 36 [22.2%] in the control group; | PMC9975910 | |
Discussion | AKI, biliary complications | CDA, SURGICAL COMPLICATIONS, COLD, SYNDROME | In this RCT, we did not find evidence that an add-on perioperative combination drug regimen delivered to the graft immediately before implantation and to the recipient attenuated the degree of IRI. In addition, no differences were found in postreperfusion syndrome, histological IRI score, liver function, and the frequencies of severe surgical complications, IC, AKI, and acute cellular rejection, and graft and patient survival were similar between groups.These findings were in contrast with those in the proof-of-concept study,Physiological differences between pigs and humans and the highly controlled and reproducible conditions of experimental models as opposed to the variability in IRI severity in the clinical setting may explain why the protective effect observed in pigs was not reproduced in this study of humans. Another factor to explain the discrepancy between the porcine model and this RCT is that the porcine studyPerhaps the design of the CDA, adapted to the clinical setting, may be another plausible explanation for the difference in results. In the proof-of-concept study,To translate the CDA regimen from the experimental to clinical setting, changes in drug composition were made, which may also have contributed to a variability in effect. The different agents, doses, and time regimens were judiciously chosen based on published evidence of their biological efficacy and pharmacokinetics (Recent developments in liver transplantation have included significant progress in the preservation of liver grafts by using dynamic preservation strategies. Preclinical and clinical studies have shown that compared with static cold storage, dynamic preservation allows for a reduction in IRI severity, frequencies of biliary complications and EAD, hospital stay, and graft and patient survival. | PMC9975910 |
Limitations | CDA | This study has some limitations. First, it was a single-center RCT. Second, individual effects of each component of the CDA in decreasing IRI were not assessed separately. As the CDA specifically aims to achieve synergistic effects, the parallel testing of individual drugs was considered not useful and, in the clinical setting, extremely complex given the multitude of possible combinations. Third, despite the fact that CDA components were administrated according to a specific timing in relation to their pharmacokinetic data with the aim to reach a peak concentration during reperfusion, blood levels of each component were not determined. Fourth, although the study was powered to detect differences in peak AST, the small sample size did not allow a claim on the absence of an effect. | PMC9975910 | |
Conclusions | CDA, COLD | In this RCT, we did not find evidence that a combined drug approach targeting the post–cold storage graft and the recipient was sufficient to decrease IRI. Targeting the graft before and/or during preservation may also be necessary. The advent of dynamic preservation may bring the opportunity to combine a downstream CDA in the recipient with upstream conditioning of the donor liver. | PMC9975910 | |
Background | ® | The FAKHRAVAC®, an inactivated SARS-CoV-2 vaccine, was assessed for safety and immunogenicity in a phase II trial. | PMC9951829 | |
Methods | ADVERSE EVENTS | We did a phase II, single-centered, randomized, double-blind, placebo-controlled clinical trial of the FAKHRAVAC inactivated SARS-CoV-2 vaccine on adults aged 18 to 70. The two parallel groups received two intramuscular injections of either a 10-µg vaccine or a placebo at 2-week intervals. The participants' immunogenicity responses and the occurrence of solicited and unsolicited adverse events were compared over the study period of up to 6 months. Immunogenicity outcomes include serum neutralizing antibody activity and specific IgG antibody levels. | PMC9951829 | |
Results | tenderness, headache | ADVERSE REACTION | Five hundred eligible participants were randomly (1:1) assigned to vaccine or placebo groups. The median age of the participants was 36 years, and 75% were male. The most frequent local adverse reaction was tenderness (21.29% after the first dose and 8.52% after the second dose), and the most frequent systemic adverse reaction was headache (11.24% after the first dose and 8.94% after the second dose). Neutralizing antibody titers two and four weeks after the second injection in the vaccine group showed about 3 and 6 times increase compared to the placebo group (GMR = 2.69, 95% CI 2.32–3.12, N:309) and (GMR = 5.51, 95% CI 3.94–8.35, N:285). A four-fold increase in the neutralizing antibody titer was seen in 69.6% and 73.4% of the participants in the vaccine group two and four weeks after the second dose, respectively. Specific ELIZA antibody response against a combination of S1 and RBD antigens 4 weeks after the second injection increased more than three times in the vaccine compared to the placebo group (GMR = 3.34, 95% CI 2.5–4.47, N:142). | PMC9951829 |
Supplementary Information | The online version contains supplementary material available at 10.1186/s12879-023-08079-1. | PMC9951829 | ||
Keywords | PMC9951829 | |||
Introduction | Different vaccine platforms have been used to develop vaccines against SARS-CoV-2 [FAKHRAVAC is an inactivated vaccine that was developed early in the course of the COVID-19 pandemic. The vaccine seed was isolated from Iranian inpatient COVID-19 cases in March 2020 and cultivated using Vero cells. A fast protein liquid chromatography (FPLC) method was used to purify the inactivated viral suspension [Accumulating safety data is the necessary next step in developing new vaccines [ | PMC9951829 | ||
Methods | PMC9951829 | |||
Study design and setting | We did a phase II, single-centered, randomized, double-blind, parallel groups, placebo-controlled clinical trial of FAKHRAVAC inactivated SARS-CoV-2 vaccine on adults aged 18 to 70. The study protocol was approved by the National Ethics Committee for Research in Medical Sciences (approval number IR.NREC.1400.003, June 8, 2021). The trial was registered in the Iranian Registry of Clinical Trials [ | PMC9951829 | ||
Participants | malignancy, allergic diseases | MAY, DISEASES, RECRUITMENT | Participants were enrolled through a website between May and July 2021. Following declaration of willingness to participate in the trial and an initial online screening, potentially eligible volunteers were invited to attend the trial unit for further psychological, clinical, and laboratory evaluations and to sign a written informed consent. At the psychological assessment session, the participants’ mental capability to give consent was assessed before proceeding with the rest of the trial. Major inclusion criteria were age between 18 and 70 with negative serology (anti-nucleocapsid antibody) and no clinical history for COVID-19, and negative RT-PCR test at the time of recruitment. Major exclusion criteria were pregnancy, breastfeeding, history of allergic diseases and reactions, having any active uncontrolled diseases, malignancy, and close contact with a person with confirmed COVID-19 for a maximum of 2 weeks before the screening day. A detailed description of eligibility criteria has been presented in the Study protocol [Additional file | PMC9951829 |
Randomization and masking | CRF | CRF | We used permuted block randomization to allocate eligible participants to the vaccine and placebo groups. Block sizes of four were used and each block contained an equal number of alternative interventions. Rand function in excel was used to generate the random sequence within each block. Randomly generated four-digit unique numbers called “randomization codes” were used to conceal the randomization sequence. An independent study epidemiologist created the random sequence and had access to it for emergency unblinding. The identical vaccine and placebo single-injection vials were labeled using the randomization codes. These codes were also embedded in the study software and successively assigned to the eligible participants, once they successfully pass all the stages before receiving the injection and their eligibility for enrollment was confirmed by the research physician. Therefore all participants and the research team were blinded to the study group allocation.We used a pair of unique codes to label every blood specimen collected for immunogenicity assessment. One of the pairs was put on the paper Case Report Form (CRF) in its relevant field, indicating the type and timing of the immunogenicity test, and the other was on the collection tube. The label used on the collection tube is concealed behind a scratch label and should be revealed by lab offices. The key to the pair was created and kept by the study epidemiologist. | PMC9951829 |
Procedures | ADVERSE EVENTS | Participants received two intramuscular injections of either a 10-µg vaccine or a placebo (an adjuvant-only preparation) at 2-week intervals. FAKHRAVAC inactivated vaccine was made of SARS-CoV-2 strains isolated from the oropharyngeal Swabs of Iranian hospitalized patients replicated using Vero cells (Cat. # 88020401), a WHO-approved cell line for vaccine production. Aluminum sulfate was used as the adjuvant. The participants' immunogenicity responses and the occurrence of solicited and unsolicited adverse events were assessed over the study period of up to 6 months (see Additional file | PMC9951829 | |
Outcomes | diarrhea, fatigue, nausea and vomiting, erythema, pain, muscle pain, headache, tenderness, anaphylactic reactions | ADVERSE EVENT, VIRUS, ANAPHYLACTIC REACTION, ADVERSE EVENTS, ERYTHEMA, SECONDARY, HAND SWELLING, ADVERSE REACTION | Our primary safety outcomes were immediate anaphylactic reactions following vaccination and local and systemic adverse events during the week after receiving each vaccine/placebo dose. Participants were kept under close observation in the trial unit for 3 h following vaccination and their vital signs were monitored hourly. Participants were provided with a mobile application to record their daily pre-specified local (pain, tenderness or pain when the injection site is touched, erythema, and swelling or stiffness) and systemic (nausea and vomiting, diarrhea, headache, fatigue, and muscle pain) adverse events up to a week and received daily text reminders to do so. Those who did not complete the relevant forms on the application were contacted and the information was collected by telephone. (see Additional file Our primary and secondary immunogenicity outcomes were serum ELIZA IgG level for SARS-CoV-2 S1-RBD antigen and serum neutralizing activity measured by conventional virus neutralization test two and four weeks after the second injection, respectively. The measurements were repeated three and six months after the first vaccination. Serum lymphokines, including IL6 and other immunologic indices, were assessed in the peripheral blood before and after vaccine/placebo injections. Secondary safety outcomes included laboratory evaluations 1 week after the first (all participants) and second (above 55 year-olds only) injections. Serious Adverse Events (SAEs), Suspected Unexpected Serious Adverse Reaction (SUSARs) and, Medically Attended Adverse Events (MAAEs) were also monitored for up to 6 months [for further details see Additional file | PMC9951829 |
Statistical analysis | Based on expert opinion, a sample of 500 volunteers was used for phase II (for participants flow diagram and exclusions see Fig. Participant flow diagram of participants | PMC9951829 | ||
Role of funding source | The sponsor conducted the immunogenicity tests. The research team coded the serum specimens and concealed their labels before sending them to the lab. The sponsor had no role in data collection, management, analysis, interpretation, and writing of the report. | PMC9951829 | ||
Discussion | ®, COVID-19 disease | ADVERSE EVENTS, DISEASE, ADVERSE REACTION, ASYMPTOMATIC COVID-19 | We found that the 10-µg FAKHRAVAC inactivated SARS-CoV-2 vaccine elicited significant neutralizing antibody response about six times the placebo group (and nine times to the baseline) four weeks after the second dose. Specific antibodies against S and RBD using the ELIZA method also showed a more than three times increase to the placebo and about six times to the baseline. No suspected unexpected serious adverse reaction (SUSAR) was observed in study participants during the follow-up period of up to 6 months. The three hospitalized COVID-19 cases occurred in the placebo group. All abnormal laboratory findings 1 week after each injection were resolved completely.The follow-up period in our study was 6 months according to the protocol. During this period we collected all medically attended adverse events among study participants and assessed their relationship to the study intervention. However, as COVID-19 vaccines became available for the Iranian general population, it was unethical to deprive the placebo group of the COVID-19 national vaccination programs. Therefore the placebo group in our study were followed for a time period about half the vaccine group.Local and systemic reactogenicity in the first week after the injections were relatively low compared to other inactivated vaccines [We observed a significant neutralizing antibody response in the conventional Virus Neutralization Test (cVNT) two and four weeks after the second dose in the vaccine group compared to the placebo (see Table We showed that FAKHRAVAC elicited a significant immunogenicity response after two doses. Although this does not necessarily translate into the clinical efficacy of the vaccine, there are hints that this may be true. We identified 22 cases of symptomatic PCR-positive COVID-19 disease occurring 2 weeks after the second dose, 8 in the vaccine and 14 in the placebo groups (see Additional file Our study had also some limitations. First, we were unable to continue the follow-up of the placebo group beyond 3 months because approved COVID-19 vaccines became available for the Iranian general population. Second, the number of participants over 50 in our study is relatively low, and the data does not include people over 70, who are an important target population in the vaccination against COVID-19. Third, we did not compare neutralizing antibody titers in our study with that of the convalescent serum samples as positive controls, which could have provided clues to the magnitude of the antibody responses.In summary, we found that the 10-µg/dose FAKHRAVAC® inactivated SARS-CoV-2 vaccine is safe and induces a significant humoral immune response in adults aged 18–70. A future phase III clinical trial is needed to find out if this observed immunogenicity will translate into clinical efficacy in preventing symptomatic COVID-19 disease. | PMC9951829 |
Acknowledgements | This work was supported by the Milad Daro Noor Pharmaceutical (MDNP) Company. The immunology lab and all other research staff involved in collecting and examining blood samples taken for immunogenicity assessment were masked to the identity of the participants and the allocated interventions. The study was overseen by an independent data and safety monitoring board. | PMC9951829 | ||
Author contributions | ASH | AA: MSD: Conceptualization, methodology, data Curation, visualization. PB, MM, AJ, FGH, KG, AA, MA, ZR, MSD: Writing original-draft preparation, writing—review and editing, methodology, project administration, supervision, conceptualization. RHF, AKR, KN, MF, SGH, PKH, MH, SKH, MSH, HM, SM, BSH, HA, AM, AKH: Resource. HB, ZT, MKN: Project Administration. FGH, MA, AA, MSD, ASH, KG: Software, formal analysis, validation, project Administration, project administration, investigation. All authors read and approved the final manuscript. | PMC9951829 | |
Funding | Milad Daro Noor Pharmaceutical (MDNP) Company provided the funding for this study and the logistics for study conduct but had no role in data management, analysis, interpretation, or writing the report. The grant number of this study is not applicable. | PMC9951829 | ||
Availability of data and materials | Data are available on reasonable request. Individual participant data will be made available when the trial is complete on requests directed to the corresponding author; after the approval of a proposal, data can be shared through a secure online platform. | PMC9951829 | ||
Declarations | PMC9951829 | |||
Ethics approval and consent to participate | The trial was conducted in accordance with the 1964 Helsinki Declaration and its later amendments. The clinical trial protocol was approved by the Iranian National Ethics Committee for research (approval number IR. NREC.1400.003, 7th June 2021). Informed consent was obtained from all participants. | PMC9951829 | ||
Consent for publication | Not applicable. | PMC9951829 | ||
Competing interests | ASH | SGH, PKH, MH, SKH, MSH, HM, SM, BSH, HA, AM, and AKH are employees of Milad Daro Noor Pharmaceutical (MDNP). MSD is an Iran University of Medical Science (IUMS) employee. MSD, AA, MA, ASH, ZR, FGH, and KG are members of the clinical trial center of the Iran University of Medical Science that acted as academic CRO. All other authors declare no other competing interests. | PMC9951829 | |
References | PMC9951829 | |||
Aim | tremor | The purpose of this study was to determine whether a low-tremor side-bridge exercise for 4 weeks improves bow tremor during archery movements. | PMC10150967 | |
Methods | tremor | Participants were 20 male college students. First, we measured the tremor during side bridges performed with trunk inclinations of 25°, 40°, 55°, and 70° using an accelerometer attached to the elbow joint and identified low-tremor side bridges. The participants were then randomly divided into intervention and non-intervention groups, and the low-tremor side bridges were performed for 4 weeks. | PMC10150967 | |
Results | tremor | The effect of the intervention was determined by measuring the total tremor value using an accelerometer attached to the bow and changes in the median power frequency (MdPF) of the middle deltoid, upper trapezius, and lower trapezius. This intervention reduced the bow tremor and the median power frequency of the middle deltoid (p < 0.05). | PMC10150967 | |
Conclusions | tremor | The findings suggested that the tremor during the archery sighting phase could be reduced by performing side bridges with a specific trunk angle for a certain period of time. This intervention was also shown to reduce the intermediate frequency of the middle deltoid. The reduced tremor can shorten the sighting phase, which can facilitate injury prevention. | PMC10150967 | |
Data Availability | All relevant data are within the manuscript and its | PMC10150967 | ||
Introduction | bowstring, tremor, shoulder girdle, tremors | SAID | Archery is a sport enjoyed by millions of people of all ages and abilities worldwide, including people with physical mobility limitations in adaptive recreational or school physical education programs [An archery shot primarily consists of three phases: 1) the stance phase; 2) the arming phase, during which the archer pulls the bowstring and pushes the bow; and 3) the sighting phase, which involves the final stretching of the bow while focusing on the target [In Japanese high schools, side-bridge exercise is performed to train the shoulder joint and shoulder girdle muscles of the pusher. This exercise resembles the shooting posture in archery and can be said to be an archery-specific exercise. Archers perform this exercise with their hands on the floor, and arm tremors often appear immediately after the start of the exercise. The tremor that appears during movement is associated with muscle activity and is caused by fatigue-related neural and mechanical mechanisms [To address this issue, we hypothesized that an analysis of arm tremors during side-bridge exercise performed under several levels of trunk inclination can reveal a threshold inclination that will exercise the slow muscle fibres associated with the tremor in archery, and that regular side-bridge exercise under these conditions will target the type of muscle fibres that are active during the sighting phase and reduce the tremor of the arm or bow. While this information is of inherent physiological interest, it can also improve the techniques currently employed in archery coaching.Therefore, in this study, we first examined various side-bridge angles to determine the extent of trunk inclination that can be performed without the appearance of arm tremor during the side-bridge exercise. Then, we conducted a randomized controlled trial involving side-bridge exercise at the previously determined trunk inclination over a 4-week period to verify whether it improved bow tremor during archery movement. The preliminary hypotheses were that a larger trunk inclination angle during the side-bridge exercise would result in greater arm tremors, and that repetitive performance of the side-bridge exercise with a trunk inclination that did not cause tremors would reduce bow tremor during the sighting phase in archery. | PMC10150967 |
Materials and methods | PMC10150967 | |||
Participants | injuries, dislocation, collegiate, pain | Twenty male collegiate students (20.8 ± 0.3, range: 20–23) participated in this study. All participants were inexperienced in archery. A completed and signed informed consent form was obtained from each participant before the study. The study protocol was approved by the Ethics Committee of the Takarazuka University of Medical and Health Care (No. 1805091), and all participants provided written informed consent. Participants were excluded if they had a history of dislocation of the shoulder, shoulder surgery, current symptoms related to the cervical spine, documented structural injuries to the shoulder complex, regular exercise habits, or hard training. Participants who reported any pain and/or discomfort in the upper extremities during the experiment were also excluded from the study. Participants were randomly assigned to the exercise and non-exercise groups using a lottery. Information on the participants in each group is presented in | PMC10150967 | |
Characteristics of the participants in this study. | PMC10150967 | |||
Archery task | bow-side shoulder joints, abduction | All 20 participants used a 9-kg (20 lb.) bow to perform archery shooting. The posture in this task was set to 90° abduction of bow-side shoulder joints ( | PMC10150967 | |
Posture during archery task. | A is the frontal plane and B is the horizontal plane. | PMC10150967 | ||
Selection of trunk inclination during the side-bridge exercise | tremor | Eleven participants were included in this study. The side bridge exercise was performed for 15 seconds in each of the four conditions and arm tremor was analysed. Since all participants were right-handed, they performed the exercise with their left hand holding a bow during archery shooting. For all side-bridge exercises, the bow-side shoulder joint was abducted at 90°, and the elbow joint was extended at 0°. The four side-bridge conditions involved trunk inclinations of 25° ( | PMC10150967 | |
Four conditions used in the side-bridge exercise. | Cond1, cond2, cond3, and cond4 represent trunk inclinations of 25°, 40°, 55°, and 70°, respectively. | PMC10150967 | ||
Exercise intervention | The intervention group exercised 5 days a week for 4 weeks, for a total of 20 days. The exercise was a side bridge performed with a trunk inclination of 40°, which was judged to be the most effective of the four side-bridge exercises (Figs | PMC10150967 | ||
The side-bridge exercise performed in the intervention. | The height of the Bow-side hand was adjusted and the trunk inclination angle was 40 degrees. A non-slip mat was used for the floor and the stand. | PMC10150967 | ||
Data analysis | PMC10150967 | |||
Analysis of tremor | tremor | For the Bow tremor measurement, the accelerometers were fixed to the handle with taping. To measure arm tremor, the accelerometers were fixed to the lateral epicondyle of the humerus with taping. Bow and arm tremor were measured using accelerometers (OE-WS2521; Oisaka, Hiroshima, Japan) fixed to the handle of the bow by taping. This device is an integrated accelerometer and surface EMG sensor that is also used to measure muscle activity.The accelerometer and EMG data obtained in this study were analyzed using Python (version: 3.10.6, packaged by conda-forge), pandas (version: 1.4.3), numpy (version: 1.22.4), matplotlib (version: 3.5.3), scipy.stats (version: 1.9.0), and scikit_posthocs (version: 0.7.0). The sampling frequency was 1 kHz, the sampling time was 15 seconds, and the obtained acceleration data (If the measurement time is Since the Fast Fourier Transform algorithm to be used later includes butterfly operations, the sample size to be analyzed should satisfy (3) when the natural number is N. The sample size for analysis is smaller than the measured sample size. In other words (4), which must be smaller than the measured sample size (15000). In the case of this study, the maximum value satisfying (3) and (4) is 8192 (= 2The data for the intermediate 8.192 s were converted into frequency data using a fast Fourier transform (FFT) (5, 6); and the power spectrum was calculated. The sum of the values in the 3–18-Hz frequency band was analysed as the tremor value. The programming code used for the analysis is attached in the ( | PMC10150967 | |
Muscle activity analysis | Bipolar surface electrodes (OE-WS2521; Oisaka, Hiroshima, Japan) were placed on three scapulothoracic muscles (the upper and lower trapezius and the serratus anterior) and a scapulohumeral muscle (deltoid middle) in accordance with previously published standardized methods [The frequency band for the analysis was 1–1000 Hz. Since the measured values are affected by electrode position and skin temperature, photographs of the target site were taken before and after the intervention, and the measurements were performed at the same sites, with the measurements for all muscles obtained simultaneously [ | PMC10150967 | ||
Statistical analysis | Statistical analysis was performed using the Statistical Package for the Social Sciences (SPSS Inc., Chicago, IL, USA) version 20.0 J for Windows®. The Steel-Dwass method was used for statistical evaluations. The baseline values of the intervention and the non-intervention groups were compared using Welch’s t-test. A paired t-test was performed before and after the training intervention. The effect size (d) was calculated from the baseline and the values after 4 weeks in the intervention and non-intervention groups. The probability level accepted as the criterion for statistical significance was set at 5%. | PMC10150967 | ||
Results | PMC10150967 | |||
Verification of optimal trunk inclination at the time of the side-bridge exercise | tremor | The arm tremor values were 0.00022 ± 0.00018(m/s | PMC10150967 | |
Comparison of tremors during side-bridge exercise. | PMC10150967 | |||
Comparison of baseline values between the intervention and non-intervention groups | tremor | The baseline age, height, body weight, and BMI were not significantly different between the intervention and non-intervention groups. The two groups also showed no significant differences in baseline tremor intensity and MdPF values for the middle deltoid, upper trapezius, lower trapezius, and serratus anterior muscles ( | PMC10150967 | |
Comparison of values before and after the intervention | tremors | Measurements obtained during shooting movements at baseline and after 4 weeks in the intervention group were compared, and significant differences were observed in the intensity of tremors and the MdPF of the middle deltoid ( | PMC10150967 | |
Comparison between the findings at baseline and 4 weeks in the intervention group. | PMC10150967 | |||
Comparison between the findings at baseline and 4 weeks in the non-intervention group. | PMC10150967 | |||
Discussion | abduction of the shoulder joint, tremor, Tremors, tremors, muscle hypertrophy | In the arming phase of archery shooting, fast muscle fibre activity is required to pull the strings strongly, and in the sighting phase, the target must be aimed while keeping the strings pulled out. In this study, we hypothesized that the activity of slow muscle fibres was necessary to reduce bow tremor in the sighting phase and identified an exercise and verified its effect by performing randomized controlled trials. A comparison of the exercise methods under the four conditions showed that the side bridge exercise, in which the trunk is tilted 40°, is the condition with the least tremor and the greatest trunk inclination. Therefore, we hypothesized that a side bridge at a 40° inclination could be performed with less tremor in the sighting phase and examined the effect of 4-week training with this exercise on tremor.The results suggested that exercises aimed at reducing tremors during the shooting action in archery are effective when the exercise itself is performed with a load that does not cause tremors to appear. The participants also showed a reduction in the MdPF of the middle deltoid after 4 weeks of exercise. Thus, side-bridge exercise performed with a trunk angle adjusted to avoid the appearance of tremors appeared to reduce the tremor in the sighting phase of archery and also changed the activity of the middle deltoid muscle. The activity of motor units that control slow muscle fibres has been shown to mainly reflect low-frequency components, while that of fast-muscle fibres reflects high-frequency components [Previous studies have shown that nervous system factors change up to 4 weeks after the commencement of exercise, and that muscle hypertrophy causes muscle strengthening 8 weeks after starting the exercise [Tremors can be divided into rest and action tremors based on their occurrence, and tremors that occur during exercise can be classified into postural, isometric, and kinetic tremors [The exercise performed in this study can be performed with 90° abduction of the shoulder joint, which is the same as the archery target posture, and the angle of the side-bridge exercise is defined from the trunk inclination, making it a completely new exercise unlike the previously performed side bridge. In addition, the exercise duration was set to 1 min per set, and five sets were performed. In previous studies, male college students were reported to perform a side bridge for an average period of 97 s, and in other previous studies, the exercise was performed as long as possible [The limitations of this study are as follows. First, the participants were not professional archers; therefore, the effectiveness of the intervention exercise on the actual shooting movements of professional archers was unclear. However, to verify the effect of an exercise in one sport, it is desirable to assess the exercise in participants who do not perform other sports, and the present study met this criterion. Second, the side-bridge exercise assessed in this study was performed at a trunk angle at which tremor did not occur, but it was unclear which of the other tremor-inducing conditions was the most effective in reducing tremors. Among the exercise conditions evaluated in this study, cond4 can be excluded because it is difficult to perform and it is difficult to set the exercise time for this condition. Third, the effect of the exercise was judged solely on the basis of the information obtained by the accelerometer and the electromyogram, and the related physiological changes are unknown. The muscles evaluated in this study were the four muscles around the shoulder joint. Since side-bridge exercise is also used for core muscle training, other muscle groups may have influenced the results of this study, but their influence could not be determined from the results of this study. | PMC10150967 | |
Conclusions | tremors, trauma | The findings of this study may provide an effective training method for athletes who cannot control their tremors during shooting movements, such as beginner archers and those experiencing yips. In future research, we would like to verify the appropriate load, such as the angle of the trunk and exercise time for actual competitive archers, and to verify the effect of the intervention in improving performance and preventing trauma. | PMC10150967 | |
Supporting information | PMC10150967 | |||
Selection of trunk inclination during the side-bridge exercise. | The code was written using Python.(TXT)Click here for additional data file. | PMC10150967 | ||
Exercise intervention. | The code was written using Python.(TXT)Click here for additional data file.The authors express their appreciation to Mr. Atsuhiro Toda and Mr. Shinji Kanegawa for supporting this research. We would like to thank Editage ( | PMC10150967 | ||
References | PMC10150967 | |||
1. Introduction | cardiovascular and/or metabolic diseases, death, hypertensive, cardiovascular or metabolic disease | DISEASES, HIGH BLOOD PRESSURE, CARDIOVASCULAR DISEASE, HBP | Background: High blood pressure is an important public health problem due to its high prevalence, the difficulty to control it, and its high contribution to morbidity. A series of changes may be linked to the aging process, compromising cardiac conduction, and reducing cardiovascular baroreceptor function. Advancing age promotes a decline in heart rate variability and this decrease can increase the probability of cardiovascular disease. The aim of this study was to analyze the autonomic modulation of heart rate in hypertensive elderly individuals during and after a session of aerobic exercise, and to compare it with elderly individuals without cardiovascular or metabolic disease. Our study was a non-randomized controlled study with hypertensive elderly (HBP group) and elderly without cardiovascular and/or metabolic diseases (control group). Data on blood pressure and heart rate variability (HRV) were collected before, during, and after 30 min of aerobic physical exercise on a treadmill. There was a reduction in HF (msCardiovascular diseases are still the biggest cause of death in the world. High blood pressure (HBP), one of the main causes, has been the focus of global health policies to improve populations’ survival. HBP is an important public health problem due to its high prevalence, difficulty in controlling it, and its high cause of morbidity [With advancing age, the increase in blood pressure has been related to damage to the mechanisms of the autonomic nervous system and the practice of aerobic physical exercise represents an adequate intervention to combat such changes [Aerobic training (AT) consists of a wide range of exercises practiced around the world by the elderly, and it has been proposed as a tool to improve the baroreceptor reflex and vagal modulation, resulting in an improvement in heart rate variability (HRV) after physical activity [The reactivation of parasympathetic activity can be measured by heart rate recovery (HRR), which is the reduction in heart rate (HR) after physical activity. The HRR can be an important predictor of mortality risk due to its importance in reducing sympathetic activity triggered by exercise [A series of changes can be linked to the aging process, including compromised cardiac conduction and reduced cardiovascular baroreceptor function [HBP has been linked with loss of autonomic modulation of HR, characterized by sympathetic dominance and often by a reduction in the vagal component, which leads to a decrease in HR and blood pressure variability [Our study aimed to analyze the autonomic modulation of heart rate in hypertensive elderly individuals during and after an aerobic exercise session, and to compare it with elderly individuals without cardiovascular or metabolic disease. | PMC9859152 |
2. Materials and Methods | PMC9859152 | |||
2.1. Study Design | knee osteoarthrosis, musculoskeletal disorders, cardiovascular and/or metabolic diseases, neurological diseases, cardiovascular and/or metabolic disease | CARDIAC EVENT, NEUROLOGICAL DISEASE, LUNG DISEASE, HBP, KNEE OSTEOARTHROSIS, LUNG DISEASES, RECRUITMENT, PULMONARY DISEASES, MUSCULOSKELETAL DISORDERS, HIGH BLOOD PRESSURE, HYPERTENSIVE CRISIS | Our study was a non-randomized controlled study conducted from June 2014 to June 2016 in a rehabilitation clinic for the elderly, located in the state of São Paulo, Brazil, where participants already practiced regular physical activity (practice light or moderate intensity physical activities for about 20 min a day). We adopted the Risk of Bias In Non-randomized Studies of Interventions (ROBINS-I) tool to reduce the likelihood of bias.Participants were recruited from an elderly rehabilitation clinic. All 100 elderly patients in the clinic were invited to participate. In total, five patients refused to participate in our research. A total of 95 elderly people were included, but five were excluded. Of those who were excluded from the HBP group, two had lung disease, while three were excluded from the control group because they had knee osteoarthrosis that made it impossible for them to walk properly on a treadmill. Although 90 participants were allocated in 2 groups (45 in each group), only 42 individuals in each group completed the study. In the HBP group, three participants reported health problems on the day of the testing procedure and three in the control group did not attend the clinic after recruitment (Elderly people were invited to be part of the intervention and control groups. All elderly people were assessed as active according to their level of physical activity, measured by the short version of the International Physical Activity Questionnaire (IPAQ).We split all participants non-randomly into two groups: a group without cardiovascular and/or metabolic diseases called the “Control Group” (CG), and another group diagnosed with high blood pressure (the HBP Group). Outcomes were measured before, during, and after 30 min of aerobic exercise on a treadmill.Inclusion criteria for the HBP group included: (1) diagnosis of cardiovascular and/or metabolic disease, (2) HBP controlled with medical clearance for physical activity, (3) practice of regular physical activity, (4) age over 65 years old, and (5) signing of the informed consent form. For the control group, the inclusion criteria included: (1) no diagnosis of cardiovascular and/or metabolic diseases, (2) practice of regular physical activity, and (3) age over 65 years old. Exclusion criteria for the CG included: (1) lung diseases, (2) concomitant neurological diseases, (3) the presence of musculoskeletal disorders that did not allow the use of a treadmill, and (4) the use of any medication that could alter autonomic modulation. Exclusion criteria for the HBP group included: (1) pulmonary diseases, (2) concomitant neurological diseases, (3) the presence of musculoskeletal disorders that did not allow the use of a treadmill, and (4) any recent cardiac event or a hypertensive crisis. They took diuretics and renin-angin-aldosterone system inhibitors, while some individuals used a combination of the two drugs. None of the study subjects took antidepressants.Our study followed the Brazilian regulations on human subject protection contained in Resolutions 466/12 and 251/97 of the National Health Council. It was approved by the Institutional Review Board of the ABC Medical School (CAEE protocol 02830612.1.0000.0082/#108.260). Brazilian Registry of Clinical Trials (REBEC): #RBR-5mgrttm.Flow chart of the study design. | PMC9859152 |
2.2. Instruments and Data Collection | After signing the Informed Consent Forms, an anamnesis form was used to measure anthropometric variables such as weight and height, and clinical history.We controlled the ambient temperature (between 21 °C and 23 °C) and humidity (between 40 and 60%), and prepared the equipment before participants arrived at the testing location. Patients were weighed on an electronic scale with a capacity of up to 150 kg and subdivisions of up to 10 g, without shoes and wearing as little clothing as possible. To measure height, patients placed their heels, calves, buttocks, and shoulders against the wall, positioning their heads according to the Frankfurt plane. We used a wall-mounted stadiometer with subdivisions in centimeters and millimeters [After this first evaluation, the IPAQ was administered. The IPAQ is a scale validated in Brazil and proposed by the World Health Organization in 1998 that is used as a global instrument to determine the population level of physical activity [Initially, measurements of systolic (SBP) and diastolic (DBP) blood pressure and heart rate were collected. SBP and DBP data were obtained as a single measurement, indirectly verified by means of a Welch Allyn aneroid sphygmomanometer positioned in the subject’s left arm and a Littmann-3M Classic II stethoscope over the median region of the antecubital fossa. To measure the respiratory rate, a stopwatch was used to count how many thoracic incursions the patient made in one min. HR was recorded using a Polar brand S800CX heart rate monitor. The capture strap was placed in the chest of participants, and the heart rate receiver watch (RS800CX, PolarAfter placement of the strap and monitor, participants were kept in the supine position and remained at rest for 10 min for baseline HRV capture. Data collection was performed from 1 p.m. to 4 p.m. to avoid changes arising from the circadian cycle in the HRV. After data collection, the heart rate monitor was connected to a wireless receiver computer and the data were transferred to an HRV analysis program (Polar Trainer 5) [We conducted our analysis using the Kubios HRV analysis software (version 2.0.; Kuopio, Finland—University of Eastern Finland—After digital filtering, the signal was divided into five moments “Rest” originated from a period of 10 min of rest and “exercise” counted as 20 min of the exercise period, that is, the first and last five mins of the 30 min of exercise were disregarded. This cut was made to remove the warm-up and deceleration period of the heart rate, characterizing only the exercise period in the elderly aerobic training zone. “Recovery” consisted of the patient’s recovery period post-exercise. The heart rate variability in this recovery period was divided into three new periods: first (Recovery 1 or R1) within the initial five mins of recovery, second (Recovery 2 or R2) between the tenth to the fifteenth min, and third (R3) from the twenty-fifth to the thirtieth min [Patients after a 10-min rest were directed to aerobic training (5-min jogging and 25-min running) on a treadmill for 30 min, maintaining the stipulated training heart rate (70% of the maximum HR). After 30 min, participants were directed to rest in the supine position for another 30 min for the data collection on their recovery time. | PMC9859152 | ||
2.3. Analysis of Heart Rate Variability | PMC9859152 | |||
2.3.1. Time Domain (TD) | In the time domain, the statistical parameters used to determine the corresponding RR intervals at any point in time [The triangular index (RRTri) was calculated from a density histogram of the normal RR intervals. The RRtri index was calculated from the density histogram of the normal RR intervals, obtained by dividing the integral of the histogram by the maximum density distribution, i.e., the modal frequency of RR intervals [The triangular interpolation of RR intervals (TINN) is the baseline width of the distribution measured as the base of a triangle, approximating the distribution of all RR intervals, in which the least squares difference was used to determine the triangle [ | PMC9859152 | ||
2.3.2. Frequency Domain (FD) | We used the spectral components low frequency (LF), high frequency (HF) in ms squared, and LF/HF ratio for the analysis of HRV in the frequency domain. To obtain the spectral indices, the frequency tachogram undergoes mathematical processing and creates a graph that expresses the variation of RR intervals as a function of time [ | PMC9859152 | ||
2.4. Statistical Analysis | HBP | Data are presented as group mean values and standard deviations. A multivariate analysis of variance (MANOVA) was used to analyze differences between study groups in all baseline variables. ExcelANOVA analysis of dependent variables were used for the HBP and control groups by five moments (rest, exercise, R1, R2, and R3) with repeated measures on the last factor. Post-hoc comparisons were carried out using the Tukey-HSD (Honest Significant Difference) test. Bonferroni corrections were not necessary because our two-by-two study design did not demand multiple testing. The significance level was set at | PMC9859152 | |
3. Results | HIGH BLOOD PRESSURE, HBP | There were 84 participants into the study, 42 in the control group and 42 in the HBP group. Baseline characteristics of those groups are described in MANOVA revealed significant effects for groups [Wilks’ lambda = 0.220, F12, 71 = 20.94, The main effect for groups was found only for mean RR, suggesting that the mean RR was higher for the HBP group than for the control group (m = 845 ± 119 ms vs. m = 787 ± 120 ms; The main effects for moments occurred in all frequency domain indexes, suggesting that the comparison between rest and exercise, R1, R2, and R3 had significant differences. The main effects for the group were not found for LF (msComparative analysis of HRV (SDNN, TINN, RRTri, and RMSSD) during rest, aerobic exercise, and recovery. MANOVA test (Mean ± SD), HBP (high blood pressure group), Control (Control Group), (R1) recovery period 1—first 5 min of the recovery period, (R2) recovery period 2—between the 10th and 15th min of the recovery period, (R3) recovery period 3—between the 25th and 30th min of the period recovery, (ms) ms, (SDNN) standard deviation of all normal RR intervals recorded at an interval of time, (bpm) beats per min, (RMSSD) root mean square of the square of differences between adjacent normal RR intervals in an interval of time, (TINN) triangular interpolation histogram of RR intervals, (RRtri) triangular index, and (SD) standard deviation. (a) Post hoc test found differences when comparing rest with exercise, (b) post hoc test found differences when comparing rest with R1, (c) post hoc test found differences when comparing rest with R2, (d) post hoc test found differences when comparing rest with R3, and (e) post hoc test found differences when comparing R1 with R3.The main effects for moments occurred again in all geometrical indexes, except in the TINN (Comparative analysis of HRV (SD1, SD2, SD1/SD2 and HF) during rest, aerobic exercise, and recovery. MANOVA test (Mean ± SD), HBP (high blood pressure group), control (control group), (R1) recovery period 1—first 5 min of the recovery period, (R2) recovery period 2—between the 10th and 15th min of the recovery period, (R3) recovery period 3—between the 25th and 30th min of the period recovery, (SD1) standard deviation of the variability instantaneous beat-to-beat or dispersion of points perpendicular to the line of identity, (SD2) standard deviation of long-term continuous RR intervals or dispersion of points along the line of identity, (SD1/SD2) ratio scatter of points perpendicular to the dispersion line identity of dots along line identity, percentage of adjacent RR intervals with a difference of duration greater than 50ms, (%) percentage, and (HF) high frequency component. (a) Post hoc test found differences when comparing rest with exercise, (b) post hoc test found differences when comparing rest with R1, (c) post hoc test found differences when comparing rest with R2, (d) post hoc test found differences when comparing rest with R3, and (e) post hoc test found differences when comparing R1 with R3. | PMC9859152 | |
4. Discussion | impairment of the HRV, cardiovascular and metabolic diseases, hypertensive, cardiovascular or metabolic pathologies, hypertension | HBP, CARDIOVASCULAR DISEASES, METABOLIC DISEASES, EVENTS, HYPERTENSION, HIGH BLOOD PRESSURE | The interpretations of our results suggest that there was no difference in the autonomic modulation of HR between the elderly participants without cardiovascular and metabolic diseases (the control group), and the hypertensive group. However, there was a reduction in parasympathetic modulation between the pre-exercise moment (rest) and the five mins of recovery in the control group. Although we hypothesized that the autonomic modulation of heart rate in hypertensive participants would be lower than that of participants without cardiovascular or metabolic pathologies, our results show that the elderly in the control group had greater parasympathetic modulation (RMSSD, HF, and SD1) of HR 30 min post-exercise compared to the initial mins of recovery. Furthermore, there was no difference in the global variability of HR between participants without cardiovascular and metabolic diseases and those with hypertension. The aging process causes reductions in the parasympathetic activity of the heart, a fact that promotes a decrease in heart rate variability indices [In our study, elderly participants with hypertension and those without cardiovascular and metabolic diseases had similar global HR variability indices (SDNN, RRTri, TINN, and SD2), with no differences in parasympathetic modulation indices (RMSSD, HF, PNN50, and SD1). Distinct results were described by Andrade et al. [Perhaps the difference between the two study results may be explained by the intensity of physical activity by the elderly with hypertension in each study because physical training can normalize the sympathetic autonomic modulation and balance the sympathovagal system, which may positively affect the prognosis of cardiovascular diseases [Masroor et al. (2018) found that in sedentary hypertensive women, four weeks of combined aerobic training with exercises performed at 50–80% of the maximum heart rate, HR training similar to that in our study, was associated with an increase in HF and RMSSD, and a decrease in LF/HF, demonstrating improvement in cardiac autonomic control. Furthermore, combined aerobic and resistance training promoted significant improvement in HRV parameters, indicating vagal dominance in middle-aged hypertensive women [Within the context of physical activity, it is essential to verify not only the heart rate response at the beginning of exercise, which expresses the integrity of the vagus nerve, but also the recovery of HR in the post-exercise moments, because it provides important prognostic information. After all, individuals who have slow HR recovery in the initial mins post-exercise have a high risk of mortality [We found that during the initial 5 min of recovery (R1), the elderly without high blood pressure and metabolic diseases showed a decrease in parasympathetic modulation (HF and SD1) in relation to rest, but those parameters were restored to levels like those at rest only after 30 min post- exercise. In addition. we observed that the HF interacted between groups and moments (The control group had lower parameters associated with global variability in the five mins of recovery (SDNN, RRTri, and TINN), which remained small even after 30 min of recovery, compared to the rest moment. However, there was an increase in SD1/SD2 indices at 30 min post-exercise. On the other hand, the elderly without hypertension and metabolic diseases did not recover from the increase in sympathovagal balance, with LF/HF indexes higher than at rest, even 30 min after exercise, and had a decrease in cardiac autonomic modulation. Differences found during the post-exercise recovery period were described in a study that evaluated the impact of aerobic exercise on heart rate variability in male adults with a mean age of 20 years. The authors reported that heart rate gradually decreased during recovery without reaching pre-exercise values within 30 min post-training, they also found that there was a gradual increase in HRV and that the time and frequency domain indices continuously increased during recovery but remained at reduced values compared to supine rest for at least 30 min [Regarding the sympathovagal balance, elevation of the LF/HF index in individuals who do not have high blood pressure may be associated with increase in blood pressure during the performance of activities, with impairment of the HRV that indirectly reflect on the system autonomic nervous [The reduction in parasympathetic and autonomic modulation verified in the 5 min post-exercise in the control but not in the HBP group may be related to the specific characteristics of the elderly in the HBP group. The HBP group in our study consisted of physically active elderly who had controlled blood pressure. Thus, it is possible that the use of medication to control blood pressure associated with physical activity and adherence to non-pharmacological therapies contributed to the differences observed between the groups. Lifestyle changes such as a low-sodium diet [Furthermore, differences in heart rate recovery may vary in elderly hypertensive individuals depending on BP control. Amaro-Vicente et al. [Although hypertension causes a delay in heart rate recovery after maximal exercise tests, physical training can normalize HR during the post-exercise period in hypertensive patients. Physical training for a duration of four months can restore the post-exercise decline rate of the recovery heart rate in patients with HBP [Despite the benefits of aerobic exercise in improving cardiac autonomic control, clinical supervision is necessary, even for elderly people who do not have hypertension and cardiovascular diseases. Thus, knowing that there are risks of cardiovascular events during and after exercise, monitoring cardiac autonomic modulation by HR variability in periods after aerobic exercise can be an important tool for the elderly, regardless of the presence of cardiovascular and metabolic diseases, such as systemic arterial hypertension.Knowledge of risks of cardiovascular events during and after exercise and monitoring cardiac autonomic modulation by HR variability in periods after aerobic exercise can be an important tool for the elderly, regardless of the presence of cardiovascular and metabolic diseases, such as systemic arterial hypertension. | PMC9859152 |
Limitations | injuries, hypertensive | COMPLICATIONS, HBP | The hypertensive elderly participants evaluated in this study were physically active, clinically able to practice physical activity, and had controlled HBP. Thus, our results do not provide information on the heart variability of hypertensive elderly in advanced stages, whose injuries may be more severe. Furthermore, since the HRV parameters were evaluated up to 30 min after recovery, the actual time when all HRV parameters return to their baseline is unknown. Further research should monitor subjects for 24 h post-exercise. Our results were somewhat unexpected because we expected greater differences between cases and controls. Reasons that may justify the effects of aerobic exercise on autonomic balance in elderly hypertensive patients without complications include: a lack of randomization, the control group belonging to a rehabilitation clinic, and physical activity. We do not have any recovery data extending the 30-min observation period, perhaps after an hour or two there might be significant changes. Finally, one of the strengths of this research is that the control group was made up of healthy elderly people who did not take drugs such as diuretics, renin-angin-aldosterone system inhibitors, or beta-blockers. However, we could not compare the two groups in relation to the use of medication. | PMC9859152 |
5. Conclusions | cardiovascular and metabolic diseases, hypertensive | There was no difference in autonomic modulation and global heart rate variability between elderly people without cardiovascular and metabolic diseases and hypertensive elderly people after a bout of aerobic exercise. The elderly in the control group showed a decrease in parasympathetic modulation and global variability between the time of rest and 5 min of recovery. However, at 30 min of post-exercise recovery, the elderly in the control group restored parasympathetic activity. | PMC9859152 | |
Author Contributions | Conceptualization, P.E.d.A. and R.D.R.; methodology, P.E.d.A., J.Z.-R. and R.D.R.; validation, all authors.; formal analysis, J.Z.-R. and T.C.M.; investigation P.E.d.A., I.C.E.S. and R.D.R.; resources, P.E.d.A. and R.D.R.; data curation, P.E.d.A., J.M.S.J. and R.D.R.; writing—original draft preparation, all authors; writing—review and editing, all authors visualization, all authors.; supervision, R.D.R. and C.E.S.; and project administration, R.D.R. and L.C.D.A. All authors have read and agreed to the published version of the manuscript. | PMC9859152 | ||
Institutional Review Board Statement | The study was conducted in accordance with the Declaration of Helsinki and approved by the Institutional Review Board (or Ethics Committee) of ABC Medical School (CAEE protocol 02830612.1.0000.0082/#108.260) and Brazilian Registry of Clinical Trials (#RBR-5mgrttm). | PMC9859152 | ||
Informed Consent Statement | Informed consent was obtained from all subjects involved in the study. | PMC9859152 | ||
Data Availability Statement | The data of this work can be requested from the corresponding author (email: | PMC9859152 | ||
Conflicts of Interest | The authors declare no conflict of interest. | PMC9859152 | ||
References | Baseline characteristics of participants according to sex, age, height, weight, body mass index, smoking, blood pressure, and heart rate.Data are expressed as mean and standard deviation. Analyzed by a Fisher test and | PMC9859152 | ||
Background | bipolar disorder | The impairing neurodevelopmental course of bipolar disorder (BD) suggests the importance of early intervention for youth in the beginning phases of the illness. | PMC10324335 | |
Objective | We report the results of a 3-site randomized trial of family-focused therapy for youth at high-risk (FFT-HR) for BD, and explore psychosocial and neuroimaging variables as mediators of treatment effects. | PMC10324335 | ||
Methods | depressive disorder, active mood symptoms | High-risk youth (<18 years) with major depressive disorder or other specified BD, active mood symptoms, and a family history of BD were randomly assigned to 4 months of FFT-HR (psychoeducation, communication and problem-solving skills training) or 4 months of enhanced care psychoeducation. Adjunctive pharmacotherapy was provided by study psychiatrists. Neuroimaging scans were conducted before and after psychosocial treatments in eligible participants. Independent evaluators interviewed participants every 4-6 months over 1-4 years regarding symptomatic outcomes. | PMC10324335 | |
Results | ideation | Among 127 youth (mean 13.2 ± 2.6 years) over a median of 98 weeks, FFT-HR was associated with longer intervals prior to new mood episodes and lower levels of suicidal ideation than enhanced care. Reductions in perceived family conflict mediated the effects of psychosocial interventions on the course of mood symptoms. Among 34 participants with pre-/post-treatment fMRI scans, youth in FFT-HR had (a) stronger resting state connectivity between ventrolateral PFC and anterior default mode network, and (b) increased activity of dorsolateral and medial PFC in emotion processing and problem-solving tasks, compared to youth in enhanced care. | PMC10324335 | |
Conclusion | FFT-HR may delay new mood episodes in symptomatic youth with familial liability to BD. Putative treatment mechanisms include neural adaptations suggestive of improved emotion regulation. | PMC10324335 | ||
Clinical Trial Registration Information | Bipolar Disorder | Early Intervention for Youth at Risk for Bipolar Disorder; | PMC10324335 | |
Keywords | PMC10324335 | |||
INTRODUCTION | manic, anxiety, mood disorders, Bipolar disorder, mood instability, hyperactivity, mania, depressive, hypo/mania, hypomania, depressive symptoms, bipolar | RECURRENCES, REMISSION | Bipolar disorder (BD) can be recognized in childhood and adolescence, typically in the form of depressive symptoms or episodes, subsyndromal mania or hypomania, anxiety, and mood instability [The developmental pathways to the onset of BD in vulnerable youth are being clarified in genetic, neuroimaging, and psychosocial studies. Certain genes appear to mediate the relation between having a parent with BD and an offspring’s likelihood of developing BD [Despite these advances, it is unclear what parents or treating clinicians should do when behavioral or familial risk factors suggest a trajectory toward illness onset in a child or teen with early symptoms. Intervening with pharmacotherapy may lead to reductions in subthreshold symptoms in high-risk youth [These challenges have inspired the nascent work on preventative psychosocial interventions for youth at risk for BD. Preventative psychosocial interventions must have efficacy in minimizing early-onset symptoms as well as preventing future episodes, either alone or in combination with pharmacotherapy. Ideally, they should have an impact on the child’s reaction to stressors that may aggravate symptoms. In prior randomized trials, we have shown that a psychoeducational intervention called family-focused therapy (FFT), when combined with adequate pharmacotherapy, is effective in delaying recurrences and reducing symptom severity in adults with BD I and II [We reasoned that FFT could be adapted as an early intervention for youth at high risk for conversion to BD. FFT for high-risk youth (FFT-HR) begins when a youth with a family history of BD shows subthreshold manic or sub- or full threshold depressive symptoms. In 12 sessions over 4 months, clinicians provide the child and family members with psychoeducation about the nature, causes and prevention of mood disorders, followed by communication and problem-solving skills training to decrease family conflict and increase cohesion. In a pilot randomized trial of FFT-HR in 40 high-risk children, family treatment plus pharmacotherapy was more effective than brief education plus pharmacotherapy in decreasing time to recovery from mood episodes, increasing time in symptom remission, and reducing hypo/mania symptoms over one year [This article describes clinical outcomes from a larger-scale randomized trial of high-risk youth recruited from three study sites. We compared FFT-HR with a duration-matched, standardized psychoeducational therapy (enhanced usual care, or EC) on symptomatic outcomes (To comprehensively investigate the engagement of progressively higher-order neural systems targeted by early intervention, we used three methods of assaying changes in corticolimbic circuits from before to after FFT-HR or EC: in the resting state, during a facial emotion processing task, and during a problem-solving task. We hypothesized that key intrinsic connectivity patterns associated with known bipolar networks, as shown in the resting state, would change with treatment, as would amygdala activation during face emotion processing. Further, because amygdala hyperactivity and diminished prefrontal inhibitory control have been associated with mood instability in BD [ | PMC10324335 |
METHODOLOGICAL APPROACH: DESIGN OF THE TRIAL | PMC10324335 |
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