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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.The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision. | PMC10642256 | ||
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. | PMC10642256 | ||
Supplementary material | infection, NLV | VIRUS, DISEASE, RECRUITMENT, INFECTION, PROLIFERATIVE | The Supplementary Material for this article can be found online at: Study design overview. Patients were randomized at visit 1 before allogeneic stem cell transplantation between day -28 and -7. Transplant procedure was carried out according to standards of the participating centers. A small fraction of the stem cell graft (3-5% of all cells) was shipped along with donor serum to the manufacturing site at the University Hospital of Erlangen. Manufacturing was started at the day of transplantation. If the T cell product could not be released or manufacturing failed, patients were able to cross over from the treatment group into the control group. Twenty-four to 48 h before each T cell product application patients were screened for acute GvHD including steroid treatment and signs of infection. If patients were not eligible for T cell product application this visit was repeated as additional visit 7 days later. The time frame for this assessment was 42-days opening a window for the first treatment from day 30 to day 72. Patients in the control group were monitored accordingly. End of study visit was 204 days after allogeneic stem cell transplantation.Click here for additional data file.Study recruitment overview. Schematic overview of the patient flow of all patients screened. In the treatment arm 3 patients crossed over to the control arm, as the product could not be released, or patient refused study medication. Four patients we not considered eligible for the study medication at visit 2 and were excluded from the study. In the control arm 2 patients were excluded due to relapse and the development of post transplant proliferative disease (PTLD).Click here for additional data file.Pat 11, Epitope specific T cell expansion during manufacturing. PBMC derived from the stem cell graft were analyzed before peptide stimulation (Day 0) and after 9 days of expansion (Day 9) by flow cytometry. Patient 11 shared 5 out the 6 HLA types for which peptides from CMV and EBV were available. Cells were gated on CD8+ T cells. Upper panel (red frame) shows specificities of CD8 for CMV epitopes, lower panel for EBV epitopes respectively (yellow frame).Click here for additional data file.Pat 11, T cell subsets and activation during manufacturing. PBMC derived from the stem cell graft were analyzed before peptide stimulation Day 0 and after 9 days of expansion Day 9 by flow cytometry. Cells were gated on CD3+ T cells. Click here for additional data file.Flow cytometry of epitope specific T cells after adoptive transfer. Example of flow cytometric assessment of virus specific T cells in the peripheral blood of patient 5, 14 days after the second infusion of the T cell product. The patient was positive for HLA*A02:01 and B*08:01. As shown in four epitopes (CLG, GLC, YVL, FLY) presented on HLA A*02:01 and two epitopes (QAK, RAK) presented on HLA*B08:01 could be used to stimulate donor-derived EBV-specific T cells. Two CMV derived epitopes (NLV, VLE) with restriction to HLA A*02:01 and two epitopes with restriction to HLA B*08:01 were available in the peptide pools to stimulate CMV specific T cells. The same peptides were used to load HLA pentamers for flow cytometric analysis. Click here for additional data file.Study Inclusion/Exclusion criteria. Inclusion criteria are shown for patients and donors separately. Only patients with serologic positive (CMV, EBV) 10/10 HLA-matched donors were included in the study. In addition, the study protocol required the presence of at least one of the following HLA class I loci: A*01:01, A*02:01, B*07:02, B*08:01, B*35:01, C*07:02. Before each T cell product transfusion “additional inclusion criteria” were applied as indicated to prevent infusion when acute GvHD or treatment with steroids, or signs of infection are present.Click here for additional data file. | PMC10642256 |
References | PMC10642256 | |||
Background | pain, Low back pain | Low back pain is one of the most common disabling pathologies in humanity worldwide. Physical exercises have been used in recent decades to reduce the pain, improve the functionality of the lumbar spine and avoid relapses. The purpose of the study is to analyze the effect of a program based on re-education exercises involving preactivation of the abdominal transverse muscle compared to conventional treatment in adults with chronic nonspecific low back pain. | PMC10483714 | |
Methods | pain | A two-arm, single-blind randomized control trial with 35 primary care patients with chronic nonspecific low back pain. Both groups received a 4-week intervention. Data were collected at baseline and at the end of the intervention. Sixteen patients participated in the intervention group, and 19 patients in the control group. | PMC10483714 | |
Results | disability, pain | For the experimental group, the outcomes of disability and activation of the abdominal transverse muscle decreased significantly (MD -2.9; CI 95% -5.6 to -0.35; η2 = 0.14; p = 0.028) and (MD 2.3; CI 95% 0.91 to 3.67; η2 = 0.25; p = 0.002) respectively, with a large effect size, compared to the control group. There were no differences between the groups in pain intensity, thickness, and resistance of the transverse abdominal muscle. | PMC10483714 | |
Conclusion | disability | A 4-week specific program based on re-education exercises of the preactivation of the abdominal transverse muscle is more effective than conventional treatment for reducing disability and increasing the activation of the abdominal transverse muscle measured by VAS scale and PBU. | PMC10483714 | |
Trial registration | Clinicaltrials.gov identifier: NCT03097497. Date of registration: 31/03/2017. | PMC10483714 | ||
Supplementary Information | The online version contains supplementary material available at 10.1186/s12875-023-02140-3. | PMC10483714 | ||
Keywords | PMC10483714 | |||
Background | lumbopelvic instability, CNLBP, LBP, Low back pain | DISEASE | Low back pain (LBP) is one of the most common disabling pathologies worldwide [In Western countries, the societal costs of this disease are estimated to be 1–2% of the gross national product, and between 80 and 90% of the costs are from productivity loss and disability [LBP does not discriminate based on age, but the incidence increases as people grow older, peaking between 45 and 59 years, when it can become more disabling [CNLBP has been associated with lumbopelvic instability [The muscle’s preactivation system gives rise to anticipatory postural adjustments that position the body before the disturbances that occur during any movement [ | PMC10483714 |
Methods | PMC10483714 | |||
Aim | CNLBP, disability, pain | This study aimed to analyze the effect of a program based on re-education exercises on the preactivation of the TrA muscle in terms of pain intensity, disability, activation measured with a pressure biofeedback unit (PBU), thickness measured with ultrasound (US), resistance measured with electromyography (EMG) compared with conventional treatment in adult people with CNLBP in primary care. We also investigated the relationship between the activation of the TrA muscle and pain and disability. | PMC10483714 | |
Design | neurological deficit, cancer, CNLBP | CANCER, CARDIAC DISEASE, METASTATIC CANCER | A longitudinal, single-blind, randomized controlled trial study was conducted between August 2017 and November 2018. This study was registered on clinicaltrials.gov (NCT03097497) on 31/03/2017 and followed the Consolidated Standards of Reporting Trials statement (CONSORT) recommendations to develop the structure and guide the performance of the study [The inclusion criteria were adults (18 to 65 years old) diagnosed with CNLBP, with a minimum of 3 months of follow-up.The exclusion criteria were signs of neurological deficit, history of spinal surgery or cardiac disease, cancer or metastatic cancer treatment in the previous five years, and pregnancy or plan to become pregnant or less than three months postpartum. | PMC10483714 |
Sample size | The sample size calculation was based on the study by Unsgaard-Tøndel et al. [Accepting an alpha risk of 0.05 (95% confidence) and a beta risk of 0.1 (statistical power of 90%), using a two-sided contrast, 17 individuals were necessary in each group (34 patients in total), accepting a patient drop-out rate of 20%. We used the sample-size calculator GRANMO version 7.12.A simple random sampling method without replacement was used to ensure a representative sample of our target population. | PMC10483714 | ||
Randomization and blinding | The researchers used a simple randomization technique. An external researcher generated the randomization assignment using a computer random number generator in Excel 2011 (version 14.0.0) and kept the assignments on a specific computer for this study. The group assignments were inaccessible to the rest of the staff. Neither the participants nor the investigators responsible for enrolling the patients could foresee the assignment because of the central allocation used for this study. To ensure that the assessment of the patients was not biased, we used an external assessor who was blinded to their group assignment. | PMC10483714 | ||
Interventions | Richardson | CONTRACTION | The intervention was carried out at the Faculty of Nursing and Physiotherapy of the University of Lleida, Spain. Based on several previous studies, the duration of the intervention was four weeks [The patients assigned to the control group followed the conventional treatment prescribed by their family physician during the primary care consultation, following the guidelines of the Catalan Health Institute [Patients assigned to the experimental group followed a program of re-education exercises for preactivation of the transverse abdominal muscle for approximately 30 min each session. The sessions were conducted individually to ensure adequate attention and individualization of the exercises. Each intervention session was divided into warm-up and TrA muscle training (Individualized parameters were established for each patient to obtain optimal results in motor control. This individualized training method has been described in several articles where a PBU has been used as an element of assessment and feedback [By transferring this procedure to the lumbar muscles combined with the optimal resistance training parameters described by Borde et al. [To facilitate the contraction of the deep trunk muscles, the PBU was used to give feedback information, and they were ordered to perform the drawing-in maneuver (bring the abdomen in and up). According to Richardson et al. [By abdominal palpation and observation, the physiotherapist verified whether the patients performed this action correctly, without compensation by pelvic retroversion, trunk rotations, or the contraction of any nearby muscles, if no verbal feedback was given to improve the movement. Furthermore, to facilitate the action of this abdominal musculature, the patient was asked to contract the pelvic floor musculature. In this case, the order given was ‘squeeze your ass’, ‘put your ass in’, and ‘hold your urine’.Verbal and tactile reinforcement was given to the patient to hold the contraction for 6 s. If the patient did not achieve that, we worked with the time that the patient was able to hold it. After the contraction, the patient rested for four seconds, and then the contraction was repeated to see how many repetitions the patient could perform. Then, the patient rested for 60 s before performing another series until a maximum of three and a minimum of two series for each exercise. Following these parameters, four different exercises were performed in each session, progressively increasing the weekly training load and difficulty.The exercises are available in a | PMC10483714 |
Outcomes | ’s lumbar spine, thoracolumbar, fatigue, pain | CREST, CONTRACTION, CONTRACTIONS | The intervention lasted for four weeks. All variables were measured pre- and post-test. For all of the variables, whenever possible, the minimal clinically important difference (MCID) to be detected was established. The study’s main variable was pain intensity measured with a VAS scale of 0–10 cm [The PBU was inserted under the subject’s lumbar spine, between the ribcage and the sacrum, in the area corresponding to the thoracolumbar fascia. It was inflated to an initial pressure of 40 mmHg. The patient was supine on a stretcher, with the knees flexed at 90º and a pillow under the neck to maintain a comfortable and neutral posture (Fig.
Pressure biofeedback unitBefore the test, all the participants were instructed to perform the abdominal contraction maneuver to focus the action on the transverse abdominis, not the rectus or obliques abdominis. Several contraction trials were allowed before the recording was taken until the performance was judged optimal by the physiotherapist. A prudential rest time of 2 min was allowed so that fatigue did not intervene in the assessment result, with the minimum being 30–60 s [The drawing-in abdominal contraction maneuver was requested to record the test result, and the peak pressure change was taken into account with a record of 10 s of contraction. The result was calculated by identifying the peak point of contraction held for more than 1 s and then subtracted from the baseline pressure. Three trials were used for statistical analyses, taking the average of the three contractions.The bioPlux surface electromyograph was used with its corresponding software and TIGA-MED gold bipolar surface electrodes.Before placing the electrodes, the detection surfaces were adequately cleaned and shaved when necessary, following the recommendations of the ISEK (International Society of Electrophysiology and Kinesiology) and SENIAM (Surface Electromyography for Non-Invasive Evaluation of Muscles) to allow a low impedance between the skin and the electrodes [First, the reference electrode or ground electrode was placed on the ankle, above the right external malleolus, since it is one of the places with the least electrical activity in the body. This electrode was connected to the G channel of the bioPlux device and waited for 30 s. The reference electrode collects the basal electrical signal, which is always present on the skin surface and is not the result of muscle activity. Next, the two electrodes of channel 1 were placed on the area corresponding to the TrA/OI (obliquus internus abdominis) muscles, located 2 cm from the anterior superior iliac spine and with a distance of 2 cm between their centers [The center and edges of the electrode detection zones were pressed firmly to ensure good contact with the patient’s skin. Initially, the patient’s basal tone was measured for 30 s. Once the result was recorded, the maximal voluntary isometric contraction of the TrA was requested following the SENIAM standards to obtain the maximum force peak. Three contractions of 5 s each with 3 s of rest between repetitions were requested. Two more repetitions of the entire sequence were performed with a 60-second rest between each sequence. By recording a very low-intensity signal mixed with other undesirable ones, the signal was amplified x1000, and the bandpass was filtered from 20 to 450 Hz, quantifying it afterwards. All these results were recorded, and the bioPlux device calculated the average, giving the mV (millivolts) values of the force test as a result.Finally, 10 s of maximum contraction of the TrA were requested to assess muscle resistance. This contraction was also recorded due to the resistance test with mV.For the measurement of TrA, we used the bioPLUX wireless System Surface US. The patient was placed in a quadruped position. The conductive gel was applied to a transducer at 7.5 MHz. This was placed transversely on the right side of the body, with the center positioned at a point 2.5 cm anterior to the axillary midline, at the midpoint between the last rib and the iliac crest. Once a clear image of the TrA was obtained, it was measured at rest, freezing the image at the end of the patient’s exhalation and measuring the width at its widest point. The patient was then asked to perform an abdominal maximal voluntary isometric contraction, and the image was re-frozen at the end of the patient’s expiration for measurement. A total of three images of the contracting TrA were captured, and muscle thickness measurements in millimeters were averaged. | PMC10483714 |
Statistical analysis | SE, disability, pain | The statistical analysis was performed using the statistical program SPSS v22, and the intention-to-treat analysis was performed with an alpha of 0.05. Quantitative variables were described using the mean, standard deviation (SD), standard error (SE), median, and interquartile range.Sociodemographic baseline characteristics were compared using the chi-square tests of independence for categorical data and the Student’s t-test for continuous data.A two-way mixed ANOVA was used to determine whether there was an interaction effect between the two independent variables, treatment (control and experimental) and time (pre- and post-test). The mean difference (MD) with 95% confidence interval (CI) was calculated to analyze continuous outcomes. We corrected p-value comparisons using Bonferroni. We used the partial Eta squared (η2) to measure the effect size. We considered a partial η2 > 0.009 as a small effect size, partial η2 > 0.058 as a medium effect size, and partial η2 > 0.137 as a large effect size [We used the Pearson bivariate correlation analysis to investigate the relationship between the TrA activation measured with the PBU and pain and disability. | PMC10483714 | |
Results | LBP, Pain | RECRUITMENT | Recruitment took place in different primary care centers of the “Institut Català de la Salut” in Lleida (Spain) from April to August 2017. Of 271 potential subjects, 155 were impossible to contact, and 78 were excluded after the telephone interview. Figure
CONSORT Flow diagram of the studyFinally, 38 patients participated in the study (see Table The initial analysis of the groups showed no significant difference in the quantitative demographic characteristics, such as age, BMI, or the onset of the first episode of LBP. For the qualitative variable sex, it was found that in the control group, 61% were men compared to 39% women, while in the intervention group, the percentage of men was only 29%, but this difference was not significant according to Pearson’s chi-square test (p = 0.23) (Table
Baseline Characteristic of participantsNotes: Values are presented as mean (standard deviation)Abbreviations: W women; M Men; LBP Low Back Pain; TrA; abdominal transversus muscle; RMQ Roland-Morris Questionnaire; PBU Pressure Biofeedback Unit; US Ultrasound; CSA: cross-sectional area | PMC10483714 |
Main outcome | SE, pain | The main outcome in this study was pain intensity measured with a 0–10 VAS scale. The measurements were taken pre- and post-test before the start of the intervention and after four weeks (Tables
Results experimental group*Statistically significant difference. SD: Standard Deviation VAS: Visual Analogue Scale. RMQ: Roland-Morris Questionnaire. TrA: Abdominal Transverse Muscle. PBU: Pressure Biofeedback Unit. US: Ultrasound. EMG: Electromyography
Results control group*Statistically significant difference. SD: Standard Deviation VAS: Visual Analogue Scale. RMQ: Roland-Morris Questionnaire. TrA: Abdominal Transverse Muscle. PBU: Pressure Biofeedback Unit. US: Ultrasound. EMG: ElectromyographyA two-way mixed ANOVA was conducted to examine the effects of time and treatment on pain intensity. The interaction effect between time and treatment on pain intensity was statistically significant (F(1, 33) = 14.33, p = 0.001, η2 = 0.3). There was a significant main effect of the intervention (differences between the measurements pre- and post-intervention) on pain intensity (F(1, 33) = 18.4, p = 0.00, η2 = 0.36). For the experimental group, pain intensity was significantly decreased post-test compared to pre-test (MD -2.12; CI 95% -2.9 to -1.33; p = 0.00) (Table
Comparative resultsVAS(0–10)Control (19)Experimental (16)-2.1 (0.38)-0.1 (0.35)RMQ(0–24)Control (19)Experimental (16)0.7 (0.8)-3.8 (0.87)Control (19)Experimental (16)-0.6 (0.37)2.5 (0.4)Control (19)Experimental (16)-0.22 (0.1)0.74 (0.2)Control (19)Experimental (16)-0.001 (0.009)0.009 (0.01)*Statistically significant difference. SE: Standard Error. CI: Confidence Interval. VAS: Visual Analogue Scale. RMQ: Roland-Morris Questionnaire. TrA: Abdominal Transverse Muscle. PBU: Pressure Biofeedback Unit. US: Ultrasound. EMG: Electromyography. Partial Eta squared, F and p-values were calculated using a two-way mixed ANOVA | PMC10483714 | |
Secondary outcomes | abdominal transverse muscle thickness, disability | SECONDARY | There were four secondary outcomes: (i) disability measured with the RMQ, (ii) activation of the transverse abdominal muscle using the pressure biofeedback unit, (iii) abdominal transverse muscle thickness measured with ultrasound, and (iv) resistance of the transverse abdominal muscle measured with electromyography. A two-way mixed ANOVA was conducted to examine the effects of time and treatment on all secondary outcomes. | PMC10483714 |
Disability (RMQ) | disability | The interaction effect between time and treatment on disability was statistically significant (F(1, 33) = 13.64, p < 0.001, η2 = 0.3). There was a significant main effect of the intervention (differences between measurements pre- and post-intervention) on disability (F(1, 33) = 6.9, p = 0.013, η2 = 0.17). For the experimental group, disability was significantly decreased compared to the control group (MD -2.9; IC 95% -5.6 a -0.35; η2 = 0.14; p = 0.028), with a large effect size (Table | PMC10483714 | |
Activation of the Abdominal Transverse Muscle (PBU) | pain | The interaction effect between time and treatment on pain intensity was statistically significant (F(1, 33) = 32.59, p = 0.00, η2 = 0.49). There was a significant main effect of the intervention (differences between measurements pre- and post-intervention) on the activation of the transverse abdominal muscle using the pressure biofeedback unit (F(1, 33) = 12.52, p = 0.001, η2 = 0.27). For the experimental group, the activation of the transverse abdominal muscle using the pressure biofeedback unit was significantly increased compared to that of the control group (MD 2.3; CI 95% 0.91 to 3.67; η2 = 0.25; p = 0.002), with a large effect size (Table | PMC10483714 | |
Abdominal Transverse Muscle Thickness (US) | abdominal transverse muscle thickness | The interaction effect between time and treatment on abdominal transverse muscle thickness was statistically significant (F(1, 33) = 12.12, p = 0.001, η2 = 0.27). For the experimental group, the abdominal transverse muscle thickness measured with US was significantly increased post-test compared to pre-test (MD 0.74; CI 95% 0.03 to 0.11; p = 0.001) (Table | PMC10483714 | |
Resistance of the Abdominal Transverse Muscle (EMG) | The interaction effect between time and treatment on the resistance of the transverse abdominal muscle was not statistically significant (F(1, 33) = 0.58, p = 0.45, η2 = 0.17). There were no statistically significant differences within and between groups (Table | PMC10483714 | ||
Correlation analysis between the Activation of the Abdominal Transverse Muscle (PBU) and pain (VAS), disability (RMQ) and Abdominal Transverse Muscle Thickness (US) | pain | A statistically significant negative correlation was found between TrA activation and pain (r= -0.358, p = 0.035).There was no correlation between TrA activation and disability.A statistically significant correlation was found between TrA activation and TrA thickness (r = 0.474, p = 0.004). | PMC10483714 | |
Discussion | decreased disability, disability, pain | Our findings suggest that a specific program based on re-education exercises on the preactivation of the transverse abdominal muscle significantly reduces disability and increases the activation capacity of the transverse abdominal muscle in the short term compared to a conventional treatment that includes education about lumbar symptoms, recommendations to be active and pharmacological prescriptions, in adults with CNLBP.Our results showed no statistically significant differences between the two groups for pain intensity measured with the VAS. This result is in contrast with the literature. A recent systematic review with meta-analysis and meta-regression showed low to moderate quality evidence of a sustainable positive effect of motor control exercise on pain intensity [The experimental group had significantly decreased disability measured with the RMQ scale compared to the control group. These results are consistent with a meta-analysis [Regarding the activation of the transverse abdominal muscle using the PBU, our results showed a statistically significant difference in favor of the experimental group. Several studies [Comparing the results obtained from the PBU and the US regarding the activation of the TrA, both measures showed a significant correlation. However, although the results obtained with the PBU are significantly increased in favor of the experimental group, the results of the US are not statistically significant. As mentioned, some evidence shows that the PBU is not a valid tool for measuring TrA activation [Finally, there were no statistically significant differences between the two groups for the thickness and resistance of the transverse abdominal muscle as measured by US and EMG, respectively. These results are in contrast with the literature. In a similar study [The literature generally establishes that greater activation of the transverse abdominal muscle occurs when we work with suspension training systems or perform CORE stabilizing exercises [Finally, in our study, we have conducted an intention to treat analysis. This method analyzes patients according to the groups they were initially assigned and randomized. For some authors, this method preserves the prognostic balance that randomization offers [ | PMC10483714 | |
Limitations | The main limitation of this study is the placement of the US. The professionals were adequately instructed in the use of it and where they must place it to perform the measurement, but due to the morphological variability of each patient, the US position could have been slightly modified, which could cause intraobserver variations [ | PMC10483714 | ||
Conclusions | disability | The main conclusion is that a 4-week specific program based on re-education exercises on the preactivation of the transverse abdominal muscle is more effective than conventional treatment for reducing disability and increasing the activation of the transverse abdominal muscle measured by the RMQ and PBU.Additional studies are necessary to estimate this treatment’s effect in the medium and long term. This program should also be compared with other exercise programs with supporting evidence, such as Pilates or fit-ball exercises. | PMC10483714 | |
Acknowledgements | We thank all physicians and patients from the Lleida primary care centers, who provided support and helped in the acquisition of data. | PMC10483714 | ||
Authors’ contributions | All authors read and approved the final version of the article. Study conception and design: FRC; FVP; JSG. Drafting the article or revising: FRC; MMA; FVP; CCS; JSG; MGE; OMN. Acquisiton of data: FRC; FVP; OMN; JSG. Analysis and interpretation of data: FRC; FVP; CCS; MGE; OMN. | PMC10483714 | ||
Funding | This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. | PMC10483714 | ||
Data Availability | The datasets generated during the current study are available from the first author on reasonable request. | PMC10483714 | ||
Declarations | PMC10483714 | |||
Competing interests | The authors declare no competing interests. | PMC10483714 | ||
Ethics approval and consent to participate | This study was conducted according to the Declaration of Helsinki [Participants agreed to sign informed consent forms and participated voluntarily without financial rewards.Organic Law 15/1999 on the Protection of Personal Data, of December 13 [ | PMC10483714 | ||
Consent for publication | Written informed consent for participate in the study was obtained for all the participants.Written Informed consent to publish the images was obtained from the volunteer. | PMC10483714 | ||
Abbreviations | Chronic Nonspecific Low Back PainElectromyographyLow back painPressure Biofeedback UnitMaximum RepetitionRoland-Morris QuestionnaireAbdominal transversus muscleVisual Analogic Scale | PMC10483714 | ||
References | PMC10483714 | |||
Background | autism | Significant challenges remain in the early identification of child developmental disabilities in the community. Implementing supports and services early in the life course has been shown to promote positive developmental outcomes for children at high likelihood of developmental disabilities, including autism. As part of a cluster randomised controlled trial, this study seeks to examine and compare the perspectives and experiences of Australian general practitioners (GPs) in relation to a digital developmental surveillance program for autism and usual care pathway, in general practice clinics. | PMC10416397 | |
Methods | Autism | A qualitative research methodology with semi-structured interviews and thematic inductive analysis underpinned by grounded theory was utilised. All GPs from South Western Sydney (NSW) and Melbourne (Victoria) who participated in the main program (“GP Surveillance for Autism”) were invited to the interview. GPs who provided consent were interviewed either over online or in-person meeting. Interviews were audio-recorded, transcribed, and coded using NVivo12 software. Inductive interpretive approach was adopted and data were analysed thematically. | PMC10416397 | |
Results | autism | Twenty-three GPs across the two sites (NSW: n = 11; Victoria: n = 12) agreed to be interviewed; data saturation had reached following this number of participants. Inductive thematic coding and analysis yielded eight major themes and highlighted common enablers such as the role of GPs in early identification and subsequent supports, enhanced communication between clinicians/professionals, relationship-building with patients, and having standardised screening tools. Specific facilitators to the feasibility and acceptability of a digital screening program for the early identification of developmental disabilities, including the early signs of autism, and encouraging research and education for GPs. However, several practical and socioeconomic barriers were identified, in addition to limited knowledge and uptake of child developmental screening tools as well as COVID-19 lockdown impacts. Common and specific recommendations involve supporting GPs in developmental/paediatrics training, streamlined screening process, and funding and resources in the primary healthcare services. | PMC10416397 | |
Conclusions | autism | The study highlighted the need for practice and policy changes, including further training of GPs alongside sufficient time to complete developmental checks and appropriate financial remuneration through a Medicare billing item. Further research is needed on implementation and scale up of a national surveillance program for early identification of developmental disabilities, including autism. | PMC10416397 | |
Supplementary Information | The online version contains supplementary material available at 10.1186/s12875-023-02121-6. | PMC10416397 | ||
Keywords | PMC10416397 | |||
Methods | PMC10416397 | |||
Study context | autism | This article forms one part of the qualitative component of the main program “A multistate trial of an early surveillance program for autism within General Practices in Australia” [ | PMC10416397 | |
Participant recruitment and interviews | A total of 53 GPs across South-West Sydney (NSW; n = 30) and Melbourne (Victoria; n = 23) recruited as part of the main study were invited to participate in this interview. A formal email invitation was sent along with a participation information sheet and consent form to the 53 practices. Twenty-three of 53 (43%) GPs across the two sites (NSW: n = 11; Victoria: n = 12) participated in the semi-structured interviews (Table
Characteristics of general practitioners (GPs) enrolled in this qualitative interview study Female Male8753 Solo Group21317 Bulk-billed Private Mixed537413 NSW Victoria9626 | PMC10416397 | ||
Data analysis | MAY | Interviews were conducted with participants between 1st May and 26th June 2021 by research staff (TW, AL, MG and RN). All interviews were audio-recorded, transcribed by professional transcription services, and coded using NVivo12 [
General interview questions for GPs.What barriers did the COVID pandemic and associated changes pose on conducting DS at your practice?Were there any specific enablers that you found helpful in conducting DS? | PMC10416397 | |
Results | The analysis yielded eight major themes and 23 subthemes across the two groups/pathways. Figure
Comparisons of barriers, enablers and suggestive improvements out of general practitioners’ perspectives between current GP developmental pathway and ASP research pathway | PMC10416397 | ||
Discussion | autism | RECRUITMENT | A number of factors emerged regarding GPs’ perceptions and experiences about feasibility after they had participated and implemented the program’s developmental surveillance assessments with families of children potentially on the autism spectrum. The findings from this study highlighted a number of enablers, barriers, and improvements in both the digital universal developmental surveillance and the routine care pathways. Although GPs in both groups identified overlapping barriers and facilitators, GPs encountered greater challenges than enablers in both the current and ASP settings while also providing their encouragements/suggestions for improvement to the overall surveillance program.Indeed, the themes and subthemes reported in this paper are similar and complimentary to the findings that emerged from our parent/caregiver cohort [GPs tended reported that the quality of their healthcare delivery towards patients is grounded in mutual trust and positive relationships, thereby improving the patient’s overall healthcare experience and wellbeing. In this regard, previous studies have shown the critical role of trust in the doctor-patient relationship through open communication, engagement, and shared decision-making [Implementing a digital developmental surveillance system within the primary healthcare setting is another innovative pathway for GPs to engage with and deliver care for their patients, in a systematic manner using standardised tools. One such program developed by our team, the ‘Watch Me Grow-Electronic’ platform (WMG-E), empowers parents/caregivers to engage in developmental surveillance using opportunistic contacts such as vaccination visits to complete developmental checks digitally and for this to be done in the family home or in the community [Several electronic or web-based screening tools have been used in various healthcare settings, including mental health services and hospital/ambulatory care settings [Despite facilitating factors and positive experiences, GPs also highlighted barriers including the language and cultural beliefs about developmental screening, socioeconomic situations of the families, lack of availability of health specialists’, and the complexity of the health system. These findings were echoed by a similar, qualitative study conducted in NSW which also highlighted the practical challenges such as limited knowledge and uptake of the use of the recommended screening tools as part of child developmental surveillance by service providers [Another key barrier GPs encountered was in relation to the COVID-19 pandemic lockdowns/restrictions, which affected routine patient care. Changes in practice management and in consultation strategies included a major switch towards telephone triage/consultations and/or patient care occurring in carparks; however, acute/chronic care delivery was mostly postponed and recruitment of patients to the study was decreased substantially during the pandemic. Other primary health research studies confirmed these same issues [General practice is a relatively busy space, with GPs often having to manage multiple processes and tasks to get routine patient care completed [Additionally, this study identified several health system barriers, such as long waiting times, service fragmentation and lack of specialist resources, particularly in the SaU pathway. These barriers have also been reported in recent studies about clinician perspectives about the care of children and adolescents with mental health conditions [The GPs in our study observed that parental/caregiver understanding of child developmental milestones is an important factor contributing to a smooth, streamlined pathway of developmental surveillance and better patient care. According to the Australian Commission on Safety and Quality in Health Care, [In the current study, GPs also emphasised the need for further training and education around child development. As alluded by Price and Rechert, [ | PMC10416397 |
Implications for health practice and policy | autistic, Autism Spectrum Disorders, autism | The findings from this study indicate the need for increased awareness about the importance of developmental screening/surveillance, including for autism, amongst primary care clinicians such as GPs. This should focus on providing education and training about developmental milestones in general and early signs of autism to facilitate early identification alongside pathways for effective support and services for those children identified to have developmental difference or found to have a likelihood of being diagnosed as autistic. Unifying the developmental surveillance approaches using relevant health policies and guidelines (e.g. National Guideline for the assessment and diagnosis of Autism Spectrum Disorders in Australia) [It is also important to increase awareness among parents/caregivers and families, including those from CALD communities, by making available freely-accessible screening tools (such as the ASDetect mobile application, which is based on the SACS tool), [Some GP clinics that have participated in our project are very much still comfortable in paper-based work and were not comfortable switching to online mode of operation. The shift to digital delivery means greater efficiencies, specifically in terms of time and instant communication of results and recommendations with the relevant healthcare professionals. However, the pandemic has seen a shift in the general attitude towards digital systems with telehealth practice becoming increasingly available and acceptable to both patients and to service providers [ | PMC10416397 | |
Strengths and limitations | autism-specific | There are a number of strengths to this study, including the use of a semi-structured interview guide for a relatively high number of participating GPs. Further, we maintained a high level of interpretive rigour and trustworthiness and quality of the study through an awareness of reflexivity, data auditing and use of quality control measures as well as coding of the analysis by a researcher independent of the data collection.There are also some limitations that need highlighting. One of the limitations is that the GPs who participated in this qualitative study were willing/interested and there may be geographic differences based on state processes and also remoteness and other characteristics. However, this study was aimed to ascertain the feasibility and also potential enablers and barriers to implementation as pilot work before scaling up the program to other contexts and settings. Further, since the GPs were from two arms of a wider cRCT program, we are confident that the responses are generalisable to the contexts in which this study was conducted and the leanings from this pilot work could still inform dissemination of the program to other contexts and settings. For example, some of the findings observed in this study regarding barriers and enablers may be related to local issues at the study sites in either NSW (South-West Sydney) and/or Victoria (metropolitan Melbourne) only, other issues relating to the process, technology and funding are relevant to other parts of Australia and even globally. Further, the findings are consistent with previous research in Australia and internationally about the use of developmental and autism-specific screening tools [ | PMC10416397 | |
Conclusion | autism | The findings from this qualitative study provides valuable insights into the perceptions and experiences of Australian GPs regarding the contextual enablers and barriers that impact their participation in developmental surveillance programs, and in particular, the potential and beneficial usage of digital screening tools for developmental surveillance including the early identification of autism.Additional policies and systems-based research are needed, particularly in relation to the role of not only GPs but other community based services that interact with preschool children and their families. We believe there needs to be a multi-prong approach of using every opportunistic contact in the preschool period for identifying developmental differences as they emerge. In this regard, the team is also trialling developmental checks using the Watch Me Grow web link in other settings using services that the families are already engaged with and trust. These include multicultural playgroups, early childhood education centres and NGOs providing social care and other community-based services to empower and engage families in developmental monitoring of their children [There is an urgent need to improve GP’s skills and confidence in the early and accurate identification of developmental disabilities, including autism, and their knowledge of pathways for providing care for these children. To undertake developmental surveillance and the early identification of autism, GPs require updated training on the early signs of developmental disabilities as well as how to raise developmental difference with parents/caregivers. Further, culturally sensitive ways of supporting children and their families is important, along with access to accurate evidence-based early identification tools. As time and financial constraints emerged as barriers to the implementation of developmental monitoring, addressing this through the creation of remuneration for GPs to specifically undertake child developmental surveillance will facilitate access to early identification of autism. Furthermore, integrated referral pathways and models of care are also critical to address some of the identified barriers. Overall, this qualitative study is one component of a larger study that, together with the other components, is expected to provide much needed evidence on the implementation of an effective national, digital developmental surveillance program for early identification of developmental disabilities, including autism, in the primary care setting. Thus, the model being tested here has the unique potential to systematically reach all children/families by using GPs or the equivalent primary care service providers that are universally available in a given population. Further the utilisation of universal service providers in the community who engage with very young children and their families for immunisation or other routine service contacts will provide a feasible framework for equitable access to early developmental checks and a systematic opportunity for early identification of all developmental differences, such as autism, early in life. | PMC10416397 | |
Acknowledgements | Autism CRC, Autism | We would like to gratefully acknowledge and thank the GP clinics who participated in this study. The authors acknowledge the financial support of the Cooperative Research Centre for Living with Autism (Autism CRC), established and supported under the Australian Government’s Cooperative Research Centres Program. | PMC10416397 | |
Authors’ contributions | AMD | JB and VE initially conceived the study. TW led this qualitative phase study and specified the methods. TW, MG, RN, FK, and AL conducted and analysed the interviews. An external researcher RI also reviewed and conducted some analysis of these interviews. TW drafted and revised the manuscript with JB, VE, MG, and AM. The rest of the authors/investigators, CD, AMD, LK, JD, JE, IH, BJ, JK, S-TL, RL, NO, CWMT and SW, provided additional inputs about the study and contributed to subsequent revisions of the manuscript and approved the final manuscript. VE acts as the guarantor for this article. | PMC10416397 | |
Funding | Autism CRC, Autism | This work was funded through the financial support of the Cooperative Research Centre for Living with Autism (Autism CRC), established and supported under the Australian Government’s Cooperative Research Centres Program. | PMC10416397 | |
Data Availability | All data generated or analysed during this study are included in this published article and its supplementary information files. | PMC10416397 | ||
Declarations | PMC10416397 | |||
Competing interests | The authors declare no competing interests. | PMC10416397 | ||
Ethics approval and consent to participate | This study was approved by the Human Research Ethics Committee of the University of New South Wales Sydney (HC190143), with reciprocal ethics granted by the La Trobe University Human Research Ethics Committee (HC190143). Written informed consent to participate in this study was provided by the participating GPs. All procedures performed in this study involving human participants were in accordance with the ethical standards of the National Statement on Ethical Conduct in Human Research (2007) and the relevant Human Research Ethics Committees, and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. | PMC10416397 | ||
Consent for publication | Not applicable. | PMC10416397 | ||
Provenance and peer review | Not commissioned; externally peer reviewed. | PMC10416397 | ||
Abbreviations | Autism | DISEASE | Autism Surveillance PathwayAges and Stages QuestionnaireAges and Stages Questionnaire-Social and Emotional ScaleCooperative Research Centre for Living with AutismCulturally and Linguistically DiverseCoronavirus Disease 2019cluster Randomised Controlled TrialGeneral PractitionerKey Age and StageLearn The Signs. Act EarlyMedicare Benefits ScheduleNational Disability Insurance SchemeNew South WalesParents’ Evaluation of Developmental StatusQuantitative Checklist for Autism in ToddlersSocial Attention and Communication SurveillanceSurveillance as UsualWatch Me GrowWatch Me Grow-Electronic | PMC10416397 |
References | PMC10416397 | |||
Subject terms | NCT05373030 | ADVERSE REACTIONS | Data on the safety and immunity of a heterologous booster (fourth dose) after three-doses of inactivated SARS-CoV-2 vaccine in Chinese adults are limited. We evaluate the safety and immunogenicity of Ad5-nCoV in a randomized, double-blind, parallel-controlled phase 4 clinical trial in Zhejiang, China (NCT05373030). Participants aged 18–80 years (100 per group), administered three doses of inactivated SARS-CoV-2 vaccine ≥6 months earlier, are enrolled and randomized 1:1 into two groups, which are administered intramuscular Ad5-nCoV or inactivated SARS-CoV-2 vaccine (CoronaVac or Covilo). All observed adverse reactions are predictable and manageable. Ad5-nCoV elicits significantly higher RBD-specific IgG levels, with a geometric mean concentration of 2924.0 on day 14 post-booster, 7.8-fold that of the inactivated vaccine. Pseudovirus-neutralizing antibodies to Omicron BA.4/5 show a similar pattern, with geometric mean titers of 228.9 in Ad5-nCoV group and 65.5 in inactivated vaccine group. Ad5-nCoV booster maintains high antibody levels on day 90, with seroconversion of 71.4%, while that of inactivated vaccine is 5.2%, almost pre-booster levels. A fourth Ad5-nCoV vaccination following three-doses of inactivated SARS-CoV-2 vaccine is immunogenic, tolerable, and more efficient than inactivated SARS-CoV-2 vaccine. Ad5-nCoV elicits a stronger humoral response against Omicron BA.4/5 and maintains antibody levels for longer than homologous boosting.Here the authors provide safety and immunogenicity data for an AdV5-based SARS-CoV-2 vaccine, administered intramuscularly as heterologous booster after three-doses of inactivated SARS-CoV-2 vaccine in Chinese adults. | PMC10409730 |
Introduction | coronavirus disease 2019 | BREAKTHROUGH INFECTION, CORONAVIRUS DISEASE 2019 | Breakthrough infection cases of coronavirus disease 2019 (COVID-19) are a continuing issue in the clinical arenaThe administration of a fourth vaccine dose (additional booster) was recommended by the WHO for individuals aged ≥60 years, immunocompromised patients, and healthcare personnel after they have received the third doseImmunity in those who had complete primary immunization was shown to be more efficiently restored by a heterologous booster than homologous boosters in clinical trials. In comparison to a third homologous dose of CoronaVac, administration of a recombinant adenoviral vectored vaccine, mRNA vaccine, or recombinant adenoviral-vectored ChAdOx1 nCoV-19 vaccine increased humoral and cellular immune responsesHere, we present the safety and immunogenicity results following heterologous booster immunization with Ad5-nCoV or homologous boosters with different inactivated SARS-CoV-2 vaccines (CoronaVac or Covilo) after three-dose priming with inactivated vaccine in healthy participants aged 18–80 years in a randomized, double-blind, parallel-controlled phase 4 trial. We further explored the potential benefits of anti-Omicron BA.4/5 protection, dynamic responses, and durations of antibody levels in individuals 3 months after the booster, as well as the relevant factors influencing the antibody responses. | PMC10409730 |
Results | PMC10409730 | |||
Study participants | MAY | Between May 14 and 27, 2022, 211 volunteers aged 18–80 years who had received three doses of inactivated vaccine (CoronaVac or Covilo) ≥ 6 months earlier were recruited and screened for eligibility for this phase 4 trial. A total of 201 participants, including 120 adults (18–59 years) and 81 older individuals (60–80 years), were sequentially enrolled and randomly assigned to groups. One individual withdrew consent after randomization. In all, 200 participants received either a fourth dose of Ad5-nCoV (treatment group, | PMC10409730 | |
Factors influencing antibody levels | ADVERSE REACTIONS | The seropositivity and seroconversion results for the BA.4/5 pseudovirus-neutralizing antibody grouped by age (i.e., 18–59 years and 60–80 years), sex, BMI, chronic conditions, and adverse reactions are presented in Table Analysis of factors influencing antibody levels (Omicron BA.4/5)Comparisons were analyzed by Fisher’s exact test or Chi-squared test, Cochran–Armitage test were applied to analyze categorical data. | PMC10409730 | |
Discussion | infection | ADVERSE EVENTS, INFECTION, VIRUS | Vaccination provides immune-protection against SARS-CoV-2, owing to the induction of neutralizing antibodies and cellular immunity. However, as we are faced with the rapid evolution of SARS-CoV-2 variants worldwide and the virus’s increasing immune escape abilityThe antibody levels following homologous booster of inactivated vaccine in participants decayed faster than with a heterologous Ad5-nCoV booster. In a study into the use of a third-dose Ad5-nCoV or inactivated vaccine, Jin et al. demonstrated that orally administering aerosolized Ad5-nCoV following two-dose CoronaVac priming was persistently more immunogenic than a third CoronaVac dose 12 months after the second dosePrevious clinical trials reported that most adverse events after Ad5-nCoV were mild or moderate in severity and might be associated with cellular immunity reactivityThe morbidity and mortality rates in older adults increase after infection with SARS-CoV-2, and an effective COVID-19 vaccine is urgently neededThis study had some limitations. First, live virus in vitro neutralization tests against WT SARS-CoV-2 and Omicron BA.4/5 were not conducted in our study, and these need to be further explored, although RBD-specific binding IgG and pseudovirus-neutralizing antibody levels induced by vaccination were shown to correlate with live virus neutralizing antibody levels in our previous studyIn conclusion, our study provided evidence that a fourth dose of Ad5-nCoV following a three-dose inactivated SARS-CoV-2 vaccination is more immunogenic, tolerable than a fourth inactivated SARS-CoV-2 vaccine. Ad5-nCoV elicits a stronger humoral response and restores higher peak and more durable antibody levels than the inactivated SARS-CoV-2 vaccine. Nevertheless, while Ad5-nCoV seems to be highly potent and protective against Omicron lineages, next-generation vaccines may be needed to provide better protection against the emergence of highly transmissible SARS-CoV-2 variants capable of immune escape. | PMC10409730 |
Methods | PMC10409730 | |||
Study design and participants | anaphylaxis, fever, laboratory-confirmed SARS-CoV-2 infection, neurologic illness, hypertension, diabetes | ADVERSE REACTIONS, RESPIRATORY DISEASE, ANAPHYLAXIS, CARDIOVASCULAR DISEASE, CORONAVIRUS, HYPERTENSION, DISEASE, DIABETES | We performed a single-center, randomized, double-blind, parallel-controlled trial of a fourth vaccine dose with heterologous booster (Ad5-nCoV) or homologous booster (inactivated SARS-CoV-2 vaccine) in a population that had completed a three-dose inactivated SARS-CoV-2 vaccine regime in Hangzhou, Zhejiang Province, China. Healthy participants aged 18–80 years with stable medical conditions were recruited from the community and divided into groups of younger adults (aged 18–59 years) and older adults (aged 60–80 years) at a 2:1 ratio. All participants had received three doses of inactivated vaccine (the third dose was CoronaVac or Covilo) 6 months before the screening visit.The exclusion criteria included a history of laboratory-confirmed SARS-CoV-2 infection (based on the epidemic information system in China); pregnant or lactating women; new onset of fever; an immunosuppressive condition; previous vaccination with any other authorized vaccine within 28 days before screening (or the intention to receive such a vaccine within 14 days after the booster dose); history of severe adverse reactions (e.g., anaphylaxis) to adenovirus-vectored vaccines or coronavirus vaccines; administration of (or the intention to receive) any blood, plasma, or immunoglobulin products within 90 days before screening; participants with severe and/or uncontrolled cardiovascular disease, respiratory disease, hypertension (systolic pressure ≥180 mmHg/ diastolic pressure ≥110 mmHg), diabetes, or neurologic illness; and any special circumstances that researchers considered may increase the risk of individuals participating in the study or interfere with the evaluation of the initial objectives of the study.All participants signed the informed consent form before enrollment. The trial protocol was reviewed and approved by the Research Ethics Committee of the Zhejiang Provincial Center of Disease Control and Prevention, and no changes were made after the initiation of the study (ethics code number: 2022-021-01). The trial was prospectively registered with | PMC10409730 |
Vaccines | Trial vaccines included CoronaVac (Vero Cell; Beijing Sinovac Research & Development, Beijing, China) and Covilo (Vero Cell; Beijing Institute of Biological Products Co., Beijing, China), which are inactivated whole virion vaccines to wild-type SARS-CoV-2 with aluminum hydroxide as the adjuvant, administered intramuscularly at 0.5 mL per dose. Convidecia (CanSino Biologics, Tianjin, China) is a replication-defective Ad5-vectored vaccine expressing the full-length spike gene of wild-type SARS-CoV-2 (WuhanHu-1) supplied as a liquid formulation with a concentration of 5 × 10 | PMC10409730 | ||
Randomization and masking | The block randomization method was used with block sizes of 2 and stratified by age group. Eligible participants in each cohort were randomly assigned at a 1:1 ratio to receive Ad5-nCoV or inactivated vaccine. Randomization was done using a sealed enveloped system integrated with the electronic case report forms in the Open Clinica platform. A random number was assigned to each participant by allocation of the next available randomized entry in the randomization list (generated by an independent statistician using SAS (version 9.4)) that was established before the start of the study.During the double-blind phase, the participants, investigators, and outcome assessors were blinded. The personnel who prepared and administered the vaccinations were not blinded, but they were not otherwise involved in other trial procedures or data collection and signed a confidentiality agreement. In addition, analyses of the safety and immunogenicity outcomes were carried out in a blinded manner by the lab technicians. | PMC10409730 | ||
Procedures | redness, nausea, itching, swelling, fever, cellulitis, muscle ache, fatigue, pain, headache | ADVERSE REACTIONS, ADVERSE EVENTS, CELLULITIS, ADVERSE EVENT, INDURATION, MAY, EVENTS | In May 2022, 200 eligible participants received one dose of Ad5-nCoV or inactivated vaccine via intramuscular injection. The variety of the fourth dose of inactivated vaccine was the same as that used for the pre-received third dose. After the booster vaccination, all participants were monitored for 30 min for any immediate adverse reactions and instructed to record adverse events for the next 14 days on a participant diary card. Solicited injection site events included pain, redness, swelling, induration, itching, and cellulitis, while systemic events included fever, malaise, muscle ache, joint pain, fatigue, nausea, and headache. Unsolicited adverse events within 28 days were also reported by the participants and recorded. Serious adverse events (SAEs) self-reported by participants were documented throughout the study. Adverse events were graded as mild (grade 1), moderate (grade 2), severe (grade 3), or life-threatening (grade 4), according to the scale issued by the China State Food and Drug Administration (version 2019), and the causality with immunization was estimated before unmasking.To assess the presence of anti-SARS-CoV-2 antibodies, a 10-ml blood sample was collected from each participant at baseline before they received the booster dose and 14, 28, and 90 days after receiving the booster dose. The quantitative measurement of wild-type SARS-CoV-2 RBD-specific IgG responses was performed using the commercial Anti-SARS-CoV-2 RBD-IgG ELISA kit (Vazyme Medical Technology, Nanjing, China). The lower limit of detection was 1:10, and values below this limit were imputed and defined as 1:10. The positive cutoff values for RBD-specific IgG antibodies were defined as titers of 1:90 | PMC10409730 |
Outcomes | SARS-CoV-2-specific RBD | ADVERSE REACTIONS, SECONDARY, ADVERSE EVENTS, CHRONIC DISEASES | The primary outcomes were the occurrence of solicited local or systemic adverse reactions and assessments of geometric mean concentration (GMC)/geometric mean titer (GMT), seroconversion/seropositive rates, and geometric mean fold increase (GMFI) of antibodies that bind SARS-CoV-2-specific RBD and pseudovirus-neutralizing antibodies against Omicron BA.4/5 on day 14 post-booster dose. Safety secondary outcomes included information on unsolicited adverse events for 28 days after immunization and serious adverse events recorded throughout the whole follow-up visits. Immunological secondary outcomes included the above indices of humoral immune responses to vaccination at 28 and 90 days after vaccination. The exploratory outcomes were analyses of influencing factors (including age, sex, BMI, and chronic diseases) to adverse reactions and immunogenicity. | PMC10409730 |
Statistical analysis | ADVERSE EVENT | The sample size calculation was based on the assumption that heterologous booster immunization with Ad5-nCoV after three-dose priming with inactivated SARS-CoV-2 vaccine would elicit non-inferior and superior concentrations of neutralizing antibodies compared with a homologous booster dose with inactivated SARS-CoV-2 vaccine. We assumed that the one-sided α of inspection level was 0.025, the ratio of Ad5-nCoV group to inactivated SARS-CoV-2 vaccine group was 1:1, the non-inferiority limit of the GMT ratio was 0.67 (after 10 is the bottom log = −0.174), and the actual GMT ratio of the two groups was 2; thus, the study needed to recruit 80 participants in each group to achieve 99.86% power. When the sample size of each group was 80, the superiority of the GMT level of the Ad5-nCoV group was greater than that of the inactivated SARS-CoV-2 vaccine group, and the estimated power of the test was 88.16%, which met the test requirements. Thus, we decided on a total sample size of 200, with 100 for each group after adjusting for an attrition rate of 20% due to loss to follow-up. Power Analysis and Sample Size software (LLC, USA version 11.0.7) was used in these calculations.Sex, age, BMI, and other clinical characteristics were collected for each vaccine recipient. We used the medians and interquartile ranges (IQR) for age and time interval, and numbers (percentages) for categorical variables. All participants who received the booster dose were included in the safety population (Safety set [SS]). Safety data are presented as counts and percentages of participants with at least one solicited (local or systemic) adverse event. The analysis was based on the intention-to-treat cohort and calculated with chi-squared test or Fisher’s exact test. The immunogenicity objectives are reported based on the per-protocol set (PPS), and missing data were not imputed. Participants experienced no major protocol violations; complied with all inclusion criteria/exclusion criteria; completed the vaccinations within the time window, as required in the protocol; and completed all blood samplings. Levels of antibodies against SARS-CoV-2 are presented as the GMC/GMT, seroconversion/seropositive rate, and GMFI with 95% CI. The 95% CI was calculated based on the t-distribution of the log-transformed values back-transformed to the original scale. We used Student’s | PMC10409730 | |
Supplementary information |
Supplementary InformationPeer Review File | PMC10409730 | ||
Supplementary information | The online version contains supplementary material available at 10.1038/s41467-023-40489-2. | PMC10409730 | ||
Acknowledgements | We thank all the generous volunteer subjects who enrolled in the study. This work was supported by the Key Research and Development Program of Zhejiang Province (2021C03200, J.J., H.L., H.Z.); the Key Program of Health Commission of Zhejiang Province/Science Foundation of National Health Commission (WKJ-ZJ-2221, H.L., H.Z.); the Major Program of Zhejiang Municipal Natural Science Foundation (LD22H190001, J.J., H.Z.); the Explorer Program of Zhejiang Municipal Natural Science Foundation (LQ23H100001, H.Z.). CanSino Biologics contributed to the study design and clinical data collection; CanSino Biologics coauthors revised and approved the final version of the manuscript. | PMC10409730 | ||
Author contributions | RECRUITMENT | H.L., J.J., and H.Z. were the principal investigators who designed and performed the research and coordinated the study; N.X., X.H., P.Q., Q.H., Y.L., and J.Y. led and participated in the site work, including the recruitment, follow-up, and data collection; S.W., J.F., L.D., Y.X., S.Z. and B.X. supervised the study; H.Z., Q.H., Y.L., and J.Y. were responsible for laboratory analyses; H.Z. and R.D. did the statistical analysis and wrote the manuscript. X.H., H.L., and J.J. interpreted the data and revised the manuscript. All authors critically reviewed the manuscript and approved the final version. | PMC10409730 | |
Peer review | PMC10409730 | |||
Data availability | The raw data on demographics and clinical status of participants, are protected and not available due to data privacy laws. The processed data are available by specific request to the corresponding author Huakun Lv(hlv@zj.cdc.cn). | PMC10409730 | ||
Competing interests | Y.X., S.Z., and B.X. are employees of CanSino Biologics and contributed to the conceptualization of the study (clinical protocol and electronic case report form design) but did not participate in the analysis or interpretation of the data presented in the manuscript. All other authors declare no competing interests. | PMC10409730 | ||
References | PMC10409730 | |||
Background | denture, edentulous, Denture | Denture adhesives can be useful in improving patients’ satisfaction with complete dentures. However, comparison clinical trials are lacking. The purpose of this randomized clinical trial was to assess the satisfaction of edentulous patients and their oral health impact profile when provided with 3 types of denture adhesives. | PMC10731830 | |
Methods | denture, edentulous | Sixty-four completely edentulous patients seeking complete dentures for their first time were randomly divided into 3 groups. Each group received a set of complete dentures, which were adjusted at review appointments until participants reported no complaints. After 1 month of using the dentures, participants rated their overall satisfaction and their satisfaction regarding comfort, retention, stability, and efficiency of mastication and speech on a 100-mm visual analog scale (VAS). Participants also filled out the oral health impact profile for edentulous patients (OHIP-EDENT) questionnaire. Each group was then given 1 type of denture adhesive to use. Group C received Corega Ultra denture fixative cream (GlaxoSmithKline), Group O received Olivafix (Bonyf), and Group S received Sea. Bond adhesive strips (Sea.Bond). Mann-Whitney U test was used to analyze the differences in VAS scores before and after using the adhesive within each group and Wilcoxon-signed rank test was used to compare OHIP scores and total OHI | PMC10731830 | |
Results | Significantly higher VAS values were detected in all groups and significantly lower values for many OHIP items in addition to total OHIP values were detected in all groups after using the adhesives ( | PMC10731830 | ||
Conclusions | denture adhesives, edentulous | Using denture adhesives for completely edentulous patients resulted in higher patient satisfaction as indicated by higher VAS scores as well as improved quality of life as indicated by lower OHIP-EDENT scores after using the adhesives. These improvements were not dependent on the type of adhesive, except for ease of cleaning as adhesive strips were easier to clean than paste type adhesives. | PMC10731830 | |
Trial registration | This trial was registered at ClinicalTrials.gov (ID: NCT05496283) on 11/08/2022. | PMC10731830 | ||
Keywords | PMC10731830 | |||
Background | denture, denture adhesives, edentulous | Complete edentulism is one of the major challenges facing the elderly populations. The majority of these patients experience difficulties with different oral functions including chewing, eating, and speaking. These difficulties can profoundly affect their oral health-related quality of life [The retention of complete dentures depends on the the interaction of various physical mechanisms, including adaptation to the supporting tissues, the presence of thin film of saliva between the intaglio of the denture and tissues, adequate peripheral edge extension, and atmospheric pressure [Denture adhesives are commercially available, nontoxic, nonmedical soluble products that have attracted more attention since guidelines for their use were published in 2019 by the Oral Health Foundation [Numerous studies have consistently demonstrated that denture adhesives help improve the retention and stability of complete dentures, improving the quality of life and satisfaction of patients [Although denture adhesives are widely accepted by patients, dental professionals have been reluctant to endorse them. Patients may use denture adhesives indiscriminately without proper prescription by the dentist, leading to dissatisfaction [The aim of this randomized clinical trial was to compare the reported outcomes and oral health impact profile for edentulous patients before and after using 3 different types of denture adhesives. The null hypotheses were that there would be no significant differences in patient satisfaction, as measured by visual analog scale (VAS) scores or oral health impact profile for edentulous patients (OHIP-EDENT) scores before and after using each type of adhesives, and that these differences would not be significant between the 3 types of adhesives. | PMC10731830 | |
Methods | dry dentures, edentulous, Denture, denture adhesives, tooth, denture | This study was designed as a randomized, single-blind, clinical trial. The study was conducted in accordance with the World Medical Declaration of Helsinki and conformed to the Consolidated Standards of Reporting Trials (CONSORT) statement for randomized clinical trials [All participants were completely edentulous patients seeking new complete dentures at the prosthodontics specialty clinics at a University Hospital. Only participants with normal alveolar ridge volume and resilience were included [Inclusion CriteriaThe fabrication of all dentures was performed by 2 experienced prosthodontists (N.E., Y.O.) and laboratory steps were performed by an experienced dental laboratory technician. After the primary impressions were made from impression compound modeling plastic material (Impression Compound; Kerr Corp., Orange, CA), they were sent to the dental laboratory where they were poured using Type III dental stone (Microstone; Whip Mix Corp., Louisville, KY) to produce preliminary casts, on which custom trays were fabricated from light-polymerizing resin sheets (Vertex Light Curing Trayplates; Vertex-Dental, Zeist, Netherlands). Custom trays were consequently border molded using impression compound modeling plastic (Kemco Tracing Sticks Green; Kemdent, Swindon, UK), and used for taking definitive impressions by using zinc oxide eugenol (Outline; Cavex, Haarlem, Netherlands). The impressions were then used to produce master casts on which record bases (Vertex Light Curing Trayplates, Vertex-Dental, Zeist, Netherlands) and wax occlusal rims (Cavex Set Up Regular Modeling Wax; Cavex, Haarlem, Netherlands) were fabricated which were later used for recording the maxillomandibular relationship. The casts were then mounted on an average value articulator (Gysi simplex OU-H3; COMATSU, Saitama, Japan), and tooth arrangement was done accordingly. After the clinical evaluation of the waxed dentures, they were sent to the dental laboratory where they were then flasked (Hanau Flask and Compress; Pearson Dental Supply Co, Sylmar, CA) and processed with heat-polymerizing acrylic resin (Lucitone 199; Dentsply Sirona, York, PA). After finishing and polishing of the dentures, they were then delivered and participants were given review appointments for post-delivery adjustments until the participants reported no further complaints. Participants were then given a review appointment after 1 month.At the review appointments, after using the dentures for a month with no denture adhesives, the participants evaluated their satisfaction with the dentures on a horizontal 100- mm VAS based on the criteria suggested by Celebic and Knezovic-Zlataric [Participants were subsequently given 1 type of denture adhesives according to the allocated group found in the sealed envelope. The C group received Corega Ultra denture adhesive (GlaxoSmithKline Brazil Ltda., Rio de Janeiro, Brazil), the O group received OlivaFix denture adhesive Cream (Bonyf, Heiligkreuz 16, Vaduz, Liechtenstein) and S group received Sea.bond denture adhesive seals (Sea.Bond, White planes, NY, USA). Adhesives used and their composition are shown in Table Denture adhesive materials used in this study, their manufacturers and compositionParticipants were given instructions for using and cleaning the denture adhesives. Participants in group C were instructed to apply the adhesive on clean and dry dentures, once a day, away from the edges as shown in the diagram on the adhesive package, rinse mouth before use, press dentures in place firmly and bite down for few seconds to secure hold. For adhesive removal, participants were instructed to remove the adhesive using warm water and soft brush and use COREGA Cleanser (GlaxoSmithKline Brazil Ltda., Rio de Janeiro, Brazil) for more thorough cleaning.Participants in group O were given similar instructions, according to the leaflet provided with the adhesive and were instructed to clean mouth and dentures properly if adhesive residues remain using a clean paper towel. Participants in group S were instructed to place dry Sea. Bond seals, white side up, onto clean dry dentures, trim any overlap with scissors, lightly moisten and gently tap seal with fingertips, put denture in mouth and bite down evenly for 5 seconds. Participants were instructed to remove the seal at the end of the day by lifting the corner and peeling it away and to change seals daily. During the month of using the adhesive, weekly phone calls were made to each participants to ensure their compliance with the instructions provided.. All participants were finally reviewed after 1 month to fill out the same forms again.Dentists who performed this study were blinded to which type of denture adhesive was given to the participants. Data collection was done by a dentist who did not participate in the treatment and was unaware of the allocated groups. A total of 60 participants were needed to detect a difference of 10 mm on the 100-mm VAS with 90% power (a = .05). To compensate for potential dropouts, 73 patients were originally included in the study, among which 9 were lost after they were given the denture adhesives. 64 participants were eventually included, with C group = 20, O group = 22, and S group = 22. This is illustrated in the flow chart in Fig. Study flowchart showing the numbers of participants in each group during the different stages of the studyStatistical analyses were conducted by using a statistical software package (IBM SPSS Statistics, v22.0; IBM Corp). The data were inspected for normality by using the Kolmogorov-Smirnov and Shapiro-Wilk tests, and the results indicated that both VAS data and OHIP-EDENT were not normally distributed ( | PMC10731830 | |
Results | Seventy-three participants were initially recruited for this study. However, 9 of them didn’t show up for the second review appointment, resulting in a dropout rate of 12%. As a result, 64 participants were eventually included in this study. The sample consisted of 39 men (61%) and 25 women (39%). The age of the participants ranged between 48 and 83 years with Mean (M) ± standard deviation (SD) of 63.8 ± 9.3 years. Characteristics of the participants included in this study are illustrated in Table Characteristics of the participants included in the studyThe results of the statistical analyses of this study are illustrated in Tables Mann – Whitney U test results showing medians and standard deviations for within group analyses of the differences in VAS scores before and after using the adhesives. * Indicates statistical significance at Wilcoxin-Signed rank test results showing medians and standard deviations for within group analyses of the differences in OHIP scores before and after using the adhesives. * Indicates statistical significance at Results of Kruskal Wallis test showing Results of Kruskal Wallis test showing | PMC10731830 | ||
Discussion | xerostomia, impaired manual dexterity, candidiasis, edentulous, mandibular dentures, denture stomatitis, denture adhesives, denture | CANDIDIASIS, XEROSTOMIA, DISEASES | This study aimed to investigate the effects of different types of denture adhesives on complete denture patient satisfaction and oral health-related quality of life. The results showed that the use of denture adhesives significantly improved patient satisfaction scores and OHIP scores in all 3 groups, except for the ease of cleaning of the dentures before and after adhesive use in groups O and S. However, there were no significant differences in these effects between the 3 groups, except for the difference in ease of cleaning between groups C and S.The findings of the present study were consistent with those of previous studies that reported positive effect for using denture adhesives [In this study, allocation of the participants was conducted by a coordinator so that the evaluators could be blinded [In our study, we did not find any significant differences in perceived adhesive effectiveness between the types of adhesives that were tested. This outcome stands in contrast to prior research that highlighted distinctions between various adhesive types [The complete removal of adhesive from dentures is important for the hygiene and the stability of the dentures [In our study, patients noted that Sea.Bond adhesive was notably easier to clean off the denture surface compared to Corega adhesive, attributed to its strip-based nature. This can make such type of adhesives an attractive option, especially for older people with impaired manual dexterity, especially that cream adhesives are usually transparent or pink in color and difficult to identify on denture surfaces [As the correlation between objective assessments and patient satisfaction has been reported to be poor [One of the limitations of this study was that only one follow-up measurement was considered although masticatory performance, patient satisfaction, and oral health-related quality of life are expected to improve with time [The extent of bone resorption has been highlighted in previous studies as a factor influencing satisfaction with dentures and OHIP-EDENT [The duration of denture use can influence the subjective assessment of new dentures. Prior studies have shown that patients with previous denture experience tend to exhibit greater satisfaction with new dentures, while individuals who have been edentulous for a short period or are first-time denture wearers may express higher dissatisfaction with new dentures [Our results showed that general satisfaction as well as all other aspects were improved by the use of denture adhesives. Therefore, it can be concluded that the improvement of general satisfaction here was a result of improvement of all factors including satisfaction with mandibular and maxillary dentures and factors such as esthetics, speech, stability, comfort, and the ability to chew. This disagrees with previous studies which concluded that only mandibular dentures influenced directly the overall satisfaction of denture wearers as their retention and comfort were improved after adhesive use and that speech and esthetics were not affected by adhesive use [Denture adhesives were reported in some previous studies to have some negative aspects including increased residual ridge resorption, development of oral diseases such as denture stomatitis and candidiasis especially in patients with xerostomia [ | PMC10731830 |
Conclusions | denture adhesives, edentulous | Within the limitations of this study, the following conclusions can be withdrawn:Using denture adhesives for completely edentulous patients resulted in higher patient satisfaction as indicated by higher VAS scores as well as improved quality of life as indicated by lower OHIP-EDENT scores after using the adhesives.These improvements were not dependent on the type of adhesive, except for ease of cleaning as adhesive strips were easier to clean than paste type adhesives. | PMC10731830 | |
Acknowledgements | Not applicable. | PMC10731830 |
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