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Results | Calcium excretion (mmol/24 h) was − 1.2877 + 0.646*[Ca] | PMC10227114 | ||
Conclusion | DEMINERALIZATION | During citrate CVVH, calcium balance was negative in most patients, despite supplementation of calcium based on plasma ionized calcium levels. This may contribute to demineralization of the skeleton. We propose that calcium supplementation should be based on both plasma ionized calcium and a simple calculation of calcium excretion by CVVH. | PMC10227114 | |
Graphical abstract | PMC10227114 | |||
Supplementary Information | The online version contains supplementary material available at 10.1007/s40620-022-01482-y. | PMC10227114 | ||
Keywords | PMC10227114 | |||
Introduction | bleeding | BLEEDING, COMPLICATIONS | Systemic anticoagulation during continuous venovenous hemofiltration (CVVH) is associated with bleeding complications. Citrate-based regional anticoagulation has a lower risk of bleeding [An alternative for guiding calcium supplementation by blood ionized calcium concentrations is monitoring the daily loss of calcium by CVVH. This is possible by measuring the calcium concentration in the ultrafiltrate. Alternatively, daily calcium excretion in the ultrafiltrate could be calculated using routinely available CVVH parameters and the blood calcium concentration.In the published literature, we were able to find two mathematical models to calculate calcium loss during citrate CVVH, both from the same study group in Shanghai, China. Neither of these models have been validated in independent populations of patients [Aim of this study is to develop and to validate an equation to calculate calcium loss in CVVH ultrafiltrate using routinely available CVVH parameters and blood calcium concentration, and to apply this equation to calculate the effects of CVVH on calcium losses and calcium balance in a retrospective cohort of ICU patients treated with CVVH with citrate anticoagulation. | PMC10227114 |
Methods | BLOOD, CLOT | This study consisted of two parts. First a model was developed to calculate calcium excretion by CVVH and, second, this model was used to retrospectively study calcium balance in CVVH patients during a 7-years period. The development and validation of a model to calculate calcium excretion by CVVH was performed as a retrospective cohort study in all consecutive patients, 18 years or older, treated with CVVH and citrate anticoagulation in the ICU of the Leiden University Medical Center (LUMC) from January 1st, 2021 until December 31st, 2021. The LUMC has a 24-bed mixed medical and surgical ICU.The retrospective calculation of calcium losses and calcium balance in ICU patients on citrate anticoagulated CVVH was performed in all consecutive patients, 18 years or older, treated with CVVH and citrate anticoagulation in the ICU of the Leiden University Medical Center (LUMC) from January 1st, 2014 until July 1st, 2021.As part of our local CVVH protocol, during 2021, total calcium was measured in an ultrafiltrate sample taken at 6:00 a.m. (EST tube, prod. no: 362725, Becton Dickinson, Rutherford, N.J., USA) on a Cobas 8000 Modular c702 system (Roche Diagnostics; Mannheim, Germany). For this study, we used measurements of total calcium and free calcium determined in the blood at the same time. Total calcium was analyzed in serum (3.5 mL SST(TM) II PET tube with clot activator (silica) and separating gel, prod. no: 367957, Becton Dickinson) using the Cobas 8000 Modular c702 system. Ionized calcium was analyzed in heparin-balanced blood (blood gas syringes RAPIDLyte, prod. no: 00925045, Siemens Healthcare, Sudbury, UK) by an ion-selective electrode method using the RAPIDPoint 500 Blood Gas System (Siemens Healthcare, Erlangen, Germany). Before analysis on the Cobas 8000 systems, samples were centrifuged (RCF 3000Citrate CVVH was performed using PrismaflexAccording to our protocols, patients received Nutrison Protein Plus enteral feeding (Nutricia, Zoetermeer, the Netherlands), 1 ml/kg body weight/h, containing 22 mmol calcium per liter) or 1 ml/kg/h parenteral feeding (SmofKabiven, Fresenius Kabi, Huis ter Heide, the Netherlands) containing 2.53 mmol calcium per liter. | PMC10227114 | |
Statistical analysis | Statistical analyses were made in SPSS version 25.0. For the development of the equation to calculate calcium loss by CVVH ultrafiltrate, the population of patients treated with CVVH in 2021 was randomly divided into a development and a validation set, both containing all measurements of a subset of 50% of patients. A mixed linear model was constructed with CVVH calcium excretion as a dependent variable, ultrafiltrate volume times total calcium concentration in plasma (UF*[Ca]The performance of the built model was validated in the independent validation set and reported as the mean of the absolute errors (differences between measured and predicted values). Differences between means in subgroups by blood flow, pre-dilution/post-dilution ratio and plasma ionized calcium were analyzed by one-way Anova. In the same validation population, we validated two models that were previously published. One model by Yu and coauthors: Calcium excretion by CVVH (mmol/h) = (0.0006938*total_ultrafiltrate(ml/min) + 0.7983)*calcium(mmol/l)*(60/1000)*(21.42 + 0.35*total_ultrafiltrate(ml/min)) [For the retrospective analysis of calcium balance during CVVH in ICU patients admitted from 2014 until July 2021, CVVH settings were retrieved on an hourly basis from the Patient Data Management System (Metavision, iMD soft, Tel Aviv, Israel). For calculation of the calcium excretion in the CVVH ultrafiltrate, we applied the equation that we developed and validated in the first part of this study. Administered calcium was calculated as the sum of calcium in the substitution fluid and calcium given intravenously. CVVH calcium balance was calculated as administered calcium minus the calcium excretion in ultrafiltrate without taking into consideration the amount of calcium lost in urine and stools and calcium intake via feeding. | PMC10227114 | ||
Results | HF1400, 127,897 | From January 1st, 2021 until December 31st, 2021, 765 daily measurements of calcium excretion in CVVH ultrafiltrate in 84 patients were analyzed for this study. Characteristics of patients and the CVVH episodes are shown in Table Characteristics of analyzed CVVH episodes (days) and patients used for developing the model to calculate calcium loss by CVVH ultrafiltrate (development) and for validation of the modelIn the development set, using a mixed linear model, we found a linear association between daily calcium excretion in the ultrafiltrate (dependent variable) and the product of plasma calcium and ultrafiltration flow ([Ca]Adding the potential covariates, i.e., citrate dose, ratio of pre-dilution to post-dilution, and used filter (HF1400 or ST150), did not improve the fit of the model (Supplementary Table 1).Figure Bland–Altman plot showing the association between the difference between calculated calcium excretion and measured calcium excretion in ultrafiltrate (From January 1st, 2014 until July 1st, 2021, 788 patients were treated with CVVH and citrate anticoagulation (Table Characteristics of patients (During the study period, 129,752 CVVH episodes (days) were analyzed, 127,897 with the HF1400 filter and 1855 with the ST150 filter. Substitution fluid was Biphozyl (Calculated calcium excretion by CVVH was 105.8 ± 19.3 mmol/24 h. Calcium administration by substitution fluid and by intravenous infusion was 92.9 ± 23.9 mmol/24 h. The CVVH calcium balance was − 12.0 ± 20.0 mmol/24 h.The mean number of CVVH days per patient was 6.7 ± 9.4 days. Cumulative CVVH calcium balance was − 86.3 ± 251.4 mmol (range − 3687 to 448 mmol). Cumulative CVVH calcium balance by time on CVVH is shown in Fig. Cumulative CVVH calcium-balance by time on CVVH (hours) in 788 patients treated with CVVH in the ICU. Calcium-balance = calcium supplementation by CVVH substitution fluid + intravenous calcium administration – calcium loss in ultrafiltrate. Calcium loss (mmol/24 h) calculated as − 1.279 + 0.646 * [Ca]In a population of patients admitted from 2014 to 2020, all treated using a protocol with calcium supplementation aiming at a target plasma ionized calcium greater than 0.9 mmol/l, the calculated daily mean calcium excretion by CVVH was higher with increasing plasma ionized calcium concentrations (data not shown). The mean daily CVVH calcium balance in subgroups by blood ionized calcium concentrations is shown in Fig. Mean and SD of daily CVVH calcium balance by plasma concentration of ionized calcium in patients admitted to the ICU from January 1st, 2014 until December 31st, 2020 with target [CaIn patients with a [CaThe mean [Ca] | PMC10227114 | |
Discussion | fits, trauma | In this study we present a simple mathematical equation to calculate calcium-excretion in the ultrafiltrate during CVVH with citrate anticoagulation using routinely available parameters. Using this equation, we found that in a population of ICU patients treated with citrate anticoagulated CVVH, cumulative CVVH calcium balance was negative in the majority of patients even if plasma concentrations of ionized calcium were normal and well above the commonly advocated target level of 1.0 mmol/l [Our mathematical model fits the data very well. In an independent, separate population from our ICU, the mean absolute error in the estimation of calcium-loss by CVVH was 4.8 mmol/24 h (4.5% of mean daily calcium excretion). We found that the performance of our model was better in patients treated with the HF1400 filter than in patients treated with the ST150 filter, but the difference was only small (mean absolute error 4.0 ± 4.2 mmol/24 h vs. 5.6 ± 5.2 mmol/24 h, The performance of our model was better than that of two different mathematical models that were previously published [We found that in ICU patients, CVVH with citrate anticoagulation and calcium supplementation guided by the plasma ionized calcium concentration resulted in a negative CVVH calcium balance of mean − 12.5 ± 20.4 mmol/24 h. The mean cumulative CVVH calcium balance was dependent of the time on CVVH. Five percent of patients had a cumulative CVVH calcium balance that was more negative than − 475 mmol (19 g). Normal total body calcium is approximately 1000During the major part of this study we adhered to a target ionized calcium concentration of 0.9–1.1 mmol/l, in accordance with recommendations in the literature [During the last 6 months of our study, due to a change in our local CVVH protocol, we adhered to a higher ionized calcium target of 1.15–1.30 mmol/l. Interestingly, mean plasma concentrations of ionized calcium were only slightly higher compared with the period with lower target plasma calcium, but the rate of calcium supplementation was higher and CVVH calcium balance changed from negative to positive. The likely explanation for this is that plasma calcium levels were hardly determined by the rate of calcium supplementation but much more by homeostatic mechanisms of the body [Some limitations of our study should be discussed. First, from a theoretical point of view, it is likely that factors not included in our model could influence calcium excretion during CVVH. The concentration of citrate used for anticoagulation will influence the ratio of protein-bound and non protein-bound calcium in the blood of the CVVH circuit and thereby the filtration of calcium to the ultrafiltrate. Likewise, the sieving coefficient of a filter is influenced by the amount of time a filter is in use. However, citrate dose and type of filter did not add to the performance of our model, and the results of our validation show that the influence of these factors is very limited. Second, validation was performed in a separate patient population, but treated in the same ICU and using the same equipment and protocols. Before using the model in other settings, its performance should be confirmed in those circumstances. This could be easily done by direct measurement of total calcium concentration in the ultrafiltrate in a number of patients. Finally, in our calculation of calcium balance we only considered calcium losses by CVVH and calcium intake if given intravenously or as part of the CVVH substitution fluids. There is additional intake by enteral or parenteral feeding and some extra losses in the urine if there is some residual kidney function. However, in a study in trauma patients in the ICU calcium losses in urine were low (mean 0.2 mmol/day in patients on renal replacement therapy and mean 3.2 mmol/day in patients without renal replacement therapy) and negligible compared to losses in the CVVH ultrafiltrate [ | PMC10227114 | |
Conclusion | HYPERCALCEMIA | During citrate anticoagulated CVVH, and following recommendations for calcium supplementation from the literature, a negative calcium balance was commonly found. Adhering to higher target levels for plasma ionized calcium will lower this risk, but can not prevent negative calcium balances in patients who have some degree of hypercalcemia, as is frequently present in ICU patients. We present a validated formula to easily calculate calcium excretion in the CVVH ultrafiltrate from plasma calcium concentrations, ultrafiltrate flow and CVVH blood flow. Our equation may be used at the bedside to help avoid calcium loss from the skeleton. | PMC10227114 | |
Author contributions | MP | EJ, FR and CEK set up the study design. MV and MP collected the data. All authors contributed to the interpretation of the data and the writing of the manuscript. All authors read and approved the final manuscript. | PMC10227114 | |
Funding | For this study there was no external funding. | PMC10227114 | ||
Availability of data and materials | The datasets analyzed during the current study are available from the corresponding author on reasonable request. | PMC10227114 | ||
Declarations | PMC10227114 | |||
Conflict of interest | On behalf of all authors, the corresponding author states that there is no conflict of interest. | PMC10227114 | ||
Ethical approval | The medical ethics committee (MEC) of the Leiden University Medical Center was informed and had no objection to this study. According to Dutch legislation, there was no need for informed patient consent, since this concerned a retrospective study on anonymized, routinely collected data (MEC waiver G21.169 and G21.191). | PMC10227114 | ||
References | PMC10227114 | |||
Background | Anatomy is a crucial part of medical education, and there have been attempts to improve this field by utilizing various methods. With the advancement of technology, three-dimensional (3D) materials have gained popularity and become a matter of debate about their effectiveness compared to two-dimensional (2D) sources. This research aims to analyze the effectiveness of 3D PDFs compared to 2D atlases. | PMC10722710 | ||
Methods | This study is a randomized controlled trial involving 87 Year-1 and Year-2 medical students at Gazi University Faculty of Medicine, Turkey. The study was conducted in two steps. In Step-1, students were randomized to watch lecture videos on liver anatomy and male genitalia anatomy supplemented with either a 3D PDF (intervention group) or 2D atlas (control group) images. Following the video lectures, a test (immediate test) was administered. In Step-2, the same test (delayed test) was administered 10 days after the immediate test. The test scores were compared between the intervention and control groups. In addition to the descriptive analyses, Chi-square and Mann-Whitney U tests were performed. | PMC10722710 | ||
Results | In the immediate test, while there was no significant difference between the groups for the liver test ( | PMC10722710 | ||
Conclusion | 3D PDF is more effective than 2D atlases in teaching anatomy, especially to initial learners. It is particularly useful for teaching complex anatomical structures, such as male genitalia, compared to the liver. Hence, it may be a valuable tool for medical teachers to utilize during lectures. | PMC10722710 | ||
Keywords | PMC10722710 | |||
Introduction | cadaver dissections | Medical education requires a holistic approach to the human body. Learning anatomy is one of the most essential elements in the preclinical education process of medical students [Throughout the years, various methods have been utilized for anatomy education. Traditional approaches included cadaver dissections and physical models, which provided a three-dimensional (3D) perspective. Additionally, two-dimensional (2D) materials such as atlases, chalk drawings, and slide presentations have played a significant role in facilitating the study outside of the laboratory. However, since these materials are limited in providing stereoscopic sight, they were highly dependent on an individual’s cognitive abilities to visualize the structures [Over time, due to reduction of laboratory hours [The literature on this topic demonstrates variations in the effectiveness of these methods when compared to one another. While some have compared physical models to computer-based 3D anatomy programs and found that 3D digital models are less effective [The utilization of these models, whether for self-learning by students or as teaching materials by instructors, may also have contributed to the emergence of disputed results in the literature. The majority of studies focused on students’ self-learning experiences. Nevertheless, according to Mayer’s cognitive theory of multimedia, the optimal way of learning for students is by using both images and narration in an electronic learning environment [Traditionally, teachers use slide presentations with atlas images and provide narration in lecture videos. Since 3D models were proposed as promising tools in many studies [In this randomized controlled experiment, we sought to investigate the effect of using 3D PDFs instead of 2D atlases on learning in lectures. The research question was “Is 3D PDF more effective than 2D atlas for using in the lectures as a visual material to teach complex and less complex anatomical structures to initial learners?”.We chose two different anatomical structures by considering their complexity to test the hypothesis that 3D PDF would be more effective than traditional atlas for teaching both complex and less complex anatomical structures. In order to investigate its effect on initial learning, the lecture videos were presented to medical students who had never studied the structures before. Subsequently, short and long-term retention performances were tested. The results of this study may shed light on the effectiveness of 3D PDF, which is a free and more accessible tool to teach anatomy. | PMC10722710 | |
Methods | PMC10722710 | |||
Trial design | LIVER | We followed the CONSORT statement [We evaluated the effectiveness of 3D PDFs and traditional 2D atlases in teaching two topics: Liver anatomy and male genitalia anatomy. These structures were specifically selected based on their different levels of anatomical complexity, with male genitalia anatomy being considered more complex in comparison to liver anatomy. The complexity was determined based on consensus among the research group that consists of professors, medical educationists, medical doctors, and medical students.The study consisted of two steps. In Step-1, students were randomly assigned to either the intervention group (who watched lecture videos included 3D PDFs) or the control group (who watched lecture videos included 2D atlas images). After the video lectures, a test (the immediate test) was administered to assess their retention performance. In Step-2, the same test (the delayed test) was administered 10 days after the immediate test. Figure
Trial process | PMC10722710 | |
Participants | RECRUITMENT | The study included Year-1 and Year-2 medical students in 2022–2023 term at Gazi University Faculty of Medicine, Ankara, Turkey. All Year-1 (n = 571) and Year-2 (n = 488) medical students were invited to the study through messaging groups covered the entire population. They had not yet taken anatomy classes on liver anatomy and male genitalia anatomy within the curriculum. Moreover, Year-1 students did not take any anatomy lecture yet. Therefore, the intervention served for them as a form of pure initial learning. It should also be noted that some of the Year-2 students were repeating their second year of study, which meant they had previously taken anatomy classes on the chosen topics. However, this did not pose any threat to the validity of the study since the grouping was randomized in Step-1 and their scores were excluded from the analysis in Step-2. Considering previous research and a power analysis table [The participation to the study was voluntary, and all participants provided informed consent. Recruitment was carried out via a participation form shared with all Year-1 and Year-2 medical students, resulting in a total of 179 students being recruited. Of these students, 87 participated in Step-1, and 72 out of the 87 students completed Step-2, as presented in Fig. | PMC10722710 | |
Materials | EXTERNAL GENITALIA | Educational materials included lecture videos on liver anatomy and male genitalia anatomy. The liver anatomy videos covered liver topography, gallbladder, and biliary system. The male genitalia anatomy videos covered male internal and external genitalia.Four videos (two for each topic) using the same written transcripts in each pair but different visual materials (images from Netter Anatomy Atlas [To assess the retention performance of the students, a written test with answer keys was developed for each topic based on the video content by the research team which comprised of medical students, medical doctors, specialists, and medical educationists who are experienced in assessment. The tests were piloted by medical students who had not participated in the test development process. After revisions based on feedback, the liver anatomy test had 10 questions worth a total of 20 points, while the male genitalia anatomy test had 19 questions worth a total of 40 points. Both tests contained open-ended and multiple-choice questions, and did not include any visual material. | PMC10722710 | |
Trial process | cognitive overload | The participants were randomly assigned to two groups (3D PDF and 2D atlas). Simple randomization was performed using SPSS v22.0 for Windows, ensuring that each participant had an equal chance of being assigned to either group.The trial took place at Gazi University Faculty of Medicine. The videos were displayed to the participants in a classroom setting through a projector. Two proctors were present in each classroom, and identical procedures were followed in all classrooms throughout the trial. At the beginning of the trial, the purpose of the study was explained to the participants, and they were instructed not to engage in any distracting or cheating behavior.In Step-1, all groups underwent the same process, including watching the liver videos twice (5 min + 5 min), completing the liver test (10 min), watching the genitalia videos twice (10 min + 10 min), and completing the genitalia test (20 min). The same videos were watched two times by considering that they had no prior learning on these topics and watching only once would lead to a cognitive overload. They were provided with printed versions of the video transcripts and were allowed to take notes while watching the videos. These paper prints were collected prior to administering each test. Step-1 lasted for one hour.In Step-2, the delayed test, which is identical to the immediate test, was administered 10 days after the completion of Step-1 to evaluate the difference in performance between the groups in the long-term. Multiple sessions were arranged to accommodate the availability of the participants, and they were instructed not to share information about the test with other participants between sessions to ensure the reliability of the study. They had not been informed that the tests will be identical. The delayed test was carried out in the same classroom settings with proctors.Both the immediate and delayed tests were administered as written exams (paper and pencil test), and their scoring involved at least two researchers using the answer key. If there were any disagreements in scoring, they were resolved with the help of the third researcher. | PMC10722710 | |
Statistical analysis | Statistical analyses were carried out using SPSS v22.0 for Windows. A In order to ensure that randomization worked well, the group characteristics in terms of gender, year, and repeating Year-2 were compared between the intervention group and the control group by using Chi-squared test.The Step-1 liver anatomy and male genitalia anatomy (immediate test) scores were compared between the groups to evaluate the difference in short-term retention. Since the data violated normality assumptions, Mann-Whitney U test was performed to investigate whether there was a significant difference in retention performance between the two groups.The same comparison was carried out in Step-2 (delayed test) for evaluating long-term retention. For the validity of the analysis, participants who were repeating Year-2 were excluded from the Step-2 analysis because they were not re-randomized into the groups. Due to the violation of normality assumptions, Mann-Whitney U test were performed to compare the scores of the two groups.Based on the fact that our participants comprised of Year-1 and Year-2 medical students, we conducted subgroup analyses (Mann-Whitney U test) both in the immediate test and the delayed test scores.To evaluate the reliability of the tests, Cronbach’s alpha values were calculated. The acceptable level of Cronbach’s alpha values was determined as 0.70 [Effect sizes were calculated using Cohen’s d, and were interpreted as small, medium, and large for values of 0.2, 0.5, and 0.8, respectively [ | PMC10722710 | ||
Results | PMC10722710 | |||
Participants | A total of 87 participants volunteered for the experiment. They were randomized into two groups: 3D PDF and 2D atlas. Group characteristics are shown in Table The 3D PDF (intervention) group had a female majority (65.9%) and the 2D atlas (control) group had again a female majority (58.1%). The two groups did not significantly differ in terms of gender, study year, and repeating Year-2 (87 participants took the immediate tests on liver and male genitalia immediately after watching each video about liver and male genitalia anatomy.
Participant Characteristics*Chi-squared test | PMC10722710 | ||
Immediate test | There was no significant difference between the performances of the 3D PDF group (Median = 15.00) and the 2D atlas group (Median = 17.00) in the liver test, U = 900.00, Z = -0.39, Among Year-2 medical students, neither in the liver test (
Statistical analysis of immediate and delayed tests*Mann-Whitney U test | PMC10722710 | ||
Delayed test | In the liver test, there was no significant difference between the performances of the 3D PDF group (Median = 12.00) and the 2D atlas group (Median = 9.50), U = 479.00, Z = -0.64, Year-1 students’ liver test performances did not differ significantly between the 2D atlas group (Median = 9.00) and the 3D PDF group (Median = 10.00), | PMC10722710 | ||
Item analysis | Item analysis was performed on both the immediate and delayed tests by calculating item difficulty and discrimination indices. In the immediate test, the mean difficulty and discrimination indices of 10 items in the liver test were 0.72 and 0.52, respectively, while they were 0.56 and 0.47 in the genitalia test. In the delayed test, the mean difficulty and discrimination indices of 19 items in the genitalia test were 0.51 and 0.43, respectively, while they were 0.42 and 0.62 in the liver test, respectively.In the immediate test, Cronbach’s alpha value was 0.70 in the liver test, and 0.78 in the genitalia test. In the delayed test, the value was 0.69 in the liver test, and 0.72 in the genitalia test. All of the values are above of or close to the acceptable level, which is 0.70. | PMC10722710 | ||
Discussion | a reduced number | Our study aimed to compare the effects of 3D PDF (intervention) and 2D atlas (control) on teaching anatomic structures with different levels of complexity in video lectures to initial learners. Their effects on short-term and long-term retention were assessed.While there were non-significant differences with little effect sizes between the intervention group and the control group in the liver tests (neither in the immediate nor in the delayed), medium effect sizes showed superiority of 3D PDF over 2D atlas in the immediate and the delayed genitalia tests. The effect sizes, which were 0.76 in the immediate test and 0.63 in the delayed test, were close to be classified as a large effect (0.80) [Our results demonstrated that 3D PDF is superior to 2D atlas for teaching the anatomy of male genitalia, which is a more complex structure, yet not for teaching the liver anatomy, which is a less complex structure, both in terms of short-term retention and long-term retention. Therefore, it indicated that if the complexity of the anatomical structures is high, teaching with 3D PDFs provides a better environment for initial learners than teaching with 2D anatomy atlases.A previous research [3D PDFs offer considerable practical benefits over 2D atlases in anatomy education, even though they are relatively recent material in anatomy education, not widely used by either teachers or students. Our findings suggest that 3D PDFs may be a favorable choice for teaching complex anatomical concepts, as stereopsis has a critical role in learning anatomy [This study has some limitations. First, it is a single-center study in a country with its unique context, therefore it may not be generalizable. Second, due to the discontinuation of a number of participants and the resulting uneven distribution of students repeating Year-2 between the groups, it was necessary to analyze the long-term scores with a reduced number of participants. While our goal was to minimize participant dropout by maintaining communication through e-messaging groups during the study, dropouts might have led to find a non-significant | PMC10722710 | |
Acknowledgements | We would like to express our gratitude to the students in Gazi University Faculty of Medicine who participated in this study. We are grateful to Korea Institute of Science and Technology Information (KISTI) for granting permission to use 3D PDFs for research purposes. | PMC10722710 | ||
Author contributions | Conceptualization: SK, FSE, YSK; Methodology: YSK, FSE, BE, SK; Data Collection: FSE, BE, SBK, ZRK, FEÇ, MÜ, MA, YSK; Analysis: BE, FSE, YSK; Interpretation: FSE, BE, SBK, ZRK, FEÇ, MÜ, MET, MA, YSK ; First Draft: FSE, BE, SBK, ZRK, FEÇ, MÜ, MET, MA ; Review and Editing: YSK, SK, IİB, ÖC ; All authors have read and approved the final manuscript. | PMC10722710 | ||
Funding | The authors received no financial support for the research, authorship, and publication of this article. | PMC10722710 | ||
Data availability | The dataset supporting the conclusions of this article is available in the Zenodo repository, accessible from 10.5281/zenodo.7830028. | PMC10722710 | ||
Declarations | PMC10722710 | |||
Ethics approval and consent to participate | All methods were carried out in accordance with relevant guidelines and regulations. All experimental protocols were approved by Gazi University Institutional Review Board (code: 2022 − 1073). Written informed consent was obtained from all subjects. | PMC10722710 | ||
Consent for publication | All participants gave written informed consent for publication. | PMC10722710 | ||
Competing interests | The authors declare that they have no competing interests. | PMC10722710 | ||
Previous presentations | Preliminary results of this study titled ‘3D PDF: A Promising Learning Tool for Anatomy Education’ has been presented at the AMEE 2023 Conference, August 26–30, 2023, in Glasgow, UK. | PMC10722710 | ||
References | PMC10722710 | |||
INTRODUCTION | RSV, pneumonia, human illness, bronchiolitis, RSV-associated lower respiratory tract disease | VACCINE VIRUS SHEDDING, RESPIRATORY DISEASE, VIRUS, PNEUMONIA, RESPIRATORY SYNCYTIAL VIRUS (RSV), CARDIOPULMONARY DISEASE, ADVERSE EVENTS, DISEASE, KENNEL COUGH, BRONCHIOLITIS | Respiratory syncytial virus (RSV) can lead to serious disease in infants, and no approved RSV vaccine is available for infants. This first in-human clinical trial evaluated a single dose of BLB201, a PIV5-vectored RSV vaccine administrated via intranasal route, for safety and immunogenicity in RSV-seropositive healthy adults (33 to 75 years old). No severe adverse events (SAEs) were reported. Solicited local and systemic AEs were reported by <50% of participants and were mostly mild in intensity. Vaccine virus shedding was detected in 17% of participants. Nasal RSV-specific immunoglobulin A responses were detected in 48%, the highest level observed in adults among all intranasal RSV vaccines evaluated in humans. RSV-neutralizing antibodies titers in serum rose ≥1.5-fold. Peripheral blood RSV F–specific CD4Intranasal RSV vaccine based on kennel cough vaccine component PIV5 is safe and immunogenic in humans.Respiratory syncytial virus (RSV) is the leading global cause of morbidity and mortality in infants due to infection-associated bronchiolitis and pneumonia, especially in those with underlying cardiopulmonary disease (RSV causes both upper and lower respiratory diseases. Recently, RSV prefusion F (preF) protein–based vaccines have been shown to be effective in reducing symptoms of RSV-associated lower respiratory tract disease in elderly (aged ≥60 years) in clinical trials and received approval for elderly (BLB201 is a live viral-vectored candidate RSV vaccine based on a parainfluenza virus 5 (PIV5) encoding the RSV F antigen. PIV5 is a negative-sense RNA virus and replicates in the cytoplasm of infected cells without a DNA phase in its life cycle. PIV5 is a component of the kennel cough vaccine commonly administered by intranasal route in dogs. Vaccinated dogs can shed virus up to 5 days after dosing, exposing humans to PIV5. However, although the vaccine has been used for 50 years, no known human illness has been reported from human exposure to vaccinated dogs ( | PMC10599610 |
RESULTS | PMC10599610 | |||
Participants and study conduct | A total of 30 subjects were enrolled in this phase 1 trial, and all received a single intranasal dose of BLB201 at 10 | PMC10599610 | ||
Trial cohort demographics. | *One participant dropped out of the study on day 8 (lost to follow-up). | PMC10599610 | ||
Safety | RSV infection | ADVERSE EVENTS, EVENTS, RSV INFECTION | After intranasal immunization with Teleflex MAD300, the safety and tolerability of BLB201 were monitored for 6 months. Participants recorded information of local and systemic adverse events (AEs) for 7 days after vaccination (solicited local and systematic events) and unsolicited AEs for 28 days using a memory aid. No serious AE (SAE) assessed as related to vaccine was reported, and no symptomatic RSV infection was reported during the 6-month trial period. In the 1-week period after vaccination, all solicited local AEs that were reported were mild in intensity (grade 1; | PMC10599610 |
Summary of local and systemic reactogenicity and AEs. | nausea/vomiting, myalgia, fatigue, fever, headache, chills | ADVERSE EVENT | Grading scale: Grade 1 = mild (awareness of a symptom but the symptom is easily tolerated); grade 2 = moderate (discomfort enough to cause interference with usual activity); grade 3 = severe (incapacitating; unable to perform usual activities; requires absenteeism from work or bed rest). AE, adverse event.In group 1, all solicited systemic AEs reported by 5 of 15 participants were mild in intensity and included fatigue, headache, and myalgia being reported by 5 of 15, 2 of 15, and 1 of 15 participants, respectively. In group 2, the solicited systemic AEs reported by 8 of 15 participants were mild or moderate in intensity and included fatigue, headache, and myalgia being reported by 2 of 15, 5 of 15, and 5 of 15 participants, respectively, as well as chills, nausea/vomiting, and breathing discomfort being reported by 1 of 15 for each symptom. The single episode of breathing discomfort was mild and resolved within 2 days after vaccination. No solicited fever was reported in either group. Throughout the 6-month study period, five medically attended AEs were reported by four participants (all in group 2), none of which was assessed as being related to study vaccine. | PMC10599610 |
Vaccine virus shedding and genetic stability | VIRUS | At day 1 before participants were immunized, no vaccine virus genomic RNA was detected as expected [i.e., below the lower limit of detection (LOD) by reverse transcription quantitative polymerase chain reaction (RT-qPCR)] in the nasal swabs of any participant ( | PMC10599610 | |
Vaccine-virus shedding. PIV5 viral genomic RNA detection by RTqPCR in individual BLB201 recipients at days 8 and 15. | The dotted line indicates the LOD at 4.6 log | PMC10599610 | ||
Immunogenicity | PMC10599610 | |||
Serum Ab titers
| All participants were seropositive for RSV nAbs at baseline, and the titer changes are presented in | PMC10599610 | ||
Serum RSV-specific Ab titers before and after vaccination. | ( | PMC10599610 | ||
Summary of RSV Ab and CMI response rates. | A positive seroresponse was defined as ≥1.5-fold rise from baseline for RSV F IgG and IgG. A positive nasal IgA Ab response was defined as ≥2-fold rise over baseline. CMI response was defined as >0.1% rise of sum of individual T cell secreting >1 cytokine after subtraction of baseline (before vaccination). CTL response was defined by the change in IFN-γ–producing CD8All participants were also seropositive for RSV F–specific serum IgA and IgG Abs at baseline (Overall, the results suggested that BLB201 boosted RSV-specific serum Ab levels in young adults (33 to 59 years old) and elderly (61 to 75 years old), although with greater magnitude in adults versus elderly. The fold increases in RSV-specific Ab titers inversely correlated with baseline titers. It is possible that the higher baseline titers were close to maximum levels.We next examined vector-specific immune responses. For PIV5 nAbs at baseline, 15 of 29 (52%) participants were seropositive as defined by a titer of 1:10 ( | PMC10599610 | ||
Serum PIV5 Ab titers before and after vaccination. | ( | PMC10599610 | ||
RSV F–specific IgA Ab titers in nasal swabs
| At baseline, RSV F–specific IgA Ab titers in nasal swabs were variable ranging from below the LOD to 514 (9.0 log | PMC10599610 | ||
Nasal IgA Ab titers before and after vaccination. | RSV IgA Abs | F-specific RSV IgA Abs by ELISA. Individual logOverall, the results suggested that BLB201 boosted RSV-specific nasal IgA levels in adults and elderly but to a lesser degree in elderly. Similar to results seen with systemic Ab responses, the fold increases in F-specific nasal IgA titers in both groups inversely correlated with baseline titers (fig. S2). | PMC10599610 | |
Cell mediated immunity
| At baseline, RSV F–specific CD4 | PMC10599610 | ||
RSV F–specific CD4 | (In both groups 1 and 2, T cells expressing a single T | PMC10599610 | ||
DISCUSSION | RSV infection, upper respiratory tract, nasal F-specific IgA Ab, RSV-specific nasal IgA, infection, human disease | INFECTION, VIRUS, RSV INFECTION | This clinical study of the PIV5-vectored RSV vaccine candidate BLB201 was the first in-human study for this vaccine and for the replicating PIV5 vector. The study showed that BLB201 administered as a single intranasal dose had an acceptable safety profile. Solicited local and systemic AEs were generally mild and only reported by approximately half of the vaccine recipients. No SAE related to vaccination was reported. This result is consistent with the long history of PIV5 vector’s use in dogs. The vector has been used in dogs for 50 years, and yet no human disease has ever been reported from human exposure to PIV5-immunized animals. In this phase 1 study, approximately half of the enrolled participants were PIV5 seropositive based on nAb titer >1:10 at baseline, suggesting that asymptomatic exposures occur in a high percentage of the U.S. population. The safety profile of BLB201 is comparable to other intranasal live virus–based vaccines including live-attenuated RSV vaccines, MEDI-534, and PanAd3-RSV in adults (Although RSV preF protein–based vaccines have been approved for reducing symptoms in lower respiratory tract of RSV-infected elderly, an RSV vaccine that prevents symptomatic infection in lower respiratory tract and even symptomatic infection in upper respiratory tract is highly desirable. While it is thought that serum Ab, nasal IgA, and CMI all contribute to protection against symptomatic RSV infection, RSV-specific nasal IgA is thought to be the most critical in preventing RSV infection (There are several intranasal RSV vaccines advanced to human clinical trials. Most are live-attenuated RSV vaccines. Because of the existing anti-RSV antibodies, these live-attenuated RSV vaccines did not generate detectable immune responses in RSV-seropositive people (The induction of cytotoxic CD8The rate of the induction of nasal F-specific IgA Ab response was higher in the younger age group than the elderly group, indicating that, similar to many other vaccines, there was an age-dependent difference in magnitude for responses to BLB201 in nasal IgA Ab. This may be attributed to age-related immunosenescence (In this study, approximately 50% (group 1) and 40% (group 2) of participants were seropositive at baseline for PIV5 nAbs. Seropositivity to PIV5 in this study was a little higher than previously reported at about 30% (The shedding of vaccine virus in nasal swabs after vaccination was transient, lasting less than 4 weeks, suggesting that BLB201 has the capacity to replicate in the nasal cavities of RSV-experienced adults. This self-limiting infection in the respiratory mucosa by BLB201 may help in the development of RSV-specific immunity. Although vaccine virus shedding was only identified in five participants, it is plausible that it had occurred in other participants but at earlier time points than were sampled here, i.e., within 1 week after vaccination. The result that over 93% participants had robust anti-RSV F cellular immune responses is consistent with replication of BLB201 in humans: BLB201 likely entered human cells and expressed RSV F that was presented by major histocompatibility complex I in infected cells.The genetic stability of the viral vaccine vector is important for its use in humans. MEDI-534 was not stable in infants, resulting in the termination of its clinical development (In conclusion, BLB201 is a PIV5-based intranasal RSV candidate vaccine that demonstrated safety and immunogenicity in this phase 1 study. The ability of BLB201 to boost pre-existing cellular, humoral, and mucosal responses in adults supports further clinical evaluation of this approach in infants and adult populations. | PMC10599610 |
MATERIALS AND METHODS | PMC10599610 | |||
Study design and vaccination | The phase 1 clinical trial of PIV5-RSV vaccine (BLB201; Primary outcome measures included (i) solicited AEs (days 1 to 8) and (ii) unsolicited AEs (days 1 to 29). Secondary outcome measures included (i) serum IgG titers to RSV protein (days 15 and 29), (ii) SAEs (days 1 to 181), and (iii) AEs of special interest (AESIs) including new onset chronic medical conditions and medically attended AEs (days 1 to181). | PMC10599610 | ||
Safety assessments | SAEs, Toxicity | EVENTS | The safety and tolerability of PIV5-RSV intranasal vaccine were assessed over the period of 6 months after vaccination. Participants recorded the information of local and systemic AEs for 7 days after vaccination (solicited local and systematic events) and unsolicited AEs for 28 days using a memory aid. SAEs and AESIs were collected at scheduled study follow-up visits or unscheduled visits for the full duration of the study (6 months). AEs were graded according to the U.S. Food and Drug Administration Center for Biologics Evaluation and Research Toxicity Grading Scale for Healthy Adult and Adolescent Volunteers Enrolled in Preventive Vaccine Clinical Trials guidelines. All unsolicited AEs were categorized by the investigator for possible causative association with vaccination (i.e., relatedness to vaccination). | PMC10599610 |
Vaccine shedding and genetic stability | VIRUS SHEDDING | Vaccine-virus shedding was analyzed by RT-qPCR of nasal swabs collected on days 1 (before vaccination) and days 8, 15, and 29 after vaccination. A regular sized flocked nylon swab was used to collect nasal secretion from one nostril, placed in 1-ml universal transport medium (VTM, Copan), and stored at −80°C until sample testing. RNA was extracted from 140 μl (group 2) or 560 μl (group 1) of nasal swab by the QIAmp Viral RNA Mini Kit (QIAGEN) and eluted in 40 μl of buffer. The primers targeted the trailer region of PIV5 genome to quantify PIV5-RSV vaccine virus genomic RNA. The PCR reaction mix included Luna Universal probe One-Step RT-qPCR (New England BioLabs), PIV5 trailer region primers/probe (sequence information is available upon request), and 8 μl of RNA in a QuantStudio 3 instrument (Thermo Fisher Scientific). The assay had a lower LOD of 4.6 logVaccine virus shedding samples with RNA genome levels greater than 5.0 log | PMC10599610 | |
Immunogenicity assessment | BLOOD, VIRUS, APC | Blood and nasal samples were collected at baseline (day 1, before vaccination), day 15, and day 29 before vaccination. To reduce sample variation, samples from the same participant were run on the same plate in a blinded fashion in all the assays. Serum RSV nAb levels were determined by a qualified RSV A2 microneutralization (MN) assay based on RSV-A2-rLuc reporter virus (RSV F–specific serum IgG and IgA Ab and nasal IgA Ab levels were determined by enzyme-linked immunosorbent assay (ELISA) assay using purified RSV F protein (25 ng per well; SinoBiological, catalog no. 11049-V08B) and twofold serial dilutions in blocking buffer (5% milk/0.5% bovine serum albumin in 1× KPL wash buffer (SeraCare) in duplicate. End-point titer was calculated by 4PL curve fitting using Prism and reported as reciprocal dilution. PIV5-specific IgG and nAb titers were determined by ELISA assay using PIV5 virus-coated plates and by PIV5-rLuc–based MN assay in Vero cells, respectively. The PIV5 IgG end-point titer was calculated by 4PL curve fitting and reported as reciprocal dilution. The PIV5 MN assay was performed similarly to the RSV-rLuc–based MN assay, except in duplicate instead of quadruplicate. Analysis of PIV5 MN was identical to the RSV-rLuc–based MN assay, and the nAb titer was defined as the reciprocal dilution that inhibited at least 50% signal of the virus control.Antigen-specific T cell frequencies were evaluated by intracellular cytokine staining assay using cryopreserved peripheral blood mononuclear cells (PBMCs) isolated from whole blood on day 1 (pre-vaccine dosing), day 15, and day 29. One million cryopreserved PBMCs were thawed in complete 10% fetal bovine serum (FBS) RPMI medium and rested overnight at 37°C before being incubated with an RSV F peptide pool from GenScript at a final concentration of 1 μg/ml in the presence of anti-CD28 ECD (1 μg/ml; Beckman Coulter, clone CD28.2), anti-CD107a fluorescein isothiocyanate (BD Biosciences, clone H4A3), and anti-CD49d (BD Biosciences, clone 9F10). In addition, PBMCs were stimulated with 1 μl of complete medium with 0.5% dimethyl sulfoxide (DMSO; negative control corresponding to the DMSO concentration of the RSV F peptide pool) or 1 μl of phorbol 12-myristate 13-acetate (PMA)/ionomycin [PMA (25 ng/ml) and ionomycin (1 μg/ml)] for negative and positive controls, respectively. After 2-hour incubation at 37°C, brefeldin A (10 μg/ml; BD Biosciences) were added and the cells were incubated for another 4 hours. The cells were washed with phosphate-buffered saline (PBS) and incubated with aqua viability dye (Invitrogen) at room temperature for 15 min. The cells were washed with PBS supplemented with 2% FBS and surface-stained at 4°C for 30 min with anti-CD3 Alexa 700 (BD Biosciences, clone SP34-2), anti-CD4 BV605 (BD Biosciences, clone L200), anti-CD8 BV450 (BD Biosciences, clone RPA-T8), and anti-CD95 phycoerythrin (PE)–Cy5 (BD Biosciences, clone DX2). The cells were washed with PBS with 2% FBS, fixed with Cytofix/Cytoperm (BD Biosciences), permeabilized with 1× Perm/Wash (BD Biosciences), and incubated with anti–IFN-γ PE-Cy7 (BD Biosciences, clone B27), anti–TNF-α allophycocyanin (APC)–Cy7 (BioLegend, clone Mab11), anti–IL-13 PE (Miltenyi Biotec, clone JES10-5A2.2), and anti–MIP-1β APC (eBioscience, clone FL34Z3L) antibodies at 4°C for 30 min. The cells were washed with 1× Perm/Wash and PBS with 2% FBS then resuspended in PBS/2% formaldehyde for acquisition on a BD FACSAria Fusion cell sorter. CD3 | PMC10599610 | |
Statistical analysis | Statistical analysis was performed using GraphPad Prism software (Version 9). Given the small sample size, statistical analysis was mostly descriptive and summative. | PMC10599610 | ||
Supplementary Materials | PMC10599610 | |||
This PDF file includes: | Figs. S1 and S2Click here for additional data file. | PMC10599610 | ||
REFERENCES AND NOTES | PMC10599610 | |||
Key Points | PMC10220519 | |||
Question | What is the effect of parent-led, infant-directed singing—initiated in the neonatal intensive care unit with support from a music therapist and extending 6 months after discharge—on parent-infant bonding at 6 and 12 months’ infant-corrected age? | PMC10220519 | ||
Findings | In this randomized clinical trial involving 213 families, mothers engaging in parent-led, infant-directed singing reported similar parent-infant bonding at 6 and 12 months’ corrected age as mothers receiving standard care only. | PMC10220519 | ||
Meaning | These results suggest that, although safe and accepted by parents, parent-led, infant-directed singing was no more effective at improving mother-infant bonding than standard care.This randomized clinical trial conducted in 5 countries examines the effect of parent-led, infant-directed singing on parent-infant bonding at 6 and 12 months. | PMC10220519 | ||
Importance | PRETERM BIRTH | Parent-infant bonding contributes to long-term infant health but may be disrupted by preterm birth. | PMC10220519 | |
Objective | To determine if parent-led, infant-directed singing, supported by a music therapist and initiated in the neonatal intensive care unit (NICU), improves parent-infant bonding at 6 and 12 months. | PMC10220519 | ||
Design, Setting, and Participants | This randomized clinical trial was conducted in level III and IV NICUs in 5 countries between 2018 and 2022. Eligible participants were preterm infants (under 35 weeks’ gestation) and their parents. Follow-up was conducted across 12 months (as part of the LongSTEP study) at home or in clinics. Final follow-up was conducted at 12 months’ infant-corrected age. Data were analyzed from August 2022 to November 2022. | PMC10220519 | ||
Intervention | Participants randomized to music therapy (MT) plus standard care or standard care alone during NICU admission, or to MT plus standard care or standard care alone postdischarge, using computer-generated randomization (ratio 1:1, block sizes of 2 or 4 varying randomly), stratified by site (51 allocated to MT NICU, 53 to MT postdischarge, 52 to both, and 50 to neither). MT consisted of parent-led, infant-directed singing tailored to infant responses and supported by a music therapist 3 times per week throughout hospitalization or 7 sessions across 6 months’ postdischarge. | PMC10220519 | ||
Main Outcome and Measure | Primary outcome was mother-infant bonding at 6 months’ corrected age, measured by the Postpartum Bonding Questionnaire (PBQ), with follow-up at 12 months’ corrected age, and analyzed intention-to-treat as group differences. | PMC10220519 | ||
Results | Of 206 enrolled infants with 206 mothers (mean [SD] age, 33 [6] years) and 194 fathers (mean [SD] age, 36 [6] years) randomized at discharge, 196 (95.1%) completed assessments at 6 months and were analyzed. Estimated group effects for PBQ at 6 months’ corrected age were 0.55 (95% CI, −2.20 to 3.30; | PMC10220519 | ||
Conclusions and Relevance | In this randomized clinical trial, parent-led, infant-directed singing did not have clinically important effects on mother-infant bonding, but was safe and well-accepted. | PMC10220519 | ||
Trial Registration | ClinicalTrials.gov Identifier: | PMC10220519 | ||
Introduction | Prematurity | PREMATURITY | Parent-infant bonding, an important contributor to quality of early parent-infant relationship and long-term infant health,Prematurity is associated with poorer cognitive development, mental health, and quality of life for the child, | PMC10220519 |
Methods | PMC10220519 | |||
Study Design | PREMATURE | Longitudinal Study of Music Therapy’s Effectiveness for Premature Infants and Their Caregivers (LongSTEP) was designed as a 2 × 2 factorial, multinational, pragmatic randomized clinical trial (RCT) evaluating longer-term effects of music therapy (MT) in neonatal intensive care unit (NICU) and after discharge on preterm infants and their caregivers until 12 months’ infant corrected age. | PMC10220519 | |
Participants | POLAND | We recruited participants from 8 NICUs (7 level III and 1 level IV) in Argentina, Colombia, Israel, Norway, and Poland, countries where social systems enable continual parental presence during infant hospitalization. Preterm infants that were born at less than 35 weeks’ gestational age, were likely to be hospitalized a minimum 2 weeks from inclusion, and had been declared by NICU staff as medically stable to start MT (typically after 26 weeks’ postmenstrual age) were eligible for enrollment if they had parents who (1) provided written, site-specific informed consent, (2) were willing to engage in at least 2 of 3 MT sessions per week, (3) possessed sufficient understanding of the respective national language(s) to answer questionnaires and participate in MT, and (4) possessed sufficient mental capacity to complete the intervention and questionnaires. | PMC10220519 | |
Randomization and Masking | Following completion of written informed consent and baseline assessments, participants were randomized to MT plus standard care or standard care alone during NICU using a computer-generated randomization list with ratio 1:1, in block sizes of 2 or 4 varying randomly, stratified by site, using an online system (Sealed Envelope Ltd). Only the first-born infant of multiple pregnancies was included and randomized, while multiple-birth siblings received a corresponding intervention for ethical reasons. Before discharge home, participants were randomized a second time to postdischarge MT or standard care in a 1:1 ratio using the aforementioned procedures. It was not possible to mask participants, clinicians, or data collectors due to nature of the intervention and outcome measures. | PMC10220519 | ||
Intervention | Infants and parents in the NICU MT group received 3 individual MT sessions per week throughout hospitalization, with maximum 27 sessions, lasting approximately 30 minutes each (with time in active music making depending upon infant tolerance). MT consisted of parent-led, infant-directed singing; our use of the concept denoted a reciprocal process wherein infants through their communicative behavior actively direct parents’ use of voice, while parents then direct their singing to infant responses in the moment. Music therapists collaborated with parents to interpret subtle infant communicative cues and supported parents’ attuned vocal responses to such. Cautious use of sung or toned voice was tailored to infant postmenstrual age and readiness to receive stimulation, and matched to infant breathing patterns, facial expressions, and movements to promote quiet alert state or sleep, depending upon the infant’s needs. Parental voice was positioned as a resource, | PMC10220519 | ||
Outcomes | Our primary outcome was mother-infant bonding measured by the Postpartum Bonding Questionnaire (PBQ) | PMC10220519 | ||
Statistical Analysis | In the absence of a generally agreed minimal clinically important difference for the PBQ, we designed the trial to have 80% power to detect a difference of 4 points (corresponding to Descriptive statistics characterizing the sample have been published elsewhere. | PMC10220519 | ||
Results | Of 213 infants randomized in NICU from August 2018 to April 2020, | PMC10220519 | ||
Study Flow Diagram | The second randomization forms the basis for all numbers thereafter. | PMC10220519 | ||
Baseline Characteristics Across 4 Study Arms | Abbreviation: MT, music therapy.For 206 participants who were randomized twice. | PMC10220519 | ||
Analysis of Covariance and Regression Results | depression, Depression, Anxiety, anxiety | DISORDER, REGRESSION | Abbreviations: ASQ-3, Ages and Stages Questionnaire, third edition; ASQ:SE-2, Ages and Stages Questionnaire: Social-Emotional, second edition; EPDS, Edinburgh Postnatal Depression Scale; GAD-7, Generalized Anxiety Disorder Assessment; PBQ, Postpartum Bonding Questionnaire; PSS, Parental Stress Scale.Based on a linear mixed-effects model including variables mother-infant bonding, maternal depression, parental anxiety, parental stress, infant development, and infant social-emotional development with site as random effect.Analysis of covariance.Regression analysis. | PMC10220519 |
Mean Observed Values for Postpartum Bonding Questionnaire (PBQ) and Secondary Outcomes | Depression, Anxiety | DISORDER | ASQ-3 indicates Ages and Stages Questionnaire, third edition; ASQ:SE-2, Ages and Stages Questionnaire: Social-Emotional, second edition; EPDS, Edinburgh Postnatal Depression Scale; GAD-7, Generalized Anxiety Disorder Assessment; MT, music therapy; PSS, Parental Stress Scale. | PMC10220519 |
Observed Group Means and Mean Differences for All Outcomes | Depression, Anxiety | DISORDER | Abbreviations: ASQ-3, Ages and Stages Questionnaire, third edition; ASQ:SE-2, Ages and Stages Questionnaire: Social-Emotional, second edition; EPDS, Edinburgh Postnatal Depression Scale; GAD-7, Generalized Anxiety Disorder Assessment; MT, music therapy; NA, not applicable; PBQ, Postpartum Bonding Questionnaire; PSS, Parental Stress Scale.We found no significant differences between groups in rate of rehospitalization at 6-month and 12-month corrected age (eFigure in | PMC10220519 |
Discussion | depression, anxiety | PREMATURE BIRTH | We used a multinational, pragmatic RCT to examine longer-term effects of parent-led, infant-directed singing supported by a music therapist on mother-infant bonding, parental well-being, and infant development from NICU hospitalization to 12 months’ corrected age. Parents had lower than anticipated levels of impaired bonding, anxiety, and depression at baseline. Although this parent-led form of music therapy was safe and well-accepted by parents, we found no clinically important effects on mother-infant bonding, nor on maternal anxiety, maternal depression, parental stress, or infant development.Participants in all 4 groups demonstrated mean baseline PBQ scores well below cutoff points for impaired bonding, contrasting with previous research suggesting potential delay or disturbance following premature birth.On average, the infants in our sample were medically quite stable and more mature than those in similar studies (including mean gestational age at birth, mean postmenstrual age at enrollment, and proportions of infants with worst cranial ultrasound at discharge).Qualitative research from this trial suggests the intervention affects the parent-infant relation in ways not captured by the PBQ, namely by facilitating parental agency, parent-infant communication, and a sense of relationship with the infant in the postdischarge period.Our findings demonstrated neither a beneficial nor detrimental effect on infant development. Notably, although statistically significant for infants in the NICU MT group only, at 12 months’ corrected age ASQ-3 scores were higher in all MT groups, indicating improved development scores. However, our confidence in the NICU MT finding is low due to the wide variance in results and nonsignificant estimated effect for those receiving MT in both phases. A lack of conclusive results regarding infant development may be due to insufficient number of MT sessions, insufficiently sensitive outcome measures, or assessment occurring too early to detect the effect on neurodevelopment. A dose-dependent effect of creative MT on preterm infant brain development has been noted in previous research, when infants received nearly double the median MT sessions in the NICU than our study. | PMC10220519 |
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