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Progestogen orchestrates estrogen signaling and influences outcomes of endocrine resistance in breast cancer | PR-positive cancers, PR-negative cancers, breast cancer | BREAST CANCER | The presence of PR in breast cancer is a well-established prognostic factor, with patients with PR-positive cancers tending to have a better prognosis than those with PR-negative cancers [The interplay between progesterone and estrogen signaling in breast cancer is complex, and recent research suggests that the use of combinatorial endocrine therapies requires careful consideration to avoid pro-tumorigenic outcomes. While progesterone has shown promise in modulating the efficacy of endocrine therapies such as tamoxifen, fulvestrant, and giredestrant against | PMC10317070 |
CONCLUSIONS AND FUTURE PERSPECTIVES | inflammation, breast cancer | METASTASIS, BREAST CANCER, INFLAMMATION, DISEASE, NODE-POSITIVE BREAST CANCER, TUMORIGENESIS | The preoperative hydroxyprogesterone administration improves disease-free and overall survival in patients with node-positive breast cancer. The mechanism behind this improvement is thought to be related to the modulation of cellular stress response and the negative regulation of inflammation through the upregulation of the kinase gene Our findings highlight the complex genomic and molecular mechanisms involved in the response to progesterone in breast cancer and the potential for non-coding RNAs to play a regulatory role in this process. The mechanisms underlying the observed effects of progesterone on breast cancer outcomes are unclear. However, progesterone may modulate the expression of genes involved in tumorigenesis and metastasis, as well as affect the expression and genomic activity of ER and other factors that play a critical role in breast cancer development and progression. Further studies are needed to elucidate the precise mechanisms by which progesterone influences breast cancer outcomes. This information may help in the development of novel treatment and diagnostic strategies to overcome this disease.Overall, while preoperative hydroxyprogesterone administration appears to be a promising strategy for improving the prognosis of patients with node-positive breast cancer, the investigation of the mechanism of actions of progesterone in breast cancer remains an important area of research that holds great promise for improving patient outcomes. | PMC10317070 |
ACKNOWLEDGMENTS | Cancer | CANCER | G.C is supported by junior research fellowship from UGC and S.A. is supported by senior research fellowship from CSIR. MSG acknowledges emoluments from Dr. Vishwanath Karad MIT World Peace University. All authors have read and approved the final version of the manuscript.
GC: visualization, writing – original draft; SA: visualization, writing – original draft; MSG: visualization, writing – original draft, writing – review and editing; SG: writing – original draft; RAB: writing – original draft; AD: conceptualization, funding acquisition, project administration, visualization, writing – original draft, writing – review and editing.
Authors have no conflicts of interest to declare.
This research was funded by an extramural grant from the DBT-Virtual National Cancer Institute (VNCI) (BT/MED/30/VNCI-Hr-BRCA/2015] awarded to A.D. The funders played no role in study design, data collection and analysis, publication decision, or manuscript preparation. | PMC10317070 |
REFERENCES | PMC10317070 | |||
Background | External randomised pilot trials aim to determine whether a future definitive randomised controlled trial (RCT) should be conducted, and if so, how. However, not every pilot trial that suggests that a definitive trial will be feasible will progress to a definitive study. In this study, we surveyed corresponding authors of external randomised pilot trial publications to assess pilot trial outcomes in terms of feasibility and progression. | PMC9871417 | ||
Methods | Web-based surveys were sent to corresponding authors of external randomised pilot trial publications, open for four weeks between January and February 2022. Four surveys were produced depending on whether the corresponding author had published a trial protocol or results publication, and whether progression criteria were reported. Surveys asked whether a future RCT was considered feasible, whether progression criteria were met (if applicable), what other factors informed the assessment of pilot trial feasibility, and whether the pilot trial has progressed to further research. Data was analysed using descriptive statistics and conventional content analysis. | PMC9871417 | ||
Results | 98 of 276 corresponding authors completed the survey (average response rate of 36% across all surveys). Of these, 89 respondents indicated that their trial had completed. Ninety per cent of respondents who were corresponding authors of completed pilot trials stated that their pilot trial was either feasible (42/89, 47%) or feasible with changes to the trial design (38/89, 43%), yet only 66% (59/89) reported the intention to conduct a future definitive trial. Availability of funding for a future definitive trial and changing priorities of the Chief Investigator were the most common barriers to progression identified. Qualitative research findings was the most frequent factor considered both by corresponding authors who reported and who did not report progression criteria when determining trial feasibility. | PMC9871417 | ||
Conclusions | Just under one quarter (21/89, 24%) of respondents who considered their external randomised pilot trial to be feasible, or feasible with changes, did not intend to conduct a definitive trial highlighting research inefficiency and waste. | PMC9871417 | ||
Trial registration | Open Science Framework osf.io/d28hr [20 December 2021] | PMC9871417 | ||
Supplementary Information | The online version contains supplementary material available at 10.1186/s13063-022-06981-8. | PMC9871417 | ||
Keywords | PMC9871417 | |||
Background | Pilot trials are a type of feasibility study that aim to determine whether a future definitive randomised controlled trial (RCT) should be conducted, and if so, how [Qualitative research conducted by members of our research group highlighted that sometimes researchers are unable to obtain funding for further research despite demonstrating the feasibility of their external pilot trial [It has been suggested that authors of external pilot trials that do not report progression criteria or report unclear progression criteria, may be more optimistic in reporting that a definitive RCT is feasible [We have since conducted an international web-based survey to explore the outcomes in terms of feasibility and progression of a recent cohort of external randomised pilot trials that we identified during our methodological review [ | PMC9871417 | ||
Methods | PMC9871417 | |||
Protocol and registration | A protocol for this research is registered on the Open Science Framework: osf.io/d28hr [ | PMC9871417 | ||
Study design | We conducted a web-based survey study that contained both closed and open-ended questions to collect quantitative and qualitative data. | PMC9871417 | ||
Sample characteristics | Trial investigators surveyed were corresponding authors of external pilot trial publications that were identified when conducting our earlier methodological review [ | PMC9871417 | ||
Survey development and administration | Two trial statisticians based at the Centre for Statistics in Medicine (CSM) piloted the surveys for authors of protocol publications and provided feedback on functionality and design. Only surveys one and three were piloted as they contained the same questions as surveys two and four but with additional questions at the start.Personalised emails (including the corresponding author’s name, the title of their publication, and a unique survey URL link) were sent to each corresponding author by KM. Where automated email responses were received that provided an alternative email the email was forwarded on. Surveys were open from the 17th of January until the 14th of February 2022 and were designed to take between 5 and 10 min to complete. Non-respondents were sent a reminder email two weeks after the initial contact email, and all respondents were invited to enter a prize draw to win a £50 One4All voucher upon survey completion. | PMC9871417 | ||
Informed consent | An electronic information leaflet was provided as a pdf from the Jisc website. Study participants provided electronic consent before they were able to proceed to survey questions. | PMC9871417 | ||
Data analysis | Descriptive statistics were produced within Jisc to describe the external pilot trial findings with regards feasibility assessment and progression. KM used conventional content analysis [ | PMC9871417 | ||
Results | PMC9871417 | |||
Survey sample and response rates | The original sample of external pilot trial publications identified from the methodological review [The survey response rate varied across the four surveys from 19 to 41%, also detailed in Table | PMC9871417 | ||
Responses from corresponding authors of protocol publications | In total, 27 (27/96, 28%) responses (survey 1 19/55; survey 3 8/41) were received from corresponding authors of protocol publications.Most indicated that their external pilot trial was in the reporting or dissemination stage (18/27, 67%). Of these, five respondents indicated that they had published their external pilot trial findings, yet these five publications were not identified when searching the literature. The other 13 respondents indicated that they had not yet published their external pilot trial findings but intend to in the future. Nine respondents described that their external pilot trial was still in set up (2/27, 7%), conduct (4/27, 15%), or analysis (3/27, 11%) stage at the time of survey completion, and therefore were unable to complete all their respective surveys (survey 1 and survey 3). | PMC9871417 | ||
Proposed changes to the future definitive trial | RECRUITMENT | Survey branching logic was used to invite participants who indicated that a future definitive trial would be feasible with changes to design (38/98, 39% of respondents across all four surveys) to specify what changes they would make. This information was offered by 37 of the 38 respondents, who often described the intention to make more than one change.The most frequent change related to the intervention (17/37, 46%) with nine respondents describing how their intervention needed further development or refinement, eight suggesting that they would change their mode of intervention delivery, and two describing how more training would be provided to those delivering the intervention. Twelve respondents suggested that they would make changes to their recruitment strategy (12/37, 32%) including recruiting more sites, recruiting sites simultaneously rather than sequentially and altering the recruitment timeframe. Changes were also often described in relation to trial outcome measures (5/37, 14%), methods of data collection or follow-up (5/37, 14%), the patient population or eligibility criteria (4/37, 11%) and the overall trial design (4/37, 11%; e.g. adding or dropping arms, and moving to a cluster randomised design). | PMC9871417 | |
Findings that informed feasibility assessment where progression criteria were not stipulated | RECRUITMENT | Of the 34 respondents who had authored external pilot trial publications that did not include progression criteria (surveys 3 and 4), 32 (32/34, 94%) provided details about the findings they considered when determining feasibility, see Table The most frequent consideration was also qualitative research findings (17/32, 53%). Fourteen respondents described that recruitment had informed their assessment of trial feasibility (14/32, 44%), such as considering the recruitment rate, recruitment processes, consent rate, and timeframe associated with recruitment. Ten respondents considered whether there was any indication of efficacy or effectiveness when deciding whether a definitive trial was feasible (10/32, 31%). Ten respondents described considering findings in relation to the definitive trial design (10/32, 31%). For example, whether the sample size required for the definitive trial was achievable and the methods of data collection. Nine respondents described considering retention or attrition when determining feasibility (9/32, 28%), and nine described considering whether there was sufficient interest, acceptability or uptake of intervention (9/32, 28%) including intervention adherence or engagement, completion or withdrawal rates, and willingness to be randomised. Seven respondents described considering whether the intervention could be implemented (7/32, 22%; for example deliverability and intervention fidelity), and four described considering implementation of the trial (4/32, 13%; for example, resources and sites required, willingness of healthcare providers to implement the study and acceptability of study procedures). | PMC9871417 | |
Identified barriers to progression of a feasible external pilot trial to a future trial | RECRUITMENT | Of the 80 respondents across all four surveys who stated that their future trial would be feasible or feasible with changes to the trial design (80/89, 90%), 18 (18/80, 23%) indicated that they did not intend to conduct a future definitive trial. Using survey branching logic these respondents were invited to provide reasons for why they did not intend to conduct a definitive trial (offered by 17/18, 94%), summarised in Table Reported barriers to progression of feasible external pilot trialsResponses presented were reported by 17 respondents who considered their external pilot trial to be feasible or feasible with changes, but did not intend to conduct a future definitive trialMost participants provided more than one reasonFunding considerations, such as whether funding for the definitive trial would be available and sufficient, were the most frequently reported reason for not doing a definitive trial, reported by six respondents (6/17, 35%). Changing Chief Investigator (CI) priorities was another more frequent barrier to external pilot trial progression (5/17, 29%): five respondents reported that they had decided to pursue other research interests instead of a definitive trial, with two stating that their external pilot trial had formed part of their PhD, and that they were not resourced to take it forward. Three respondents (3/17, 18%) described how changes to the healthcare context e.g. service delivery, implementation of other interventions, or the impact of COVID-19 meant that they could not justify a definitive trial. Two respondents described that they would not pursue a definitive trial because there was no indication of efficacy, and one described how efficacy had since been proven in a different fully powered RCT (2/17, 12%). Other barriers included the number of resources required (2/17, 12%), the definitive trial sample size was too large (1/17, 6%), further feasibility assessment was needed (1/17, 6%), a lack of interest in the intervention (1/17, 6%), challenges with recruitment (1/17, 6%), reliability of data collection (1/17, 6%) and unsuccessful stakeholder collaborations (1/17, 6%). | PMC9871417 | |
Discussion | PMC9871417 | |||
Summary of main findings | Ninety per cent of the 89 respondents across all four surveys whose external pilot trial had completed stated that their pilot trial was either feasible (42/89, 47%) or feasible with changes to the trial design (38/89, 43%), yet only two-thirds reported the intention to conduct a future definitive trial (59/89, 66%). This suggests that just under one quarter (21/89, 24%) of respondents who considered their external pilot trial to be feasible (or feasible with changes) did not intend to conduct a definitive trial. Respondents described varied barriers to external pilot trial progression, with the availability of funding for a future definitive trial and changing priorities of the CI most common. | PMC9871417 | ||
Strengths and weaknesses of the study | A study strength is our comprehensive use of open and closed questions to appropriately address the study aim and objectives, with open-ended questions allowing respondents to expand on answers provided. However, only one researcher conducted the content analysis of open-ended questions which might have led to coding errors.Although our response rate (average 36%) could be considered low, it was on par with response rates observed in other studies where trialists have been surveyed [A further limitation was that our email was not delivered to all identified corresponding authors for example where researchers were on leave or had moved to a new role as suggested by automated email responses. This meant that some identified corresponding authors did not get the opportunity to participate. | PMC9871417 | ||
Meaning of the study: possible explanations and implications for clinicians and policymakers | It has been suggested that authors of external pilot trials that do not report progression criteria or report unclear progression criteria, may be optimistic in reporting that a definitive RCT is feasible [The feasibility rates observed in this study were higher than those that have been previously reported in external pilot trials, ending between 1995 and 2019, that were registered on the International Standard Randomised Controlled Trials Number (ISRCTN) registry (83%) [It has also been previously suggested that some external pilot trials might be redundant, i.e. they are conducted without sufficient uncertainty about feasibility that they are likely to show that an RCT will be feasible, and so waste time and resources [ | PMC9871417 | ||
Unanswered questions and future research | Our findings suggest that more guidance is needed to ensure that external pilot trial protocol and results publications can be identified from the literature. Five respondents who were sent the appropriate survey for corresponding authors of external pilot trial protocols indicated that they had published their pilot trial results, yet we did not identify these publications. This highlights the difficulty in linking external pilot trial protocols to results publications, even when a systematic approach is used. Possible explanations for this are that the corresponding first author changed, that the external pilot trial title or acronym changed, or that the results publication was published in the time between the literature search and sending of the survey.Our findings also highlight the need for clearer guidance for progression criteria reporting. Some authors did not necessarily agree with our assessment of progression criteria reporting. Potential explanations for this are that authors had prespecified progression criteria, but this was not clearly reported in the publication, or that interpretations of progression criteria differ, which is perhaps likely given that there is no clear guidance for progression criteria. To address this, research is ongoing to develop guidance specific to the application and reporting of progression criteria in external randomised pilot trials. | PMC9871417 | ||
Conclusions | We found that although 90% of respondents across all surveys whose trial had completed considered their external pilot trial to be either feasible or feasible with changes, only two-thirds reported the intention to conduct a future definitive trial, indicating potential inefficiency and research waste. Availability of funding and changing CI priorities were the two most frequent barriers to progression identified. | PMC9871417 | ||
Acknowledgements | We acknowledge Nicholas Peckham and Jamie Stokes for piloting surveys and providing feedback. We acknowledge and thank all corresponding authors who completed this survey. | PMC9871417 | ||
Authors’ contributions | This study was conceived and designed as part of KMs doctoral thesis under the supervision of SH and SD. KM designed the study and wrote the study protocol, SH and SD provided feedback. KM designed the surveys and SH and SD provided feedback and input to inform their development. KM collected and analysed the data. KM drafted the manuscript. All authors reviewed and commented on manuscript drafts. All authors approved the final manuscript. | PMC9871417 | ||
Authors’ information | SD | KM is a DPhil candidate at the University of Oxford investigating how progression criteria are used to inform decisions around progression of external randomised pilot trials to future definitive randomised controlled trials. SD is a senior trial statistician with expertise in statistics and clinical trial methodology. SH is a senior trial methodologist with expertise in the design, conduct and transparent reporting of randomised trials and systematic reviews. KM and SH contribute to a Pilot and Feasibility Studies working group. | PMC9871417 | |
Funding | This work was supported by Medical Research Council Doctoral Training Partnership funding [grant number MR/N013468/1] awarded to KM. The funder had no role in the design, conduct, analysis or reporting of this study. | PMC9871417 | ||
Availability of data and materials | Data will be made available upon request and included in a DPhil thesis published open access through the Oxford University Archive upon KM’s DPhil completion. | PMC9871417 | ||
Declarations | PMC9871417 | |||
Ethics approval and consent to participate | R78375/RE001 | Ethical approval for this study was provided by the University of Oxford MS IDREC, reference R78375/RE001. | PMC9871417 | |
Consent for publication | Not applicable. | PMC9871417 | ||
Competing interests | KM and SH contribute to a Pilot and Feasibility Studies working group. | PMC9871417 | ||
References | PMC9871417 | |||
Background/Purpose | Cancer | LUTZ, CANCER | Edited by: Yongjun Sui, National Cancer Institute (NIH), United StatesReviewed by: Stephen Lockhart, Pfizer, United Kingdom; Elizabeth De Gaspari, Adolfo Lutz Institute, BrazilOptimizing vaccine efficacy is of particular concern in patients undergoing hematopoietic stem cell transplantation (HSCT), which mainly have an inadequate immune response to primary SARS-CoV-2 vaccination. This investigation aimed to explore the potential prime-boost COVID-19 vaccination strategies following autologous (auto-) HSCT. | PMC10427916 |
Methods | tetanus, RBD | ADVERSE EVENTS, TETANUS, SECONDARY | In a randomized clinical trial, patients who had already received two primary doses of receptor-binding domain (RBD) tetanus toxoid (TT) conjugated SARS-CoV-2 vaccine during three to nine months after auto-HSCT were randomized to receive either a homologous RBD-TT conjugated or heterologous inactivated booster dose four weeks after the primary vaccination course. The primary outcome was comparing the anti-S IgG Immune status ratio (ISR) four weeks after the heterologous versus homologous booster dose. The assessment of safety and reactogenicity adverse events was considered as the secondary outcome. | PMC10427916 |
Results | ADVERSE EVENT | Sixty-one auto-HSCT recipients were recruited and randomly assigned to receive either homologous or heterologous booster doses four weeks after the primary vaccination course. The mean ISR was 3.40 (95% CI: 2.63- 4.16) before the booster dose with a 90.0% seropositive rate. The ISR raised to 5.12 (95% CI: 4.15- 6.08) with a 100% seropositive rate after heterologous (P= 0.0064) and to 3.42 (95% CI: 2.67- 4.17) with a 93.0% seropositivity after the homologous booster doses (P= 0.96). In addition, the heterologous group suffered more AEs following the booster dosage than the homologous group, but this difference was not statistically significant (p = 0.955). In multivariable analysis, the prime-boost vaccination strategy (heterologous versus homologous), the level of ISR before the booster dose, and the length of time between auto-HSCT and booster dose were the positive predictors of serologic response to a booster dose. No serious adverse event is attributed to booster vaccination. | PMC10427916 | |
Conclusion | ADVERSE EVENTS | In patients who were primed with two SARS-CoV-2 vaccine doses during the first year after auto-HSCT, heterologous prime-boost COVID-19 vaccination with inactivated platform resulted in considerably enhanced serologic response and non-significantly higher reactogenicity adverse events than homologous RBD-TT conjugated prime-boost COVID-19 vaccination strategy. | PMC10427916 | |
Background | coronavirus disease 2019, hematologic malignancies | CORONAVIRUS DISEASE 2019, HEMATOLOGIC MALIGNANCIES | In light of the recent coronavirus disease 2019 (COVID-19) outbreak, a serious medical crisis has been announced that is extremely harmful to patients with hematologic malignancies and those who have undergone hematopoietic stem cell transplantation (HSCT) (The approach of giving an additional COVID-19 vaccine as a homologous or heterologous prime-boost is an interesting object of research that has been addressed in several studies on healthy subjects so far (Most of the reported data on SARS-CoV-2 vaccination in HSCT patients employed mRNA-based vaccines, while a minority used an adenovirus-based vector platform (A recent publication demonstrated that the serologic response to two primary doses of RBD-TT conjugated SARS-CoV-2 vaccine (PastoCovac) shortly after autologous HSCT (auto-HSCT) was effective but not as effective as in healthy controls ( | PMC10427916 |
Methods | PMC10427916 | |||
Trial design and participants | allergy, SARS-CoV-2 infection | DISEASE, ALLERGY, SARS-COV-2 INFECTION | An investigator-initiated, participant and observer-blinded, randomized controlled trial was performed to compare the serological response following the homologous prime-boost vaccination using RBD-TT conjugated (PastoCovac, Pasteur Institute, Tehran, Iran) compared with the heterologous prime-boost using an inactivated platform (Vero Cell, Beijing Institute of Biological Products, China) in auto-HSCT recipients more than 18 years old who had received two primary doses of RBD-TT conjugated vaccine, independent of the pre-booster immunogenicity. Prior treatment with rituximab within six months, relapse of the underlying disease, previous allergy to the vaccine’s components, and history of SARS-CoV-2 infection following HSCT were the major exclusion criteria. The patients were recruited to study from Jul 22, 2022, to Jan 2, 2023, at the Hematology-Oncology-Stem Cell Transplantation Research Center (HORCSCT) of Tehran University, Tehran, Iran. | PMC10427916 |
Registration and ethical approval | The trial was registered with the Iranian Registry of Clinical Trial (IRCT20140818018842N24). It was approved by the research ethics committee of the HORCSCT (IR.TUMS.HORCST.REC.1401.005) and the School of Public Health and Neuroscience Research Center-Shahid Beheshti the University of Medical Science (IR.SBMU.PHNS.REC.1401.112). The study was conducted following the principle of the Declaration of Helsinki and Good Clinical Practice. All study participants provided written informed consent for the vaccine booster dose, blood samples to be collected, and results to be published. | PMC10427916 | ||
Randomization and blinding | Participants were randomly assigned to the homologous or heterologous arms in parallel with equal probability. The balanced block randomization list was generated using the block size of 4 and sample size through the research institute’s web-based software.Trained vaccine administrators enrolled the participants and assigned them to the trial groups according to the randomization list. While maintaining confidentiality, the vaccine administrators loaded the vaccines in a separate cubicle and administered them in the vaccination room. All other team members were blinded to the randomization list, including those responsible for the safety evaluation, collecting information, data analysis, laboratory assessors, and participating patients. | PMC10427916 | ||
Intervention | cytopenia, CRF | DISEASE, CRF, CYTOPENIA | Randomized patients received 0.5 mL of either homologous RBD-TT conjugated or heterologous inactivated COVID-19 booster dose injected intramuscularly into the deltoid area. All patients were visited before (at baseline) and four weeks ( ± 7 days) after the booster, and their blood samples were taken for immunogenicity assessment. All participants were also followed-up through weekly telenursing calls for safety monitoring, any occurrences of COVID-19, relapse of underlying disease, or cytopenia to Mar 21, 2023. Data from the case report forms (CRF) were entered and managed on electronic data capture forms developed on the web-based software of the institution.We employed the ChemoBind SARS-CoV-2 Neutralizing Antibody Test Kit (ChemoBind, Tehran, Iran) to assess the overall antibodies targeting the receptor-binding domain (RBD) spike protein of SARS-CoV-2 through a semi-quantitative immunoassay. As per the manufacturer’s guidelines, an immune status ratio (ISR) for immunoglobulin G (IgG) below 0.8 indicates a negative result, while an ISR above 1.1 indicates a positive result. Ratios falling between these thresholds are inconclusive and require repetition. | PMC10427916 |
Outcomes | ± | As a primary outcome, the anti-S serologic response at four weeks (± seven days) after the booster dose was compared between the two intervention groups by measuring IgG Immune status ratio (ISR), and positivity rate, defined as an increase in the ISR to the cut-off point for a positive result in the semiquantitative test, as described previously ( | PMC10427916 | |
Statistical analysis | REGRESSION, ADVERSE EVENT | The sample size of 29 per group would give 90% power to determine the significant difference in ISR between the two intervention groups, with a two-tailed test, 0.75 effect size, 0.05 significance level, and 1/1 allocation ratio, using Gpower software version 3.1.9.7.In a randomized clinical trial, the intention to treat (ITT) is the primary analysis. Given that the study population included all randomly assigned patients who received the allocated booster dose, ITT and per protocol (PP) analyses will invariably produce identical results. Descriptive analysis was reported as mean with standard deviation (SD), median with interquartile range (IQR) for quantitative variables, and frequency with percent for qualitative variables. The variability of ISR was reported using a 95% Confidence interval (CI) around the point estimate.The Chi-squared test was used to compare the distribution of a categorical variable. Adverse events were compared between groups using the Fisher exact test.The linear regression approach was used to investigate the predictors of serologic response following the booster dose. In univariate analysis, predictors associated with higher ISR value (p ≤ 0.2) are incorporated into a multivariable model. All the tests were considered two-way, and a p-value < 0.05 was reported as statistically significant. All statistical analyses were conducted using STATA version 17 (StataCorp, LP, College Station, TX, USA). GraphPad Prism software, version 9.5.1 (GraphPad Software Inc., San Diego, CA, USA), was used for the graphical presentation. | PMC10427916 | |
Results | PMC10427916 | |||
Participants | ± | LYMPHOMA, MULTIPLE MYELOMA (MM) | The flow chart of study selection was presented in detail in Flowchart of the randomized controlled trial. The chart depicts the subjects screened before the study, those recruited for Vaccination, and the processes for selecting or excluding patients.
Baseline characteristics of participants based on the homologous and heterologous prime-boost COVID-19 vaccination in autologous hematopoietic stem cell transplant (auto-HSCT) recipients.Data are presented as frequency (%), mean (± standard deviation) and median (Q1- Q3)RBD-TT-Conjugated, Receptor-Binding Domain (RBD)-Tetanus Toxoid (TT); ISR, Immune Status RatioHSCT, Hematopoietic Stem Cell Transplantation; MM, Multiple MyelomaThe indications for auto-HSCT in the RBD-TT conjugated and inactivated booster groups were multiple myeloma (MM) (53%, 61%) and lymphoma (47%, 39%). Before auto-HSCT, 83% of patients in the RBD-TT conjugated arm and 90% in the inactivated arm were completely immunized against SARS-CoV-2. Seventeen (57%) of the homologous arm and 19 (61%) of the heterologous arm had a history of PCR-positive COVID-19 before auto-HSCT. Nevertheless, there were no statistically significant differences between the two randomized groups’ baseline characteristics. | PMC10427916 |
Primary endpoint | Two of the thirty-one blood samples collected in the heterologous arm were lost. Moreover, the serological responses of 30 patients in the homologous arm and 29 patients in the heterologous arm were compared as the primary outcome.
Scatter plot of the SARS-CoV-2 IgG immune status ratio in homologous and heterologous prime-boost arms before and after the booster dose in autologous hematopoietic stem cell transplant recipients. | PMC10427916 | ||
Secondary endpoints | DISORDER, RECURRENCE, ADVERSE EVENTS, COVID-19 INFECTION, REACTOGENICITY | Data on vaccine-related AEs are shown in Reactogenicity adverse events up to 7 days after homologous and heterologous boosting in autologous hematopoietic stem cell transplant recipients.At a mean follow-up of 171.95 (95% CI: 157.36 - 186.53) days after the booster dose, 2 of the 31 (6%) heterologous and 4 of the 30 (13%) homologous arm patients developed PCR-documented COVID-19 infections presented with mild respiratory symptoms; nonetheless, only one patient, from the homologous arm, was hospitalized. Through this, no recurrence of the underlying disorder appeared. | PMC10427916 | |
Predictors of immune response | REGRESSION |
Graphical display of immunity predictors after a SARS-CoV-2 booster dose in autologous hematopoietic stem cell transplant recipients.Univariate and multivariable linear regression analysis to determine the predictive factors of the immunogenicity following booster SARS-CoV-2 vaccine in auto-HSCT recipients.Data are presented as mean (standard deviation); ISR, Immune Status Ratio; HSCT, Hematopoietic Stem Cell transplantationRBD-TT-Con, Receptor-Binding Domain (RBD)-Tetanus Toxoid (TT)-Conjugated.The bold values shows the statistically significant P values. | PMC10427916 | |
Discussion | The present study is the first trial comparing the homologous than heterologous prime-boost COVID-19 vaccination regimens throughout auto-HSCT recipients. In auto-HSCT patients who received two primary SARS-CoV-2 vaccines using RBD-TT conjugated platform, it was demonstrated that heterologous boosting with an inactivated platform yielded a superior serologic response and non-significantly more reactogenicity than homologous RBD-TT conjugated boosting. Exposure to various vaccine antigens could be attributed to the increased immunogenicity and reactogenicity identified following heterologous prim-boost COVID-19 immunization.In numerous investigations on the general population in Brazil, Korea, and Chile, consistent results on improved immune response following the heterologous than homologous booster immunization among participants who received two primary doses of the COVID-19 vaccine have been shown (Several studies have compared the immunogenicity of heterologous versus homologous booster vaccinations in solid organ transplants and immunocompromised patients (Study findings demonstrated that both homologous and heterologous booster vaccinations exhibited reasonable reactogenicity AEs during the first week following administration, either mild or moderate. Although there were more reactogenicity AEs with heterologous than homologous boosters, the two arms had no significant difference. Numerous studies undertaken in the general population have revealed greater reactogenicity with heterologous than homologous prime-boost vaccinations, supporting the study findings (Considering the predictors of immune response to booster doses, as shown in The study’s limitations, advantages, and other relevant considerations are as follows. The present study could not determine the exact amount of anti-S antibodies using a semiquantitative serologic test. Since it was impossible to access a functional assay kit for SARS-CoV-2-specific T-cell responses, cellular immunity could not be evaluated. Regarding benefits, all patients received two primary doses of RBD-TT conjugated SARS-CoV-2 vaccine (In conclusion, this blinded, randomly assigned controlled clinical trial shows that both homologous and heterologous prime-boost COVID-19 vaccination strategies are immunogenic and safe in auto-HSCT recipients primed with RBD-TT conjugated early after HSCT. However, heterologous prime-boost COVID-19 vaccination with inactivated platform resulted in considerably enhanced immune response and insignificantly higher reactogenicity than homologous RBD-TT conjugated prime-boost. | PMC10427916 | ||
Data availability statement | The original contributions presented in the study are included in the article/supplementary material. Further inquiries can be directed to the corresponding author. | PMC10427916 | ||
Ethics statement | The studies involving human participants were reviewed and approved by the research ethics committee of the HORCSCT (IR.TUMS.HORCST.REC.1401.005) and the School of Public Health and Neuroscience Research Center-Shahid Beheshti the University of Medical Science (IR.SBMU.PHNS.REC.1401.112). The patients/participants provided their written informed consent to participate in this study. | PMC10427916 | ||
Author contributions | RECRUITMENT | LS: Study concept and design; patient recruitment; randomization, data gathering, analysis of data, drafting of the manuscript; critical revision of the manuscript. MK: Study concept and design, critical revision of the manuscript. MB: Study concept and design; patient recruitment; data gathering, drafting of the manuscript; critical revision of the manuscript. SH: Confirming analysis of data, critical revision of the manuscript. AK: Confirming analysis of data, critical revision of the manuscript. MA: Performed antibody measurements and critical revision of the manuscript. MV: Critical revision of the manuscript. All authors contributed to the article and approved the submitted version. | PMC10427916 | |
Acknowledgments | COMMUNICABLE DISEASE | We thank all the patients who participated. We thank Dr. Shahnam Arshi from the Iranian communicable disease center of the Ministry of Health and medical education for providing the vaccines. We thank our colleagues for medical management and our medical personnel for their support. We thank Mona Asadi Milani, Hamidreza Pedram, and Fatemeh Goli for the Sampling of patients. We thank Aram Halimi, Zohreh Shahabi, and Fahimeh Bagheri Amiri for their support. | PMC10427916 | |
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. | PMC10427916 | ||
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. | PMC10427916 | ||
References | PMC10427916 | |||
1. Introduction | SECONDARY | Academic Editor: Aron WellerFood insecurity, defined as unpredictable access to food that may not meet a person's nutritional needs, is paradoxically associated with higher BMI (kg/mFood insecurity due to lack of regular access to food that meets their nutritional needs [There is a strong relation between food insecurity and elevated body mass index (BMI = kg/mShah and colleagues [While DD assesses a person's style of decision-making that tends to focus on smaller, immediate rewards versus larger, later rewards, there are other approaches to studying how people make decisions that focus on the balance between immediate and long-term needs. This is the basis for prospective thinking or a person's temporal orientation towards the future rather than the present. A widely used measure of temporal orientation is the Consideration of Future Consequences Scale (CFCS) [People with low income and food insecurity often experience stress [The primary goal of this study is to assess whether DD, CFCS, and stress can help understand the relationship between food insecurity and higher BMI in mothers. A secondary goal is replicating the moderating effect of DD on the low-income-high food insecurity relationship that we observed in a previous study in which DD and financial planning moderated the relationship between low income and food insecurity [ | PMC10522429 | |
2. Methods | PMC10522429 | |||
2.1. Subjects and Design | SECONDARY, RECRUITMENT | This study was approved by the University at Buffalo Institutional Review Board and was conducted online in November 2018. The study was a secondary analysis of data collected for a cross-sectional study of parents recruited from ResearchMatch.org, a crowdsourcing platform. The parent study was designed to study the relationship between stress and parenting. No publications were generated from the analysis of these relations. A recruitment message was sent to randomly selected individuals who met our study target (e.g., adults 18–55). E-mail addresses of those interested in participating were exported from ResearchMatch.org, and potential participants were sent an e-mail with the link to a Qualtrics questionnaire. An IRB-approved consent was presented to the participant upon opening the link, and consent was obtained by the participant indicating (e.g., clicking) “I agree to the terms described above.” 569 people consented and were eligible to participate (e.g., an adult 18–55 with at least one child between 2 and 15), and of those, 369 participants provided full, complete, and valid responses to all of the study questionnaires, including the DD task [ | PMC10522429 | |
2.2. Measures | Participants completed the MacArthur network socio-demographic questionnaire (e.g., age, gender, marital status, employment status, education, income, race, and perceived social status) [Participants completed an adjusting amount DD task [For each participant, indifference points, or the amount of money offered now that was just as appealing to them as $100 at a future time point, were calculated for each delay. The ordinal area under the curve (AUCIn addition, in a sensitivity analysis, we calculated discount rates using a hyperbolic discounting model [The CFCS is a 12-item scale that measures how much a person considers the long-term consequences of their current behavior [The Perceived Stress Scale (PSS) is a 10-item survey with questions that indicate how stressed an individual perceives themselves to be and how well equipped they are to deal with that stress (e.g., “In the last month, how often have you felt nervous and “stressed”?”, “In the last month, how often have you felt that you were unable to control the important things in your life?”) [ | PMC10522429 | ||
2.3. Analytic Plan | Preliminary analyses used zero-order correlations to explore relations among variables. To understand the income-food insecurity relation, analysis of variance (ANOVA) was used to explore the effect of income expressed as a three-category classification of low income ( | PMC10522429 | ||
3. Results | Mothers had an average food security score of 1.02 (2.00) (mean ± SD), with 21% reporting food insecurity and 12.9% reporting high food insecurity. These numbers are greater than the 11.8% of the U.S. population reporting low food security and 4.3% of the U.S. population reporting very low food security in 2018 [The relations among variables (The indirect effects of food insecurity on BMI through DD, CFCS, and perceived stress are shown in | PMC10522429 | ||
4. Discussion | obesity, food insecurity | OBESITY, SECONDARY | We found that people who discounted the future more had lower income, greater food insecurity, and higher BMI, consistent with previous research [The narrow temporal window observed for people with food insecurity may be due in part to the unpredictable nature of access to food and meals. Basic preclinical research in different animal species has shown that animals that are provided unpredictable access to food gain more weight and find food to be more reinforcing than animals that are provided the same amount of food, but with predictable access [The current study suggests that DD, a behavioral task designed to measure the relative strengths of immediate versus delay rewards, is more strongly related to the food-insecurity BMI relation than a more general measure of prospective thinking. We think this may be the case for two reasons. First, CFCS is a self-report measure of how people report they think about the future, as opposed to a direct behavioral measurement of this construct, and while these constructs are related, the correlation is modest. Second, the CFCS focuses on how someone might act to improve their future, but it does not compare the value of immediate versus future decisions, which is central to DD. It may be quite different to think about what you would do in the future if you have access to a very powerful, immediate reinforcer. Third, CFCS focuses on decision-making in regard to general future consequences, while the DD task involves monetary decision-making.While stress is known to be associated with food insecurity [These data suggest that DD may be a novel target to reduce obesity in those with food insecurity. DD is associated with a short temporal window, and the desire for immediate gratification, rather than taking into account possibilities associated with inhibiting the immediate desires for food [As a secondary aim, we replicated the finding that income is related to food insecurity and that DD moderates the relation between low income and high food insecurity [ | PMC10522429 |
4.1. Limitations | obesity, weight gain | OBESITY, PATHOLOGY | Despite the fact that the study used a large sample and replicates previous studies showing that DD is related to both food insecurity and obesity, and DD may help explain the food insecurity-obesity paradox, there are limitations to the study. First, the study only included women, as food insecurity has a greater impact on obesity in women than men [While the atemporal mediational model suggested an influence of DD on the relation between food insecurity and BMI, the study was cross-sectional. We believe that cross-sectional studies can provide ideas for future prospective analyses of mediators, but prospective research testing whether DD mediates the relation between food insecurity and weight gain is needed. One hypothesis for a prospective study might be that low income is associated with food insecurity only when people have a narrow temporal window for decision-making and discount the future, and that discounting of the future also mediates the relation between food insecurity and weight gain. Since research has shown that low income is associated with greater food reinforcement, unpredictable access to food can increase the reinforcing value of food, including food reinforcement plus DD using reinforcer pathology theory in future research may provide greater explanatory power than DD alone. Another potential limitation is that only discounting of money was measured, and discounting of food may be a more sensitive measure for people with food insecurity, as shown by Rodriguez and colleagues [ | PMC10522429 |
5. Conclusions | Steeper discounting of the future is associated with greater food insecurity and higher BMI, and DD adds to our understanding of factors that influence the relationship between food insecurity and body weight. | PMC10522429 | ||
Acknowledgments | Digestive and Kidney Disease, Diabetes | DIABETES | We acknowledge the work of Kelseanna Hollis-Hansen who collected the data used in these analyses. This study was funded as part of MINDD, funded by the National Institute of Diabetes, Digestive and Kidney Disease (U01HL131552), registered at clinicaltrials.gov ( | PMC10522429 |
Data Availability | Data can be made available after contacting the senior author. | PMC10522429 | ||
Conflicts of Interest | food insecurity | The authors declare that they have no conflicts of interest.Display of the parallel influences of delay discounting, consideration of future consequences, and perceived stress on the food insecurity-BMI relation.Food insecurity ratings (Mean ± SEM) (a), percent of participants with food insecurity (≥2; (b)), and percent of people with high food insecurity (≥5; (c)) in relation to income expressed as percent over poverty index adjusted for household size.Participant characteristics.Relations among variables.All bold values are significant (p < 0.05).Models the indirect effect and effect ratios of delay discounting and food choice on the relation between food insecurity and BMI, controlling for education, age, stress, income, house size, and exercise.CFCS = consideration of future consequences scale; significant paths A and B are bolded and noted by | PMC10522429 | |
Introduction | While progress has recently been made in the early identification of developmental delay in children using screening tools adapted to local cultures [Early developmental screening of children living in low-income homes, followed by programs which encourage parents to support their preschool child’s cognitive development, has been shown to produce beneficial effects [One idea is to use remote interventions based on online solutions. However, many of the population in low- and middle-income countries (LMICs) report no internet connection or access to online services. Before the pandemic, out of the 2.6 billion people living in LMICs, 40% had access to an internet connection, compared to 75% of the people in high-income countries [ | PMC10306226 | ||
A solution for remote screening administrated by parents: The CARE booklet | Early developmental screening (EDS) with well-designed tools has been deployed to assess the effect of intervention programs on specific outcomes [In the last decade, various studies have evaluated EDS tools deployed at primary healthcare services in LMICs [The design of CARE was associated with an intervention program in Colombia called the The HLL and DDST items included in CARE and the rest of the design process for the booklet follow the components recommended for the construction and validation of assessment tools used in instrumental screening [ | PMC10306226 | ||
Parental interventions in LMIC | Two recent meta-analyses of early parenting interventions [However, only a few studies have examined the impact of early parenting interventions on the cognitive performance of children living in poverty, and most of these have reported only limited data about early learning or intervention conditions [Likewise, several intervention studies that focused on the development of children’s language and communication skills by providing direct training to parents have shown significant benefits in LMIC contexts [ | PMC10306226 | ||
The CARE Booklet-Intervention (CBI) | The CARE booklet acts as a guide for parents on how to assess and track their child’s developmental progress, and how to provide scaffolding activities to promote their child’s development. However, the strict delivery of any screening tool for parent administration, like CARE, is not sufficient as an intervention. A structured intervention that combined the measurement of children in scenarios like children’s centers for low-income families in Colombia, with remote protocols for registering parent-child interactions at home, was developed and labeled the CARE Booklet Intervention (CBI). The CARE booklet assessing children’s characteristics is a form of home-based records (HBR). An HBR such as CARE, regularly and frequently running in parallel with a full intervention for optimal health and educational systems, is desirable because it can increase parental confidence and engagement in activities with children at home [Also, the CBI could work well at home in cases where interactions with children might be a parental burden. Constant recall and demand for interactions at home might increase parental stress and the possibility of burnout. Recent studies in the prevalence of parental burnout show that cultural and social values like individualism and the number of hours spent paying attention to children play a significant role in many LMICs, including Colombia [In the CBI, the relevance of parental screening it is not a matter of how much children change and develop but a matter of how, when and with whom they interact. The child might develop in ways that was not anticipated by the report and might not perform according to the kind of development they were expected to show. However, before any hypothesis about indulgence and parental stress or engagement [The present study reports findings from a pilot quasi-RCT study of a parent-training intervention program for families in poverty with preschool children: the CARE booklet intervention (CBI). Given the generally promising results of parental interventions in LMICs, it is relevant to evaluate the impact of a remote intervention in a small sample of families living in a Spanish-speaking LMIC. This pilot study could be a starting point for more extensive investigation of prompting, guiding, or scaffolding interventions such as the CBI, scaling this to larger samples of participants (parents and caregivers of toddlers and preschool children). We attempted to answer the following research question for our pilot design: Would the CARE booklet intervention (CBI) with parents from vulnerable and scarcity-conditions neighborhoods in Colombia benefit their children’s cognitive development and language abilities? As a pilot design, it is necessary to note the exploratory conditions for the current study and be cautious in the analysis of the results. | PMC10306226 | ||
Method | RECRUITMENT | The study essentially followed the protocol for a randomized controlled trial (RCT), but the control group was selected based on not attending the randomized session, and therefore the study was classified as a pilot quasi-RCT (Q-RCT) [Participants were eligible for the study if they:Had at least one child between 24 and 59 months of age.Had completed the recruitment process and the general developmental screening report (HLL table).Had a classification of “at risk” according to the HLL table, defined as the child presenting ≥1 Delay or ≥2 Cautions.Were able to complete written records in Spanish.Had at least an active phone number, a chat app, or an email address, and to complete an intervention session each week for six weeks and promised to review the intervention materials and answer some questions via phone, chat, or email.The baseline assessment was conducted if the child met the entry criteria and the parents consented to participate. Prior to the COVID-19 pandemic (July 2019 –February 2020), the screening process identified 268 families (see | PMC10306226 | |
CARE booklet intervention pilot-study CONSORT flow. | RESOLUTION | Participants for the unreported intervention had no relation to the completed CARE booklet intervention (CBI) or the results from the intervention development process [The study and the intervention involving human participants were reviewed and approved by the board at the Faculty of Psychology of the Universidad de la Sabana, Colombia. The General Directorate of Research at the same university also granted ethical approval for the study (CAG resolution #1517 of 11/19/2015). Permission for data collection was granted in agreement with the legal ruling of Resolution #008430 of 1993 of the Ministry of Health of the Republic of Colombia, which sets out ethical, scientific, technical, and administrative norms for research activity with human participants. Written informed consent from the participant’s legal guardian/next of kin was required to participate in this study, following the aforementioned national legislation and institutional requirements.According to the participant information and preliminary data analysis (see | PMC10306226 | |
Sociodemographic description of children and mothers in the CBI and Control groups compared with the whole sample. | Notes: | PMC10306226 | ||
Procedure | The training program was delivered to the parent who identified as the principal caregiver of their child with two in-person sessions at Children’s Centre (CC) and other sessions delivered via phone call, chat, and email message. The CARE booklet intervention (CBI) promoted the use of a printed booklet for written reports of different activities at home in four developmental dimensions commonly used for early screening. The intervention involved two in-person parent meetings in small groups (4–6 persons) and receiving instruction from a trained facilitator over one-hour sessions. The dosage per session was less than 50 minutes, to fit in with the high number of other scheduled activities in the CC. One facilitator, a final year-undergraduate student of Psychology at Universidad de la Sabana, oversaw the intervention. CBI required the use of a CARE booklet and materials delivered by the facilitator to parents in an initial session. Each other weekly session, was informed and delivered via phone call, chat, and email message. The remote weekly sessions were about specific activities presented for parents to carry out and report using their CARE booklet. The parental training emphasized the use of CARE to obtain information about daily interactions between parents/caregivers and children, and how the CARE booklet could help them to enhance their children’s development through regular monitoring of these interactions at home. The CARE booklet had a section for every activity with an area for daily marking, below instructions for how to report interactions daily for four weeks (see | PMC10306226 | ||
Area for daily marking in every activity of CARE booklet. | At the second session (see | PMC10306226 | ||
Session by week description of the CARE booklet intervention and corresponded modality of participation. | Note: CC: Children Center. | PMC10306226 | ||
Description of input from the Children’s Centre local services | All the children participating in the study received 70% of their daily nutritional requirements (breakfast, two snacks, and lunch) in the Children’s Centre (CC). Additionally, before the COVID-19 pandemic, all children (The parents in the control group only received the instruction to “write or sketch” in a blank paper booklet any activity that they had carried out with their children that month. This control procedure can be classed as a placebo [ | PMC10306226 | ||
Outcome measures | SECONDARY, BLIND | The outcomes were assessed exclusively in Spanish at a post-intervention assessment conducted 7–8 weeks following the baseline assessment. The assessments were conducted in-person at the Children’s Centre by two native Spanish-speaking graduate psychologists who were blind to group membership and trained in the specific measures used. The full set of assessments took 60–90 minutes. The following primary and secondary outcomes were administered at baseline and follow-up using the official or standardized version in Spanish. | PMC10306226 | |
Data analysis | All statistical analyses were conducted using IBM SPSS Statistics for Macintosh, Version 25.0 [ | PMC10306226 | ||
Results | PMC10306226 | |||
Initial and follow-up group outcomes | Group mean and standard deviation (SD) scores for all variables at the initial and follow-up assessments are shown in | PMC10306226 | ||
Group means and standard deviations (SD) of scores at initial and interim follow-up assessments for primary and secondary outcomes. | Note: CBI: CARE booklet intervention; CC: Children’s Centre; HLL: Haizea-Llevant. | PMC10306226 | ||
Sociodemographic effects on pre-post assessments for CBI and Control Group | Two-way ANCOVA indicated statistically significant interactions between the CBI intervention and both child gender and family socioeconomic status, on post-test measurements of HLL Caution items and on the WPPSI-IV Picture Naming subtest, controlling for pre-test measurement values (see | PMC10306226 | ||
Two-way ANCOVAs results for sociodemographic significative interactions with post measurements by CBI or Control condition and premeasurements values. | Notes: DV = Dependent variable: Post measurements; HLL = Haizea-Llevant; SES = Socioeconomic status. | PMC10306226 | ||
Primary outcomes comparison in pre-post assessments for CBI and Control Group | One-way ANCOVAs were conducted to compare the effectiveness of the CARE Booklet Intervention (CBI) in the post-test measurements, controlling for pre-test measurement values. Levene’s test and normality checks were carried out and the assumptions were met. There was a significant difference between the CBI and control groups on the HLL Delay items, | PMC10306226 | ||
Secondary outcomes comparison in pre-post assessments for CBI and Control Group | One-way ANCOVAs were conducted to compare the effectiveness of the CARE Booklet Intervention (CBI) in the post-test measurements, controlling for pre-test measurement values. Levene’s test and normality checks were carried out and the assumptions were met. There was a significant difference between the CBI and control groups on the Frog Story’s narrative devices scores, | PMC10306226 | ||
General screening (Haizea-Llevant) developmental dimensions comparison in pre-post assessments for CBI and Control Group | Group mean and standard deviation ( | PMC10306226 | ||
Group mean and standard deviation (SD) for initial and follow-up delays and cautions in developmental dimensions in Haizea-Llevant assessment. | One-way ANCOVAs were conducted to compare the effectiveness of CBI in post-test measurements for the four developmental dimensions in the HLL screening, while controlling for pre-test measurement values. Levene’s test and normality checks were carried out. There was a significant difference between the CBI and control groups in HLL fine motor-adaptive Delays, | PMC10306226 |
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