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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 ...
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 o...
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...
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...
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 we...
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%...
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 d...
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 t...
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...
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 inte...
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,...
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 re...
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%). T...
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 e...
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...
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 t...
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 ...
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 ...
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....
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...
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 fou...
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) w...
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 p...
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 hom...
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 inactivate...
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...
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 as...
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 ...
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 t...
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 tre...
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 an...
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 pr...
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 (1...
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 pr...
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 inactivat...
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 prov...
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 manus...
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, Hamidrez...
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 ...
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 insecuri...
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 re...
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 tha...
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 re...
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 ...
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 impa...
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 percen...
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 developmen...
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...
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, severa...
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 s...
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 a...
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 l...
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 repo...
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 pape...
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 specifi...
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 ...
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 ...
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 ...
PMC10306226