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Open Access funding enabled and organized by CAUL and its Member Institutions
PMC10261239
Introduction
cancers, type II diabetes
CANCERS, CARDIOVASCULAR DISEASE, AIDS, DISEASE, DISEASES, TYPE II DIABETES
The health benefits of exercise for reducing the risk of non-communicable diseases such as cardiovascular disease, type II diabetes and some cancers, are well documented (Centers for Disease Control & Prevention, The number of hours in a day is fixed and finite, distributed between obligatory time (such as time spent w...
PMC10261239
Methods
weight loss, ’
SECONDARY
This study was registered with the Australian New Zealand Clinical Trials Registry (Participants were recruited from the local community and metropolitan universities via electronic media and print advertising. Interested individuals were screened for eligibility by web-based or telephone survey, which included stage o...
PMC10261239
Discussion
How individuals restructure the timing of their behaviors can influence the effectiveness of exercise, and have important health consequences, depending on what activities are displaced (Chastin et al., According to baseline estimates, on average, participants spent approximately two hours per day watching television (...
PMC10261239
Supplementary Information
Below is the link to the electronic supplementary material.Supplementary file1 (DOCX 53 kb)
PMC10261239
Authors’ contribution
PB was responsible for conceptualisation and design of the study, the acquisition, analysis and interpretation of data, and manuscript writing. SG contributed to design of the study, data interpretation and critical revision of the manuscript. NM contributed to the acquisition and analysis of data, and critical revisio...
PMC10261239
Funding
Open Access funding enabled and organized by CAUL and its Member Institutions. PB was supported by an Australian Government Research Training Programme scholarship.
PMC10261239
Availability of data and material
The datasets generated during and/or analysed during the current study are available from the corresponding author on reasonable request.
PMC10261239
Code availability
Not applicable.
PMC10261239
Declarations
PMC10261239
Conflicts of interest
Not applicable.
PMC10261239
Human and animal rights and Informed consent
This study was approved by the Bellberry Human Research Ethics Committee (HREC2016-02–130). All procedures, including the informed consent process, were conducted in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and with the Helsinki Declaration...
PMC10261239
Consent for publication
Not applicable.
PMC10261239
References
PMC10261239
Subject terms
Activated brown fat (aBAT) is known to affect the evaluation of Open Access funding enabled and organized by Projekt DEAL.
PMC10713612
Introduction
Hodgkin Lymphoma, young lymphoma
HODGKIN LYMPHOMA
Activated brown adipose tissue (aBAT) on In young lymphoma patients In the second prospective trial of the European Network for Pediatric Hodgkin Lymphoma (EuroNet-PHL-C2; EudraCT: 2012-004053-88; ClinicalTrials.gov Identifier: NCT02797717), The aim of this study was to investigate retrospectively different factors, wh...
PMC10713612
Methods
PMC10713612
Data sources and data acquisition
Every EuroNet-PHL-C2 trial patient received All imaging data (For the current study, 528 consecutive The scans were checked for aBAT by two experienced technologists (both > 20 years of working experience). Beforehand, both underwent an intensive training conducted by a nuclear medicine physician who served as the refe...
PMC10713612
Ethics declarations
Written informed consent was obtained from all patients and/or their legal guardians before inclusion into the EuroNet-PHL-C2 trial. The trial was performed in accordance with good clinical practice and the Declaration of Helsinki. The Ethics Committee of the Medical Faculty of the University of Leipzig which is regist...
PMC10713612
Statistics
This is a retrospectively performed observational study. The preventive measures analyzed were not randomized or prescribed, but followed mainly site-specific policies. Therefore, our strategy of analyses was to first look at single factors (gender, age, BMI_sds, outside temperature, predisposition to aBAT) which may h...
PMC10713612
Results
PMC10713612
General results
aBAT was detected on 94 of the 528 Overview of performed or not performed measures to prevent aBAT.General policy (*) means that young patients who undergo
PMC10713612
Univariate analysis of factors with possible influence on aBAT
PMC10713612
Gender
Table Frequency of aBAT in relation to gender.
PMC10713612
Age
Patients included in our analysis were between 2 and 18 years old. They were divided into two groups setting a cut-off at 11 years. The intention of this cut-off was to distinguish pre-pubertal from pubertal or post-pubertal patients.The numbers in Table Frequency of aBAT in relation to age.
PMC10713612
BMI_sds
BMI_sds was only calculable for the patients of 506 of the 528 Influence of BMI_sds on the frequency of aBAT (blue curve). Green circles = no aBAT, red circles = aBAT. Dashed line = basis rate of aBAT.
PMC10713612
Outside temperature
Figure Influence of the average outdoor temperature on the frequency of aBAT (blue curve). Green circles = no aBAT, red circles = aBAT. Dashed line = basis rate of aBAT.
PMC10713612
Influence of outside temperature on preventive measures
We first explored whether the outside temperature had an influence on the choice of the preventive measure: Fig. Interrelation between the outside temperature and the execution of preventive measures: (As a next step, we conducted the same analysis for propranolol: Fig. 
PMC10713612
Patient predisposition
We looked at pairs of
PMC10713612
Model analysis on the effect of preventive measures
REGRESSION
To synthesize our findings, we fitted a logistic regression model (with patient as random effect to account for multiple images per patient) with all factors found to be relevant in the preceding analyses. From the model, we calculate the predicted probability of aBAT as a function of average outside temperature (in °C...
PMC10713612
Discussion
PEDIATRIC CANCER
aBAT on Our results show that aBAT frequency did not differ between male and female patients, which is in line with several previously performed studies (one with 385 scans, the other with 2792 scans in pediatric cancer patients)With regard to age, we observed that pediatric patients under the age of 11 had less aBAT c...
PMC10713612
Conclusion
Warming is a simple, cheap and non-invasive method to reduce the risk of aBAT. However, the effect of warming decreases with increasing outdoor temperatures and might be completely neutralized, e.g. as soon as air conditioning systems are in operation during the tracer uptake phase. The administration of propranolol ap...
PMC10713612
Acknowledgements
PD, der Technischen Universität, Christoph Rischpler
NEUMANN, FRANK, DER
We acknowledge the efforts made by all nuclear medicine physicians and technologists to provide necessary information and image data: Prof. Dr. Peter Bartenstein, Department of Nuclear Medicine, LMU Munich; Prof. Dr. Frank M. Bengel, Department of Nuclear Medicine, Medizinische Hochschule Hannover; Prof. Dr. Ambros J. ...
PMC10713612
Author contributions
L.K.
L.K., C.P., D.H., D.S., and R.K. analyzed the data and wrote the manuscript. C.M.K., D.K., and M.C. provided patient data. C.P. and S.N. analyzed the
PMC10713612
Funding
Open Access funding enabled and organized by Projekt DEAL.
PMC10713612
Data availability
The data (tables) that support the findings of this study are available from the corresponding author upon reasonable request.
PMC10713612
Competing interests
The authors declare no competing interests.
PMC10713612
References
PMC10713612
Background
The phase III MONALEESA-3 trial included first- (1L) and second-line (2L) patients and demonstrated a significant overall survival (OS) benefit for ribociclib + fulvestrant in patients with hormone receptor–positive, human epidermal growth factor receptor 2–negative (HR+/HER2−) advanced breast cancer (ABC) in the final...
PMC10469877
Methods
CFS
DISEASE
Postmenopausal patients with HR+/HER2− ABC were randomized 2:1 to 1L/2L fulvestrant + ribociclib or placebo. OS in 1L patients (de novo disease or relapse > 12 months from completion of [neo]adjuvant ET) was assessed by Cox proportional hazards model and Kaplan–Meier methods. Progression-free survival 2 (PFS2) and chem...
PMC10469877
Results
CFS
At data cutoff (January 12, 2022; median follow-up time, 70.8 months), mOS was 67.6 versus 51.8 months with 1L ribociclib versus placebo (hazard ratio (HR) 0.67; 95% CI 0.50–0.90); 16.5% and 8.6% of ribociclib and placebo patients, respectively, were still receiving treatment. PFS2 (HR 0.64) and CFS (HR 0.62) favored r...
PMC10469877
Conclusions
This analysis of MONALEESA-3 reports the longest mOS thus far (67.6 months) for 1L patients in a phase III ABC trial. These results in a 1L population show that the OS benefit of ribociclib was maintained through extended follow-up, further supporting its use in HR+/HER2− ABC.
PMC10469877
Supplementary Information
The online version contains supplementary material available at 10.1186/s13058-023-01701-9.
PMC10469877
Keywords
PMC10469877
Introduction
The addition of CDK4/6 inhibitors (CDK4/6is) to endocrine therapy (ET) has greatly improved outcomes for patients with hormone receptor–positive (HR+)/human epidermal growth factor receptor 2–negative (HER2−) advanced breast cancer (ABC) [First-line palbociclib in combination with the nonsteroidal aromatase inhibitor (...
PMC10469877
Methods
PMC10469877
Study design
Details of the MONALEESA-3 trial have been described previously [
PMC10469877
Participants
Tumors, advanced/metastatic disease
ONCOLOGY, DISEASE, LYTIC BONE LESION, TUMORS
Men and postmenopausal women aged ≥ 18 years, with histologically or cytologically confirmed HR+/HER2− ABC (locoregionally recurrent or metastatic and not amenable to curative therapy) were eligible for the study. An Eastern Cooperative Oncology Group performance status of 0 or 1 and measurable disease according to Res...
PMC10469877
Endpoints
ADVERSE EVENT, SECONDARY, ADVERSE EVENT
The final prespecified analyses of the primary endpoint of investigator-assessed PFS and the secondary endpoint of OS, as well as the extended follow-up (median, 56.3 months) analysis of MONALEESA-3, have been reported previously [Survival follow-up continued for patients who discontinued study treatment. Adverse event...
PMC10469877
Statistical analysis
CFS
EVENTS
In this exploratory analysis of OS, mOS and OS rates were estimated using the Kaplan–Meier method. The HR for OS was estimated using a Cox proportional hazards model. Patients without events were censored at the date they were last known to be alive. Analyses were performed on the data in the overall trial population, ...
PMC10469877
Results
PMC10469877
Patient disposition
death
DISEASE PROGRESSION
Overall, 726 postmenopausal women were randomly assigned between June 18, 2015, and June 10, 2016: 484 to the ribociclib arm and 242 to the placebo arm. The baseline characteristics of the patients were included in the previously published analyses [In the first-line (de novo or late relapse) subgroup, 237 patients wer...
PMC10469877
PFS2 in patients in first-line subgroup
DISEASE PROGRESSION, PROGRESSION
Following study treatment in the first-line setting, 130 of 237 patients (54.9%) in the ribociclib arm and 93 of 128 patients (72.7%) in the placebo arm had disease progression while receiving subsequent therapy. The median PFS2 was 16.1 months longer in the ribociclib arm (50.7 months; 95% CI 42.1–58.9 months) versus ...
PMC10469877
Safety
With this extended follow-up analysis at 70.8 months, no new safety signals were observed. Overall, AEs for the overall trial population were consistent with those previously reported in the prior analyses of MONALESSA-3 [
PMC10469877
Discussion
death, CFS, breast cancer
BREAST CANCER
This exploratory analysis of MONALEESA-3, with a median follow-up of 70.8 months, reports the longest mOS benefit to date (67.6 months in the ribociclib + fulvestrant arm) for a first-line population (de novo or late relapse) in a phase III clinical trial setting in ABC. First-line ribociclib + fulvestrant demonstrated...
PMC10469877
Conclusions
In MONALEESA-3, with a follow-up of nearly 6 years, ribociclib + fulvestrant demonstrated the longest mOS observed to date for a first-line population in a phase III clinical trial. This is the third phase III study of ribociclib demonstrating a significant OS advantage in first-line treatment of patients with HR+/HER2...
PMC10469877
Acknowledgements
The study was sponsored by Novartis. We thank the patients who participated in this trial, their families, and their caregivers; members of the data monitoring committee; members of the study steering committee; staff members who helped with the trial at each site; and Shashank Tandon, PhD, of MediTech Media for medica...
PMC10469877
Author contributions
All authors have reviewed and approved the data, contributed to the development and approval of the manuscript, and acknowledged the decision to submit the manuscript for publication.
PMC10469877
Funding
This work was supported by Novartis Pharmaceuticals Corporation. The funder of this study, in agreement with the authors and the study steering committee members, designed this study. Representatives of the trial sponsor performed data collection and the subsequent analysis.
PMC10469877
Availability of data and materials
Novartis made the study protocols available for MONALEESA-3 at the time of primary publications. Individual participant data will not be made available.
PMC10469877
Declarations
PMC10469877
Ethics approval and consent to participate
All patients provided written informed consent. This trial was conducted in accordance with the Good Clinical Practice guidelines and Declaration of Helsinki. An independent ethics committee or institutional review board at each site approved the study protocol and any modifications. The study conduct was supervised by...
PMC10469877
Consent for publication
All named authors have contributed to the manuscript and agreed to its submission.
PMC10469877
Competing interests
TG, MM
ONCOLOGY, PAF
PN has nothing to disclose. PAF reports personal fees for advisory boards and invited speaker fees from Novartis, Pfizer, Daiichi Sankyo, AstraZeneca, Eisai, Merck Sharp & Dohme, Lilly, Seagen, Roche, and Gilead; institutional funding from BioNTech and Cepheid; research grant from Pfizer; and personal fees for advisory...
PMC10469877
References
PMC10469877
Abstract
Nutrition‐sensitive
EVENTS, UNDERNUTRITION
Bangladesh struggles with undernutrition in women and young children. Nutrition‐sensitive agriculture programmes can help address rural undernutrition. However, questions remain on the costs of multisectoral programmes. This study estimates the economic costs of the Targeting and Re‐aligning Agriculture to Improve Nutr...
PMC9749601
Key messages
Nutrition‐sensitive agriculture programmes
UNDERNUTRITION
Nutrition‐sensitive agriculture programmes can improve rural undernutrition but lack information on costs.We use a standardised approach to estimate the total incremental costs of an integrated nutrition intervention in Bangladesh to improve maternal and child undernutrition.Costs per household compare favourably with...
PMC9749601
BACKGROUND
Nutrition‐sensitive, overnutrition, stunting, malnutrition
CHILD MALNUTRITION, OVERNUTRITION, UNDERNUTRITION, UNDERNOURISHED, MALNUTRITION, WASTED
Child and maternal malnutrition is a persistent problem in Bangladesh. The prevalence of stunting in Bangladesh is 31% for children under 5, with 9% severely stunted and 2% severely wasted. Further, children in rural areas of the country are more likely to be stunted than their counterparts in urban areas. In Banglades...
PMC9749601
The TRAIN intervention
BCC, APPENDIX
TRAIN was a 3.5‐year project (2016−2020) designed to address evidence gaps on agriculture‐based interventions to improve maternal and child nutrition. BRAC started the programme in 2016 in the Dhaka, Khulna and Rangpur divisions. A total of 5040 households were selected from 144 unions of 36 Subdistricts from 10 distri...
PMC9749601
METHODS
APPENDIX
This study used a novel standardised costing approach that contributes to gaps in the literature on the costs of multisectoral nutrition programmes (Margolies et al., The cost analysis was conducted from the payer and societal perspectives. The analysis included costs incurred by BRAC, frontline workers and programme b...
PMC9749601
Data collection
EVENTS, SECONDARY, MAY
The cost analysis captures the total costs of the TRAIN intervention incremental to the existing microcredit programme. Primary and secondary cost data were collected for the period of October 2016−January 2020, which included 6 months of start‐up and 3 years of full implementation. The SEEMS mixed‐methods approach com...
PMC9749601
Data analysis
SECONDARY
We analysed secondary expenditure and process evaluation data and combined these with primary data on economic costs. First, we analysed process evaluation data on beneficiary time allocation and OOP expenditures for participating households using Stata 16 statistical software. Second, we obtained financial expenditure...
PMC9749601
Personnel costs
APPENDIX
First, all nonshared financial and economic personnel costs were allocated across programme activities. We combined expenditure and time allocation data from BRAC staff and frontline workers (IDIs and FGDs). This information was used to allocate personnel costs to programme activities (Supporting Information: Appendix ...
PMC9749601
Economic costs of frontline workers
Estimates of frontline worker (PK) costs include personnel costs from BRAC expenditures combined with estimates of OOP costs and the valuation of time above the contracted 36‐h week. Economic costs such as OOPs and overtime hours/travel were not reimbursed by BRAC. PK personnel costs, gleaned from both financial expend...
PMC9749601
Beneficiary opportunity costs
EVENTS, APPENDIX
Beneficiaries participated in programme activities such as household counselling and community events. We estimated the opportunity costs of participation in TRAIN activities from process evaluation data. Opportunity costs were based on information on beneficiaries’ OOP expenses and the average time per year spent on p...
PMC9749601
Start‐up and capital costs
One‐time start‐up costs, capital and equipment costs for durable goods valued over USD$100 and lasting over 1 year were annuitized. These costs were annuitized over the implementation period using a discount rate of 3% and an expected useful life of 10 years. Annuitization ensures an equivalent annual cost is estimated...
PMC9749601
Unit costs
Total incremental costs were broken down by their financial and economic components. The total incremental cost per beneficiary is defined as the total cost divided by the total number of beneficiaries. We also present cost breakdowns by intervention typology, programme activity, inputs and timing (start‐up and recurre...
PMC9749601
Sensitivity analyses
A Monte Carlo probabilistic sensitivity analysis was performed using Oracle's Crystal Ball software (Overtime and OOP expenses for frontline workers (PKs): The estimate of overtime includes labour and travel time that was not reimbursed during the salaried work week. PK overtime varied by geographical location and by w...
PMC9749601
RESULTS
The total incremental cost of the TRAIN programme including economic and financial costs over 3.5 years was USD$795,040.34 (Table Summary of total incremental costs for the TRAIN intervention (USD, 2019)Abbreviation: TRAIN, Targeting and Realigning Agriculture to Improve Nutrition.
PMC9749601
Cost drivers
Figure Cost drivers for the TRAIN intervention in Bangladesh by activity type (Source: Authors). TRAIN, Targeting and Realigning Agriculture to Improve Nutrition.The main costs disaggregated by input category were dominated by personnel (68%), 48% of which came from hired labour. The remaining 20% of personnel costs re...
PMC9749601
Costs by treatment arm
Total incremental costs per household per year ranged from a minimum of USD$36.62 (arm 2, only nutrition components) to a maximum of USD$87.50 for arm 4, which included all programme components (nutrition, nutrition‐sensitive agriculture, and gender). Arm 3 included two components—nutrition and nutrition‐sensitive agri...
PMC9749601
Sensitivity analyses
The tornado diagram shown in Figure Tornado plot from the sensitivity analysis for total incremental costs
PMC9749601
DISCUSSION
household‐level, two‐thirds
EVENTS, BCC, SENSITIVITY
Integrated agriculture and nutrition interventions can provide effective platforms to reach vulnerable populations (Ruel et al., For intervention unit costs, the average incremental cost per household was USD$63.10 regardless of the treatment arm. Similar to most nutrition‐sensitive programmes, TRAIN provided benefits ...
PMC9749601
CONCLUSIONS
This study presents the financial and economic incremental costs of implementing an integrated agriculture‐nutrition intervention through a micro‐credit platform in Bangladesh. Cost‐per beneficiary estimates compare favourably with multisectoral nutrition‐sensitive interventions implemented through different platforms....
PMC9749601
AUTHOR CONTRIBUTIONS
Giang Thai led data collection and cost analyses and contributed to the manuscript. Amy Margolies contributed to the cost study methodology, conducted cost analyses and led drafting of the manuscript. Aulo Gelli contributed to the cost study methodology and to conception and design, provided technical advice, drafted a...
PMC9749601
CONFLICT OF INTEREST
The authors declare no conflict of interest.
PMC9749601
Supporting information
Supplementary information.Click here for additional data file.
PMC9749601
ACKNOWLEDGEMENTS
We would like to thank BRAC employees and staff in Bangladesh for their collaboration on this study. This study was supported, in whole or in part, by the Bill & Melinda Gates Foundation (INV‐00808). Additional support was provided by the CGIAR Programme on Agriculture for Nutrition and Health (A4NH).Microcredit is a f...
PMC9749601
DATA AVAILABILITY STATEMENT
Data available on request from the authors.
PMC9749601
REFERENCES
PMC9749601
Subject terms
stroke, Upper-extremity impairment, post-stroke, upper-extremity impairment
ADVERSE EVENTS, STROKE, CORTEX
Upper-extremity impairment after stroke remains a major therapeutic challenge and a target of neuromodulation treatment efforts. In this open-label, non-randomized phase I trial, we applied deep brain stimulation to the cerebellar dentate nucleus combined with renewed physical rehabilitation to promote functional reorg...
PMC10504081
Main
stroke, Ischemic stroke, post-stroke, traumatic
SAID, STROKE, ISCHEMIC STROKE
Ischemic stroke can have devastating consequences to individuals and their families while simultaneously carrying a high social and economic burden. Major advances have been achieved in prevention and treatment of stroke by means of population-health management of risk factors and acute interventions. Innovation and de...
PMC10504081
Illustrated overview of dentatothalamocortical pathway depicting a single deep brain stimulation lead implanted in the left dentate nucleus (brown).
stroke, upper-extremity motor impairment, impaired post-stroke, disability, upper-extremity impairment
ADVERSE EVENTS, STROKE, EVENT, CEREBRAL ISCHEMIA, SECONDARY, CORTEX
The crossed dentatothalamic projections (blue in upper-left illustration) terminate across multiple contralateral thalamic (green) nuclei that, in turn, project (orange), to broad regions of cerebral cortex. The dentatothalamocortical pathway represents the ascending component of a robust, reciprocal loop interconnecti...
PMC10504081
Results
PMC10504081
Patient disposition
upper-extremity hemiparesis, post-stroke, ischemic stroke
ISCHEMIC STROKE
Electronic medical record screening was used to identify individuals with a first-time, unilateral, ischemic stroke affecting the middle cerebral artery territory, sparing the diencephalon and basal ganglia, 12–36 months before surgery. Each candidate had to show persistent moderate-to-severe upper-extremity hemiparesi...
PMC10504081
Primary outcomes: safety and feasibility
ADVERSE EVENTS, ADVERSE EVENT
The study accumulated 168 participant-months of DBS implant experience and 72 months of DN stimulation experience, with no device failures and no study-related, serious adverse events throughout the trial. A total of 51 adverse events were recorded during the trial, including 21 deemed related to study participation. T...
PMC10504081
Secondary outcomes: motor impairment and function
reductions in impairment, Depression, Anxiety
SECONDARY
Our evaluation of changes in motor impairment and function during the trial focused primarily on differences observed across five key intervals (Fig. To learn if reductions in impairment would be associated with gains in function, given that both are important indicators of recovery, we also evaluated surgical and trea...
PMC10504081
Effect of distal motor function preservation at enrollment
A post hoc analysis was performed to characterize the effect of level of preservation of distal motor function at enrollment on treatment-related changes in impairment and function. Preservation was defined as the presence, at screening, of active extension of the wrist and two digits plus active thumb abduction/extens...
PMC10504081
Effect of time post-stroke on treatment-related gains
post-stroke
As it is generally considered that there is an optimal period for facilitating post-stroke motor recovery, marked by a nonlinear process that begins to plateau by several months after injury
PMC10504081
Discussion
post-stroke, physical disability, reduction of motor impairment, chronic post-stroke hemiparesis, post-stroke motor impairment, disability
SECONDARY, PHYSICAL DISABILITY
Data from this phase I trial of 12 individuals with chronic, moderate-to-severe post-stroke motor impairment support the safety and feasibility of chronic stimulation of the ascending cerebellothalamocortical pathway. Furthermore, it provides an in-human demonstration of significant and clinically meaningful effects of...
PMC10504081