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Keywords | 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 working, sleeping, domestic activities, commuting or eating) and discretionary time (the remaining ‘free’ time) (Goodin et al., To improve compliance and adherence to exercise, the concept of temporal consistency has been proposed. Regularly performing an activity at a specific time, may be important for long-term adherence as it aids in creating a ‘protected time’ for exercise habits (Kaushal & Rhodes, The activity swaps in response to morning or evening exercise are not understood, and are likely to be different. For example, a person who embarks on a new morning exercise program may forego their recreational walk (Sahlqvist et al., Therefore, the objective of this study was to investigate how previously inactive adults restructure their time when they undertake morning or evening exercise. This study was conducted within a larger randomized controlled trial aimed at investigating the influence of time-of-day of exercise on cardiometabolic health (Brooker et al., | 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 one of the Adult Pre-exercise Screening System, developed by Exercise and Sports Science Australia (Exercise & Sports Science Australia, This study used a three-armed, randomized controlled trial design, with a 12-week lifestyle intervention. Following baseline testing, participants were randomized into one of two intervention groups, or a waitlist control group (CON) at a 2:2:1 ratio using permuted block randomisation with multiple, randomized block sizes by a researcher external to the study. Due to the nature of the intervention, participant blinding was not possible. Participants allocated to CON were asked to continue with their day-to-day activities and were offered the exercise program after all formal testing was completed. The two intervention conditions comprised of a 12-week exercise program in which participants were prescribed a minimum of 250 min of moderate-vigorous exercise per week; the dose of exercise recommended by the American College of Sports Medicine to elicit clinically significant weight loss (Donnelly et al., The exercise program included both supervised and unsupervised exercise sessions. Participants completed an initial four-week supervised exercise training phase, of five 50 min sessions per week. Over the remaining eight weeks, exercise sessions were tapered by one session per fortnight until two sessions per week was reached, which was then maintained for the remainder of the intervention. Supervised sessions consisted of self-paced brisk-walking or running on a treadmill. All supervised exercise sessions were conducted at the School of Human Movement and Nutrition Sciences at The University of Queensland, St. Lucia, Australia. The secondary component of the intervention involved several constituents of theoretical approaches to encourage behavior change. Informational and behavioral approaches were the focus of the intervention. Strategies used to enhance behavior change are outlined in Supplementary Table A1.Self-reported use-of-time was measured using the adult version of the MARCA; a computerised 24-h recall tool which asks participants to recall all activities from their previous day (midnight to midnight), in increments as small as five minutes. The MARCA was administered by a computer-assisted telephone interview in an open-ended format, using meal times as reference points in a segmented day format, on two occasions approximately one week apart. Each time, two consecutive days were recalled; therefore, at each measurement participants were asked to recall four days (two weekend and two weekdays). Where possible, recalled days were kept consistent between measurement occasions. During the recall, the interviewer selected an appropriate activity from a list of over 500 activities, based on an expanded version of the Ainsworth compendium (Ainsworth et al., Time use profiles were cleaned and checked; firstly, any activities entered as ‘other’ were identified and replaced with a similar activity (based on body position and energy expenditure) from the compendium; next, any time use profiles with missing data (< 24-h, or 1440 min) were identified and excluded; finally, participants with < 2 time use profiles recorded or did not include one weekend day per assessment period were excluded. To determine time use, participants’ individual time use profiles were established by calculating the time spent in major ‘activity sets’ and collapsed hierarchically into domains based on similarity and to preserve comparability with previous studies(Gomersall et al., All data were analysed using the statistical package for social sciences (SPSS) version 25 (IBM, New York, USA). Statistical significance was set at an alpha of | 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 (range 114 to 157 min·dayBoth intervention groups reported an increase in Active Transport at mid-intervention and higher levels of both Active Transport compared with participants in the control group. However, these changes and differences were no longer significant post-intervention. By design, the number of supervised exercise sessions reduced from mid- (4 sessions·wkRegular exercise is advocated to improve sleep quality, either by accelerating sleep onset or increasing the depth of sleep, and is routinely included in sleep hygiene recommendations (Buman & King, This is the first study to examine changes in use-of-time in response to an exercise intervention prescribed at specific times of the day. In response to a 12-week exercise program performed in the morning (0600–0900) and the evening (1600–1900), we found no difference in how previously insufficiently active individuals spend, or reorganise their time to accommodate the new activity. Gomersall and colleagues investigated the changes in use-of-time across a 6-week physical activity intervention prescribed either 150 min·wkTraditionally, time use surveys have been used to capture data such as, how respondents spend their ‘free time’; residual time that remains after accounting for time spent in ‘paid labour’, ‘unpaid household labour’ and ‘personal care’. As in the case for the Time Use Survey conducted by the Australian Bureau of Statistics, respondents are asked to keep a diary of their daily activities for two consecutive days (Goodin et al., Patterns of time use present a novel way of examining the ripple effects of changes in daily activity patterns to accommodate for the time cost of exercise. This study used a randomized controlled trial to investigate how previously inactive adults restructure their time when they undertake morning or evening exercise. The time for exercise was larglely drawn from a discretionary time (watching TV), and the patterns of change in time use was similar when exercise was performed in the morning compared with the evening. | 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 revision of the manuscript. NK and ML contributed to design of the study, data interpretation and critical revision of the manuscript. | 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 of 1975, as revised in 2000. | 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, which may have an influence on the occurrence of aBAT on | 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 reference reader for the EuroNet-PHL-C2 trial. Subject of the training was a set of 30 In addition to reviewing the 528 Mean outside temperature in the respective town for the period of the All 41 nuclear medicine departments were asked for their general policy to prevent aBAT and to provide detailed information on preventive measures for every | 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 registered as Institutional Review Board (IBF) at the Office of Human Research Protections (OHRP) approved the evaluation presented here (498/17-ek). | 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 have an impact on aBAT using univariate statistical methods for all scans together (Chi | 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) and the preventive measures (warming and/or propranolol or none). The corresponding results are shown in Table Results of the aBAT prediction logistic regression model including average outside temperature and the two preventive interventions (warming, propranolol, and the combination of both).Probability of aBAT as a function of the average outdoor temperature and use of preventive measures. | 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 compared to patients over the age of 11. This result was of borderline significance on univariate analysis and turned out to be of non-significance on multivariate analysis. Nevertheless, it corresponds well to the trend seen in the data published by Brady et al.: In this study, the frequency of aBAT in patients under the age of 12 ranged from 7 to 17%, whereas it ranged from 22 to 29% in patients in between 12 and 20 years. Gilsanz et al.We were able to confirm that the occurrence of aBAT is dependent on the outdoor temperature, whereby aBAT frequency increased with decreasing outdoor temperatures and decreased with increasing outdoor temperatures, respectivelyAnother finding of our research was that propranolol as an unselective beta-blocker had the same effect as warming. However, this result was of borderline significance, probably because propranolol was less often used as single preventive measure in our dataset. Nevertheless, this result corresponds well with evidence in the literature. Thereafter propranolol is highly effective in preventing aBATFinally, there is the suggestion that combining warming and propranolol may further reduce the risk of aBAT. However, this remains a hypothesis, which requires further confirmation since our data lack the power to prove this additive effect.Few limitations of our study should be considered: it was a retrospective observational study without randomization. The group in which only propranolol was used was too small to obtain final results on its effectiveness. Information from the centres on the use of air conditioning systems in uptake rooms would have been of interest, since all data came from nuclear medicine departments in Germany and Czech Republic. The use of air conditioning systems is expectedly less frequent in these two countries compared to warmer regions in the European Union (e.g. Spain, Italy) or the United States. | 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 appears to be similarly effective to warming and may be considered the first choice in countries where air-conditioning is regularly used. Warming and propranolol seem to have additive effects particularly when outdoor temperatures are low. | 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. Beer, Department of Nuclear Medicine, University Hospital Ulm; Prof. Dr. Winfried Brenner, Department of Nuclear Medicine, Charité Berlin; Prof. Dr. Jan Alexander Bucerius, Department of Nuclear Medicine, University Hospital Göttingen; Prof. Dr. Andreas Buck, Department of Nuclear Medicine, University Hospital Würzburg; Dr. Elke Conrad, Department of Nuclear Medicine, Helios-Klinikum Erfurt; Prof. Dr. Stefan Dresel, Department of Nuclear Medicine, Helios-Klinikum Berlin-Buch; Prof. Dr. Alexander Drzezga, Department of Nuclear Medicine, University Hospital Cologne; Prof. Dr. Markus Essler, Department of Nuclear Medicine, University Hospital Bonn; Prof. Dr. Samer Ezziddin, Department of Nuclear Medicine, University Hospital Homburg; Prof. Dr. Christiane Franzius, ZEMODI, Bremen; Prof. Dr. Martin Freesmeyer; Department of Nuclear Medicine, University Hospital Jena; Prof. Dr. C. la Fougère, Department of Nuclear Medicine, University Hospital Tübingen; Prof. Dr. Frederik L. Giesel, Department of Nuclear Medicine, University Hospital Düsseldorf; Prof. Dr. Frank Grünwald, Department of Nuclear Medicine, University Hospital Frankfurt/Main; Prof. Dr. Uwe Haberkorn, Department of Nuclear Medicine, University Hospital Heidelberg; Prof. Dr. Dr. Alexander Heinzel, Department of Nuclear Medicine, University Hospital Halle (Saale); Prof. Dr. Dirk Hellwig, Department of Nuclear Medicine, University Hospital Regensburg; Prof. Dr. Ken Herrmann, Department of Nuclear Medicine, University Hospital Essen; Prof. Dr. Jörg Kotzerke, Department of Nuclear Medicine, University Hospital Dresden; Prof. Dr. Bernd J. Krause, Department of Nuclear Medicine, University Hospital Rostock; Prof. Dr. Susanne Klutmann, Department of Nuclear Medicine, University Hospital Hamburg-Eppendorf; Prof. Dr. Michael Kreißl, Department of Nuclear Medicine, University Hospital Magdeburg; Prof. Dr. Torsten Kuwert, Department of Nuclear Medicine, University Hospital Erlangen; Prof. Dr. Constantin Lapa, Department of Nuclear Medicine, University Hospital Augsburg; PD Dr. Ulf Lützen, Department of Nuclear Medicine, University Hospital Schleswig-Holstein Kiel; Prof. Dr. Dr. Ph. T. Meyer, Department of Nuclear Medicine, University Hospital Freiburg; Prof. Dr. F. M. Mottaghy, Department of Nuclear Medicine, University Hospital Aachen; Dr. C. Neumann, Department of Nuclear Medicine, Evangelisches Klinikum Bethel; Prof. Dr. Michael J. Reinhardt, Department of Nuclear Medicine, Pius Hospital Oldenburg; PD Dr. Christoph Rischpler, Department of Nuclear Medicine, Klinikum Stuttgart; Prof. Dr. Juri Ruf, Department of Nuclear Medicine, Städtisches Klinikum Karlsruhe gGmbH; Prof. Dr. M. Schäfers, Department of Nuclear Medicine, University Hospital Münster; Prof. Dr. Mathias Schreckenberger, Department of Nuclear Medicine, University Hospital Mainz; Dr. Dagmar Steiner, Department of Nuclear Medicine, University Hospital Giessen; Prof. Dr. Wolfgang Weber, Department of Nuclear Medicine, Klinikum rechts der Isar an der Technischen Universität Munich; Prof. Dr. Philipp Wiggermann, Department of Radiology and Nuclear Medicine, Städtisches Klinikum Braunschweig; Prof. Dr. Klaus Zöphel, Department of Nuclear Medicine, Klinikum Chemnitz—all in Germany; and Prof. MUDr. Jiri Ferda, Radiologieplzen.eu, Plzen, Czech Republic. This study was supported by the Mitteldeutsche Kinderkrebsforschung—Stiftung für Forschung und Heilung, Leipzig, Germany. | 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 protocol-specified and exploratory (longer follow-up) OS analyses. At the time of these analyses, the full OS benefit of 1L ribociclib was not completely characterized because the median OS (mOS) was not reached. As CDK4/6 inhibitor (CDK4/6i) + endocrine therapy (ET) is now a preferred option for 1L HR+/HER2− ABC, we report an exploratory analysis (median follow-up, 70.8 months; 14.5 months longer than the prior analysis) to fully elucidate the OS benefit in the MONALEESA-3 1L population. | 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 chemotherapy-free survival (CFS) were analyzed. MONALEESA-3 is registered with ClinicalTrials.gov (NCT02422615). | 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 ribociclib versus placebo. Among those who discontinued treatment, 16.7% and 35.0% on ribociclib or placebo, respectively, received a subsequent CDK4/6i. No new safety signals were observed. | 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 (NSAI) letrozole failed to demonstrate a statistically significant improvement in OS over letrozole alone in postmenopausal patients in the PALOMA-2 trial (median OS [mOS], 53.9 vs. 51.2 months [hazard ratio (HR) 0.96; 95% CI 0.78–1.18; Ribociclib has demonstrated a significant PFS and OS benefit in all three of its pivotal phase III clinical trials in patients with HR+/HER2− ABC. In MONALEESA-2, first-line ribociclib + letrozole in postmenopausal women demonstrated a significant 12.5-month improvement over letrozole alone, with an mOS of 63.9 versus 51.4 months (HR 0.76; 95% CI 0.63–0.93; As the combination of a CDK4/6i + ET is the recommended first-line option for patients with HR+/HER2− ABC, it is highly clinically relevant to understand the OS benefits of ribociclib + fulvestrant in this population [ | 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 Response Evaluation Criteria in Solid Tumors version 1.1 or at least one predominantly lytic bone lesion was required.Patients receiving treatment in the first-line setting were those with no prior treatment for ABC, including those who relapsed > 12 months after the end of (neo)adjuvant ET (late relapse) or patients with de novo advanced/metastatic disease (no prior exposure to ET). Patients characterized as receiving treatment in the second-line setting included those who relapsed ≤ 12 months from completion of (neo)adjuvant ET (early relapse) or progressed on first-line ET for ABC. Despite receiving treatment in the advanced setting for the first time, patients with early relapse were analyzed with the second-line population of patients due to having a more similar prognosis to this population compared with the otherwise defined first-line population in the study. Patients who had received previous chemotherapy for advanced disease or any previous treatment with fulvestrant or a CDK4/6i were not included. | 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 events (AEs) were monitored and graded according to the Common Terminology Criteria for Adverse Events (version 4.03) [ | 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, on patients receiving first-line therapy (de novo or late relapse), and on patients receiving second-line therapy (early relapse or one prior ET for ABC). In addition to the OS analyses, in patients receiving first-line therapy, CFS, TTC, and PFS2 were analyzed using the Cox proportional hazards model and Kaplan–Meier method. In the current extended follow-up (data cutoff, January 12, 2022), a sufficient number of events was reported in the first-line ribociclib arm to provide an estimate of mOS. For patients receiving first-line therapy, the rank-preserving structural-failure time model was used as a sensitivity analysis on OS to determine the effects of crossover and administration of subsequent CDK4/6is in the placebo group. | 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 were randomized to the ribociclib arm and 128 to the placebo arm. A total of 39 of 237 patients (16.5%) in the ribociclib arm and 11 of 128 patients (8.6%) in the placebo arm were still receiving study treatment at the cutoff date. Following the final OS analysis, 2 patients (1.6%) in the placebo arm elected to cross over and received at least one dose of ribociclib. A total of 133 patients (56.1%) in the ribociclib arm and 101 patients (78.9%) in the placebo arm discontinued first-line treatment due to disease progression. AEs (7.7%), patient/guardian decisions (7.1%), physician decision (6.8%), death (0.3%), and protocol deviation (0.3%) were other reasons for discontinuing first-line treatment (Additional file | 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 the placebo arm (34.6 months; 95% CI 29.9–42.6 months [HR 0.64; 95% CI 0.49–0.84]; Fig. Progression free survival 2 in patients who received ribociclib plus fulvestrant as first-line therapy | 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 a nearly 16-month improvement in mOS versus fulvestrant alone, with a 33% relative reduction in the risk of death. Additionally, even though more patients in the placebo versus ribociclib arm (35.0% vs. 16.7%) received a CDK4/6i after discontinuing study treatment, patients in the ribociclib arm still experienced an OS benefit. These extended follow-up results clearly demonstrate the magnitude of survival benefit with ribociclib in the first-line setting, which was not fully revealed in the prior exploratory OS analysis of MONALEESA-3 for this subgroup [Postdiscontinuation observations are particularly helpful in providing additional insights into benefit beyond study treatment. The benefit of first-line ribociclib + fulvestrant was demonstrated after discontinuation of study treatment, with prolongation of median PFS2 by 16.1 months. Furthermore, median CFS was delayed by 20.2 months in patients receiving ribociclib in the first-line setting, with a 43% relative reduction in the risk of chemotherapy, compared with those receiving placebo. These postdiscontinuation results, along with the survival benefit demonstrated in MONALEESA-3, strengthen the efficacy profile and confirm the lasting benefit of first-line ribociclib treatment that extends well beyond study treatment. Recently the results of SONIA, which studied first-line NSAI + CDK4/6i followed by second-line fulvestrant versus first-line NSAI followed by second-line fulvestrant + CDK4/6i, were reported, with no significant difference in PFS2 or OS between the treatment arms [This is the third pivotal trial to demonstrate a significant improvement in OS with ribociclib in a first-line setting, and these data align with those of the MONALEESA-2 (first line in combination with letrozole in postmenopausal patients) trial and MONALEESA-7 (first line in combination with NSAI in pre/perimenopausal patients) trial, which demonstrated a 63.9- and 58.7-month mOS, respectively, in patients treated with ribociclib + ET [OS results with other CDK4/6is in combination with fulvestrant have been reported. However, it is important to understand the relevant differences in the patient populations of these studies to help put the data in context. MONALEESA-3 included a broad-spectrum patient population, in which first line was defined as either no prior treatment for breast cancer (de novo patients with no prior exposure to ET) or relapse > 12 months after (neo)adjuvant ET (late relapse) and second line was defined as one prior ET for ABC or relapse ≤ 12 months after the end of (neo)adjuvant therapy (early relapse) [ | 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− ABC. This analysis adds to the robust body of evidence on the efficacy of ribociclib use across the MONALEESA program and confirms its long-term, consistent OS benefit in treating patients with HR+/HER2− ABC irrespective of ET partner or menopausal status. | 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 medical editorial assistance with this manuscript. Ribociclib was discovered by Novartis Institutes for BioMedical Research in collaboration with Astex Pharmaceuticals. | 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 a steering committee comprising participating investigators and Novartis representatives. The safety data were assessed by an independent data monitoring committee. | 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 boards from Pierre Fabre, Hexal, Agendia, and Sanofi Aventis. SC reports personal fees for advisory boards and institutional grants for participation in clinical trials from Novartis, Pfizer, Hoffmann-LaRoche, and Eli Lilly during the conduct of the study and outside the submitted work. GJ reports personal fees and nonfinancial support from Novartis during the conduct of the study; personal fees and nonfinancial support from Novartis, Roche, Pfizer, Lilly, Amgen, BMS, AstraZeneca, AbbVie, Daiichi Sankyo, and Seagen outside the submitted work; and nonfinancial support from MedImmune and Merck KGaA outside the submitted work. MDL reports personal fees for speaker honoraria and advisory board honoraria from Pfizer, Novartis, Roche, AstraZeneca, Eisai, Eli Lilly, and Pierre Fabre outside the submitted work and personal fees for advisory board honoraria from MSD outside the submitted work. S-AI reports research grants from AstraZeneca, Eisai, Daewoong, Pfizer, and Roche; personal fees and nonfinancial support for presenting results of clinical trial from Novartis; and personal fees from AstraZeneca, Hanmi, Pfizer, Eisai, Amgen, GSK, MSD, Roche, and Lilly outside the submitted work. KP reports personal fees for advisory boards from Novartis, AstraZeneca, Roche, and Pfizer outside the submitted work. GVB reports personal fees for advisory boards from Roche, Novartis, Eli Lilly, Seagen, AstraZeneca, Daiichi Sankyo, and MSD outside the submitted work. MM reports personal fees for speaker honoraria and honoraria for participation in advisory boards from Lilly and Pfizer; honoraria for participation in advisory boards from AstraZeneca, GlaxoSmithKline, PharmaMar, and Taiho Oncology; and research grants and honoraria for participation in advisory boards from Novartis and Roche/Genentech outside the submitted work. AN reports personal fees for consulting/advisory roles and travel/accommodation/expenses and research funding from Novartis and personal fees for consulting/advisory role from Amgen during the conduct of the study. GSS reports institutional reimbursement for patient accrual during the conduct of the study; institutional reimbursement for education and steering committee activities from Novartis; and institutional research support from Merck, AstraZeneca, Roche, and Seagen outside the submitted work. LDlCM reports personal fees from BMS, MSD/Merck, Roche, and Gilead outside the submitted work. JTB reports grants for institutional funding for doing research from AbbVie, Alliance, Argenx, Ascentage Pharma Group, AstraZeneca, Biodesix, Bio-Thera, Bristol Myers Squibb, Celgene, Eli Lilly, Genentech/Roche, Hutchison, Immunomedics, Gilead, MT Group, Merck, Nektar, Pfizer, Polynoma, Seagen, Serono/EMD, Tesaro, TG Therapeutics, Daiichi Sankyo, Exact Sciences, Boehringer Ingelheim, Laekna, Novocure, Mirati Therapeutics, Tarveda Therapeutics, Sumitomo Dainippon Pharma Oncology, Elpiscience Biopharma, Takeda, Vaccinex, Vincerx Pharma, Ultimovacs, and Mersana during the conduct of the study. JPZ, YW, AC, and CW report employment with and stock ownership of Novartis. DS reports board of directors (stock) and travel expenses from BioMarin; stock ownership, research funding, and travel expenses from Pfizer; advisory board, consulting, research funding, and travel expenses from Novartis; consulting fees from Eli Lilly; and stock ownership of Amgen and Seattle Genetics outside the submitted work. | 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 Nutrition (TRAIN) programme, which integrated nutrition behaviour change and agricultural extension with a credit platform to support women's income generation. We used the Strengthening Economic Evaluation for Multisectoral Strategies for Nutrition (SEEMS‐Nutrition) approach. The approach aligns costs with a multisectoral nutrition typology, identifying inputs and costs along programme impact pathways. We measure and allocate costs for activities and inputs, combining expenditures and micro‐costing. Quantitative and qualitative data were collected retrospectively from implementers and beneficiaries. Expenditure data and economic costs were combined to calculate incremental economic costs. The intervention was designed around a randomised control trial. Incremental costs are presented by treatment arm. The total incremental cost was $795,040.34 for a 3.5‐year period. The annual incremental costs per household were US$65.37 (Arm 2), USD$114.15 (Arm 3) and $157.11 (Arm 4). Total costs were led by nutrition counselling (37%), agriculture extension (12%), supervision (12%), training (12%), monitoring and evaluation (9%) and community events (5%). Total input costs were led by personnel (68%), travel (12%) and supplies (7%). This study presents the total incremental costs of an agriculture‐nutrition intervention implemented through a microcredit platform. Costs per household compare favourably with similar interventions. Our results illustrate the value of a standardised costing approach for comparison with other multisectoral nutrition interventions.
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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 similar interventions.This study provides evidence on the costs of integration to support the design and implementation of multisectoral nutrition programmes.Our results illustrate the value of standardising costing to facilitate comparisons with other multisectoral nutrition interventions.
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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 Bangladesh, 24% of ever‐married women between the ages of 15−19 years of age are undernourished and rural women are more likely to suffer from undernourishment than urban women. At the same time, the proportion of overweight women has increased to 32%, highlighting the problem of both under and overnutrition in the country (NIPORT & ICF, Nutrition‐specific interventions that address the immediate causes of malnutrition have long been used to target undernutrition. Nutrition‐sensitive interventions—that address intermediate or underlying causes of malnutrition and address multiple outcomes—have also shown promise. Nutrition‐sensitive agriculture (NSA) programmes, in particular, have the potential to accelerate progress in addressing child malnutrition (Ruel & Alderman, The Targeting and Realigning Agriculture to Improve Nutrition (TRAIN) project was a multisectoral nutrition‐sensitive intervention implemented in rural Bangladesh by the nonprofit Building Resources Across Communities (BRAC). The intervention was designed to be evaluated by a randomised controlled trial (RCT). The RCT baseline survey was implemented in 2016−2017 by the International Food Policy Research Institute (IFPRI).This study presents the incremental costs of implementing an integrated agriculture‐nutrition intervention through an existing BRAC microcredit platform.Financial costs represent the implementing partner's actual expenditures on goods and services purchased to deploy the intervention. Economic costs, on the other hand, are defined as the opportunity cost of all of the resources used to produce something; and can include the value of resources that may not have been paid for, such as volunteer frontline worker time or programme participant time. Once data becomes available from an ongoing impact evaluation, these costs will be combined with programme benefits for a full economic evaluation including cost‐benefit and cost‐effectiveness analyses.Our findings serve many purposes. A robust understanding of the costs of multisectoral nutrition strategies is critical for priority‐setting and for motivating donors. This study is useful for governments and development partners to target investments in multisectoral nutrition programmes. Standardised unit cost data provides a cost benchmark for governments, donors and non‐profit organisations on how to design, budget and measure the resource requirements of interventions. Lastly, this analysis contributes to an effort to build an evidence base on the costs of multisectoral nutrition programmes across different settings and platforms. This study was conducted by the Strengthening Economic Evaluation for Multisectoral Strategies for Nutrition (SEEMS‐Nutrition) consortium, led by the University of Washington in partnership with IFPRI. SEEMS‐Nutrition develops standardised approaches and tools to assess the costs and benefits of multisectoral nutrition programmes. | 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 districts. TRAIN incorporated a BCC strategy for maternal and child health and nutrition into a female‐focused microcredit programme promoting production diversity and income generation.BRAC has led microcredit programmes in Bangladesh since 1974. Dabi, a credit platform lending only to women, has coverage through 2146 local branches with more than 3.5 million borrowers. Dabi provides loans to women to increase income and production in agriculture and to promote empowerment. Dabi disburses $1.8 billion in loans annually, the majority for agriculture (60%).The TRAIN programme had an additive design with three different treatment arms and a control group. Each arm built an additional component onto the control arm (the existing Dabi microfinance platform) (Supporting Information: Appendix Figure TRAIN had a 6‐month start‐up period (October 2016−March 2017). This paper presents the cost analysis from 40 months (3.5 years) of programme implementation (October 2016−January 2020). Given that the last 3 months of implementation were disrupted by COVID‐19 and extended until October 2020, our study only covers the pre‐COVID period. | 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 beneficiaries. Costs related to third‐party external research were excluded. The SEEMS‐Nutrition framework uses a four‐step approach. Costs are aligned with a multisectoral nutrition typology that identifies resource use and outputs along the programme impact pathways to achieve standardised unit costs and the basis for benchmarking and economic evaluation. Step 1 aligns the TRAIN programme to a typology of nutrition‐sensitive value (NSV) chain interventions that (1) increase the supply of nutrient‐rich foods, (2) increase the demand for nutrient‐rich foods, and (3) promote the enabling environment for nutrition. Step 2 maps the programme impact pathways to clearly articulate the linkages from activities to outputs and outcomes. Step 3 identifies all activities, inputs and costs along the impact pathway. Step 4 identifies outputs and outcomes for each activity to define the components of total and unit costs. The four‐step framework estimates the direct intervention costs and opportunity costs associated with all programme activities.Multisectoral nutrition approaches may include one or more of the intervention typologies with different components, services and outputs. Therefore, it is important to clearly define the unit cost for one or more outputs. Supporting Information: Appendix Table | 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 combines financial expenditure data with micro‐costing methods to identify and value resources and allocate costs to activities and inputs. The Activity‐Based‐Costing‐Ingredients (ABC‐I) method (Kaplan & Anderson, We leveraged secondary data from programme monitoring and reports. When available, planning and progress reports were reviewed retrospectively for randomly selected programme staff and frontline workers. Costs were disaggregated into start‐up and recurrent categories. Start‐up costs occurred in the first 6 months, such as planning, materials development and staff training. Recurrent costs included ongoing activities like household visits, community events and monitoring.Primary cost data were collected in two rounds (May 2019 and February 2020) through semistructured in‐depth interviews (IDIs) and focus group discussions (FGDs). IDIs and FGDs gathered data on interviewees' opportunity costs and out‐of‐pocket (OPP) expenses. In the first round of data collection, we organised IDIs and FGDs at a centralised location. FGDs were conducted with FOs (We estimated the opportunity cost of beneficiary participation with data from the process evaluation. The process evaluation included information on beneficiary time use for the index female respondent and the index husband in each household.Data were stored in secure password‐protected computers and servers according to IFPRI and BRAC data governance policies. The data were only accessible to the research team. All hard copies of consent forms, structured interviews and timesheets were kept in a safe location only accessible to the research team. Ethical clearance for the impact evaluation including cost analyses was obtained from the IFPRI Institutional Research Board, BRAC University, Bangladesh, and the Bangladesh Medical Research Council. The study was registered on the Registry for International Development Impact Evaluation. | 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 data from BRAC. These data were entered into a SEEMS‐Nutrition expenditure analysis template in Microsoft Excel (Version 16). We then mapped line‐item expenditures to standardised input and activity codes using the template. Third, we used Excel to summarise and analyse micro‐costing data from the qualitative interviews and focus group discussion.Most line‐item expenditures were easily mapped to standardised SEEMS activity and input codes. However, there were some exceptions: (1) BRAC personnel who contributed to multiple activities; and (2) shared capital and supply costs. For the first, we developed allocation rules for each activity using data from KIIs and FGDs. For example, using qualitative interviews we found PKs spent 80% of their time on nutrition counselling, 10% on training, 5% on planning and 5% on coordination meetings. PK salaries were allocated accordingly to those activities. Shared inputs or capital costs were allocated proportionally across the related activities. Shared costs are described in greater detail below. | 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 Table | 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 expenditure and economic cost data were allocated based on time spent on programme activities. | 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 programme activities. To value beneficiaries' time accurately, we used daily wage rates for agricultural labour for men and women from a 2017 IFPRI survey in implementation villages. We used mean daily wage rates for male and female agricultural workers to value beneficiaries' time. Once we obtained all personnel and beneficiary costs aligned to programme activities, we mapped them onto the standardised SEEMS activity categories (Supporting Information: Appendix Table | 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 and reflects the value‐in‐use of capital items, rather than reflecting the financial cost from the time of purchase (Brooker et al., | 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 recurrent). We estimate annual cost per beneficiary and the annual cost per household by treatment arm. The cost profile is the share of the disaggregated cost over the total programme costs for the 3.5‐year period. | 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 which treatment arm they supported with their activities. Variation in overtime by treatment arm was due to the additive design of the intervention. For example, Arm 4 involves more programme activities than Arm 2 or 3. The geographical spread of intervention households and the frontline workers' ability to afford transportation costs also affected their time investments. Variations in frontline worker overtime and OOP expenses were simulated using the means and standard deviations from actual data collected from the sample of PKs converted into shape and scale parameters for the gamma distribution.Beneficiary opportunity costs: Beneficiary participation in the programme was estimated using process evaluation data on the amount of time spent on TRAIN activities. The baseline survey provided local wage rates for men and women. The sensitivity analysis varied opportunity costs separately for men and women using means and standard deviations from the process evaluation and assumes a gamma distribution (Table | 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 represent beneficiary opportunity costs. This category was followed by travel/per diems (12%), supplies (7%), contracted services (6%) and overhead (6%).Programme activities were then mapped to a NSV chain typology (Figure Cost drivers mapped to the nutrition‐sensitive value chain typology for the TRAIN intervention in Bangladesh (Source: Authors). TRAIN, Targeting and Realigning Agriculture to Improve Nutrition. | 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 agriculture, and fell in between at USD$65.18. As many activities occurred at the household level, the programme was designed to target more than one household member. Considering both the index female and male in the household, the cost per household drops to USD$19.61, USD$34.25 and USD$47.13 by arm, respectively (Table Summary of unit costs for the TRAIN intervention in Bangladesh (USD, 2019)Abbreviation: HH, Household. | 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 beyond the targeted beneficiaries. Factoring in others in the household, unit costs are considerably lower. To gauge the potential range of unit costs, we calculated alternative scenarios for costs per beneficiary based on the average size of participating households. When considering the index female and male as the direct beneficiaries, the unit cost decreases to USD$33.64. When considering the index parents and all childrenUnsurprisingly, total incremental costs and unit costs vary by the level of implementation intensity across the three intervention arms. With an increase in training intensity (frequency of sessions) and/or programme complexity (number of components), the unit cost per household increases. These increases are driven by personnel costs for additional activities such as agriculture extension or gender sessions (Arms 3 and 4). Similarly, beneficiary opportunity costs increased with programme complexity. Opportunity costs increased because beneficiaries spent more time in community events; home visits are longer with additional counselling components. Our results showed the index beneficiary women had higher opportunity costs across all treatment arms in all three scenarios; nearly double the costs of their husbands. This is likely because household visits targeted women. However, if programme impacts do not differ significantly by treatment arm, additional complexity may not be worth the cost.We also examine the costs of incorporating women's empowerment activities. Women's empowerment activities accounted for 30% of programme costs, as part of facilitating the enabling environment for nutrition. As noted, the unit cost per household increased with programme complexity. Thus, Arm 4, which has the most activities, including gender forums and men's sensitisation, had the highest unit costs per beneficiary. Women spent almost twice the amount of time than men; our sensitivity analysis emphasises the range of higher opportunity costs for women (Table Unit cost range estimates from the sensitivity analyses (USD, 2019)Abbreviations: BDT, Bangladesh Taka; HH, household; OOP, out‐of‐pocket costs; PK, Pushti Kormi (nutrition frontline worker); SD, standard deviation.Sensitivity analysis results of varying key inputs on total economic and unit costsExamining costs by activity, the main driver was household nutrition counselling. Coupled with the agricultural household visits, training, and community events, beneficiary outreach accounted for over half of the costs. This finding reflects the intensive nature of activities to reach beneficiaries. Examining costs by input, the main cost driver was personnel. Personnel costs were driven by frontline workers, accounting for over two‐thirds of total personnel costs. Salary data were gathered from BRAC expenditures. We also estimated frontline workers economic costs in overtime work and OOP costs. Our analysis found variations in opportunity costs that have important implications for scale‐up and sustainability. Among frontline workers, PKs spent a substantial amount of their time and resources conducting their work. These costs could limit the ability of PKs to conduct their activities in the long run. BRAC addressed this constraint by increasing PK travel stipends over time.We then mapped costs to the NSV chain typology. We found similar results to the first programme costed with the SEEMS approach: a nutrition‐sensitive agriculture programme, with agriculture and nutrition BCC delivered through community‐based preschools in Malawi (Margolies et al., Currently, comparisons with the literature on the costs of integrated agriculture and nutrition interventions are limited. These limitations are due to the small number of studies available, the heterogeneity in intervention design and the absence of a standardised methodology capturing activities across sectors. We found that for TRAIN, the incremental cost per household is within the range in the literature. The costs of an intervention promoting orange‐fleshed sweet potato (OFSP) production and consumption in Kenya were USD$155 per pregnant woman or USD$110 per beneficiary when mothers and infant children were included (C. E. Levin et al., Incorporating frontline worker opportunity costs in the TRAIN cost analysis highlights the programme's sustainability concerns. Despite the travel stipend provided in the second year, frontline workers shouldered additional OOP costs given the intensive nature of household‐level interventions. SEEMS‐Nutrition is underlining such questions in building evidence on the costs and cost‐effectiveness of nutrition‐sensitive interventions. This study presents full programme costs in the pre‐COVID period and is an important step toward a comprehensive economic evaluation. As noted above, a recent systematic review has found that nutrition‐sensitive agricultural interventions have a significant positive impact on dietary diversity among children 6−60 months old (Margolies et al. | 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. These results demonstrate that a standardised approach for measuring the costs of multisectoral nutrition strategies enhances comparability and transparency, increasing the application of cost data for assessing affordability for use in evaluation, planning and policymaking. | 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 and reviewed manuscripts. Nasrin Sultana co‐led data collection and reviewed the manuscript. Esther Choo contributed to the data analysis and reviewed the manuscript. Neha Kumar reviewed the manuscript. Carol Levin contributed to the cost study methodology and to conception and design, provided technical advice, participated in data collection, edited the manuscript and reviewed manuscripts. | 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 financial service offered by microfinance programmes, which target the poor and others unable to access traditional banks.BRAC. The index husband is the spouse of the primary female respondent.Source: Index parents and children include all children listed from the RCT survey roster, which could potentially include children of the primary respondent female from a prior marriage, for example.
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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 reorganization of ipsilesional cortex in 12 individuals with persistent (1–3 years), moderate-to-severe upper-extremity impairment. No serious perioperative or stimulation-related adverse events were encountered, with participants demonstrating a seven-point median improvement on the Upper-Extremity Fugl-Meyer Assessment. All individuals who enrolled with partial preservation of distal motor function exceeded minimal clinically important difference regardless of time since stroke, with a median improvement of 15 Upper-Extremity Fugl-Meyer Assessment points. These robust functional gains were directly correlated with cortical reorganization evidenced by increased ipsilesional metabolism. Our findings support the safety and feasibility of deep brain stimulation to the cerebellar dentate nucleus as a promising tool for modulation of late-stage neuroplasticity for functional recovery and the need for larger clinical trials. ClinicalTrials.gov registration: A phase I trial of cerebellar deep brain stimulation to enhance chronic post-stroke motor rehabilitation supports the safety and feasibility of the approach while providing encouraging evidence of motor improvements. | 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 development of new technologies have played a substantial role in improving outcomes in the early hours after insult, including advances in emergency healthcare delivery networks, imaging technologies and medical devices. The same cannot be said, however, for the post-acute phase where, despite substantial effort and investment, technological leaps have been slower. Even with contemporary techniques, up to 50% of survivors experience chronic disabilityNeuroplasticity is a well-documented phenomenon that is associated with gradual spontaneous or therapy-driven improvements in post-stroke motor function. The extent of recovery varies considerably across individuals and is known to depend largely on lesion location and sizeWe have proposed and investigated a new, invasive surgical approach for extending the degree and temporal window of neuroplasticity after ischemic and traumatic insults to the brain. Specifically, the approach involves continuous stimulation of the cerebellar dentate nucleus (DN) to modulate neural activity and ipsilesional cortical excitability through activation of the robust, endogenous dentatothalamocortical pathway (Fig. | 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 interconnecting the cerebral cortex with the contralateral cerebellar hemisphere. DN is shown in brown. RN, red nucleus; PN, pontine nuclei.Here we report a first-in-human translation of this research in a group of 12 stroke survivors with persistent, moderate-to-severe upper-extremity impairment. In this open-label, phase I clinical trial, we evaluated the safety and feasibility of surgical implantation and chronic DBS of the cerebellar DN. Overall, we found that our surgical approach and chronic stimulation was feasible and well tolerated in the target population, with no study-related serious adverse events encountered across the trial. Additionally, participants underwent a battery of secondary assessments to begin to characterize and understand the effect of therapy on upper-extremity motor impairment and function. We report significant improvements in motor function across all individuals who, at the time of enrollment, had even minimal residual distal motor function in the affected upper extremity and correlated effects on cortical metabolism. Of particular interest to stroke survivors, the magnitude of benefit was not found to depend on time after stroke, with robust improvements observed in participants who enrolled as late as 3 years after their index event. These early findings support that this new neuromodulation-based approach is safe and feasible in a moderately-to-severely impaired post-stroke population and shows promise for promoting recovery of function and influencing neuroplastic processes after cerebral ischemia, even in the later stages of disability. | 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 hemiparesis and sufficient upper-extremity motor ability to engage in rehabilitation (CONSORT diagram and outcomes for an open-label, single-arm phase I study of DBS to enhance post-stroke rehabilitation. EMR, electronic medical record. | 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. Table Incidence of adverse events during the trialAE, adverse event; SAE, serious adverse event; rehab, rehabilitation. | 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 treatment-related changes using the Arm Motor Ability Test (AMAT). Individual scores for each study participant during the trial are presented for the functional ability (FA) subscale in Extended Data Fig. No significant treatment-related effects were observed across any of the remaining secondary metrics, including the Nine-Hole Peg Test, the Bilateral Box and Block Test, the Short Form Health Survey (SF-12), the EuroQol (EQ-5D), the Beck Depression Inventory or the Beck Anxiety Inventory. Detailed pretreatment/posttreatment scores are provided for the motor outcome metrics in Extended Data Table | 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/extension, repeatable three times over a 1-min period, similar to what was applied successfully in the EXCITE and more recent VNS trials | 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 DN-DBS combined with rehabilitation on motor impairmentStroke remains the leading cause of physical disability in the industrialized world, with post-acute care costs exceeding those of acute hospital careWe observed significant and meaningful benefits in the form of both a reduction of motor impairment and gains in motor function in this cohort. It is noteworthy that these improvements were achieved: (1) in patients with overall poor function at enrollment, evidenced by a mean FM-UE of 22.9 points, and deemed to have poor natural prognosis and (2) after participants underwent a 3-month period of supervised rehabilitation aimed at minimizing the impact of renewed rehabilitation alone on impairment and function. In line with prior reportsGiven our prior animal model evidence that potentiation of corticomotor excitability and ipsilesional reorganization mediates the therapeutic effects of DN-DBSThe study has limitations inherent to an early stage, Phase 1 investigation. Overall interpretation of the data presented is limited by the open-label nature of the design, the heterogeneity in baseline impairment level across the sample population, and, finally, the limited size of that same sample that are typical of a phase I neurological device trial. The latter two issues likely contributed to the lack of observed effects on several of the additional secondary measures applied, including the Nine-Hole Peg Test, the Bilateral Box and Block Test and the EQ-5D. Next, although we made some effort to overcome confounds related to chronic physical deconditioning before initiating DBS by including a rehabilitation-only phase, we are not able to distinguish, with certainty, the effects of rehabilitation from the effects of DBS. This is particularly the case given that structured rehabilitation has been shown to result in meaningful improvements even in chronic post-stroke stagesIn summary, this phase I study presents the first evidence of safety and feasibility of DN-DBS in individuals with chronic post-stroke hemiparesis with encouraging rehabilitative effects and associated neurophysiological gains observed across the DBS + rehab phase. This emerging intervention has shown translational potential to modulate the magnitude of neuroplastic reorganization toward recovery of function and to extend its time window to late phases of disability. | PMC10504081 |
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