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Author contributions
C.O., T.L., E.L., M.B., A.S., A.Z., G.C. and T.O. designed the study. C.O., T.L., E.L., M.B., A.S., A.Z., G.C., T.O. and F.N. helped with implementation. T.L. is the funding holder. B.A., C.O. and M.G. provided statistical expertise. E.G. and F.N. conducted the statistical analysis. E.G. wrote the first draft. All co-a...
PMC10114123
Funding
This study was supported by the Bill and Melinda Gates Foundation (OPP1187628).
PMC10114123
Conflict of interest
None declared.
PMC10114123
References
PMC10114123
Subject terms
Mineral deficiencies
REGRESSION, ZINC DEFICIENCY, ZINC DEFICIENCY
Mineral deficiencies are common in children living in low-resource areas. Eggs are a rich source of essential nutrients and have been shown to improve growth in young children, although little is known about their impact on mineral status. Children aged 6–9 months (n = 660) were randomized to receive either one egg/day...
PMC10125967
Introduction
Multiple deficiencies, stunting, malnutrition
MALNUTRITION
Adequate mineral status is necessary for normal cellular function, and deficiencies directly affect childhood growth and developmentChildren with malnutrition rarely have deficiencies in only one of these minerals. Multiple deficiencies are prevalent, and have a compounding detrimental effect on children’s healthThe Ma...
PMC10125967
Methods
PMC10125967
Study design
The Mazira Project was a randomized controlled trial (clinicaltrials.gov registry NCT03385252; 12/28/2017), conducted in the Lungwena and Malindi areas of Mangochi District in rural Malawi from February 2018 to January 2019. Full details of the study protocol have been previously published
PMC10125967
Randomization, masking, and intervention
Randomization occurred at the end of a baseline study visit, using a 1:1 allocation ratio in blocks of 10. A member of the study team invited each household caregiver to select and open a sealed, opaque envelope from a basket containing the child’s group, under the supervision of a study-independent community member wh...
PMC10125967
Participants
acute illness or injury, allergic reactions, oedema, ill
SEVERE ANEMIA, FOOD ALLERGY, ALLERGIC REACTION, OEDEMA
Infants born out of a singleton pregnancy, aged 6–9 months, residing within the catchment areas of St. Martins Rural Hospital in Malindi and the Lungwena Health Center were eligible to participate in the study. Children with conditions that might affect growth and development, such as, severe anemia (hemoglobin < 5 g/d...
PMC10125967
Data collection
Assessments for growth, development, and dietary intake were obtained from all participating children at baseline and at the six-month follow-up. Anthropometric measures were converted to z-scores per the World Health Organization (WHO) Growth StandardsBlood was then placed into a trace metal certified, S-Monovette® 5....
PMC10125967
Plasma analysis
mineral deficiency, ®
MINERAL DEFICIENCY
Analysis to quantify mineral abundances in plasma samples drawn at baseline and 6-months was conducted by the Jay Turner Group in the McKelvey School of Engineering at Washington University. Samples were digested with microwave assistance based on a protocol adapted from Harrington et al., to optimize recovery of iron,...
PMC10125967
Statistical analysis
A detailed Statistical Analysis Plan was developed for this analysis and is publicly available at Effect modification analysis with the primary outcome of mineral status was used to examine the interaction of maternal education and child sex on the intervention. Significant interactions were considered for
PMC10125967
Results
PMC10125967
Plasma mineral distributions and prevalence of deficiency
The distributions of plasma copper, magnesium, selenium, zinc, and iron concentrations were similar from baseline to follow-up (Fig. Distribution of plasma mineral concentrations of participants in the Mazira Project, 2018–2019
PMC10125967
Effect modification of mineral status
Effect modification analyses did not identify any significant modifiers in the relationship between the intervention and plasma mineral levels.
PMC10125967
Discussion
mineral deficiency
ZINC DEFICIENCY, MINERAL DEFICIENCY
Minerals are necessary for proper cellular function in infants and children, especially during critical periods of growth and development. In this study of young Malawians, the egg intervention did not change plasma magnesium, copper, selenium, or zinc concentrations compared to the control group. At the 6-months, plas...
PMC10125967
Conclusions
mineral deficiencies
MALNUTRITION
Young children living in LMICs are particularly vulnerable to malnutrition, multiple mineral deficiencies, and their compounding detrimental effects. To our knowledge, this is the first study to examine multiple plasma mineral concentrations in infants and young children following the provision of one egg per day. Our ...
PMC10125967
Supplementary Information
The online version contains supplementary material available at 10.1038/s41598-023-33114-1.
PMC10125967
Acknowledgements
The authors wish to acknowledge and thank the study staff involved with collection, processing, and storage of biological samples: John Kamwenda, Feston Sikina, Atupele Chaponda, Anthony Mchizi, and Austin Nkhoma.
PMC10125967
Author contributions
Designed research: C.S., B.C., L.I., C.L., K.M. Conducted research: C.S., K.M., B.C. Analyzed data or performed statistical analysis: C.D.A., J.D., J.T., X.L., P.P. Wrote paper: M.P., J.D., E.G. Prepared figures: M.P., J.D., X.L. Prepared tables: M.P., J.D., P.P., J.T. Had primary responsibility for final content: M.P....
PMC10125967
Funding
Bill & Melinda Gates Foundation, Grant/Award Number: OPP1169033.
PMC10125967
Data availability
Data described in this manuscript will be made publicly and freely available, along with the code book without restriction at
PMC10125967
Competing interests
The authors declare no competing interests.
PMC10125967
References
PMC10125967
Introduction
StatesPeriodontitis
DISEASE
Edited by: Vânia Pobre, Universidade Nova de Lisboa, PortugalReviewed by: Thuy Do, University of Leeds, United KingdomCamille Zenobia, AbbVie, United StatesPeriodontitis is a biofilm-mediated disease that is usually treated by non-surgical biofilm elimination with or without antibiotics. Antibiotic treatment in periodo...
PMC10765594
Methods
In the current manuscript, we have developed a method to culture subgingival samples
PMC10765594
Results
bleeding
BLEEDING, DENTAL PLAQUE
Antibiotic selection was different in over 80% of the cases. Clinical parameters such as periodontal pocket depth, attachment level, and bleeding upon probing improved in both groups. However, dental plaque was significantly reduced only in the group where antibiotics were selected according to the
PMC10765594
Discussion
The results of clinical and microbiological parameters, together with the reduced cost and low analysis time, support the use of the impedance system for improved individualized antibiotic selection.
PMC10765594
Introduction
EPS
DISEASE, PERIODONTAL DISEASES, PATHOLOGY
Biofilms are defined as bacterial communities composed of single or various bacterial species attached to each other on biotic/abiotic surfaces and encased in a self-secreted extracellular polymeric substance (EPS) (Despite the significant advances in the treatment of periodontal diseases, this pathology continues to i...
PMC10765594
Materials and methods
PMC10765594
Sample collection, transportation, and storage
STERILE, PLAQUE
To select the most suitable transport media and optimal storage time for periodontal biofilm samples, subgingival plaque from 5 individuals was collected by introducing 10 sterile paper-points (size 20) into the deepest subgingival pockets (≥ 6 mm) for 30-60 seconds and placed into 2 mL of three different transport med...
PMC10765594
Study design and patients’ selection
PD, allergic, bleeding, diabetes
BLEEDING, PERIODONTITIS, STERILE, SEVERE PERIODONTAL DISEASE, PERIODONTAL DISEASE, PLAQUE, DIABETES
To evaluate the use of the RTCA system in antibiotic selection for the individualized treatment of patients with periodontal disease, and to compare the Required sample size was calculated by a power estimation based on the differences in clinical attachment level (CAL) of 1 mm between the groups with variation in the ...
PMC10765594
Randomization and blinding
A randomized, double-blind clinical trial was carried out where patients and dentists were unaware of which methodology was used to select the antibiotic as part of the periodontal therapy. In detail, after consent form approval, dental clinic staff responsible for the prescription of the periodontal antibiotic treatme...
PMC10765594
Real-time biofilm growth monitoring
PLAQUE
To select the most suitable transport media for periodontal biofilm samples, the subgingival plaque samples were collected in 2 mL of three different transport media, as indicated above, and homogenized by vortexing for 60 sec. Paper points were discarded, samples were vortexed again for 30 sec and split into three equ...
PMC10765594
Evaluation of periodontal biofilm susceptibility to antibiotics by real-time monitoring of biofilm growth
SEVERE PERIODONTAL DISEASE, PLAQUE
To identify the best individual treatment for each patient with severe periodontal disease, three systemic antibiotics commonly used in dental practice, namely amoxicillin, metronidazole and azithromycin (SIGMA), and the combination of amoxicillin and metronidazole, were tested, by evaluating their effect on biofilm fo...
PMC10765594
DNA extraction, 16S rRNA gene sequencing and bioinformatic analyses
DENTAL PLAQUE
Genomic DNA from samples of the subgingival dental plaque collected before (initial inocula, t0) and 1 and 2 months after antibiotic treatment (t1 and t2, respectively), and the corresponding biofilms grown in xCELLigence impedance system for eight hours (alone and in combination with antibiotics) was isolated using Ma...
PMC10765594
Data availability
Reads have been publicly deposited at the SRA database (accession number: PRJNA892459). All other datasets generated during and/or analysed during the current study are available from the corresponding authors.
PMC10765594
Results
PMC10765594
Evaluation of different transport media and growth conditions for periodontal biofilm cultivation
In order to select the most suitable transport media for biofilm samples from deep periodontal pockets, subgingival biofilms from five volunteers were collected in three different transport media (RTF, VMGIII and VMGIII Agar) and stored at room temperature for 0h, 24h and 48h (We also performed principal component anal...
PMC10765594
The effect of conventional antibiotics on periodontal biofilm formation in real-time
periodontal disease, biofilm mass
PERIODONTAL DISEASE, PLAQUE
Once the most suitable conditions for periodontal biofilm transportation and growth were established, we grew subgingival biofilms of 64 patients with periodontal disease Biofilm growth derived from subgingival plaque samples grown in real time in an impedance-based monitoring system in the presence/absence of amoxicil...
PMC10765594
Antibiotic selection
After determining the most effective antibiotic treatment
PMC10765594
Changes in microbial composition depending on antibiotic selection methodology and antibiotic treatment
On average, 112,000 16S rRNA reads/sample were sequenced, from which 47,600 reads/sample were annotated at the species level. Using the minimum number of reads annotated to the species level in a sample (22,900 reads), rarefaction analyses were performed, and the curves flattened after 20,000 sequences, showing that ba...
PMC10765594
Clinical and microbiological outcomes one and two months after antibiotic treatment
PLAQUE
Clinical evaluation showed that all clinical parameters significantly improved after one month of treatment (BT vs AT1M) in both methodologies (Microbial composition of subgingival plaque samples before and one (AT1) or two months (AT2) after antibiotic treatment.
PMC10765594
Discussion
inflammation, periodontitis, PD, Periodontitis
INFLAMMATION, PERIODONTITIS, DENTAL PLAQUE, PERIODONTAL DISEASE, PERIODONTITIS, INFLAMMATORY DISEASE
Periodontitis is an inflammatory disease that occurs due to prolonged inflammation of the gingiva, accumulation of opportunistic pathogens within subgingival dental plaque, their interaction with the host and the dysbiosis of microbiota embedded in dental biofilms (In the current manuscript, we have developed a fast me...
PMC10765594
Data availability statement
The data presented in the study are deposited in the SRA repository, accession number PRJNA892459.
PMC10765594
Ethics statement
The studies involving humans were approved by Ethics Committee of the University of Valencia (Spain) (H1547805836517). The studies were conducted in accordance with the local legislation and institutional requirements. The participants provided their written informed consent to participate in this study.
PMC10765594
Author contributions
MŽ: Data curation, Formal analysis, Investigation, Methodology, Writing – original draft. AL-R: Methodology, Supervision, Visualization, Writing – original draft. MC-D: Data curation, Formal analysis, Methodology, Writing – original draft. MR-S: Methodology, Writing – original draft. AR: Methodology, Writing – original...
PMC10765594
Conflict of interest
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
PMC10765594
Publisher’s note
All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or ...
PMC10765594
References
PMC10765594
Background
Niger has the highest rate of adolescent fertility in the world, with early marriage, early childbearing and high gender inequity. This study assesses the impact of Reaching Married Adolescents (RMA), a gender-synchronized social behavioral intervention designed to improve modern contraceptive use and reduce intimate p...
PMC10243049
Methods
REGRESSION, SECONDARY
We conducted a four-armed cluster-randomized trial in 48 villages across three districts in Dosso region, Niger. Married adolescent girls (ages 13–19) and their husbands were recruited within selected villages. Intervention arms included home visits by gender-matched community health workers (CHWs) (Arm 1), gender-segr...
PMC10243049
Results
Baseline and 24-month follow-up data were collected April–June 2016 and April–June 2018. At baseline, 1072 adolescent wives were interviewed (88% participation), with 90% retention at follow-up; 1080 husbands were interviewed (88% participation), with 72% retention at follow-up. Adolescent wives had higher likelihood o...
PMC10243049
Supplementary Information
The online version contains supplementary material available at 10.1186/s12978-023-01609-9.
PMC10243049
Plain language summary
Although Niger has both the highest levels of fertility and of child marriage in the world, as well as substantial gender inequity, there have been no high-quality evaluations of public health programs aiming to increase contraceptive use or decrease intimate partner violence. In this study, we conducted a high quality...
PMC10243049
Supplementary Information
The online version contains supplementary material available at 10.1186/s12978-023-01609-9.
PMC10243049
Keywords
PMC10243049
Background
WEST, SECONDARY
The West African Francophone country of Niger has the highest prevalence of girl child marriage (marriage < 18 years) in the world [Across sub-Saharan Africa, adolescent girls face myriad structural, community, and interpersonal barriers to contraceptive use [At the interpersonal level, power dynamics favor husbands’ c...
PMC10243049
Methods
PMC10243049
Study design and participants
We evaluated the effects of the RMA intervention using a factorial, 4-arm cRCT, including a control arm and three intervention arms: household visits only (Arm 1), small group sessions only (Arm 2), and both household visits and small group sessions (Arm 3); all intervention arms included community dialogues. Full stud...
PMC10243049
Randomisation
The three eligible districts in the Dosso region were randomly assigned to an intervention condition using a computer-generated random number list. Within each district, we used a different computer-generated random number list to select 16 villages among those meeting inclusion criteria; four of those 16 villages in e...
PMC10243049
Procedures
RMA is a community-based, gender-synchronized program implemented by Pathfinder International and designed to increase use of modern spacing contraception among married adolescent girls and their husbands. Based on the Theory of Reasoned Action [Gender-matched, trained community health workers (CHWs) conducted househol...
PMC10243049
Outcomes
SECONDARY, CHOKED, LACTATIONAL AMENORRHEA
The primary outcome of this study was current use of modern contraceptives among female study participants. To assess this use, women were first asked whether they had ever done anything to delay or limit their number of pregnancies. Those answering in the affirmative were then asked about whether they had ever used ea...
PMC10243049
Statistical analysis
REGRESSION
Power calculations were conducted a priori based on the primary study outcome, modern contraceptive use. We assumed an intra-cluster correlation coefficient of kappa = 0.05. To provide 80% power at capturing an effect size of 2.0 greater odds of modern contraceptive use across four arms with 12 clusters of equal size n...
PMC10243049
Role of the funding source
The funder of the study had no role in study design, data collection, data analysis, data interpretation, or writing of the report.
PMC10243049
Discussion
WEST, EVENTS, SECONDARY
RMA, a community-based and gender-synchronized program to promote modern contraceptive use and gender equity, resulted in increased current modern contraceptive use and reduced IPV among married adolescent girls and their husbands in the Dosso region of Niger in this first randomized experimental evaluation of a progra...
PMC10243049
Conclusions
In sum, the RMA social behavioral intervention, inclusive of household visits from health workers and gender synchronized small groups for husbands and wives, demonstrated effectiveness in improving modern contraceptive use and reducing victimization from IPV among married adolescent girls in the Dosso region of Niger....
PMC10243049
Acknowledgements
Not applicable.
PMC10243049
Author contributions
All authors had full access to all the data in the study and had final responsibility for the decision to submit for publication. JGS: led conceptualization and writing; MIB, SA, AR: co-conceptualized and provided critical review of the manuscript; NEJ, SC: co-led design and conduct of analyses, participated in writing...
PMC10243049
Funding
This work was funded by the Bill and Melinda Gates Foundation (OPP1195210). The funding source had no role in the study design, analysis, interpretation of data, or decision to publish results.
PMC10243049
Availability of data and materials
De-identified data and analysis code are available from the corresponding author upon reasonable request.
PMC10243049
Declarations
PMC10243049
Ethics approval and consent to participate
Ethics review boards of the University of California San Diego (protocol number 160407S) and the Niger Ministry of Health approved all study procedures.
PMC10243049
Consent for publication
Not applicable.
PMC10243049
Competing interests
The authors declare that they have no competing interests.
PMC10243049
References
PMC10243049
Abstract
tumor, tumors, pancreatic cancer, HER2‐positive urothelial bladder cancer
TUMOR, TUMORS, RECRUITMENT, PANCREATIC CANCER
The antibody‐drug conjugate trastuzumab emtansine (T‐DM1) is approved for human epidermal growth factor receptor 2 (HER2/The phase II KAMELEON study investigated the efficacy of T‐DM1 in selected HER2‐positive non‐breast tumors. Although KAMELEON was terminated prematurely due to recruitment difficulty, the study demon...
PMC10278525
INTRODUCTION
tumor, breast cancer, breast and gastric cancers),In, breast tumor, colorectal, and bladder cancers
TUMOR, BREAST CANCER, DISEASE, SOLID TUMORS, BREAST TUMOR, METASTATIC BREAST CANCER
Gene amplification or overexpression of the protein encoded by the erb‐B2 receptor tyrosine kinase 2 (By IHC, a breast tumor is considered HER2‐positive if scored as IHC 3+ based on circumferential membrane staining that is complete, intense, and in >10% of tumor cells. By ISH, a breast tumor is considered HER2‐positiv...
PMC10278525
MATERIALS AND METHODS
PMC10278525
Determination of
breast and gastric cancers, tumor
TUMOR
Although the cutoffs for HER2‐positivity in breast and gastric cancers may be useful in defining similar values in other tumor types, the thresholds for treatment benefit may differ across indications. Thus, in preparation for KAMELEON (
PMC10278525
Study design and patients
Tumors, tumor, tumors, cholangiocarcinoma
TUMOR, SOLID TUMORS, TUMORS, PANCREATIC CANCER, TUMORS, CHOLANGIOCARCINOMA
KAMELEON was a multicenter, exploratory, non‐randomized, single‐arm, phase II study (NCT02999672). It was investigator‐initiated, but eventually received corporate sponsorship (Roche). KAMELEON, which was conducted at 10 sites across Italy, Spain, and the Netherlands, sought to determine the best tumor response followi...
PMC10278525
Outcomes
tumor, death, cancers, congenital anomaly/birth defect, BOR, disability/incapacity, Cancer
DISEASE PROGRESSION, TUMOR, ADVERSE EVENT, CANCERS, ADVERSE EVENT, EVENT, CANCER
The primary efficacy objective was to evaluate the best overall response (BOR), with tumor responders defined as individuals with confirmed complete response (CR) or partial response (PR), as determined by the study investigator using RECIST 1.1. Secondary efficacy endpoints included PFS (time from the first day of stu...
PMC10278525
Statistics
pre‐dose, BOR, BOR ≤
EVENTS
The sample size calculation was based on Simon's two‐stage design with early futility analysis to test the null hypothesis (BOR ≤ 5%) against the alternative hypothesis (BOR ≥ 20%). With a one‐sided alpha of 5%, 27 patients were required to reject the null hypothesis with 80% power. To allow for a dropout rate of 10%–1...
PMC10278525
RESULTS
PMC10278525
Patients
PD, UBC, urothelial bladder cancer
RECRUITMENT, DISEASE, METASTATIC DISEASE, ADVERSE EVENT, PANCREATIC CANCER, ONCOLOGY, PRIMARY TUMOR, METASTASES, DISEASE CHARACTERISTIC, CHOLANGIOCARCINOMA
KAMELEON was conducted between October 25, 2016, and April 10, 2018. Recruitment was halted on September 22, 2017, due to the difficulty in recruiting enough patients for the primary efficacy analysis within a reasonable timeframe. In the UBC cohort, screening was performed on the primary tumor in ~80% of patients and ...
PMC10278525
Efficacy and safety
pulmonary sepsis, craniocerebral injury, urothelial bladder cancer
ADVERSE EVENT, URINARY TRACT INFECTION
Five patients in the UBC cohort and one in the pancreatic cancer/cholangiocarcinoma cohort exhibited a PR, corresponding to an overall response rate (ORR; 90% CI) of 38.5% (16.57–64.52%) and 14.3% (0.73–52.07%), respectively. No patient in either cohort had a CR (Table In total, 84.6% (11/13) of patients in the UBC coh...
PMC10278525
Pharmacokinetics
T‐DM1 exposures at cycle 1, as measured by maximum concentration (C
PMC10278525
Gene‐protein assay
tumor, tumors, UBC, pancreatic cancer, cholangiocarcinoma
TUMOR, TUMORS, CHOLANGIOCARCINOMA
Of the 284 patients successfully screened for HER2 overexpression via IHC, 207 consented to the biomarker analyses. However, biomarker data were not available for 55 patients, owing to insufficient or poor‐quality tumor tissue or to assay‐related issues. Thus, the biomarker‐evaluable population was comprised of 152 pat...
PMC10278525
DISCUSSION
urothelial cancer, tumor, cancers, pembrolizumab, UBC, breast and gastric cancers, tumors, PD‐L1
TUMOR, CANCERS, BREAST CANCER, RECRUITMENT, SECONDARY, PANCREATIC CANCER, TUMORS, CHOLANGIOCARCINOMA
In this phase II study of non‐breast tumor types, HER2‐positivity was detected via gene‐protein assay in 24.3% of patients with UBC, 1.5% with pancreatic cancer, and 8.2% with cholangiocarcinoma. The relatively low prevalence of HER2‐positivity resulted in poor accrual and premature termination of the study. Although c...
PMC10278525
AUTHOR CONTRIBUTIONS
PMC10278525
CONFLICT OF INTEREST STATEMENT
JN, Cancer
ONCOLOGY, BREAST, CANCER
EGEdV reports institutional financial support for serving as an advisor to Daiichi Sankyo, Merck, National Surgical Adjuvant Breast and Bowel Project, Pfizer, Sanofi, and Synthon, as well as institutional financial support for participating in clinical trials or undertaking contracted research for Amgen, AstraZeneca, B...
PMC10278525
Supporting information
Data S1. Click here for additional data file.
PMC10278525
ACKNOWLEDGMENTS
Medical writing support for the development of this manuscript, under the direction of the authors, was provided by Tiffany DeSimone, PhD, and Sachi Yim, PhD of Ashfield MedComms (US), an Inizio company, and was funded by Roche.
PMC10278525
DATA AVAILABILITY STATEMENT
Qualified researchers may request access to de‐identified patient‐level data through the Clinical Study Data Request platform (
PMC10278525
REFERENCES
PMC10278525
1. Introduction
virologic failure, VF, HIV drug resistance
REGRESSION
Increasing HIV drug resistance (DR) among children with HIV (CHIV) on antiretroviral treatment (ART) is concerning. CHIV ages 1–14 years enrolled from March 2019 to December 2020 from five facilities in Kisumu County, Kenya, were included. Children were randomized 1:1 to control (standard-of-care) or intervention (poin...
PMC10612029
2. Materials and Methods
SUPPRESSION
The Optimizing Viral Suppression in Children on ART in Kenya (Opt4Kids) study protocol and primary findings have been described previously [
PMC10612029
2.1. Study Procedures
VF, provider-determined
NAIROBI
Whole blood was collected from study participants for POC VL testing and separated into plasma for testing using a GeneXpert system (Cepheid, Nairobi, Kenya) on site at study facilities or via daily transport to a facility less than 2 km away [Children in the intervention group underwent DRT at episodes of VF detection...
PMC10612029
2.2. Study Setting
First-line ART regimens in Kenya during the study period for children included lamivudine with either abacavir (preferred) or zidovudine (alternative) and lopinavir/ritonavir for those less than three years of age and lamivudine with either abacavir (preferred) or zidovudine (alternative) and efavirenz for those three ...
PMC10612029