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Sensitivity analysis | SE, chronic neck pain, NDI, NRS | SENSITIVITY | The results of the sensitivity analysis are presented in Table
Results of uncertainty analysisFor the base case analysis, QALY was calculated with EQ-5D in societal perspectives. The distribution of cost and QALY was calculated by non-parametric bootstrap. The incremental net benefit (INB) was calculated using the 1xWTP threshold ($26,375) and 1xGDP per capita ($31,838)In the main analysis, patients assigned to each group were followed-up up to 12 weeks, and missing values were imputed with multiple imputation. The costs from the healthcare system perspective include the costs of formal and informal healthcare involved in chronic neck pain treatment and the transportation and time costs. For the costs in the societal perspective, productivity costs from chronic neck pain are included.Sensitivity analysis. 1 was a per-protocol analysis, which included patients who received at least six treatment sessions (47 in the pharmacopuncture group and 45 in the physical therapy group). Sensitivity analysis 2. Assuming that only employed patients suffered income loss due to time and productivity losses. Sensitivity analysis 3. We applied $26 by multiplying 1.5 with the pharmacopuncture cost in the base case analysis. Sensitivity analysis 4. We applied $35 by multiplying 2 with the pharmacopuncture cost in the base-case analysis. Sensitivity analysis 5. Cost effectiveness analysis based on NRS and NDI.
First, a cost-effectiveness analysis was performed on patients who had received at least six treatment sessions. The difference in costs was $1,149 from a societal perspective and $36 from a healthcare perspective. On the CE plane, CE pairs showed the highest distribution of 81.3% in the SE quadrant; thus, the probability of pharmacopuncture being more cost-effective from a societal perspective was 100% based on QALY. | PMC10666315 |
Discussion | chronic cervical pain, NDI, chronic neck pain, neck pain, NRS | MINOR, SENSITIVITY | This economic evaluation was performed based on an RCT that compared pharmacopuncture and usual care for chronic neck pain. Compared to the usual care group, the pharmacopuncture group had higher intervention costs, lower direct non-medical costs, and lower indirect costs (costs due to productivity loss). Consequently, the costs from a societal perspective were significantly lower in the pharmacopuncture group during the entire study period (12 weeks), whereas there were no significant differences in the costs from a healthcare perspective. The pharmacopuncture group tended to show a slightly higher QALY based on EQ-5D and SF-6D, although the differences between two groups were not significant. However, the costs were lower in the pharmacopuncture group. Therefore, ICER analysis was dominant, indicating that pharmacopuncture is more cost-effective from both the societal and healthcare perspectives. Sensitivity analyses with the pharmacopuncture fee set at 1.5 and 2.0 times showed higher costs in the pharmacopuncture group from a healthcare perspective. The ICER was lower than the WTP when the fee was set to 1.5, which confirmed that it is an alternative that is acceptable from a societal perspective not only for base cases but also when the fee is increased by a factor of 1.5. When the pharmacopuncture fee was increased by two times, the costs were still lower from a societal perspective, while the probability of pharmacopuncture being cost-effective was higher.In the sensitivity analysis of this study, not only cost-utility analysis but also cost-effectiveness analysis was performed. Costs were compared with clinical outcomes (NRS score for neck pain and NDI). In many cases of economic evaluation, costs are compared to the QALY based on utility. However, utility is broad in nature and therefore does not accurately reflect disease-specific health status and is relatively insensitive to detecting small changes [Meanwhile, there was little difference in QALY between the two groups when based on the EQ-5D and SF-6D. Both the EQ-5D and SF-6D measure quality of life, but there are minor differences; SF-6D focuses more on social functioning, whereas EQ-5D focuses on physical functioning Direct medical costs were higher in the pharmacopuncture group due to the difference in costs between pharmacopuncture and PT. Medical costs, other than the intervention costs, during the trial were higher in the usual care group, indicating that they had more hospital visits for treatment of neck pain in addition to the treatment in the protocol. Among direct non-medical costs, time cost was significantly lower in the pharmacopuncture group, which was due to the length of the pharmacopuncture treatment being shorter than the usual care time. Compared to PT, which requires more than a certain amount of time, pharmacopuncture is completed with needling; thus, the time required for the treatment is very short. The results showed that pharmacopuncture had a superior effect despite the relatively short procedure time.The indirect costs estimated by the productivity loss score were significantly lower in the pharmacopuncture group, and the difference between the two groups was relatively large. In the primary analysis performed in the present study, productivity loss among waged workers was calculated as overall work productivity, considering both absenteeism and presenteeism. Many economic evaluation studies, including those on chronic neck pain, generally use absenteeism to calculate costs [This economic evaluation offered the benefit of being conducted alongside a well-designed, pragmatic RCT. The pragmatic approach is a design for overcoming the limitations of traditional explanatory RCTs, which could increase the generalizability of the findings by carrying out the trial in an environment closer to the real world and contributing to actual clinical and policy decision making [This study investigated validity indicators and cost expenditures over 12 weeks of follow-up (F/U). This short time horizon is the present study’s limitation. The results of this study couldn’t show the long-term effect of pharmacopuncture on the quality of life of patients with chronic cervical pain. Longer follow-up period studies or modeling studies should be performed in the future. To the best of our knowledge, there have been no economic evaluations of pharmacopuncture for chronic neck pain. While there have been some studies on acupuncture being more cost-effective than usual care [ | PMC10666315 |
Conclusions | neck pain, chronic neck pain | Pharmacopuncture is more cost-effective than the usual care for chronic neck pain. The same results were found in various sensitivity analyses. The current study’s findings provide useful information to clinicians and policy makers who are considering new treatment options for neck pain. Additional studies are needed to strengthen the evidence supporting the findings of the present study. | PMC10666315 | |
Acknowledgements | Not applicable. | PMC10666315 | ||
Authors' contributions | IHH | DRK and ESK had the original idea, collected data, performed the analyses, interpreted the analyses, and wrote the original draft. HJS, SYP, KSP, YJL, and IHH supervised the progress of the project, financed the acquisition, and approved the final version. | PMC10666315 | |
Funding | This research was supported by a grant from the Traditional Korea Medicine R&D Program through the Korea Health Industry Development Institute, funded by the Ministry of Health and Welfare, Republic of Korea (grant number: HB16C0035). | PMC10666315 | ||
Availability of data and materials | Patient samples can be obtained via the HIRA website by completing the End User Agreement for Patient Samples. Patient samples are provided in a DVD (text file) format and a fee for the samples may be charged. See | PMC10666315 | ||
Declarations | PMC10666315 | |||
Ethics approval and consent to participate | RECRUITMENT | The study protocol was approved by the institutional review board (IRB) of Jaseng hospital of Korean medicine at each institution before the participant recruitment process commenced (JASENG 2019-06-009, JASENG 2019-06-010, JASENG 2019-06-011, and JASENG 2019-06-008). Written informed consent was obtained from all patients. All methods were carried out in accordance with relevant guidelines and regulations. | PMC10666315 | |
Consent for publication | Not applicable. | PMC10666315 | ||
Competing interests | The authors declare no competing interests. | PMC10666315 | ||
References | PMC10666315 | |||
ABSTRACT | The authors report no commercial, proprietary or financial interest in the products or companies described in this article. | PMC10202449 | ||
Objective: | The objective of this two-arm parallel randomized controlled trial was to evaluate the treatment effects and lip profile changes in skeletal Class II patients subjected to premolars extraction treatment | PMC10202449 | ||
Methods: | BLIND | Forty six subjects fulfilling inclusion criteria were randomly distributed into Group PE (mean age 13.03±1.78 years) and Group FF (mean age 12.80±1.67 years) (n=23 each). Group PE was managed by therapeutic extraction of maxillary first premolars and mandibular second premolars, followed by mini-implant-supported space closure; and Group FF, by fixed functional appliance therapy. Skeletal, dental, and soft-tissue changes were analyzed using pre and post-treatment lateral cephalograms. Data obtained from this open label study was subjected to blind statistical analysis. | PMC10202449 | |
Results: | Extraction treatment resulted in greater increase of nasolabial angle (NLA: 3.1 [95% CI 2.08, 4.19], | PMC10202449 | ||
Conclusions: | maxillary incisors, overjet | Premolar extraction therapy is a better treatment modality, compared to fixed functional appliance therapy for Class II patients with moderate skeletal discrepancy, increased overjet, protruded maxillary incisors and protruded lips, as it produces better dentoalveolar response and permits greater improvement of the soft tissue profile and lip relationship. | PMC10202449 | |
RESUMO | PMC10202449 | |||
Objetivo: | O objetivo desse estudo randomizado controlado paralelo de dois braços foi avaliar os efeitos do tratamento e as mudanças no perfil labial em pacientes esqueléticos Classe II submetidos a tratamento com extração de pré-molares (EP) | PMC10202449 | ||
Métodos: | MOLES | Quarenta e seis indivíduos que preencheram os critérios de inclusão foram distribuídos aleatoriamente em Grupo EP (idade média 13,03±1,78 anos) e Grupo FF (idade média 12,80±1,67 anos) (n=23 cada). O grupo EP foi tratado com extração dos primeiros pré-molares superiores e segundos pré-molares inferiores, seguida de fechamento do espaço com ancoragem em mini-implantes; e o Grupo FF, com tratamento usando aparelhos funcionais fixos. As alterações esqueléticas, dentárias e de tecidos moles foram analisadas usando cefalogramas laterais pré e pós-tratamento. Os dados obtidos desse estudo aberto foram submetidos a análise estatística cega. | PMC10202449 | |
Resultados: | ANL | O tratamento com extrações resultou em maior aumento do ângulo nasolabial (ANL: 3,1 [IC 95% 2,08, 4,19], | PMC10202449 | |
Conclusões: | MOLES | O tratamento com extração de pré-molares é uma modalidade de tratamento melhor do que os aparelhos funcionais fixos para pacientes Classe II com discrepância esquelética moderada, sobressaliência aumentada, incisivos superiores protruídos e lábios protruídos, pois produz melhor resposta dentoalveolar e permite maior melhora do perfil dos tecidos moles e relacionamento labial. | PMC10202449 | |
Keywords: | PMC10202449 | |||
INTRODUCTION | Class II malocclusion, malocclusion, orthodontic | Class II malocclusion is a frequent condition, with a prevalence of around 30% of the patients seeking orthodontic treatment.Depending on the underlying condition, multiple treatment strategies are available for the management of Class II malocclusion.Treatment by both fixed and removable functional appliances is effective in correcting the Class II malocclusion.The last decade has witnessed a steady upsurge in the interest for facial esthetics. Therefore, soft tissues changes following orthodontic treatment are given more importance than ideal occlusion. Presently, data is lacking on the relationship of soft tissue profile changes and both treatment modalities, with and without extractions. | PMC10202449 | |
MATERIAL AND METHODS | PMC10202449 | |||
TRIAL DESIGN AND SETTING | This study was conducted as a two-arm parallel randomized controlled trial. There were no changes after commencement of the study. Subjects for the trial were recruited and treated in the outpatient clinic of Department of Orthodontics of a tertiary care centre, from 2016 to 2019. | PMC10202449 | ||
SAMPLE SIZE CALCULATION | The sample size was calculated using G*Power software v. 3.0.8 (Universität Kiel, Germany), based on a significance value of 0.05 and a power of 80%. Power analysis determined that a minimum of 18 subjects were required in each group to demonstrate a significant change of upper lip to H line of 1.25mm, which was similar to previously published studies. | PMC10202449 | ||
PARTICIPANTS AND ELIGIBILITY CRITERIA | Patient selection and follow-up were conducted in accordance with CONSORT guidelines (
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Descriptive statistics of the participants. | * Group PE (Premolar extraction treatment). * Group FF (Fixed Functional appliance therapy).
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Patient selection and follow up flow chart. | skeletal Class II malocclusion, systemic disorders, orthodontic, overjet | Selection criteria included skeletal Class II malocclusion, at least – Class II molar and canine relationship, Cervical Vertebrae Maturity Index (CVMI) confirming circumpubertal phase of skeletal development, average or horizontal growth pattern, no crowding in the maxillary arch, minimal crowding (<3mm) in the mandibular arch, and overjet greater than 5mm but less than 8mm. Patients with history of previous orthodontic treatment, systemic disorders, or syndromic cases were excluded from the study. Finally, 17 subjects presented with bilateral Class II molar relationship, 14 had bilateral – Class II molar, 15 had Class II molar on one side and – Class II molar on the other side. | PMC10202449 | |
RANDOMIZATION | RECRUITMENT | Following recruitment and consent, a random list of all the subjects was created online (https://www.random.org/) by an individual who was not involved in the trial. The allocation sequence was concealed from research personnel and assessor, using sealed opaque envelopes, which were numbered sequentially and were chosen by the patients. Subjects were randomly allocated in 1:1 ratio into the two arms of this study i.e.: Group PE - Premolar extraction treatment (mean age = 13.03±1.78 years) and Group FF - Fixed Functional Appliance Therapy (mean age = 12.80±1.67 years), with 23 subjects each. There was no restricted randomization. | PMC10202449 | |
INTERVENTION | overbite, overjet, Fatigue | ROTH | Clinical management in Group PE included extraction of maxillary first premolars and mandibular second premolars. Since subjects had varying pretreatment molar relationship, extractions were carried out in the mandibular arch in order to achieve similar molar relation bilaterally at the end of the treatment. The 0.018 x 0.028-in slot brackets (Roth prescription) were bonded, and levelling and alignment was carried out using 0.016-in nickel-titanium (NiTi) archwire, followed by 0.016 x 0.022-in NiTi. Working archwire (0.016 x 0.022-in stainless steel) was left In Group FF, similar bracket prescription was used and working archwire was 0.017 x 0.025-in stainless steel. Forsus™ (Fatigue Resistant Device, L-pin Spring Module, 3M), a fixed functional appliance, was used during the functional phase. The appliance selection and stepwise activation using 1.5-mm split rings was done according to the manufacturer’s instructions. Whenever more than one split ring was required for activation, the next size push rod was used. Average duration of the functional phase was 6.95±1.53 months. Functional phase continued until bilateral Class I molar and canine relation, optimized overbite and overjet were achieved. Following, non-activated appliance (i.e. spring module not compressed by the push rod as the patient bites down) was left All the subjects were scheduled every three weeks during the course of treatment. Post-debonding, patients were followed periodically during retention. | PMC10202449 |
OUTCOME | Class II malocclusion | Primary outcome was to test the hypothesis that there would be no statistically significant difference in soft tissue and profile change of patients with Class II malocclusion treated with premolars extraction and those treated with fixed functional treatment. Lateral cephalograms (Pretreatment - T1 and Post-treatment - T2) were recorded, to monitor treatment changes. Skeletal (n=14), dental (n=13) and soft tissue (n= 3) measurements were recorded, to determine the changes produced by the treatment (
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Angular measurement (degrees) and linear measurements (mm) used in the study: (1) SNA; (2) SN - ANS PNS; (3) U1 - ANS PNS; (4) SNB; (5) FMA; (6) SN -GoGn; (7) IMPA; (8) ANB; (9) N - A - Pog; (10) Interincisal angle; (11) A - VP; (12) N - ANS; (13) N - PNS; (14) U1 - VP; (15) U1 - HP; (16) U6 - VP; (17) U6 - HP; (18) B - VP; (19) Pog - VP; (20) CoGn; (21) GoPog; (22) L1 - VP; (23) L1 - GoMe; (24) L6 - VP; (25) L6 - GoMe; (26) B’ - VP; (27) Pog’ - VP; (28) Overjet; (29) Overbite; (30) NLA; (31) UL - E line; (32) LL - E line; (33) UL - S line; (34) LL - S line; (35) UL - SnPog’ (36) LL - SnPog’; (37) UL thickness; (38) LL thickness; (39) N’ - Sn - Pog’. (Refer Supplementary Table 1 and Supplementary Table 2 for definitions of landmarks and cephalometric parameters). | PMC10202449 | |||
Landmarks used for cephalometric evaluation. | PMC10202449 | |||
Cephalometric parameters. | SECONDARY | The secondary outcome included skeletal and dental treatment changes, overall treatment duration and overall failure rate of implants / fixed functional appliance. | PMC10202449 | |
INTERIM ANALYSES AND STOPPING GUIDELINES | Not applicable. | PMC10202449 | ||
BLINDING | BLIND | It was not feasible to blind for the clinical procedures. Blinding was done for statistical analysis only. | PMC10202449 | |
ERROR OF THE METHOD AND STATISTICAL ANALYSIS | Ten cephalograms were randomly selected and retraced after a two-weeks interval, to determine the intra and inter-operator reliability. Allocation of all the traced cephalograms was done by a random list created online (https://www.random.org/). The reliability of recorded measurements was determined using intra-class correlation coefficient (ICC): ICC closer to 1 indicated highly reliable measurement. The data collected were compiled in Excel spreadsheet (Microsoft, Redmond, Wash) and transferred to SPSS v. 22.0 software (SPSS Inc., Chicago, IL, USA). Normality of the data distribution was verified using the Shapiro-Wilk test, and was found to be non-significant for all the variables. Gender comparison was performed using the Mann-Whitney U test. Age and treatment duration of the groups were compared using Student | PMC10202449 | ||
RESULTS | PMC10202449 | |||
OUTCOME | The mean age of the subjects of Groups PE and FF at the start of study was 13.03±1.78 and 12.80±1.67 years, respectively. Average duration of premolar extraction treatment was 2.22±0.28 years, and of fixed functional treatment was 2.08±0.24 years, with no significant difference between the two groups (Table 1). Subjects of both groups demonstrated no difference in distribution in terms of age, gender and cephalometric parameters investigated (
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Superimposition of average cephalometric tracings of Group PE (Premolar extraction treatment) and Group FF (Fixed functional appliance therapy) at T1. | ICC of intra-examiner and inter-examiner measurements was 0.96 and 0.92, respectively, depicting highly reliable measurements. The Student
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Comparison of cephalometric parameters of Group PE (Premolar extraction treatment) and Group FF (Fixed Functional appliance therapy) at T1. | NS - Not Significant.
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Comparison of soft tissue changes (T2-T1) between Group PE (Premolar extraction treatment) and Group FF (Fixed Functional appliance therapy). | NS = Not Significant, * p < 0.05, ** p < 0.001.
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Comparison of skeletal changes (T2-T1) between Group PE (Premolar extraction treatment) and Group FF (Fixed Functional appliance therapy). | NS = Not Significant, * p < 0.05, ** p < 0.001.
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Comparison of dental changes (T2-T1) between Group PE (Premolar extraction treatment) and Group FF (Fixed Functional appliance therapy). | overbite, overjet | NS = Not Significant, * p < 0.05, ** p < 0.001.Both treatment mechanics were compared for 40 cephalometric parameters. Apart from the skeletal changes in the maxilla and mandible, growth pattern, overjet, overbite, interincisal angle and soft tissue chin position (With regard to the soft tissue changes (
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Superimposition of average cephalometric tracings of Group PE (Premolar extraction treatment) and Group FF (Fixed Functional appliance therapy) at T2. | With regard to the skeletal changes (Along the vertical plane, effect of both protocols had no significant difference (SN-ANS PNS; N-ANS; N-PNS; FMA; SN-GoGn, With regard to the dentoalveolar changes ( | PMC10202449 | ||
APPLIANCE / IMPLANT FAILURE | Failure of the functional appliance | The implant failure rate was 7.9% - i.e., only 7 of the total implants placed became loose. Failure of the functional appliance was reported in 3 cases: One of the subjects had recurrent breakages of the functional appliance spring and was thus excluded from the present study. | PMC10202449 | |
DISCUSSION | malocclusion, overbite, mesial displacement, L6-GoMe, overjet, Maxillary incisors, mandibular incisors | SECONDARY, ROOT RESORPTION | Successful orthodontic treatment is not just about establishing a static as well as dynamic occlusal relationship, but also to achieve an esthetic soft tissue profile.In the present study, there was a possibility of treatment outcome being influenced by associated growth. To overcome this, use of untreated Class II controls was advocated by Stahl et al.Ideally, the subjects of a trial should demonstrate no difference in characteristics prior to the treatment, as phenotypic differences may influence the response to growth and treatment mechanics.Severity of sagittal molar relationship directly influences the amount of retraction in Class II cases; hence, considering it during a trial was proposed in a systematic review.Soft tissue response secondary to aging and treatment assists clinician in planning the best suited treatment for the patient. Bishara et alChange in lip projection of Group PE (UL-E line, -2.91mm; LL-E line, -0.68mm) and Group FF (UL-E line, -1.50mm; LL-E line, 0.45mm) were in partial agreement with Janson et alLee et alGroup PE demonstrated statistically significant change of nasolabial angle (3.14±2.05, Improvement of facial esthetics is usually the primary objective of patients undergoing treatment for skeletal Class II malocclusion.Clinical significance of the statistically significant findings of the present study could not be differentiated, due to the dichotomy in available literature. Cozza et alWith regard to the skeletal changes, both treatment mechanics had a retrusive effect on the maxillary sagittal growth, resulting in the remodeling of point ‘A’, but the differences were not significant.Compared to the premolar extraction treatment, functional fixed therapy demonstrated slightly larger sagittal growth of the mandible, but posttreatment differences were not statistically significant. Although improvement of maxillomandibular skeletal relationship was greater with functional treatment, compared to premolar extraction treatment, the differences were not significant. Similar changes were referred by a previous study.Effects of both treatment modalities on the vertical plane did not differ significantly among treatment groups. However, functional fixed treatment resulted in clockwise rotation of both jaws, whereas counter-clockwise mandibular rotation was observed in the subjects who underwent premolar extractions. Similar changes were reported by previous studies.With regard to the dentoalveolar changes, highly significant differences were observed between the two treatment strategies. Group FF had significant distal displacement of maxillary molar, whereas Group PE demonstrated mild mesial displacement, which is in agreement with the findings of Kizinger et al.Effect on maxillary molar along the vertical plane was not significantly different between the groups. Findings of the present study regarding functional fixed treatment were in accordance with previously published studies.Groups PE and FF presented statistically significant difference for L6-VP and L6-GoMe at the posttreatment stage. A difference in sagittal positioning was consequent to protraction of mandibular molar to the extraction space. Maxillary incisors were significantly retroclined in Group FF (U1-ANS PNS, -5.73Despite cinching and lingual crown torque in the lower archwire during the functional phase, unfavorable labial movement of the mandibular incisors could only be minimized. Compared to Group PE (IMPA - 2.05Both treatment modalities reduced the overjet and the overbite to normal limits, with almost similar proportional correction. In Group PE, overall change of overjet and overbite was -4.23mm and -2.64mm, respectively; whereas Group FF demonstrated reduction of -4.73mm and -3.27mm, respectively. Similar changes were reported by Janson et al.Treatment duration is one of the major factors influencing satisfaction among patients undergoing orthodontic treatment.Mini-implants were used in Group PE in order to optimize the maxillary anterior teeth retraction and mandibular molar protraction. A recent systematic reviewHighly promising overall success rate of mini-implants (86.5%) was reported by a meta-analysis.ForsusNone of the participants asked to be removed from the study, reflecting acceptance of both treatment modalities. Premolar extraction treatment has limitations in terms of increased risk of root resorption, | PMC10202449 |
LIMITATIONS | Ideally untreated Class II subjects should have been included in the present study as control. Although closely matched groups were included in the study, findings of the present study should be considered with caution, due to the short term observation period. Further studies with larger sample composition and long term follow-up are recommended to validate the findings. Lateral cephalograms have inherent limitations in terms of two dimensional (2D) evaluation of hard and soft tissues. Future studies using 3D technologies, such as color mapping and cone beam computed tomography, are strongly recommended. | PMC10202449 | ||
GENERALIZABILITY | The results can be generalized to the average patient of most orthodontic clinical settings, as the present study was conducted in orthodontic departments of a government institute, based on broad inclusion criteria, and treatments were performed by experienced clinicians. | PMC10202449 | ||
CONCLUSION | maxillary incisors, malocclusion, mandibular incisors, overjet | LIP | The null hypothesis of this study was rejected. Management by extraction of premolars is a better treatment modality than functional treatment for managing skeletal Class II division 1 malocclusion in Class II subjects with moderate skeletal discrepancy, increased overjet, protruded maxillary incisors and protruded lips.
Both treatment modalities resulted in significant dentoalveolar changes; however, inclination of maxillary as well as mandibular incisors was better maintained in premolar extraction treatment. Lip position relative to nose and chin, as well as nasolabial angle, improved significantly in maximum anchorage premolar extraction treatment cases.Extraction treatment resulted in significant improvement of soft tissue profile. | PMC10202449 |
REFERENCES | PMC10202449 | |||
Supplementary Information | psychiatric, violent | Preventing dropout (attrition) from clinical trials is vital for improving study validity. Dropout is particularly important in justice-involved populations as they can be very challenging to engage and recruit in the first instance. This study identifies factors associated with dropout in a double-blind, placebo-controlled randomised control trial of a selective serotonin reuptake inhibitor (SSRI) aimed at reducing reoffending in highly impulsive men with histories of violent offending. Age, education, social support, psychiatric history, and length of previous incarceration were identified as factors that predict attrition. These findings are consistent with previous research examining variables associated with attrition in clinical trials for community and offender populations. We also explored referral source and treatment allocation as attrition predictors. Although neither significantly predicted attrition, we identified that there are discernible differences in the median time to attrition among the referral source subgroups. Understanding factors that predict treatment completion and attrition will allow researchers to identify participants for whom additional provisions may optimise retention and inform development of targeted interventions.The online version contains supplementary material available at 10.1186/s13063-023-07774-3. | PMC10657031 | |
Keywords | anger, violent offenders, violent crimes, learning disability, alcohol abuse, violent offending [, impulsivity, depression | In 2016, 2.2 million adults in Australia were estimated to have been victims of domestic violence by age 15 [Randomised control trials (RCT) represent the gold standard in medical research [One reason proposed to account for the lack of RCTs with offenders is that they fall into a group dubbed “hard to treat” by many researchers [Typically, RCTs with offenders report that around half of the sample is lost to attrition. For example, Butler et al., Coccaro et al., Cullen et al., Kraanen et al., Lardén, and Stone et al. report an average attrition rate of 53% [In Australia, those who commit violent crimes such as homicide, assault, sexual assault, and robbery, tend to commit repeat offences [Efforts to predict attrition of violent offenders in clinical trials and treatment programmes have identified “attrition risk factors” among offenders convicted of domestic violence or sex crimes (e.g. sexual assault or child sex offences). These include a lack of social support; a history of alcohol abuse or poor mental health; being younger, unemployed, single, childless, expelled from school, or an ethnic minority; and having low incomes, little formal education, a learning disability, insecure accommodation, dysfunctional expressions of anger, or prior history of criminality [A limited number of studies have looked at predicting attrition from clinical trials and treatment programmes among individuals who commit violent crimes other than domestic violence and sex crimes (e.g. armed robbery, grievous bodily harm, manslaughter, malicious wounding, or assault). These studies show that impulsivity, depression, and indigenous heritage are associated with attrition [This study aimed to identify factors that predict attrition from pharmacological-based treatments. Specifically, we investigated predictors of attrition in a double-blind, randomised, placebo-controlled trial (ReINVEST) by men with histories of repeat violent offending [ | PMC10657031 | |
Methods | PMC10657031 | |||
Data source | The study design, which has been extensively described in previous publications [ | PMC10657031 | ||
Ethics | This study has received ethical approval from the University of New South Wales (HC17771), Aboriginal Health & Medical Research Council (AHMRC; 822/11), Corrective Services NSW (09/26576) and the NSW Justice Health (G8/14) and the ReINVEST study is registered with the Australian and New Zealand Clinical Trials Registry (ACTRN12613000442707). | PMC10657031 | ||
Participants | psychiatric | RECRUITMENT | The study population is comprised of 628 (After screening, eligible participants then underwent a comprehensive psychiatric assessment and medical examination, administration of a number of behavioural measures, and collection of demographic data. A detailed list of all study assessments (including abbreviations) used during the recruitment phase of the ReINVEST clinical trial is available in Butler et al. (2021) [Details of study assessments | PMC10657031 |
Outcome and definitions | death | ADVERSE EVENTS, SECONDARY, ATTRITION | The primary outcome of interest in this study was time to attrition post-randomisation from the ReINVEST trial. The secondary outcomes were socio-demographic, justice-related and mental health factors associated with attrition from ReINVEST trial. Attrition was defined as the termination of a participant's involvement in the trial before its completion. Attrition was assessed based on several reasons, including the occurrence of adverse events, loss to follow-up (three consecutively missed appointments with no further contact), physical or mental health concerns, reincarceration, perceived lack of benefit, and personal choice.For this study, the follow-up period was defined as the timeline from randomisation (baseline) until the earliest of the following: attrition, death, and completion of the study at 24 months post-randomisation. Although participants could cease protocol treatment at 12 months, 24 months was used to capture those participants who opted to remain in the study beyond 12 months. | PMC10657031 |
Covariates | juvenile violent, psychiatric, violent offences within 5 | The following covariates were included in the present analysis: randomisation status (main exposure), age, Aboriginal status, relationship status, accommodation type, number of children, highest educational level, requiring educational support during school, being expelled from school, history of juvenile violent offending, time spent in juvenile detention, number of violent offences within 5 years prior to randomisation, length of incarceration within 5 years prior to randomisation, psychiatric history, referral source, scores on the DSSI [ | PMC10657031 | |
Statistical analysis | death, Death | REGRESSION, EVENTS | Descriptive statistics were used to summarise participant characteristics at randomisation (baseline). The time at risk was calculated as the duration from randomisation until the earliest of the following events: attrition, death, or 24 months post-randomisation. Kaplan–Meier method was used to estimate the cumulative incidence of attrition, overall and stratified by referral source. To identify factors associated with attrition, univariable and multivariable Cox regression models were fitted. Death was considered as a competing risk in this study. However, no participants died during the follow-up period. The multivariate model incorporated all covariates of interest.The initial multivariate model incorporated all covariates with a | PMC10657031 |
Discussion | anger, psychiatric, alcohol abuse, impulsivity, irritability, violent | ADVERSE EFFECTS, DISORDERS | The current study explored factors associated with attrition from a clinical trial involving pharmacotherapy aimed at treating impulsive individuals with a history of violent offending. Specifically, we investigated whether attrition from the ReINVEST trial could be predicted by demographic and psychosocial factors identified as attrition risk factors from the literature. Our results found that older age, higher levels of social support, higher levels of education, and psychiatric history were all protective factors against attrition at 24 months, whereas less time spent incarcerated in the past 5 years is associated with dropout. We found no association between referral source or treatment allocation on attrition.Our findings that older age is associated with decreased attrition at 24 months are in line with past studies [Our finding that increased social support is protective against attrition is also in line with past research [Adopting a holistic approach when designing RCTs that foster quality in participants' social networks would enhance study retention. For example, employing case management or peer support strategies for those who report low social support at baseline may minimise dropout and enhance successful rehabilitation. Klaehn et al. (2022, p.294) [Our finding that lower levels of education are associated with increased attrition is consistent with other research [We also found that participants who had spent less time incarcerated in the 5 years prior to randomisation had an increased rate of attrition. While this finding contradicts Zanis et al.’s (2009) [Zapryanavo’s (2020) [Our findings also indicate that those with a history of psychiatric conditions requiring treatment, medication, or hospital admission are significantly less likely to drop out. This is contrary to past research suggesting that psychiatric disorders predict the attrition of violent offenders from programmes [Our finding that referral source does not predict attrition is consistent with past studies that also report a null effect regarding referral source [If a relationship between referral source and attrition exists, it is possible the relationship is mediated by other factors. For example, research on why offenders dropout of psychological treatments indicates that younger, less educated men are more likely to remain in treatment if they are court mandated. In contrast, older, better-educated men may be more likely to remain in treatment if they are not court-ordered [Interestingly, we did not see an effect of treatment allocation on attrition. While this finding is consistent with Coccaro [It is possible that the unique nature of ReINVEST as a community-based trial that offered free access to follow-up appointments with research clinicians and a psychiatrist influenced retention, regardless of treatment allocation. It allowed participants, irrespective of their treatment allocation, to receive ongoing professional healthcare attention and support. This could be appealing, given services can be difficult to access and costly outside of the trial setting. Further, regular appointments provided an opportunity for participants to discuss any concerns or adverse effects, and to feel heard and validated. This sense of support may have enhanced motivation to remain in the trial regardless of treatment allocation. It is possible that for control participants regular appointments with clinicians and a psychiatrist reinforced any experienced placebo effect. The positive psychosocial benefits of attention and care offered as part of an effective treatment team may have been perceived as an improvement in their condition. This suggests that providing offenders access to frequent, consistent, high-quality healthcare can support retention in trials. Further, offenders may be more likely to remain committed to the study, regardless of treatment allocation, if offered empathetic communication that ensures they feel observed and cared for.Previous research indicated that Aboriginal status, relationship status, number of dependents, accommodation type, impulsivity, anger, irritability, and alcohol abuse predict offender dropout from research interventions and clinical trials [ | PMC10657031 |
Limitations | anger, psychiatric, alcohol abuse, impulsivity, irritability | A limitation of this study is it is based on a sample of highly impulsive repeat-violent offenders. Additionally, reliance on self-report to ascertain the impact of some of the variables on attrition (e.g. relationship status, number of dependents, accommodation type, impulsivity, anger, irritability, and alcohol abuse) may be subject to recall or response bias. It is possible that individuals who have a history of committing violent offences may feel the need to manage their public identity and may have modified their responses. Notwithstanding these limitations, this study also possesses considerable strengths. We have identified age, social support, education, time spent incarcerated, and psychiatric history are associated with attrition. | PMC10657031 | |
Conclusions | violent crimes | The problem of offender attrition from clinical trials and programmes is ongoing and a serious concern given it is linked to recidivism. Identifying ways to reduce the attrition from clinical trials of offenders who commit violent crimes is vital. This study identified a number of risk factors that support researchers to predict attrition of men with a history of violence from clinical trials. Awareness of these factors can support researchers working with samples that are justice-involved to determine, at baseline, participants for whom additional provisions may optimise retention. | PMC10657031 | |
Acknowledgements | Not applicable. | PMC10657031 | ||
Authors’ contributions | PWS, TB | ND, YIW, TGB, and PWS conceived and designed the study and/or acquired the funding. TB, PWS, LK, and BT obtained ethics approval. ND, YIW, TGB, EA, MG, LK, and CK drafted and revised the manuscript. EA, ND, YIW, and TGB. All authors read and approved the final manuscript. | PMC10657031 | |
Funding | Initial funding for ReINVEST was provided from an Australian National Health and Medical Research Council partnership grant in 2009 (NHMRC; No. 533559). From 2018, subsequent funding has been provided by the NSW Department of Communities and Justice. | PMC10657031 | ||
Availability of data and materials | Records management is guided by systems implemented by the NHMRC Clinical Trials Centre, in line with requirements for record keeping in the NSW private sector, medico-legal requirements and the NSW State Records Act 1998. Trial documents are stored under medical records conditions for 15 years post publication in the secure UNSW Shared File storage, with access restricted to the appropriate researchers who have access to UNSWnetworks. On the case report forms and other documents, a unique study code is used to identify the records. The datasets used and/or analysed during the current study are available from the corresponding author on reasonable request. | PMC10657031 | ||
Declarations | PMC10657031 | |||
Ethics approval and consent to participate | This study has received ethical approval from the University of New South Wales (HC17771), Aboriginal Health & Medical Research Council (AHMRC; 822/11), Corrective Services NSW (09/26576) and the NSW Justice Health (G8/14)and the ReINVEST study is registered with the Australian and New Zealand Clinical Trials Registry (ACTRN12613000442707). | PMC10657031 | ||
Consent for publication | Not applicable. | PMC10657031 | ||
Competing interests | The authors declare that they have no competing interests. | PMC10657031 | ||
References | PMC10657031 | |||
Background | Provision of small-quantity lipid-based nutrient supplements (SQ-LNSs) during early life improves growth and development. In the International Lipid-Based Nutrient Supplements DYAD–Ghana trial, prenatal and postnatal SQ-LNS reduced social–emotional difficulties at age 5 y, with greater effects among children in less-enriched home environments. | PMC10447494 | ||
Objectives | We aimed to investigate the effect of prenatal and postnatal SQ-LNS on children's social–emotional problems at age 9–11 y. | PMC10447494 | ||
Methods | In 2009–2011, 1320 pregnant women ≤20 wk gestation were randomly assigned to receive the following daily until 6 mo postpartum: | PMC10447494 | ||
Results | We assessed outcomes in 966 children, comprising 79.4% of 1217 participants eligible for re-enrolment. No significant differences were found between the SQ-LNS and control (non-LNS groups combined) groups. Few children (<2%) experienced high parent-reported social–emotional difficulties at 9–11 y, in contrast to the high prevalence at age 5 in this cohort (25%). Among children in less-enriched early childhood home environments, the SQ-LNS group had 0.37 SD (−0.04 to 0.82) lower self-reported conduct problems than the control group ( | PMC10447494 | ||
Conclusions | Overall positive effects of SQ-LNS on social–emotional development previously found at age 5 y are not sustained to age 9–11 y; however, there is some evidence of positive effects among children in less-enriched environments. The lack of effects may be owing to low prevalence of social–emotional problems at preadolescence, resulting in little potential to benefit from early nutritional intervention at this age in this outcome domain. Follow-up during adolescence, when social-emotional problems more typically onset, may yield further insights.This trial was registered at | PMC10447494 | ||
Keywords | PMC10447494 | |||
Abbreviations used | Brief Problem Monitor–ParentChildren’s Emotion Management ScalesEarly Adolescent Temperament Questionnaire–ParentEarly Childhood Home Observation for the Measurement of the Environmentiron and folic acidInternational Lipid-Based Nutrient Supplementslipid-based nutrient supplementMiddle Childhood Home Observation for the Measurement of the EnvironmentMood and Feelings Questionnairemultiple micronutrientScreen for Child Anxiety-Related Emotional Disordersstrengths and difficulties questionnairesmall-quantity lipid-based nutrient supplement | PMC10447494 | ||
Introduction | wasting, −0.12, anemia, micronutrient deficiencies, breast milk | WASTING, ANEMIA | Millions of pregnant women and children globally consume inadequate diets, resulting in conditions among children such as stunting, wasting, anemia, micronutrient deficiencies, and poor cognitive, motor, and social-emotional development [Meta-analyses of data from a large number of randomized trials and children (7 to 18 trials and 2700 to 41,000 children, depending on the outcome) have shown that providing SQ-LNS to children aged 6 to 24 mo resulted in better health, such as 27% reduction in mortality [A follow-up study of the International Lipid-Based Nutrient Supplements trial in Ghana at age 4–6 y showed reduced social–emotional difficulties (−0.12 SD) in the group who was exposed to SQ-LNS (indirectly in utero and through breast milk before 6 mo of age, and directly at 6–18 mo of age), compared with control groups, with greater effects among children in less-enriched home environments (−0.22 SD) [ | PMC10447494 |
Methods | PMC10447494 | |||
Objectives and hypotheses | Our objective was to investigate the effect of prenatal and postnatal SQ-LNS on social–emotional problems and self-regulation at age 9–11 y and in the context of children’s home environments. Our first hypothesis was that, compared with children who were not exposed to SQ-LNS in early life, those exposed to SQ-LNS would experience fewer social–emotional problems and better self-regulation. Our second hypothesis was that children in less-enriched home environments during early childhood would experience more social–emotional problems and worse self-regulation. Our third hypothesis was that greater effects of SQ-LNS would be found among children from less-enriched home environments. | PMC10447494 | ||
Participants and procedure | 9–11 y. | The methods of the International Lipid-Based Nutrient Supplements-DYAD–Ghana randomized controlled trial (RCT), performed in 2009–2014 [Nutrient and energy contents of the dietary supplements.IFA, iron and folic acid capsule; MMN, multiple micronutrient supplement capsule; SQ-LNS, small-quantity lipid-based nutrient supplement. Information from table previously published [For the 10-y follow-up study, data collection was performed from December 2020 to December 2021, when children were aged 9–11 y. Field workers contacted caregivers of 1217 children eligible for re-enrolment, excluding those known to have not survived. At a home visit, field workers obtained informed consent, collected sociodemographic information, assessed the home environment, and scheduled the caregiver to bring the children to the project office. At the project office visit, field workers assessed children's health, anthropometric status, and cognitive development and obtained parent and child reports on child social–emotional and behavioral problems. Field workers also visited each child’s school to administer teacher report and school quality interviews.On the basis of our successful follow-up of ∼1000 children at age 4–6 y, we expected to reenroll ∼900 at age 9–11 y. Because children in the 2 control groups (IFA and MMN) did not receive any nutrition supplements, the main goal of the follow-up assessments was to compare the lipid-based nutrient supplement (LNS) with non-LNS (IFA + MMN groups combined) groups. A sample size of 900 (300 LNS, 600 non-LNS) provides 80% power to detect an effect size, that is, a mean difference between 2 groups, of >0.20 SD for continuous outcomes at a significance level of | PMC10447494 | |
Assessment of background characteristics and home environment | Depression, depressive symptoms | At enrolment into the parent trial, maternal and household information, such as maternal age, parity, education, and household assets, was collected by trained field workers using a questionnaire. Trained laboratory personnel measured maternal blood hemoglobin concentration at a clinic visit using a digital Hemocue (HemoCue model 301, AG, Switzerland). Infant weight and length were measured within 48 h of birth or between 3 and 14 d after birth for 87 children (9.4%) for whom the former was not possible.At the 5-y follow-up, we assessed the home environment using the Early Childhood Home Observation for the Measurement of the Environment (EC-HOME) inventory [At the 10-y follow-up, we assessed the home environment using the Middle Childhood version of the HOME inventory (MC-HOME), which is designed for use in children aged between 6 and 10 y. Our adapted version contained 58 items measuring parental responsivity, physical environment, learning materials, active stimulation, encouraging maturity, emotional climate, parental involvement, and family participation. We also assessed maternal depressive symptoms using the Center for Epidemiological Studies–Depression test [ | PMC10447494 | |
Assessment of outcomes | ’s behavior | We assessed children social–emotional problems through the following tools: We administered the strengths and difficulties questionnaire (SDQ) by parent report, teacher report, and child self-report. A set of 20 questions rate children’s behavior during the past 6 mo in 4 subscales: emotional symptoms, conduct problems, hyperactivity/inattention, and peer relationship problems [We assessed child self-regulation through the following tools: We administered the Revised Early Adolescent Temperament Questionnaire (EATQ-P) by parent report [Each item was translated into the local languages (Krobo, Ewe, and Twi) and backtranslated to English. If any discrepancies were found between the original item and the backtranslation, the translation was revised and backtranslation was repeated until the meanings matched. Adapted assessments were evaluated for test–retest reliability in a series of 2 pilot tests, each with a sample of 30 children aged 9–11 y in the study area. Assessments that showed low reliability were revised and reevaluated. Test–retest reliability (Pearson r) ranged from 0.45 to 0.83, with most scores (9/12) >0.65 ( | PMC10447494 | |
Statistical analyses | A statistical analysis plan was posted to Open Science Framework before performing analyses ( | PMC10447494 | ||
Group characteristic comparisons | We examined whether children in the SQ-LNS and control groups were similar in key baseline characteristics by presenting descriptive statistics for each intervention group. To evaluate potential bias in the sample, we compared baseline characteristics between the sample included in the analysis and the sample enrolled in the parent trial but lost to follow-up, using | PMC10447494 | ||
Effect of SQ-LNS | We conducted a complete case intention-to-treat analysis. To test hypothesis 1, for each of the 8 outcomes described earlier (SDQ-Child, SDQ-Parent, SDQ-Teacher, BPM-P, MFQ, SCARED, EATQ-P, and CEMS), we examined the difference between the intervention (SQ-LNS) and control (non-LNS) groups using multivariate analysis of covariance (MANCOVA) models for outcomes with multiple subscales and ANCOVA models for single scale outcomes. Our primary comparison of interest was the SQ-LNS group with the control group (IFA and MMN groups combined). However, we also compared the IFA and MMN groups to confirm that it was appropriate to combine them, as demonstrated by no significant difference at Three versions of each model were assessed. The first model was adjusted for child age at follow-up only. The second model was additionally adjusted for child sex, developmental assessment data collector, and any of the following baseline variables that were significantly associated (To test hypotheses 2 and 3, we added to models 1 and 3 the EC-HOME score at 5 y, then the interaction between the intervention group and EC-HOME scores. As reported previously, EC-HOME scores did not differ between the intervention groups [ | PMC10447494 | ||
Effect modifiers | In exploratory analyses, we evaluated potential effect modification by 5 additional variables: baseline household asset index, maternal education, prepregnancy BMI, primiparity, and child sex. We tested the interaction between each potential effect modifier and intervention groups. Significant interactions ( | PMC10447494 | ||
Results | REGRESSION | We successfully reenrolled 979 children at the home visit and collected data from 966 children at the project office visit, representing 107% of our target sample size (900), 73.2% of the 1320 pregnant women enrolled in the parent trial, and 79.4% of the 1217 children eligible for re-enrolment (excluding those known not to have survived). We successfully completed teacher interviews at school visits for 906 children. The proportion lost to follow-up was balanced between the intervention groups (Trial profile. IFA, iron and folic acid; MMN, multiple micronutrient; SQ-LNS, small-quantity lipid-based nutrient supplement.The 966 included in the analysis were similar to the 354 enrolled in the parent trial but lost to follow-up regarding most background characteristics, such as baseline maternal age, education, and BMI (Among those included in the analysis, background characteristics were similar in the SQ-LNS and control groups (Group characteristic comparisons.EC-HOME, Early Childhood Home Observation for the Measurement of the Environment Inventory; MC-HOME, Middle Childhood Home Observation for the Measurement of the Environment Inventory; SQ-LNS small-quantity lipid-based nutrient supplement.Values are given as mean (SD) or % [Estimated prepregnancy BMI was calculated from estimated prepregnancy weight (based on polynomial regression with gestational age, gestational age squared, and gestational age cubed as predictors) [Proxy indicator for household socioeconomic status constructed for each household based on ownership of a set of assets (e.g., radio and television), lighting source, drinking water supply, sanitation facilities, and flooring materials. Household ownership of this set of assets is combined into an index (with a mean of zero and standard deviation of one) using the principal components analysis. A higher value represents a higher socioeconomic status. | PMC10447494 | |
Effects of SQ-LNS on child social–emotional problems and self-regulation (hypothesis 1) | Children in the SQ-LNS group did not significantly differ from those in the combined control group in any outcome score, with mean differences ranging from −0.3 to 0.5 points and Effect of SQ-LNS on each outcome score.Control refers to iron and folic acid + multiple micronutrient groups. Results based on MANCOVA. For all assessments, a higher score indicates higher social–emotional problems, except the EATQ-P for which a higher score indicates a higher self-regulation.SQ-LNS, small-quantity lipid-based nutrient supplement.Model 1 was adjusted for child age at follow-up only. Model 3 was additionally adjusted for child sex, developmental assessment data collector, and any of the following variables that were significantly associated at the | PMC10447494 | ||
Association of home environment with children social–emotional problems and self-regulation (hypothesis 2) | Children with higher EC-HOME scores, indicating higher responsive care and learning opportunities in the home environment during early childhood, showed lower SDQ conduct problems (by parent and teacher reports) and lower SDQ hyperactivity/inattention (by parent report). They also demonstrated lower BPM-P externalizing and attention problems and higher EATQ-P self-regulation in attention and inhibitory control. EC-HOME scores were not significantly associated with self-report SDQ or MFQ scores or parent-report SCARED or CEMS scores (Association of home environment scores with each outcome.EC-HOME, Early Childhood Home Observation for the Measurement of the Environment; MC-HOME, Middle Childhood Home Observation for the Measurement of the Environment.Estimates are unstandardized Model 1 was adjusted for the child age at the follow-up and for the intervention group only.Model 3 was additionally adjusted for child sex, developmental assessment data collector, and any of the following variables that were significantly associated at the MC-HOME scores were included as a covariate in model 3 if they were independently associated with the outcome at | PMC10447494 | ||
Interaction of SQ-LNS with home environment (hypothesis 3) and other potential effect modifiers | The interaction between the intervention group and EC-HOME score was significant for self-report SDQ conduct problems (Association of SQ-LNS with self-reported SDQ conduct problems by Early Childhood Home Observation for the Measurement of the Environment (EC-HOME) scores. Among children with low EC-HOME scores (<23), the SQ-LNS group showed significantly lower conduct problems than the control group, whereas there were no significant differences between SQ-LNS and control groups amoung children with high EC-HOME scores. SDQ, strengths and difficulties questionnaire; SQ-LNS, small-quantity lipid-based nutrient supplement.Because the parent-report SDQ was the only measure administered at both 4–6 y and 9–11 y, we examined the mean SDQ total difficulties scores at both time points by the intervention group and high compared with low EC-HOME scores (split at the median = 28) (Total difficuties score on the parent-reported SDQ at age 4–6 y and 9–11 y by the intervention group and high compared with low EC-HOME scores. At the age 4–6 y, there were significantly greater effects of SQ-LNS among children with low HOME scores (less than the median). At the age 9–11 y, there were no signficiant differences between the groups. HOME, Home Observation for the Measurement of the Environment; LNS, lipid-based nutrient supplement; SDQ, strengths and difficulties questionnaire.For the exploratory effect modifiers, of the 115 interaction tests (23 outcomes by 5 exploratory effect modifiers), 14 (12%) were significant at | PMC10447494 | ||
Discussion | EARLY PREGNANCY | In this long-term follow-up study of an RCT that provided a comprehensive daily nutritional supplement during most of the first 1000 d, from early pregnancy to 18 mo postpartum, we did not find effects on social–emotional problems at age 9–11 y. Thus, the previous finding showing reduced social–emotional difficulties in the SQ-LNS group at age 4–6 y was not sustained to age 9–11 y. We did find that children who experienced less-enriched early childhood home environments tended to have higher social–emotional difficulties at age 9–11 y for 8 of the 23 social–emotional scores examined. These associations were attenuated, but 7 remained significant, when adjusting for concurrent home environment, which was significantly associated with 11 of the 23 social–emotional scores. Among children who experienced less-enriched early childhood home environments, those in the SQ-LNS group recorded 0.37 SD lower self-reported conduct problems than those in the control group. This is consistent with the previous finding at age 4–6 y in the same cohort that SQ-LNS buffered children from social–emotional difficulties associated with less-enriched home environments.To our knowledge, this is the first RCT in Africa to report a long-term follow-up assessment after nutritional supplementation with both macronutrients and micronutrients in both the prenatal and postnatal periods, which is a foundational period for brain development. We are aware of only 2 previous studies with a similar design, both of which were conducted in Latin America in the 1970s. One of these randomized only 4 villages to the intervention and control groups [The lack of overall effects of SQ-LNS on child social–emotional problems may have been due to the low prevalence of social–emotional problems at 9–11 y of age, such that there was little potential to benefit from early nutritional intervention at this age in this outcome domain. Few children (<2%) experienced high social–emotional difficulties on the parent-reported SDQ at 9–11 y, in contrast to the high prevalence on this measure at age 5 y in the same cohort (25%). As shown in The finding that a less-enriched home environment during both early and middle childhood was associated with higher child social–emotional problems is consistent with findings among children in high-income countries [Our hypothesis that greater effects of SQ-LNS would be found among children from less-enriched home environments was partly supported by the interaction found for self-report conduct problems. Among children in less-enriched early childhood home environments, those in the SQ-LNS group scored substantially lower than the control group (0.37 SD) in this domain. This pattern is consistent with developmental theories that posit that children who experience biological vulnerabilities may show similar outcomes compared with children without biological vulnerabilities when raised in positive environments but may falter under conditions of environmental stress [Strengths of the study were the individually randomized design, large number of children assessed 10 y after the trial was completed, balance of background characteristics between the intervention groups, a comprehensive assessment of various types of social–emotional problems using multiple tools and multiple respondents (self, parent, and teacher), and demonstrated reliability of the translated tools in the local context. One limitation was that those lost to follow-up differed significantly from those included in the analysis in gestational age at delivery and maternal parity. However, it is unlikely that this led to bias in the results because the difference in gestational age was small (38.9 vs. 39.3 wk) and there was no interaction between the intervention group and parity for most outcomes. Another limitation was that the minimum effect size we were able to detect with our sample size was 0.2 SD, whereas previous studies have shown positive effects of nutritional supplementation on developmental outcomes of ∼0.1 SD [Our study adds to the evidence base for the effectiveness of nutritional interventions such as SQ-LNS during the prenatal and postpartum periods. Although we did not find long-term effects on children's social–emotional problems, we found some evidence that there may be a positive effect among children in less-enriched home environments. Future work will examine other outcomes at this age, such as direct assessments of child behavior and physiology, and will follow up the cohort later in adolescence. | PMC10447494 | |
Acknowledgments | CDA | We thank the families, teachers, and schools who participated in and supported this follow-up study and the Assistant Data Manager, Richard Azumah, for his contribution to data collection and cleaning. The authors’ responsibilities were as follows—KGD, SAA, ELP, PDH, AEG, AM, BMO: designed the research; SAA, EA, HB, MM, MO: conducted the research; CDA, XT, ELP: analyzed the data; ELP: wrote the paper, with critical input and comments from all other authors; ELP: had primary responsibility for final content; and all authors: have read and approved the final manuscript. The authors report no conflicts of interest. | PMC10447494 | |
Funding | This publication is based on research funded by grants to the | PMC10447494 | ||
Data availability | Deidentified individual participant data (such as data dictionaries) will be made available on request to researchers who provide a methodologically sound proposal and statistical analysis plan contingent on approval by the principal investigators. Proposals should be submitted to the corresponding author. | PMC10447494 | ||
References | PMC10447494 |
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