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4. Discussion | low back pain, tachycardia, faintness, palpitations, pain, CM, disability, strokes | CHRONIC LOW BACK PAIN, HEART, DISEASES, STROKES | A wide variety of treatment methods have been used for CMLBP over the years.There are several factors that negatively affect the results of this study. Precautions were taken when planning the study to avoid negatively affecting results.First, the “minimization” method used for randomization ensured that the participants were assigned to the groups equally by considering many parameters (age, gender, occupation). We maintained the laboratory environment under the same conditions during the evaluation and treatment to prevent negative effects that may arise from the environment. The laboratory was kept between 21°C to 25°C, not directly sun light, and the participants rested before the procedures. Finally, participants who had adapting problems to the procedures were excluded from the study.In general, CM is used more often than CTM for the pain treatment. The mechanisms of the 2 massages are similar. Touching and pulling strokes activate subcutaneous mechanoreceptors and reveal the therapeutic effects. This results in decrease pain, regulation of autonomic response, and increase relaxation. When we look at the pain decreasing mechanisms, CTM and CM uses presynaptic and postsynaptic pathways to decrease pain.The autonomic response regulating mechanism of CTM was explained as stimulation of cutaneo-visceral reflexes with pulling strokes,Previous studies found that CTM and CM were successful in treating low back pain and other diseases.In another study, patients with chronic low back pain were divided into 3 groups as CTM, placebo CTM, and control.In a different study, the researchers compared the effectiveness of CM and routine treatment in subacute and chronic low back pain.Thai massage and CM were compared in a study.In autonomic responses, this study’s scientific results provided information to reflect on from a clinical perspective. CTM and CM produce a measurable physiological response and avoid the unwanted autonomic side effects of faintness, palpitations, and tachycardia. It was also an indication that the effects of CTM and CM lasted for a long time. There are studies that support the results of the current study and those that had different results. Similar studies reported that massage created changes in autonomic functions.In a study, a single-session CTM was applied to healthy women with different physical activity levels.In a different study, Holey et alIn a different study, Gholami-Motlagh et alThere are several studies that used massage therapy in disability due to CMLBP. In a study examining the effects of CTM and sham CTM on disability,In a study comparing CM and Thai massage, disability was measured using the ODI.CMLBP decreases health-related quality of life. From the study, it was seen that CTM was more effective in improving quality of life. In a similar study, individuals with chronic low back pain were divided into CTM, sham CTM, and control groups.It was found that 50% of individuals with chronic low back pain suffer from sleep problems.This study has several strengths. Firstly, pain intensity was measured every 5 sessions to identify which massage reduced pain better. In this way, the change in pain intensity could be observed each week.There are expensive and complex techniques to assess the autonomic changes. Heart rate variability, galvanic skin response, and thermal camera systems are among these techniques. Heart rate, blood pressure, and skin temperature were measured in this study. These measurements are low-cost and easy-to-use, which was the second strength side of this study.This study also had a limitation. The study was planned as 5 sessions per week. In this design, some individuals were short of time. Setting the number of sessions to 3 or 4 per week would have made it easier to continue treatments. | PMC10101266 |
5. Conclusion | CM, pain | As a result of this study, CM and CTM had almost similar effects on all parameters. They improved the participants very well, and the effects continued at the end of the 6-week follow-up. Although CTM is the first choice for modulating autonomic responses and CM for pain, we found that both massages were as effective. Considering these results, the rate of use of CM, which is the most preferred method in the clinic, will increase. | PMC10101266 |
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Abbreviations: | MECHANICAL LOW BACK PAIN | Classical massageChronic mechanical low back painConnective tissue massageOswestry disability indexPittsburgh sleep quality indexShort form 36Visual analog scaleThe datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.The authors have no funding and conflicts of interest to disclose.How to cite this article: Er G, Yüksel I. A comparison of the effects of connective tissue massage and classical massage on chronic mechanical low back pain. Medicine 2023;102:15(e33516). | PMC10101266 |
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References | PMC10101266 |
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1. Introduction | SAM, B12 deficiency, malnutrition | BLOOD, MALNUTRITION | Severe acute malnutrition (SAM) is treated with ready-to-use therapeutic foods (RUTF) containing a vitamin–mineral premix. Yet little is known about micronutrient status in children with SAM before and after treatment. We aimed to investigate vitamin B12 status in children with uncomplicated SAM, aged 6–59 months in Burkina Faso, before and after treatment with a standard or a reduced dose of RUTF. Blood samples were collected at admission and discharge. Serum B12 was determined with microbiological assay and serum methylmalonic acid (MMA) and total homocysteine (tHcy) were analyzed with gas chromatography-tandem mass spectrometry. B12 status was classified using the combined indicator (3cB12). Among 374 children, the median [interquartile range] age was 11.0 [7.7–16.9] months, and 85.8% were breastfed. Marked or severe B12 deficiency, as judged by 3cB12, decreased from 32% to 9% between admission and discharge (Vitamin B12 (cobalamin) is of major importance for child development and growth [Vitamin B12 is essential for DNA, RNA, and protein synthesis; DNA methylation; myelination of neurons and, hence, brain development [Vitamin B12 status is assessed predominantly by direct measurement of total serum B12 concentration [The objective of the present study was to investigate B12 status before and after treatment with a standard or a reduced dose of RUTF and explore factors associated with the B12 status. | PMC10458940 |
2. Materials and Methods | PMC10458940 |
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2.1. Study Design and Settings | This study was based on data from the Modeling an Alternative Nutrition Protocol Generalizable to Outpatient care (MANGO) trial for which the methodology is described in detail elsewhere [ | PMC10458940 |
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2.2. Study Participants | Children with SAM were admitted to the trial based on anthropometric entry criteria of a mid-upper arm circumference (MUAC) <115 mm, and/or weight-for-height z-score (WHZ) <−3 [ | PMC10458940 |
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2.3. Intervention | Malnutrition, death | MALNUTRITION | Treatment of children with SAM followed the Burkina Faso national Community-based Management of Acute Malnutrition (CMAM) guidelines [Children were followed weekly until discharge and were classified as recovered, referred, non-response, defaulting, lost to follow-up, death, or false discharge [ | PMC10458940 |
2.4. Data Collection | Socio-demographic characteristics were collected at admission, anthropometry and 2-week retrospective morbidity were collected at each visit [ | PMC10458940 |
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2.5. Blood Sampling and Storage | Venous blood was collected in Vacutainer | PMC10458940 |
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2.6. Biochemical Analyses | Serum B12 was determined with microbiological assay based on a colistin sulphate-resistant strain of | PMC10458940 |
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2.7. Data Management | All preparation and statistical analyses were performed using Stata version 17 (Stata Corp, Texas, USA). Anthropometric z-scores were calculated using the 2006 World Health Organization (WHO) growth standards [ | PMC10458940 |
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2.8. Data Analyses | ±, acute illness | REGRESSION | Population characteristics were reported as proportion, means ± standard deviation (SD), or median with Inter Quartile Range (IQR) (25th- and 75th-percentiles) as appropriate, with corresponding group size. Right-skewed outcomes were log-transformed prior to analysis and estimates were back-transformed. The baseline characteristics of children included in the B12 sub-study were compared to those who were not included.Among children included in the B12 sub-study, the proportion of deficiencies at admission and discharge were calculated according to 3cB12 thresholds presented above. T-tests were used to investigate the effect of the intervention on mean biomarker concentrations by comparing the change from admission to discharge for all children combined, and presented as mean difference with 95% confidence intervals (CIs). Study site (health center) and research team were treated as a random effect, and we adjusted for age and sex at admission. False discharge children were not included in the analysis.Linear mixed-effects modelling was used to investigate the effect of the intervention on mean biomarker concentrations, comparing the change from admission to discharge, according to RUFT group (standard vs. reduced dose) with adjustment for age, sex, and outcome measure at admission, and including study site and research team as random factors. Only samples from recovered children were used to estimate the effect of the RUTF dosage on B12 status.Factors (age, gender, breastfeeding status, duration of treatment, acute illness, biochemical profile) potentially associated with B12 status (defined by 3cB12) in children with SAM at admission and discharge were explored using multivariate logistic mixed-effects regression [ | PMC10458940 |
2.9. Ethical Considerations | This study was approved by the National Ethics Committee of Burkina Faso (deliberation number 2015-12-00) and the national clinical trials board of Burkina Faso (Direction Générale de la Pharmacie, du Médicament et des Laboratoires (DGPML)). The trial was registered in the International Standard Randomized Controlled Trial Number (ISRCTN) registry as ISRCTN50039021. A second approval was obtained in October 2020 from the National Ethics Committee of Burkina Faso (N°2020/000148/MS/MESRSI/CERS) to analyze remaining sera for vitamin B12 analyses. | PMC10458940 |
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3. Results | PMC10458940 |
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3.1. Characteristics of Children in Vitamin B12 Sub-Study | MINOR | Of the 801 children included in the MANGO trial, 374 (47%) were included in the B12 sub-study: 180 from the reduced and 194 from the standard RUTF arm (There was no difference at baseline in demographic characteristics between the children included in the B12 biomarker sub-study compared to those not included from the MANGO cohort, and only minor differences in the occurrences of acute illnesses and serum ferritin concentrations ( | PMC10458940 |
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3.2. Biomarkers of Vitamin B12 Status in Children with SAM Treated with RUTF | B12 deficiency | At admission, only 16% showed a 3cB12 value indicating adequate B12 status (3cB12 > 0), while 32% had 3cB12 values suggesting marked to severe B12 deficiency (3cB12 < −1.4) (The following cut-points for 3cB12 were employed for the classification of B12 status: adequate if >0, moderate deficiency when ≥−1.4 but ≤0, marked deficiency when ≥−2.4 but <−1.4, and severe deficiency when <−2.4 [Treatment improved the B12 biomarker profile from intake to discharge by increasing serum B12 and decreasing tHcy, MMA, and 3cB12 ( | PMC10458940 |
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3.3. Vitamin B12 Biomarkers with a Reduced or a Standard RUTF Dose | No differences at admission or discharge in B12 biomarkers and response were observed according to intervention (a reduced or a standard RUTF dose) ( | PMC10458940 |
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3.4. Factors Associated with B12 Status | diarrhea | Factors or indicators potentially associated with vitamin B12 status, indicated by 3cB12, at admission and discharge are presented in At admission, children with diarrhea had higher B12 status ( | PMC10458940 |
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4. Discussion | pernicious anemia, B12 deficiency, cognitive impairment, Deficiencies, toxicity, diarrhea, cognitive and psychomotor development | PERNICIOUS ANEMIA, IRON DEFICIENCY ANEMIA | To our knowledge, this study is the first to describe biomarkers of vitamin B12 status in children with SAM before and after outpatient treatment. Low concentrations of serum B12 alongside elevated serum tHcy and MMA were observed at admission with only 16% of children deemed to have adequate B12 status according to the 3cB12 index. Using 3cB12, 32% of children were judged to have marked to severe B12 deficiency at admission to treatment. Treatment with RUTF significantly reduced the proportion of children with marked to severe B12 deficiency, however, 9% of the children remained in this category at discharge. All non-breastfed children at discharge had adequate or moderate B12 status, and all children who still had a marked or severe B12 status deficiency at discharge (9%) were still breastfed (11% of breastfed children). Thus, while treatment of SAM, beyond correcting the anthropometric deficits, seems to be effective in improving vitamin B12 status, it appears to be insufficient to fully correct severe or marked deficiencies in some children.The serum B12 levels we observed at admission in this study were lower than those found in healthy children aged 6–30 and 6–59 months in India [Functional consequences of a low B12 status are pernicious anemia and cognitive impairment as B12 is involved in myelination of neurons. These could explain the delay in cognitive and psychomotor development reported in children suffering from SAM [Up to 67% of children still presented with some degree of deficiency in vitamin B12 at discharge from SAM treatment. This raises the question of whether RUTF could be further fortified to improve vitamin B12 status at discharge. Because vitamin B12 is water-soluble and any excess is excreted in urine, the risk of reaching toxicity with higher fortification levels is unlikely [Our study demonstrates that treatment with both standard and reduced RUTF improved the B12 biomarker profile in children with SAM. The Recommended Nutrient Intake (RNI) for vitamin B12 is 0.7–1.2 µg/d for children aged 6–59 months [Deficiencies in B12 were markedly higher in young and breastfed children, under 2 years. This was also found in previous studies [No diarrhea at admission and iron deficiency anemia at discharge were associated with lower B12 status. This is in line with previous studies among 6- to 35-month old Nepalese children [Treatment length appeared to have no impact on 3cB12. The lack of association between duration of treatment and change in B12 status would suggest low B12 status was corrected soon after treatment commenced and thereafter, the B12 biomarker concentrations stabilized over the course of the treatment period. However, with only admission and discharge blood sampling we can only speculate and are unable to investigate time to B12 repletion more thoroughly. | PMC10458940 |
4.1. Strengths and Limitations | The original MANGO study was not designed to investigate changes in vitamin B12 status specifically. However, this sub-study included three individual biomarkers of B12 status as well as a composite score (3cB12). The 3cB12 composite score is considered to give a better judgment of B12 status than use of the individual biomarkers [One of the limitations of this study is that samples were stored for between 3 and 5 years prior to analyses at a non-optimal, −20 °C, temperature. For serum vitamin B12, an almost linear decrease has been observed during the time of storage at −80 °C [ | PMC10458940 |
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4.2. Generalizability | Our findings are, to a certain extent, generalizable to children with SAM of comparable age in other low-income countries with similar socioeconomic conditions, and where the food habits are comparable. Food groups most consumed by children in our study were grains, roots or tubers (96%), and legumes and nuts (72%) [ | PMC10458940 |
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5. Conclusions | breast-fed, anemia, IDA | ANEMIA | Children with SAM presented with a low B12 status, as judged by 3cB12, and generalized deficiencies (IDA and anemia) at admission to treatment. However, treatment with RUTF significantly improved B12 status though it did not normalize 3cB12 in all children. Reduction of the RUTF dose did not impact the final status of B12 biomarkers. Up to 67% of young and breast-fed children still showed B12 status deficiency as judged by 3cB12 at the end of the treatment. More research is needed on the potential benefits of higher levels of RUTF fortification or dietary improvement strategies to increase B12 intake during treatment, or of supplementation after treatment of SAM to normalize B12 status. | PMC10458940 |
Supplementary Materials | The following supporting information can be downloaded at: Click here for additional data file. | PMC10458940 |
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Author Contributions | A.B., L.T., H.F. | Conceptualization, V.N., S.T.K. and C.S.; methodology, V.N., S.T.K., C.S., A.B., L.T., H.F., C.R., E.N. and A.M.; laboratory method development and biological sample analysis: E.N., A.M.; software, V.N. and E.N.; validation, V.N., S.T.K., C.S., A.B., L.T., H.F., C.R., E.N. and A.M.; formal analysis, V.N.; investigation, V.N. and S.T.K.; resources, V.N. and C.S.; data curation, V.N. and A.M.; writing—original draft preparation, V.N.; writing—review and editing, V.N., S.T.K., C.S., A.B., L.T., H.F., C.R., E.N. and A.M.; visualization, V.N., S.T.K., C.S., A.B., L.T., H.F., C.R., E.N. and A.M.; supervision, A.M.; project administration, C.S.; funding acquisition, V.N. and C.S. All authors have read and agreed to the published version of the manuscript. | PMC10458940 |
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Institutional Review Board Statement | This study was conducted in accordance with the Declaration of Helsinki. This study was approved by the national Ethics Committee of Burkina Faso (deliberation number 2015-12-00) and the national clinical trials board of Burkina Faso (Direction Générale de la Pharmacie, du Médicament et des Laboratoires (DGPML)). The trial was registered in the International Standard Randomized Controlled Trial Number (ISRCTN) registry as ISRCTN50039021. A second approval was obtained in October 2020 from the national Ethics Committee of Burkina Faso to analyze remaining sera for vitamin B12 analyses. | PMC10458940 |
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Informed Consent Statement | Informed consent was obtained from all subjects involved in the study. | PMC10458940 |
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Data Availability Statement | Data of this study has been attached as a | PMC10458940 |
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Conflicts of Interest | The authors declare no conflict of interest. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript; or in the decision to publish the results. | PMC10458940 |
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Objectives: | IBD | INFLAMMATORY BOWEL DISEASE | Physical activity programs have been suggested as adjunctive therapy in adult inflammatory bowel disease (IBD) patients. We assessed the effects of a 12-week lifestyle intervention in children with IBD. | PMC10348627 |
Methods: | IBD, fatigue | DISEASE | This study was a randomized semi-crossover controlled trial, investigating a 12-week lifestyle program (3 physical training sessions per week plus personalized healthy dietary advice) in children with IBD. Endpoints were physical fitness (maximal and submaximal exercise capacity, strength, and core stability), patient-reported outcomes (quality of life, fatigue, and fears for exercise), clinical disease activity (fecal calprotectin and disease activity scores), and nutritional status (energy balance and body composition). Change in maximal exercise capacity (peak VO | PMC10348627 |
Results: | Fifteen patients (median age 15 [IQR: 12–16]) completed the program. At baseline, peak VO | PMC10348627 |
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What Is Known | IBD | INFLAMMATORY BOWEL DISEASE | Children with inflammatory bowel disease (IBD) have decreased levels of physical activity compared to healthy peers.Physical activity programs have been suggested as adjunctive therapy in adult IBD patients. | PMC10348627 |
What Is New | ulcerative colitis, fatigue, Crohn disease, UC, IBD | INFLAMMATORY BOWEL DISEASE, ULCERATIVE COLITIS, DISEASE, CROHN DISEASE, CHRONIC INFLAMMATORY DISEASE, REMISSION | This study shows that a 12-week tailored physical training program including healthy dietary advice resulted in an increased submaximal exercise capacity and core stability, improved parent and self-reported quality of life, and less parent-reported fatigue.The intervention also seemed to have a positive effect on IBD as suggested by the lower clinical disease activity and fewer IBD symptoms.Inflammatory bowel disease (IBD), including Crohn disease (CD) and ulcerative colitis (UC), are chronic inflammatory diseases of the gastrointestinal tract, characterized by periods of remission and relapse of symptoms ( | PMC10348627 |
METHODS | MAY | This was a prospective single-center randomized semi-crossover controlled trial, conducted between December 2019 and May 2021 at the Department of Pediatric Gastroenterology at Erasmus MC—Sophia Children’s Hospital in Rotterdam, The Netherlands. The trial was registered in the Dutch trial register: | PMC10348627 |
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Ethical Approval Statement | Erasmus MC | The study was performed in accordance with the Declaration of Helsinki and was approved by the Ethics Committee of Erasmus MC Medical Centre (NL.70912.078.19) and registered at | PMC10348627 |
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Patient Consent Statement | All patients and parents signed informed consent. | PMC10348627 |
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Clinical Trial Registration | Erasmus MC | Ethics Committee of Erasmus MC Medical Centre (NL.70912.078.19), and registered at | PMC10348627 |
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Participants | IBD, UC | Children, aged 6–8 years, with a diagnosis of IBD (CD, UC, or IBD-unclassified) confirmed by ileocolonoscopy and upper endoscopy with histology on multiple mucosal biopsies were eligible for enrollment. Exclusion criteria were: children with a physical inability to perform a cardiopulmonary exercise test (CPET), participation in organized exercise programs, and medical contra-indications for exercise. | PMC10348627 |
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Study Design and Intervention | Ulcerative Colitis, Crohn disease, Fatigue | CROHN DISEASE, ULCERATIVE COLITIS | Figure Study design and visits and measurement assessments. 6MWT = 6-minute walking test; BODPOD = body composition measurement system; CF = child form; CHQ = child health questionnaire; CPET = cardiopulmonary exercise test; MFS = Multidimensional Fatigue Scale; PCDAI = Pediatric Crohn disease Activity Index; PF = parents form; PUCAI = Pediatric Ulcerative Colitis Activity Index. | PMC10348627 |
Outcome Measurements | fatigue | DISEASE | The primary study endpoint was the change in maximal exercise capacity measured by peak oxygen uptake (peak VOSecondary study endpoints included:(1) Physical fitness: submaximal exercise capacity, muscle strength, motor function, core stability, psychical activity levels.(2) Patient-reported outcomes: quality of life, fatigue, and fear of exercise.(3) Clinical disease activity: fecal calprotectin, blood draw, and validated disease activity scores.(4) Nutritional status: caloric intake, energy balance, and body composition. | PMC10348627 |
Physical Fitness | PMC10348627 |
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Exercise Capacity | Exercise capacity was assessed by maximal CPET and submaximal CPET using an electric brake bicycle ergometer, and a 6-minute walking test (6MWT). Details regarding CPET protocols can be found in our previously published exercise study protocol ( | PMC10348627 |
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Muscle Strength and Core Stability | All muscle strength measurements were performed in a standardized manner by either L.J.G. or L.E.S. using hand-held dynamometry and compared to normal values of Beenakker et al ( | PMC10348627 |
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Physical Activity Levels | During the consultation with the sports physician, children and parents were asked about the amount of time spent on physical activity a week. Subsequently, physical activity levels were measured with a validated Actigraph GT3X+ accelerometer (firmware v3.2.1, ActiGraph Inc, Pensacola, FL) ( | PMC10348627 |
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Patient-Reported Outcomes | PMC10348627 |
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Quality of Life, Fatigue, and Fear of Exercise | The validated child health questionnaire (CHQ) child form (CF) and parent form (PF) and the pediatric IBD-specific IMPACT-III questionnaire were used to assess health-related quality of life before and after the intervention ( | PMC10348627 |
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Clinical Disease Activity | Crohn disease, Ulcerative Colitis | DISEASE, CROHN DISEASE, ULCERATIVE COLITIS | To assess the effects of the intervention program on disease activity fecal calprotectin, laboratory measurements [c-reactive protein (CRP), erythrocyte sedimentation rate (ESR)], and clinical disease activity scores [Pediatric Crohn disease Activity Index (PCDAI) or Pediatric Ulcerative Colitis Activity Index (PUCAI)] were observed ( | PMC10348627 |
Nutritional Status | PMC10348627 |
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Body Composition, Intake, and Energy Balance | Patient’s height and weight were measured, and body composition was assessed using a skinfold caliper (4 skinfolds method) and air displacement plethysmography on whole-body densitometry using the BOD POD ( | PMC10348627 |
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Sample Size Calculation and Statistical Analysis | IBD | In a previous Dutch study, untrained children with IBD had a mean peak VO | PMC10348627 |
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RESULTS | PMC10348627 |
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Patient Characteristics | Crohn Disease, Ulcerative Colitis | DISEASE, CROHN DISEASE, ULCERATIVE COLITIS | In total 50 subsequent patients visiting the clinic were asked to participate in the study by L.E.S. Given reasons not to participate were lack of time due to school obligations (n = 24), far distance from the hospital (n = 5), already performing sports 3 times a week (n = 3), and personal reasons (n = 2). A total of 16 patients were included in the study, age, gender, and distribution of disease were similar between included patients and patients who refused participation. In total, 15 patients completed the exercise intervention, 1 patient dropped out after 1 training session due to motivational problems. The median age of the patients was 15 years [12–16], 40% were female, and 67% were diagnosed with CD. Patient characteristics and maintenance treatments can be found in Table Patient characteristicsValues are shown in mean ± SD or as median [IQR]. BMI = body weight index; PCDAI = Pediatric Crohn Disease Activity Index; PUCAI = Pediatric Ulcerative Colitis Activity Index; SDS = standard deviation score; vs = versus.
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Physical Fitness | PMC10348627 |
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Exercise Capacity | Peak VOExercise capacityValues are shown as median [IQR]; effect size is shown with 95% confidence interval. 6MWT = 6-minute walking test; CPET = cardiopulmonary exercise test; HR = heart rate; kg = kilogram; Max = maximal; min = minutes; mL = millilitres; VO
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Core Stability and Muscle Strength | Core stability improved significantly compared to the control period ( | PMC10348627 |
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Physical Activity Levels | Five out of 16 children participated in sports activities before the COVID-19 lockdown. None of the children had to quit sports activities due to IBD-related symptoms earlier (<3 months). Median percentage of time spent in moderate-to-very vigorous activity measured with the Actigraph was 12.1% at baseline; this is below the recommended Dutch norm of 1 hour a day and did not change significantly after training ( | PMC10348627 |
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Patient-Reported Outcomes | PMC10348627 |
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Quality of Life, Fatigue, and Fear of Exercise | multi fatigue, Fatigue | Quality of life, measured by the IBD-specific IMPACT-III questionnaire, improved on 4 domains out of 6 domains compared to the control period with an effect size of +13 points on the total score (Table IMPACT-III and multi fatigue dimension scaleValues are shown in mean ± SD or as median [IQR]. MFS = Multidimensional Fatigue Scale.= | PMC10348627 |
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Clinical Disease Activity | DISEASE | No disease exacerbations were observed during the training period. | PMC10348627 |
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Nutritional Status | PMC10348627 |
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Body Composition and Energy Balance | Median measured REE was increased (+14%) compared to healthy peers ( | PMC10348627 |
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DISCUSSION | IBD, fatigue | DISEASE | This study is the first to investigate the effects of a lifestyle intervention on a broad set of outcomes in children with IBD. The lifestyle intervention resulted in improved physical fitness, quality of life, and parent-reported fatigue and also seemed to have a positive effect on the IBD as suggested by the lower clinical disease activity accompanied by reports of fewer bowel symptoms. | PMC10348627 |
Physical Fitness | PMC10348627 |
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Exercise Capacity | At baseline, peak VO | PMC10348627 |
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Physical Activity Levels | The intervention did not increase physical activity levels measured with the Actigraph. This might be related to measurement timing since baseline measurements were performed before the COVID-19 pandemic and post-intervention measurements. In addition, children might have taken some time off from exercise during the week after 12 weeks of training. | PMC10348627 |
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Patient-Reported Outcomes | PMC10348627 |
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Quality of Life, Fatigue, and Fear of Exercise | depression, fatigue, IBD, anxiety | Children and adolescents with IBD experience decreased quality of life, increased anxiety and depression, and more fatigue compared to healthy peers ( | PMC10348627 |
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Clinical Disease Activity | IBD | DISEASE, REMISSION | After the lifestyle program, PCDAI scores and thereby number of patients in remission decreased significantly. This was mainly declared by a decrease in self-reported bowel symptoms on the PCDAI/PUCAI. Fecal calprotectin decreased, but not compared to the control period, mainly due to relatively large intra-patient fluctuations in the control period. As none of the participants experienced any side effects of training or exacerbation of disease, we think the intervention was safe; our sample size is too small to draw definite conclusions and longer-term effects remain unknown. Whether the decrease in clinical disease activity can be attenuated by our intervention is hard to verify. The only other long-term exercise intervention (8 weeks of exercise gaming) in pediatric IBD patients, also showed a decrease in inflammatory markers ( | PMC10348627 |
Nutritional Status | muscle mass | DISEASE | Although most children did not consume sufficient calories according to their food diaries, growth was comparable to healthy peers. Body fat measured over the control period (by both skinfold and BODPOD; body composition system, COSMED, Ltd, Concord, CA) decreased, leading to a significantly higher body fat percentage measured by skinfold over the exercise period compared to the control period. It has to be noted that one patient experienced an exacerbation of disease during the control period and lost 20 kilograms; she gained weight again during the exercise period. Whether children also gained muscle mass, is uncertain; REE as percentage of predicted tended to increase, indicating a higher muscle mass, but did not reach significance. Both the BODPOD and skinfold caliper only measure fat mass and fat-free mass; further studies may need to use dual X-ray absorptiometry to investigate training effects on muscle mass. | PMC10348627 |
Strengths and Limitations | weakness, IBD | MUCOSAL INFLAMMATION, DISEASE, REMISSION | Our study has several strengths. This study is the first to prospectively investigate the effects of a lifestyle intervention in pediatric IBD patients on a broad set of outcomes, which are never investigated before in this population. The program was well received, as reflected by the high training adherence, making this program feasible in a clinical setting. Whether patients were also adherent to the tailored diet advice, was hard to verify. A weakness of our study is the small study population, especially the control group (n = 7). Researchers in the study could not be blinded by following strict protocols and consulting a second reviewer when filling in the PCDAI/PUCAI questionnaires; this bias was minimized. Due to the invasive nature of the procedure, we did not measure mucosal inflammation by endoscopy before and after the intervention. A major limitation of our study is the prolonged control period due to the COVID-19 lockdown. Although we still executed the generalized estimation approach model to measure change during the control period versus the exercise period, comparing these periods is less accurate, as a 6-month control period leads to more intra-patient fluctuations, especially in a disease that is characterized by periods of remission and relapse. | PMC10348627 |
CONCLUSIONS | IBD, fatigue | INTESTINAL INFLAMMATION, DISEASE | The 12-week lifestyle intervention resulted in improved physical fitness, quality of life, and parent-reported fatigue. In addition, a combination of lower clinical disease activity scores accompanied by fewer IBD symptoms suggests positive effects on intestinal inflammation. Children and adolescents with IBD should be motivated and supported to acquire and maintain a healthy lifestyle. | PMC10348627 |
Acknowledgments | DER | We would like to thank all patients for participating in our trial and all physiotherapists for training the patients. Abir Bougrine & The Rotterdam Exercise Team: W.A. Helbing, M.W. Pijnenburg, A.T. van der Ploeg, J. Noske, A. van den Broek, and J. Olieman. | PMC10348627 |
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Supplementary Material | J.C.E. received institutional research support from MSD, AbbVie, and Janssen. L.E.M.v.d.B. has received research support from “Maag Darm Lever Stichting,” “Stichting Vrienden van Sophia,” and the “Beatrix spierfonds.” The remaining authors report no conflicts of interest.Supplemental digital content is available for this article. Direct URL citations appear in the printed text, and links to the digital files are provided in the HTML text of this article on the journal’s Web site (Trial registration number: Sources of Funding: This study was supported by the “Stichting Vrienden van Sophia,” grant number: B19-01.Data availability Statement: The data underlying this article will be shared on reasonable request to the corresponding author. | PMC10348627 |
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REFERENCES | PMC10348627 |
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1. Introduction | MP, Stunting | STUNTING | These authors contributed equally to this work.Stunting affects 22% children globally, putting them at risk of adverse outcomes including delayed development. We investigated the effect of milk protein (MP) vs. soy and whey permeate (WP) vs. maltodextrin in large-quantity, lipid-based nutrient supplement (LNS), and LNS itself vs. no supplementation, on child development and head circumference among stunted children aged 1–5 years. We conducted a randomized, double-blind, community-based 2 × 2 factorial trial in Uganda (ISRCTN1309319). We randomized 600 children to one of four LNS formulations (~535 kcal/d), with or without MP (Child stunting is one of the most important impediments to human development, globally affecting 22% of children under 5 years [In low- and middle-income countries (LMICs), 43% of children under 5 years are at risk of not reaching their developmental potential [As a notable predictor of development, head circumference is measured routinely especially in the first two years of life, a period during which the brain grows rapidly and the open sutures between the bones of the skull close. The increase in head circumference is more rapid at a younger age with up to 90% of the adult head size attained by two years. Head circumference increases by about 0.7 cm during the fifth year compared to 11 cm in the first year [To improve early child development in line with the 2030 agenda for sustainable development [Studies examining the effect of small-quantity, lipid-based nutrient supplement (LNS) with complementary feeding on development have had mixed findings [Therefore, we aimed to measure the effect of milk protein (MP) vs. soy and whey permeate (WP) vs. maltodextrin, as part of large-quantity LNS (~535 kcal/d), as well as the effect of LNS itself vs. no supplementation on early child development among stunted children aged 1–5 years. We hypothesized that dairy in LNS, and/or LNS irrespective of dairy would affect child development. | PMC10301406 |
2. Materials and Methods | PMC10301406 |
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2.1. Study Design | MP | SECONDARY | This study reports secondary outcomes from the MAGNUS trial, a community-based randomized 2 × 2 factorial trial assessing the role of MP and WP in LNS on growth and development among stunted children (ISRCTN13093195). The primary outcome of the original trial was the effect of the intervention on height and knee-heel length as reported elsewhere [ | PMC10301406 |
2.2. Study Participants | disability, oedema, malnutrition | MILK ALLERGIES, MEDICAL COMPLICATION, OEDEMA, MALNUTRITION | This study was conducted at two public health facilities in Walukuba division and Buwenge town council in Jinja district. The district is located about 75 km east of the capital city Kampala forming part of the ten districts in the Busoga sub-region in East-Central Uganda.Study participants were identified from the surrounding villages and those found with height-for-age z-score (HAZ) < −2 and weight-for-height z-score (WHZ) > −3 were invited to the study clinic for eligibility screening. At the study clinic, children were enrolled if they met the following inclusion criteria: lived in the catchment area, caregiver willing to return for follow-up visits, and agreed to phone-follow-up plus home visits. Children who had severe acute malnutrition (WHZ < −3 or bilateral pitting oedema), medical complications that necessitated hospitalization, history of peanut or milk allergies, obvious disability impeding ability to eat or measure their length/height were excluded from the study. Children who were participating in another study, whose family planned to move away from the catchment area in the next six months, or had another child from the same household already included were excluded as well. | PMC10301406 |
2.3. Randomization, Allocation Concealment and Blinding | As described previously [All investigators and outcome assessors were blinded with respect to LNS or no LNS, and to the ingredients contained in the differently coded LNS sachets. Caregivers and children were blinded with respect to the type of LNS allocated since all the four supplements were indistinguishable in appearance, smell and taste. | PMC10301406 |
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2.4. The Intervention | All caregivers, irrespective of study arm, received nutrition counselling at inclusion, in line with the national policy on infant and young child feeding [Compliance to LNS intake was measured by counting returned empty sachets and asking the caregiver how many sachets the child had consumed since the last visit. Missing sachets or data were all considered as lack of intake. | PMC10301406 |
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2.5. Study Visits | All caregivers returned fortnightly to collect LNS or laundry soap until the 12th week. Distribution took place in a closed room only after all other on-site study activities were completed for the participant. At baseline, data on the following were collected: demographic information, dietary intake including breastfeeding (defined as any breastfeeding in the previous 24 h), food insecurity assessment, anthropometry. Child development was assessed and blood samples collected for micronutrient and other clinical data analyses at baseline and endline. | PMC10301406 |
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2.6. Sample Size Consideration | MP | This was based on the primary outcome of the main trial (height and knee-heel length) where detecting 0.35 SD or a greater difference in any outcome between any of the two groups, at 5% significance level and 80% power, while allowing for 10% attrition, allowed us to recruit 150 children per group (600 in total based on the 4 combinations of MP and WP). If there were no interactions between the two experimental arms, then two groups of 300 children could be compared enabling differences of 0.24 SD to be detected. | PMC10301406 |
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2.7. Outcomes | Child development, the main outcome of the current study, was assessed using the Malawi development assessment tool (MDAT) version 6 [Head circumference (mm) was measured in triplicate using a windowed, nonelastic paper-head circumference tape (SECA 212, Hamburg, Germany), in line with accepted international standards [ | PMC10301406 |
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2.8. Additional Data | The child and caregiver’s participation during the MDAT assessment was observed by the CDO. This was evaluated based on an adapted version of the Behaviour Observation Inventory from the Bayley Scales of Infant and Toddler Development [The child’s developmental stimulation at home was assessed using an African validated family care indicators (FCI) questionnaire [All anthropometric measurements were repeated in triplicate and the median used. Weight was obtained using an electronic scale with a double weighing function (Seca 876, Hamburg, Germany). Length (measured in children < 24 months) and height (measured in children 24 months and older) was obtained using a wooden Shorrboard (Weigh and measure LLC, Olney, MD, USA) ensuring five points of contact with repositioning between measurements. Mid-upper arm circumference (MUAC) was measured using a non-elastic MUAC tape (UNICEF SD, Copenhagen, Denmark). All caregivers received nutrition counselling using the national guidelines on infant and young child feeding (IYCF) [Venous blood was drawn from each child, transported to the field laboratory, processed, temporarily stored at −20 °C before being transported to Kampala for storage at −80 °C. Processed samples were later transferred to Denmark and Germany in dry ice for analysis of the acute phase proteins using a sandwich enzyme-linked immunosorbent assay (VitminLab, Willstaett, Germany). | PMC10301406 |
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2.9. Statistical Analyses | fits, MP, stunting, inflammation | INFLAMMATION | Paper case report forms were used to collect data, which were then doubly entered in EpiData with inbuilt range checks before uploading to REDCap (Open-Source Vanderbilt University) to a secure server at UCPH weekly. Data comparison was performed and any discrepancies were verified by both entrants with the aid of the hard-copy case report forms and consultations from respective research assistants before rectification. Statistical analysis was performed using Stata SE14 and descriptive statistics presented as mean ± SD, median [IQR], or % (n).We generated internal MDAT developmental age-adjusted z-scores. This involved using the 2-parameter logistic (2PL) model [Statistical analyses were based on the intention-to-treat (ITT) principle using available case data. We analyzed the 2 × 2 factorial design using linear mixed effects models in all analyses, utilizing the ‘xtmixed’ command in Stata version 14. We first tested for any interactions between the two interventions in the matrix (MP and WP). In case of no interaction effect, we then tested for the main effects on child development. The compound symmetry variance–covariance structure was assumed, and no robust standard errors were applied because the linear mixed model fits showed no marked departures from the model assumptions. Furthermore, we compared the intervention (LNS) irrespective of milk ingredients among 600 children against the 150 un-supplemented group. Prespecified subgroup analyses were performed for all outcomes, testing for any effect modifications by sex, breastfeeding, stunting severity, inflammation (serum α-1 acid glycoprotein, AGP ≥ 1.2 g/L), and stimulative home environment (having any children’s book at home, with >2 sources of play materials of >3 varieties, and with >3 engagements with older family members in interactive activities).All linear mixed models were adjusted for the baseline value of the outcome, age, sex, and season, as fixed effects, as well as site, as a random effect. Restricted maximum likelihood estimation was used, and model assumptions were assessed visually using residual and Q–Q plots. Estimates, and 95% CI, were reported, and a significance level of 0.05 was used.A per protocol analysis was performed, retaining only those children who remained until the study-endline visit, and had at least 80% compliance with LNS supplementation for those in the interventional group. Details on the measure of compliance are reported in the main paper [ | PMC10301406 |
2.10. Ethics | This study was approved by the Makerere University School of Medicine Research and Ethics Committee (#REC REF 2019-013) and the Uganda National Council of Science and Technology (SS 4927). We also obtained consultative approval from the Danish National Committee on Biomedical Research Ethics (1906848). All study staff took courses in Good Clinical Practice and Human Subject Protection prior to study start. We obtained oral and written informed consent in Lusoga, Luganda or English from all participants’ caregivers. Illiterate caregivers were taken through the process in the presence of a literate witness. All caregivers consented after their understanding of the information was double checked by a different study or facility staff member, using an informed consent questionnaire. | PMC10301406 |
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3. Results | PMC10301406 |
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3.1. Participant Characteristics | ± | Between February and September 2020, we screened 7611 children at various village sites. Of these, 1193 were stunted, 750 of whom were enrolled and randomized into one of five groups (At inclusion, the median [interquartile range, IQR] age was 30 [23; 41] months, 45% (338) were girls, and the mean ± SD HAZ was −3.02 ± 0.74. The mean ±SD MDAT Z-scores for gross motor, fine motor, language, social and total MDAT scores were −0.19 ± 1.02, −0.13 ± 1.04, −0.15 ± 1.03, −0.13 ± 1.03, and −0.20 ± 1.00, respectively. Generally, the randomization resulted in baseline equivalence with respect to potential confounders ( | PMC10301406 |
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3.2. Development among the Unsupplemented Children | Over the 12-week follow-up period, there were increments in developmental scores across all domains among the un-supplemented children ( | PMC10301406 |
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3.3. Main Effect of Milk Ingredients and/or LNS on Development | MP | The primary intention-to-treat analysis assessed the effects of MP and WP based on the factorial design among the 600 children who received LNS. There was no interaction between MP and WP for any of the outcomes ( | PMC10301406 |
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3.4. Subgroup Effect of Milk Ingredients, and LNS in Itself, on Development | MP, stunting | INFLAMMATION | We assessed whether the effects of MP and WP were modified by sex, breastfeeding, stunting severity, baseline inflammation, and a stimulative home environment. The effect of MP on social skills was modified by sex and breastfeeding (interaction, The effect of MP on cognition was modified by a stimulative home environment but with marginal significance. This was due to a larger effect of MP on fine motor (interaction, Whey permeate was associated with lower motor and social skills among children with severe compared to moderate stunting. This corresponded to 0.07 (95%CI: −0.15; 0.29) and 0.22 (95%CI: −0.01; 0.44) lower gain in gross and fine motor scores, respectively, among severely compared to moderately stunted children (The adherence to the nutritional intervention was reported elsewhere [ | PMC10301406 |
4. Discussion | MP | INFLAMMATION, CURB, MALNUTRITION | In our nutrition intervention study using large-quantity LNS, neither MP nor WP had an effect on any development domain or head circumference. Irrespective of milk ingredients, LNS vs. no supplementation had no effect on any development domain but seemed to increase head circumference. A further test for interactions revealed that the effect of MP on social skills was modified by sex and current breastfeeding. The effect of WP on motor and social skills was modified by stunting severity while the effect of LNS irrespective of dairy was modified by current breastfeeding and inflammation.Several nutrition studies have shown that milk protein, or milk per se [Despite the scant literature on the developmental effects of supplementation with large-quantity LNS, studies using small-quantity LNS have also had inconsistent results [Among other challenges, comparability is difficult across studies due to variations in definitions and measurements used for the different variables. Additionally, most previous studies have used small-quantity LNS, which provides minimal energy (~100 kcal/d), to meet the part of the child’s daily energy requirements (~1000 kcal/d). To some extent, our results concur with these studies that LNS intervention does not generally result in development, despite using large-quantity supplements providing more energy (~535 kcal/day), and fully satisfying the child’s daily micronutrient requirements. We already reported that the same milk ingredients had no effect, but rather, LNS, irrespective of milk ingredients, benefited growth [In the management of malnutrition, there were concerns about the polyunsaturated fat acid (PUFA) composition of earlier WHO standard LNS versions in facilitating neurocognitive and immune recovery. This was mainly due to the content of linoleic acid in those products when given at high doses (150–200 kcal/kg/day), thus, calls for data on optimal omega-6 and omega-3 PUFA content. Studies testing novel products revealed that adding omega-3 DHA or a reduction of omega-6 linoleic acid by using high-oleic peanuts improved overall omega-3 (DHA) status with subsequent development [A stimulative home environment may have interacted with MP, resulting in more rapid ontogenetic development, hence, a higher increase in cognitive scores among those with stimulative compared to non-stimulative home environment. It may have also been more of an interaction with the household’s socioeconomic status (SES), consequently resulting in better cognitive development. This is a key research gap noted by some scholars as to whether it is lack of stimulation or poverty that is responsible for poor development [Studies have reported lower early child development scores among stunted than non-stunted children [From the literature, breastfeeding has been associated with improved cognitive performance and socio-affective response [Key strengths of our study are the randomized 2 × 2 factorial design with an un-supplemented group for comparison, a very low attrition rate, use of a contextually developed and local tool to measure the outcome and pre-specified subgroup analysis plan to avoid chance findings. Limitations may include the incomplete blinding of the caregivers with respect to supplementation, despite measures in place to curb this, recall, and information bias from caregiver’s reports on the family care indicators. | PMC10301406 |
Supplementary Materials | The following supporting information can be downloaded at: Click here for additional data file. | PMC10301406 |
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Author Contributions | The authors’ contributions were as follows: H.F., B.G., E.M., H.P., J.M. and R.M. designed the study; H.P., B.G., H.F., E.M., J.M. and R.M. wrote the protocol; H.F. and E.M. were principal investigators; J.M., R.M., H.P. and B.G. implemented the study and E.M., J.M., H.P., R.M. and B.G. supervised data collection. The statistical analysis plan was developed by H.F., C.R. and M.F.O.; statistical analysis was performed by J.M. and H.F. and all co-authors interpreted the results. This manuscript was written by J.M. with input from H.F. and M.F.O.; all authors critically reviewed and approved the final version of the manuscript. B.G., J.M., R.M. and H.F. accessed and verified the data. J.M. and M.F.O. had final responsibility for the decision to submit the manuscript for publication. All authors have read and agreed to the published version of the manuscript. | PMC10301406 |
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Institutional Review Board Statement | The study was conducted in accordance with the Declaration of Helsinki and was approved by the Makerere University School of Medicine Research and Ethics Committee (#REC REF 2019-013) and the Uganda National Council of Science and Technology (SS 4927). We also got consultative approval from the Danish National Committee on Biomedical Research Ethics (1906848). | PMC10301406 |
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Informed Consent Statement | Informed consent was obtained from all subjects involved in the study. | PMC10301406 |
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Data Availability Statement | The Ugandan act on Data Protection and Privacy and the European act on General Data Protection Regulation do not allow for personal data to be made available to other researchers without prior written approval from relevant institutions and authorities. For further information, please contact the corresponding author. | PMC10301406 |
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Conflicts of Interest | H.F. and C.M. have received research grants from ARLA Food for Health. H.F., B.G. and C.M. have received research grants from the Danish Dairy Research Foundation. C.M. and K.F.M. also received funds from Arla Foods Amba and finally H.F., C.M., K.F.M., B.G., S.F. and A.B. have had research collaboration with Nutriset, a producer of LNS. Other authors declare no financial relationships with any organisations that might have an interest in the submitted work in the previous five years, and declare no any other relationships or activities that could appear to have influenced the submitted work. | PMC10301406 |
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