Low back pain (LBP) is a common symptom that affects almost 80% of the global population. LBP manifests as diverse pathologies and has different causes. The focus of this paper is nonspecific chronic low back pain (NSCLBP) wherein the pain lasts for more than 12 weeks, and for which there is no definite cause. Although there are various treatment options for NSCLBP, including medication and exercise, each option has its own limitations. Although electroacupuncture (EA) has been known to have useful analgesic effects on chronic LBP, there is no systematic review (SR) on EA in the literature. Therefore, this study aims to systematically review and validate the effectiveness and safety of EA for NSCLBP.We will search for randomized controlled trials on the use of EA for NSCLBP in multiple electronic databases, manual searches, and contacting authors. We will screen and select studies according to the predefined criteria and extract the data needed for this SR. The primary outcome will be the pain index , and the secondary outcomes will be the functional status (Roland-Morris Disability Questionnaire), patient-centered outcomes, and adverse events. We will perform a meta-analysis using Review Manager software  and assess the risk of bias using Cochrane Collaboration “risk of bias” tools and the quality of evidence using the Grades of Recommendation, Assessment, Development and Evaluation.Our SR will investigate the effectiveness and safety of EA on NSCLBP.Our SR will support the published clinical evidence of the usage of EA for NSCLBP to assess the effectiveness and safety of EA.INPLASY; INPLASY2020120039 According to the duration, LBP can be classified into acute (<6 weeks), subacute (6–12 weeks), and chronic (>12 weeks) types. When the symptoms last for more than 12 weeks, and the cause of pain is unknown, the condition is referred to as nonspecific chronic low back pain (NSCLBP).Low back pain (LBP) is a common disorder that affects nearly 80% of the global population and is associated with a number of causes such as fracture, radiculopathy, malignancy, and inflammatory disorder. and that nonspecific LBP accounts for 90% to 95% of LBP after excluding the possibility of spinal pathology and radicular syndrome. Thus, NSCLBP poses an economic burden by increasing the cost of treatment and having negative effects on work productivity, quality of life (QOL), as well as on social and psychological status of the affected individual.Although the exact prevalence of NSCLBP has not been determined, it can be inferred from existing reports. Some articles have reported that up to 60% of LBP patients did not recover fully by 12 weeks, However, NSAIDs are not recommended for long-term use because of their side effects on the renal, gastrointestinal, and cardiovascular systems.,10 Combined with education, exercise is effective only in preventing LBP, with little evidence of its therapeutic effect. Other physical therapies, including transcutaneous electrical nerve stimulation and shock wave therapy, also have no significant effects.,13Although there are several therapies for NSCLBP, nonsteroidal anti-inflammatory drugs (NSAIDs) and exercise have been recommended in the 2018 Clinical Practice Guideline.–16 Electroacupuncture (EA), a type of acupuncture, has been widely used for musculoskeletal disorders. Studies on the analgesic mechanism of EA have reported its association with endogenous opioid peptides. EA has been suggested as a therapeutic option for chronic pain to safely reduce the use of opioid medication and as an effective option for chronic LBP in combination with exercise.,19 However, there are no SRs focusing on the use of EA for NSCLBP. Therefore, the purpose of this SR was to evaluate the effectiveness and safety of EA by examining published randomized controlled trials (RCTs) in the literature.Because of the aforementioned dissatisfaction with conventional treatments, recent guidelines and systematic reviews (SRs) have recommended acupuncture as a cost-effective treatment for NSCLBP.22.1This SR will be conducted in accordance with the Preferred Reporting Items for Systemic reviews and Meta-Analyses Protocols (PRISMA-P) 2015 Statement.2.2No ethical statement is required, as there is no need for patient recruitment and personal data collection.2.3The protocol was registered in INPLASY (Registration number: INPLASY2020120039).2.42.4.1Patients aged 18 years and more and diagnosed with NSCLBP will be included in this SR. LBP patients with pain lasting for more than 3 months without any pathological and anatomical abnormality will be included. We will exclude patients who have specific reasons for LBP including acute sprain, herniated disc, and fracture.2.4.2RCTs that investigated the effects of EA will be included in this study. The combination of conventional therapies will be accepted if the only difference between the groups is EA. Studies that used EA, but compared the treatment duration and different acupuncture points will be excluded.2.4.3We will only include RCTs for the use of EA for NSCLBP. We will exclude non-RCTs including case reports, observational studies, cross-sectional studies, pilot studies, and SR. If the study did not describe the randomization method or used an incorrect method, it will be excluded from the SR.2.4.4Pain index  will be the primary outcome measure. Secondary outcome measures will include functional status (Roland-Morris Disability Questionnaire), patient-centered outcomes, and adverse events.2.4.5There will be no limits on the language.2.5The following electronic databases will be used from their inception to May 2021: MEDLINE, EMBASE, Cochrane library, China National Knowledge Infrastructure (CNKI), CiNii, J-STAGE (Japanese database), KoreaMed, Korean Medical Database, Korean Studies Information Service System (KISS), National Digital Science Library (NDSL), Korea Institute of Science and Technology Information (KISTI), and Oriental Medicine Advanced Searching Integrated System (OASIS). Researchers will perform a search using terms with a combination of LBP-related terms  and treatments  in each database's own language. If necessary, a manual search will also be carried out to include textbooks and references on EA, and the corresponding authors will be contacted  and screen the studies. After excluding the duplicates and irrelevant articles, the 2 researchers will review the studies by reading the full-texts and confirm the eligibility. Disagreement between the 2 researchers will be resolved by the discussion. If necessary, a third reviewer will mediate the discussion Fig. .2.7Researchers will manage the studies using Endnote X9.2.8Two reviewers will extract information about the first author, publication year, the characteristics of the patients and control, the intervention characteristics , outcome measures, results, and study quality. Any disagreement between the 2 reviewers will be resolved by discussion or additional mediation as indicated above. If relevant data are not usable, we will contact the original author to obtain the missing data by e-mail. If the author or data are not available, we will mention this in the SR for that particular paper.2.9The changes between the baseline and the completion of the intervention in the included studies will be used for the meta-analysis by using Review Manager software . If the outcome measures are the same, the mean difference and 95% confidence intervals (CIs) will be calculated. For the different outcome measures, the standardized mean difference and 95% CI will be calculated to estimate the effect.I-squared tests. The interpretation of the heterogeneity will be as follows:The statistical heterogeneity between the studies will be determined by Chi-squared and I-squared: 0% to 40% unimportant heterogeneity; 30% to 60% moderate heterogeneity; 50% to 90% substantial heterogeneity; and 75% to 100% considerable heterogeneity. If possible, subgroup analysis will be conducted based on the control interventions. If quantitative synthesis is not possible, a narrative synthesis will be performed based on the available data.Publication bias will be assessed by using the funnel plot if more than 10 identified studies are included in the meta-analysis. For determining the quality of evidence, the Grading of Recommendations Assessment, Development and Evaluation (GRADE) method will be utilized.2.10 Two reviewers will independently assess the risk of bias, and any disagreements will be resolved through discussion. If consensus is not reached, a third party will participate in mediation.Two reviewers will conduct the assessment of risk of bias. They will use the Cochrane Collaboration “risk of bias,” which consists of 6 domains .3NSCLBP is a condition that affects the QOL by causing persistent pain. Although conventional treatments are helpful, they have their limitations; hence, acupuncture has been suggested as an alternative option for chronic LBP. EA, a type of acupuncture, could be helpful for NSCLBP; however, no SR has not been published on the use of EA for NSCLBP. Our study will provide the clinical evidence for the effectiveness and safety of EA on NSCLBP, which should be useful as a resource for health policy makers, practitioners, patients, and researchers.Conceptualization: Won-Suk Sung, Eun-Jung Kim.Funding acquisition: Dongwoo Nam.Investigation: Kyungbok Park, Inae Youn, Hye Won Yeum, Sungyoon Kim.Methodology: Jeong Ryul Park, Yejin Hong.Project administration: Yeoncheol Park, Eun-Jung Kim, Dongwoo Nam.Supervision: Dongwoo Nam.Writing – original draft: Jeong Ryul Park, Won-Suk Sung.Writing – review & editing: Jieun Choi, Yeeun Cho, Yejin Hong, Won-Suk Sung, Dongwoo Nam.


Graves’ disease is the most common cause of hyperthyroidism. Antithyroid drugs, radioiodine ablation, and surgery are the main treatments. Research has demonstrated that adding thyroxine to antithyroid therapy can improve the remission rate, and many similar studies have been conducted subsequently. The purpose of this systematic review was to investigate whether adding thyroxine to various treatments for Graves’ disease has a clinical benefit in remission/relapse rate, stable thyroid function, occurrence of Graves’ ophthalmopathy, etc. A total of 27 studies were included, and the risk of research bias was moderate to high. We discuss the role of thyroxine both in pharmacological and non-pharmacological therapeutic regimens. Overall, the available evidence does not support the indiscriminate addition of thyroxine to various treatments for Graves’ disease, especially in combination with oral antithyroid drugs. Further clinical studies are required to explore the indications of thyroxine addition in the treatment of Graves’ disease. There are two ways to use ATD: titration, and block & replace. With titration, the dose of ATD is titrated over time to the lowest dose needed for maintaining an euthyroid state. In the block-and-replace regimen, a higher dose of ATD is used with concurrent replacement with levothyroxine. A meta-analysis including twelve studies in 2010 investigated the effects of B&R and titration block protocols. Although there were adverse reactions, the recurrence rate was the same in the two groups, 51% in the B&R group and 54% in the titration block group . Withdrawal due to side effects  was significantly greater in the B&R group . Although the block-and-replace regimen is controversial in many studies, it is still used in many regions.Hyperthyroidism is characterized by increased thyroid hormone synthesis and secretion. The most common cause of hyperthyroidism is Graves’ disease, followed by the toxic multinodular goiter. The worldwide prevalence of hyperthyroidism varies by region. A meta-analysis of studies that evaluated the prevalence and/or incidence of thyroid dysfunction in Europe showed a prevalence of about 0.8%, while the National Health and Nutrition Examination Survey in the United States showed a prevalence of 1.3% . Global The role of thyroxine in the treatment of Graves’ disease needs to be evaluated on multiple aspects. The purpose of this study was to examine the addition of thyroxine for the treatment of Graves’ disease and explore its benefits and deficiencies. This study was designed as a systematic review.Randomized controlled trials (RCT), non-RCT, crossover studies, retrospective studies, and comparative studies were included in this analysis. Protocols and case reports were ruled out. Abstracts and non-English language publications were equally excluded.We included patients with a clinical diagnosis of Graves’ disease. There were no restrictions on the age or gender of patients.We included studies that combined thyroxine in the treatment of Graves’ disease, where the primary endpoint was the remission/relapse rate of Graves’ disease with and without thyroxine. Other effects of this combination therapy in the treatment of Graves’ disease were also considered for demonstration in this study, including stable thyroid function, occurrence of Graves’ ophthalmopathy, quality of life, operative process, postoperative complications and so on. If patients with Graves’ disease developed hypothyroidism and used thyroxine, the respective studies were excluded.,We searched the following publication databases: PubMed, Embase, Cochrane Library, and Web of Science. Studies published in English before December 31, 2019, were included. Selected keywords included Graves’ disease, Basedow’s disease, thyroxine, levothyroxine, L-thyroxine. Keywords were customized for each scientific database. The references of all retrieved articles were examined to ensure that all relevant articles were included for data synthesis. The retrieval strategy and process are illustrated in the Two authors (J.L. and L.B.) independently reviewed all potential studies for inclusion against the eligibility criteria. They examined the title and abstract and, where necessary, the full text of the studies to assess if they were eligible for inclusion. In cases where they were not able to reach an agreement, a third author (W.Y.) made the final decision concerning eligibility.Two authors, M.W. and Y.X., independently assessed and selected studies eligible for this systematic review based on their title and abstract. Disagreement was resolved by consensus. Two authors, J.L. and L.B., read the full texts of the remaining articles and made a final selection. Data were extracted and presented in a table, including author, year, country, study design, sample, sex ratio , age (years), medication, intervention process, follow-up, assessments, results, side effects.The included studies were evaluated for the risk of bias using the Cochrane Collaboration’s tool for randomized trials. The following aspects of the study were evaluated: random sequence generation, allocation concealment, blinding of participants and personnel, blinding of outcome assessment, incomplete outcome data addressed , selective reporting, other bias. The non-RCT studies were assessed using the MINORS score, which serves as a methodological index for non-randomized studies. It has 12 domains for which non-comparative studies use the first 8 domains. Each domain is scored out of 2 with ideal scores being at least 16 for non-comparative studies and 24 for comparative studies.The search resulted in 6,209 potential articles from PubMed , Cochrane Library (n = 95), Embase , and Web of Science (n = 665). In total, 6,139 articles were excluded based on the double-blind screening of the title and abstract, including 904 duplicates. The remaining 70 full text articles were assessed, and 27 articles were found eligible for this review (21 RCT and 6 non-RCT). The “block-and-replace” (B&R) regimen is well known to endocrinologists, but it is not routinely recommended in clinical practice. The B&R regimen completely blocks the thyroid hormone synthesis with high-dose ATD, while supplementing exogenous thyroxine to replace normal thyroid function. As per the 2016 American Thyroid Association guidelines, B&R therapy should be avoided or, if necessary, should be used after addressing compliance, in patients whose condition was inadequately controlled with one dose of methimazole (MMI) and who then become hypothyroid after a minimal dose increase . Nine ofThree studies including Perozim et al., Jorde et al., and Grebe et al. reported that the B&R regimen had some benefits in the recurrence of Graves’ disease , 20, 23.In four other clinical studies, including Edmonds and Tellez, McIver et al., Lucas et al., and Nedrebo et al., the results showed that the B&R regimen for the recurrence rate of Graves’ disease was not superior to titration therapy , 22, 24.Therefore, the included studies showed that thyroxine addition during the B&R regimen or after stopping the ATD did not show more benefits than the titration regimen in the long-term recurrence rate of Graves’ disease.The titration regimen is widely used in clinical practice. Throughout the course of the treatment, the dose of ATD is adjusted according to the condition and thyroid hormone concentrations, which can generally be divided into initial, decrement, and maintenance phases. There were 11 RCTs , 28–37 aAmong the 11 studies, only the study by Hashizume et al. showed a positive effect . The resThese results have not been confirmed in subsequent studies, and all the remaining nine studies drew contrary conclusions. Similar to the study by Hashizume et al. , in the The treatment of Graves’ disease in special groups, such as children and pregnant women, has its special features. In the study by Hashizume et al., 78 patients with Graves’ disease received MMI for 1–3 years before pregnancy and thyroid function remained normal during the first two months of pregnancy . MMI wasParents generally consider non-pharmacological treatments for children with Graves’ disease because of the poor compliance or severe side effects caused by ATD. Due to concerns about post-intervention complications, non-pharmacological treatments are often not accepted by children’s parents when the patient is very young . Vigone Although such studies are few and insufficient as clinical evidence, they can also provide some basis for clinical treatment and further research.Four of the clinical studies screened were on the non-pharmacological treatment of Graves’ disease, two of which were RCT , 43. Non’ disease into group A  or group B (follow-up every 4 weeks and treated with L-T4 when needed), and the follow-up period was 6 months (’ quality of life, but the optimal strategy for L-T4 dosage and timing remained to be determined. Tallstedt et al. retrospectively analyzed the clinical data of 492 patients who received RAI treatment, divided in 2 groups (’ ophthalmopathy. The remaining two studies were related to the role of thyroxine in thyroid surgery.Taïeb et al. randomly divided 94 patients with Graves6 months . The res2 groups . One gro’ disease to three treatment groups, first using ATD to normalize thyroid function, and then supplementing with thyroxine (’s iodine treatment. In the second group, only ATD and thyroxine were used for treatment until surgery. In the third group, ATD and thyroxine continued until the day of surgery, and patients also received Lugol’s iodine treatment for 10 days. The main role of iodine is to inhibit the release of thyroxine from the thyroid gland, which is often used in preparations for thyroidectomy. The results of the study showed that in patients who had used ATD and thyroxine to normalize the thyroid function, preoperative iodine therapy had no effect on the blood vessels of the gland, blood loss from surgery, or size of the thyroid follicles. Zhu et al. divided 471 patients with hyperthyroidism into an experimental group and a control group (“sequential thyroid defunctionalization followed by thyroxine supplementation.” The four subgroups received different doses of ATD and thyroxine at different time periods. The results showed that “sequential thyroid defunctionalization followed by thyroxine supplementation” could effectively reduce the bleeding volume and the incidence of postoperative complications of partial thyroidectomy.Kaur et al. randomly assigned 34 patients with Graveshyroxine . The firol group . The conFrom these results, some clinical benefits could be seen, but these studies were small in size and scattered in purpose. If these conclusions are to be confirmed, high-quality clinical research is needed.The relative advantages and disadvantages of various treatments for Graves’ disease are still controversial. Each method is effective, but none is perfect. The choice depends on the treating physician, and increasingly on the wishes of the patient and local medical resources. Therefore, it is necessary to study the clinical efficacy of various treatments, including remission/relapse rate, quality of life and so on, which can provide the basis for the choice of treatment.ATD have been part of the standard treatment for Graves’ disease for many years and may lead to long-term remission. Searching through the results, we found two modes of combined use of oral ATD and thyroxine : the B&RA prospective multicenter observational cohort study of 344 patients showed that the prediction of biological euthyroism during treatment with antithyroid drugs is higher during titration compared to B&R regime. Whether one regimen is clinically more advantageous than the other remains unclear . With reThese clinical trials have shown some benefits in adding thyroxine to the surgical treatment of Graves’ disease. Recurrent laryngeal nerve injury, parathyroid injury, and postoperative bleeding are serious complications of thyroid surgery and are closely related to the adequacy of preoperative preparation. Preoperative preparation for thyroid surgery, including ATD use to restore thyroid function, usually requires the use of a saturated potassium iodide solution to reduce the blood flow to the thyroid gland to limit the perioperative blood loss . HoweverA study of 2,430 patients with Graves’ disease followed for 6 to 10 years showed that only 35.7% of all patients reached a normal thyroid hormone status without levothyroxine replacement . HypothyIn addition, there are many meaningful case reports showing the use of thyroxine in Graves’ disease. ATD overuse in pregnant women with Graves’ disease can cause hypothyroidism in fetuses, and intraamniotic injections of levothyroxine have been proven successful in fetal treatment .In summary, the available evidence does not support indiscriminate thyroxine supplementation in the treatment of Graves’ disease, especially when used in combination with oral antithyroid drugs. The focus of future research is to further clinical studies to explore the indications for adding thyroxine to the treatment of Graves’ disease.The original contributions presented in the study are included in the article/JL and LB designed the work of review. JL, LB, and FW reviewed the literature available on this topic and wrote the paper. MW, YX, and WY contributed to the scientific writing of the manuscript. JL, LB, and JW revised the manuscript. All authors approved the paper for publication. JL, LB, FW, MW, YX, and WY contributed equally to this work. All authors contributed to the article and approved the submitted version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Background: Pain has been associated with structural changes of the brain. However, evidence regarding white matter changes in response to acute pain protocols is still scarce. In the present study, we assess the existence of differences in brain white matter related to pain intensity reported by patients undergoing surgical removal of a mandibular impacted third molar using diffusion tensor imaging (DTI) analysis.Methods: 30 participants reported their subjective pain using a visual analog scale at three postsurgical stages: under anesthesia, in pain, and after the administration of an analgesic. The diffusion data were acquired prior to surgery.Results: DTI analysis yielded significant positive associations of fractional anisotropy in white matter areas related to pain processing  with the differences in pain between the three postsurgery stages. Extent and location of these associations depended on the magnitude of the subjective pain differences. Tractography analysis indicated that some pain–tract associations are significant only when pain stage is involved in the contrast (posterior corona radiata), while others  are only when anesthesia is involved in the contrast.Conclusions: The association of white matter fractional anisotropy and connectivity, measured before the pain stages, with subjective pain depends on the magnitude of the differences in pain scores. Chronic pain has been associated with structural changes of the brain, including prefrontal, somatosensory and occipital areas and subcortical nuclei  Anesthesia, applied before the surgery and lasting approx 3 h, (2) pain, cessation of the anesthetic agent, and (3) analgesia, postoperative medication prescribed. Patients were asked to indicate their pain intensity at the three stages . We hypothesize that subjective pain will differ between stages, so that pain is greater than anesthesia, pain is greater than analgesia, and anesthesia is greater than analgesia, but the associations of these differences in subjective pain and white matter structure must remain constant, as there is no time for structural changes to happen, as our protocol lasted 4 h, and there is no scientific literature pointing out to changes in white or gray matter in such a sort of period of time. Furthermore, if changes were observed this will indicate that these associations reflect the recruitment of more (or less) structures to process pain, rather than a change in the nature of the pain–brain structure relationships.This prospective study was conducted after approval by the University of Granada Ethics Committee on Human Research (n° 877) and in accordance with the Declaration of Helsinki for treatment of experimental human subjects  were recruited for the present study . Participants were healthy and were included only if they had a mandible impacted third molar which needed surgical procedure to be removed, but they were completely free of pain at the start of the study. All molars were located in the mandible (50% left). Participants were recruited from the pool of patients/students of the School of Dentistry of the University of Granada and were part of a larger study on the effects of oral surgery on brain structure and function. Power analysis  on subjective measures suggested a total sample size of 27 participants. We added three more participants, assuming a dropout of 10%.The third molars were extracted by an expert oral surgeon (PGM) following a standardized surgical procedure performed at the School of Dentistry at University of Granada. In short, an inferior alveolar and buccal nerve block was given using 1.8-mL carpule of 2% articaine with adrenaline 1:100,000. Surgical access was routinely achieved buccally through a triangular flap. Bone removal around the tooth was then performed with a round bur on a straight hand-piece under continuous irrigation. Crown and/or roots were sectioned when necessary. After extraction, the socket was inspected and the flap was sutured back by 2–4 interrupted stitches using a 3–0 silk suture. Gauze impregnated with either chlorhexidine or hyaluronic acid was applied over the socket, and the usual post extraction instructions were given written to the patient. All the patients received routinely the following postoperative medication: amoxicillin/clavulanic acid 2 g twice a day and dexketoprofen 25 mg three times a day for 7 days; metamizole 565 mg was given as a rescue analgesic. The duration of surgery (from the incision to the extraction) and the duration of the anesthetic agent in minutes, among others, were recorded.Patients were asked to report their subjective pain using a visual analog Likert-type scale , in which 0 meant “no pain at all” and 10 meant “worst pain imaginable,” at three different times: anesthesia, pain, and analgesia. The anesthesia scoring was taken 30 min after the surgical procedure, and patients were still under anesthesia effects (anesthesia stage). The second measure was taken either when local anesthetic ceased its function, as reported by the participant, or 3 h after the extraction (pain stage). At this moment, patients were supposed to be at the pain peek, caused by the surgical trauma provoked by the dental surgery. The length of these two intervals (30 min and 3 h.) was selected according to Senes et al. , who rep2. A non-diffusion scan was obtained with b-value = 0 s/mm2. The in-plane resolution was 1.8 mm. The slice thickness was 5.2 mm. A T1-weighted anatomical scan was also obtained for each participant using a MPRAGE sequence . The average interval between session and third molar surgery was 23.6 (±42.41) days.Participants were scanned before the surgery using a DTI diffusion scheme. The diffusion images were acquired on a SIEMENS Trio Tim scanner located at the Mind, Brain and Behavior Research Center of the University of Granada using a 2D EPI diffusion sequence, with TE = 90 ms, and TR = 3,300 ms. A HARDI scheme was used, and a total of 30 diffusion sampling directions were acquired, three times each. The b-value was 1,000 s/mmhttps://fsl.fb.ox.ac.uk/fsl Jenkinson et al., https://fsl.fb.ox.ac.uk/fsl/fslwiki/data/FB58_FA.html) and aligned to the Montreal Neurological Institute space. A FA skeleton was created by first averaging all the FA volumes and thinning the average, with a 0.2 FA threshold. The aligned FA volume of each participant was projected onto this FA skeleton and submitted to the statistical analysis. A randomization procedure  was used to perform the multiple regression analysis, in which the variables of interest were the between-stage differences in pain intensity, and the nuisances were age and gender. The results were corrected using threshold-free cluster enhancement (TFCE) correction for multiple comparisons (family-wise error rate p = 0.05). The same analyses were applied to the MD and AD volumes, after aligning them into the MNI space and projecting them onto the mean FA skeleton using the non-FA script included in FSL. No significant effects were observed in MD and AD.Diffusion tensor imaging analysis was carried out using the FB Software Library  to control for the multiple-comparison problem. FDR was estimated in a total of 2,000 random permutations to determine the null distribution of track length. All the analyses were done using DSI Studio.Diffusion magnetic resonance imaging (MRI) connectometry  = 4.15, p < 0.001] and analgesia  stages and were higher at anesthesia than at analgesia .Subjective pain intensities were higher at the pain stage than at the anesthesia [averages = 4.3 and 5.5, respectively, p > 0.22). Moreover, the number of significant voxels seems to depend on the size of the difference between postsurgical stages, that is, between subjective pain intensities  are displayed in ensities . No diffp < 0.05) related to pain–anesthesia, to pain–analgesia, and anesthesia–analgesia subjective pain differences. We observed significant associations in cerebral peduncles, corticospinal tracts, medial lemniscus, splenium of the corpus callosum, and posterior limb of the internal capsule. Middle cerebellar peduncle and superior corona radiata are involved only when analgesia postsurgical stage enters into the contrast . No tracts showed significant decreased connectivity related to any of the differences between subjective pain intensities.The connectometry analysis  identifiTwo main results have been observed in this study: first, the association of pain with white matter integrity and connectivity, and second, the dependency of these associations of the level of pain experienced during the protocol. The causal role of pain on brain structure has been a matter of intense research during the last decades. Nowadays, data on brain gray matter volume and white matter integrity suggest that pain is strongly associated with brain morphology changes and plasticity  seem to be altered in chronic pain  associated with pain are a function of the differential level of acute pain. Connectometry results suggest that the white matter tracts  typically involved in pain processing are related to the differences in pain intensity in between the postsurgical stages , but the strength of these relationships, as measured by the total count of fibers, seems to depend more on the differences between types of pain relief . Specifically, we observed that the difference between the pain stage and the anesthesia stage (the lower difference in subjective pain) embraced much more bilateral tracts than that between pain–analgesia or anesthesia–analgesia (that uniquely involved middle cerebellar peduncle and pontine crossing). Thus, it seems that the number of fibers showing a significant association can depend more on the action mechanisms or the pain-relief effectivity of anesthesia and analgesia than on the action mechanisms of subjective pain.The association of white matter fractional anisotropy and connectivity, measured before the pain stages, with subjective pain depends on the magnitude of the differences in pain scores.The original contributions presented in the study are included in the article/supplementary materials, further inquiries can be directed to the corresponding author/s.The studies involving human participants were reviewed and approved by University of Granada Ethics Committee on Human Research (n° 877). The patients/participants provided their written informed consent to participate in this study.AC and PG-M: conceptualization, methodology, and supervision. AC: data curation and resources. AC, LT-M, and CS-G: formal analysis. AC and LT-M: investigation. AC, PG-M, and LT-M: project administration. AC, PG-M, LT-M, MP-M, CS-G, and FO'V: visualization and writing. All authors contributed to the article and approved the submitted version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Packaging is a powerful tool for brands, which can not only catch consumers’ attention but also influence their purchase decisions. The application of neuromarketing techniques to the study of food packaging has recently gained considerable popularity both in academia and practice, but there are still some concerns about the methods and metrics commercially offered and the interpretation of their findings. This represents the motivation of this investigation, whose objective is twofold: (1) to analyze the methodologies and measurements commonly used in neuromarketing commercial research on packaging, and (2) to examine the extent to which the results of food packaging studies applying neuromarketing techniques can be reproduced under similar methodologies. Obtained results shed light on the application of neuromarketing techniques in the evaluation of food packaging and reveal that neuromarketing and declarative methodologies are complementary, and its combination may strengthen the studies’ results. Additionally, this study highlights the importance of having a framework that improves the validity and reliability of neuromarketing studies to eradicate mistrust toward the discipline and provide brands with valuable insights into food packing design. While touring supermarket shelves, each consumer may pass up to 300 different products per minute . This meThe importance of packaging in marketing strategies has been extensively studied since packaging not only is the container to hold, protect, preserve and facilitate the handling and commercialization of products , but it Some previous research on packaging has emphasized the multifunctionality of packaging ,9,10,11,Due to the importance of the food industry at the global level, the analysis of the factors that drive purchase intent is of vital importance . AccordiGiven the above, consumers’ perception packaging is essential, especially regarding food products where people usually have to choose among relatively similar products . By undeTo improve our understanding, a rapidly growing area of research interest is neuromarketing, whose main advantage lies in the possibility of using neuroscience techniques to evaluate the product packaging more directly, that is, without having to rely on what consumers say about which packaging they prefer . By usinThe application of neuromarketing techniques to packaging has recently gained considerable popularity both in academia and practice. Evidence of this can be seen in companies such as Nielsen, Kantar or Ipsos, which have included neuromarketing in their commercial offers. However, despite the development of the discipline, there is a concern with some commercial neuromarketing studies that have been conducted to date regarding the methods and metrics offered and the interpretation of their findings . AccordiThus, whereas academic studies are based on rigorous protocols and are subject to a scientific approach that involves endorsement of ethics committees and are published after a peer review system , the valRegarding the evaluation of food packaging, Spence et al.  mentioneTaking into account the importance of identifying whether neuromarketing methods are valuable and whether these measures actually translate into real-life success, the objective of the present study is twofold: (1) to analyze the methodologies and measurements commonly used in neuromarketing commercial research on packaging, and (2) to contrast whether neuromarketing studies are consistent concerning the results obtained, and therefore to examine the extent to which the results of food packaging studies, applying neuromarketing techniques, can be reproduced under similar methodologies.Since neuromarketing refers to “practitioner and commercial interest in neurophysiological tools to conduct company-specific market research”  (p. 651)Hypothesis 1 (H1). There are differences in the participants’ attitudes, preferences, purchase intention, attention, emotional response and memory regarding the tested packaging.Hypothesis 2 (H2). The use of the same methods and metrics in two separate studies, with comparable samples, leads to the same results and conclusions.Hence, the hypotheses that guide this work establish the following:To test the established hypotheses, we conducted two separate experiments: Study 1 was used to analyze the conscious and unconscious reactions of consumers to five different food packaging, by using a combination of neuromarketing and declarative techniques and following the methodology of a standard commercial study of neuromarketing. Study 2 was designed to examine whether neuromarketing studies were consistent with respect to the obtained results, and therefore to examine to what extent the results of the food packaging studies, applying neuromarketing techniques, could be reproduced under similar methodologies.M/SD = 23.3/2.81) who were recruited to participate in the study by using convenience sampling. None of them informed us of any history of neurological or psychiatric illness, nor visual problems. In accordance with the local legislation and institutional requirements, ethical review and approval were not required for this study. However, the research was conducted in compliance with the guidance of the Helsinki Declaration. All participant signed informed consent forms before participation and received monetary compensation at the end of the experiment as a token of appreciation.Participants included 43 healthy right-handed adults (22 women-21 men) aged between 18–25 years  See . ProductThe data collection process entailed the application of two research methodologies: neuromarketing and declarative techniques. The employed neuromarketing techniques were: (1) electroencephalogram (EEG) (2) galvanic skin response (GSR) and (3) eye-tracking (ET). For the declarative techniques, a questionnaire was applied. All instruments and the measurements provided by each one are described in the following sections and can be found in Electroencephalography (EEG)EEG is a non-invasive technique that measures the activity of brain areas, revealing the subjects’ state of cortical activation . EEG recAlthough in the field of food packaging most of the studies using neuroimaging have been oriented toward identifying the neural correlates of packaging processing by using fMRI , EEG hasTo achieve the objectives of this study, we monitored the brain signal of participants using a BitBrain Versatile EEG .Galvanic Skin Response (GSR)The GSR device measures subjects’ electrodermal activity (EDA), which is a psychophysiological indicator of their emotional arousal . EDA occIn the marketing context, EDA has been used in consumer research to obtain real-time data on consumers’ emotional state, captured without any verbalization , and speThe GSR device used in the present study was the BitBrain GSR ring, a wireless device for real-time monitoring of EDA and cardiac activity.Eye-Tracking (ET)ET technology measures eye movements composed by fixations and saccades to determine precisely where the subjects’ attention is directed . FixatioThe ET technique is based on the hypothesis that what people are looking at reflects the cognitive processes taking place in their mind, and, consequently, what people are looking at reflects where their attention is oriented. Thus, ET metrics are used to assess where, when, and what people look at. To obtain such information, ET operates by using an optical camera that reflects a near-infrared light onto the cornea, allowing it to identify the position of the eyes. .ET is increasingly being applied in the fields of consumer research and marketing as a means of exploring how consumers process visual information , and it Frontal Alpha Asymmetry (FAA)The EEG index that is most often used in neuromarketing is the FAA . The undTaking into account that decreases in the alpha power  in a particular brain region are related to a higher cortical activation , a positAs aforementioned, FAA is broadly employed in neuromarketing research since it is widely accepted as an index of approach–withdrawal attitude toward stimuli ,54,55. RCognitive LoadThe concept of cognitive load relates to the amount of mental or physical resources that people need to complete a particular task . IncreasIn this research, the cognitive load was calculated according to the existing literature ,61,62,63Regarding food evaluation, some studies have examined the impact of cognitive load on the processing of packaging information  or even Memory EncodingHow information is stored in memory is a question widely studied, since human experience in the world depends on memories. Memory has been studied from different points of view: cognitive, anatomical and neurophysiological ,68,69. FAs memory is made up of a number of interrelated systems, organized structures and behavioral and cognitive correlates , to studLong-term memory is composed of declarative and non-declarative systems. Declarative memory is considered as consciously represented and retrievable and made up of memory for facts (semantic memory) and memory for events (episodic memory), whereas non-declarative memories are classified into procedural, priming, associative, as well as non-associative conditioning, and are largely unconscious .Food products can be represented in semantic memory as well as in episodic memory . SemantiAccording to previous studies, the encoding process is reflected in the theta band (3–8 Hz) ,68,69. IIn the present study, global field power (GFP) was used to quantify the global activity in prefrontal channels  filtered on the theta band.Emotional ArousalEmotional experiences can be described by two factors: (1) valence, related to how negative or positive the experience is, and (2) arousal, which describes how calming or exciting it is . VariatiAs aforementioned, the GSR device measures the electrical properties of the skin, referred to as the subjects’ electrodermal activity (EDA), which is a psychophysiological indicator of their emotional arousal . BecauseVisual AttentionAttention is defined as the ability to focus on certain aspects of the environment while ignoring others . ET provEye movements are closely coupled with visual attention, making them eminent indicators of the visual attention process . As a coTo evaluate participants’ attitude towards the tested packaging, a questionnaire was applied. The dependent variables were (1) appreciation, (2) perceived complexity and (3) purchase intention. Appreciation was assessed by using two semantic differential items: not appealing/very appealing and dislike/like. The response options were on a seven-point Likert scale. Cronbach’s alpha for this construct was 0.905. The degree of perceived complexity was operationalized on the basis of the semantic differentials: straightforward–unclear and easy to understand–difficult to understand, on a seven-point Likert scale. Cronbach’s alpha for this construct was 0.955.Finally, two questions were used to assess the purchase intention. Responses were also given on a seven-point Likert scale, with answer options ranging from 1 (strongly disagree) to 7 (strongly agree). The internal consistency  of the questions “I would consider buying this product” and “I would recommend this product” was 0.964.The experiment was developed at the Neuromarketing Laboratory of Commerce and Tourism School at the Complutense University of Madrid. The average duration for each participant was 45 min, including neurophysiological recording and the declarative questionnaire. After briefing participants about the protocol, the EEG and GSR devices were affixed. The ET used was fixed on the computer screen in front of participants, and to calibrate it, subjects had to follow the points on the screen with their eyes, keeping their heads static. When the ET was calibrated, the signal of EEG and GSR were checked, and if corrected, the experiment began. Using the SensLab software, developed by BitBrain, subjects visualized five food packaging, while their neurophysiological reactions on the three neuromarketing devices used were recorded simultaneously. The stimuli were presented individually and randomly, and the exposure time was uniform for all participants (5.000 ms).In the second stage, once neuromarketing devices were removed, participants answered the declarative questionnaire where they had to evaluate the stimuli individually.A band-pass filter between 1 and 25 Hz with a four-order Butterworth filter was used to filter the raw EEG data. Then, a three-step filter pipeline was implemented: (1) to remove large amplitude artefacts, we used the artefact subspace reconstruction (ASR) ; (2) to With the signal clean, the EEG indexes  were computed as described in the available literature. To obtain the frequency bands, the Welch method was applied to obtain the power spectral density. Theta and alpha bands were individualized using IAF  analysis . In order to obtain the EDA data, the first step was the deconvolution of recorded data to subsequently conduct the computation of tonic and phasic activity. We then applied a low-pass filter to remove the muscle noise and detect the sweating peaks in the GSR signal. Since according to the previous literature, SCR is a reliable indicator of arousal states , in the Firstly, we analyzed the results by comparing the implicit and explicit measurements of the tested packaging. Subsequently, we carried out the analysis to identify the substrate of the identified differences. p = 0.04). A post hoc test using the Bonferroni correction revealed differences in encoding between yoghurt (M = 2.27) and juice (M = 0.35). No statistical differences were found for the remaining EEG measures, nor for arousal.Regarding the neurophysiological measurements, the results of a repeated-measures ANOVA showed that the EEG memorization index yielded statistically significant differences among the different products  = 2.453, p = 0.05). Post hoc tests using the Bonferroni correction revealed significant differences in time in AOI between coffee (M = 5.31) and juice (M = 4.61) packaging. Moreover, statistically significant differences were found in the number of fixations  = 6.020, p = 0.00). A post hoc test revealed differences between juice (M = 5.07) and all other packaging .We also found differences in visual attention measured by using ET. A repeated-measures ANOVA concluded that the different food packaging yield statistically significant differences in time in AOI  = 2.370, p = 0.02). According to the performed post hoc test, there were differences between milk packaging (M = 6.44) and all other packaging . It is important to note that participants scored the most complex images with one and the least complex with seven. Thus, milk packaging was categorized as easy for participants. Regarding the declarative measurements, there was only statistically significant differences in the perceived complexity among the tested packaging  = 3.224, r(42) = 0.326, p = 0.035), (2) between appreciation and purchase intention (r(43) = 0.689, p = 0.000) and (3) between time in AOI and the number of fixation in AOI (r(43) = 0.558, p = 0.000).To analyze the relationship between the variables, a correlation analysis was performed. Results showed three strong and positive correlations, which were statistically significant: (1) between memorization and cognitive load  were invited to participate in the study. The stimuli were nine food products belonging to three different categories: (1) soft drinks , (2) snacks  and (3) appetizers   See .As in the first study, all participants had normal or corrected-to-normal vision, were right-handed and signed an informed consent according to the Declaration of Helsinki. In addition, at the end of the experiment, all participants received monetary compensation.To achieve our goal of analyzing the reliability of the first study, the experimental design was the same for both studies. Thus, both instruments and measurements were the same as in the first study. The information of Data analysis was conducted in three stages. First, we analyzed the inter-category differences to subsequently analyze the intra-category differences. Finally, we test the relationship among the dependent variables. p = 0.000) and (2) time spent exploring the packaging  = 159.3, p = 0.000). Post hoc tests using the Bonferroni correction revealed significant differences in both metrics between drinks and the other two categories. No statistically significant differences were found in declarative metrics.Regarding the inter-category differences, a repeated-measures ANOVA determined that there were not any differences in the EEG and GSR metrics among the three tested food categories. In contrast, the same test showed statistically significant differences in visual attention, in the two ET metrics included (1) the number of fixations  = 245.5, p = 0.000) and (2) time spent exploring the packaging  = 7.44, p = 0.001). Post hoc tests using the Bonferroni correction revealed significant differences in the number of fixations between cookies (M = 1.61) and cereal bars (M = 3.17) and chocolates (M = 2.95). In regard to the time spent exploring the packaging, differences were found between the three tested products .Concerning the intra-category differences, repeated-measures ANOVA was performed to analyze the differences between the three products included in each food category. The obtained results determined statistically significant differences between products of the appetizers category in (1) the number of fixations  = 34.28, p = 0.000) and (2) time spent exploring the packaging  = 9.28, p = 0.000). Post hoc tests using the Bonferroni correction revealed significant differences in the number of fixations between nachos (M = 4.03) and chips (M = 2.23) and nuts (M = 2.60). Regarding the time spent exploring the packaging, differences were found among nuts (M = 3.35), chips (M = 1.95) and nachos (M = 2.53).The same situation was found in the category of snacks, where repeated-measures ANOVA determined statistically significant differences among the three products of category in (1) the number of fixations  = 8.69, There were no statistically significant differences in EEG and GSR metrics, nor in declarative metrics.r(40) = 0.680, p = 0.000), and (2) between time in AOI and the number of fixations in AOI (r(40) = 0.749, p = 0.000). Concerning the relationship between memorization and cognitive load, a positive and statistically significant correlation was found only between the products belonging to the snacks category (r(38) = 0.325, p = 0.047).Finally, regarding the relationship among the dependent variables, two positive and statistically significant correlations were found, not only inter-category but also intra-category. Correlations between inter-categories were as follows: (1) between appreciation and purchase intention , this iWith reference to limitations, a common criticism against the use of neuroscience methods to study consumer behavior is the use of relatively small sample sizes, perceived as resulting in low statistical power . HoweverOn the other hand, as stated by Mast and Zaltman , a greatFurthermore, given that this is an exploratory study using a convenience sample of people between the ages of 18 and 25, it would be interesting to conduct more research to show if different results can be found in other age groups. Additionally, it would be productive to analyze how the use of larger samples and/or other product categories can influence the results.Finally, although our experimental approach was motivated by the desire to test the reliability of commercial studies of neuromarketing, the fact that the tested packagings were highly familiar to participants, in addition to the experimental design based on a spectral EEG, provided no significant results. Therefore, further research is needed to test whether using a stimuli-induced reaction results might provide statistically significant differences. Furthermore, it is extremely important to advance in the study of the validity and reliability of neuromarketing studies to eradicate mistrust around the discipline and provide brands with valuable insights into food packing design.


Children with Developmental Language Disorder (DLD) often struggle learning to spell. However, it is still unclear where their spelling difficulties lie, and whether they reflect on-going difficulties with specific linguistic domains. It is also unclear whether the spelling profiles of these children vary in different orthographies. The present study compares the spelling profiles of monolingual children with DLD in France and England at the end of primary school. By contrasting these cohorts, we explored the linguistic constraints that affect spelling, beyond phono-graphemic transparency, in two opaque orthographies. Seventeen French and 17 English children with DLD were compared to typically developing children matched for age or spelling level. Participants wrote a 5 min sample of free writing and spelled 12 controlled dictated words. Spelling errors were analyzed to capture areas of difficulty in each language, in the phonological, morphological, orthographic and semantic domains. Overall, the nature of the errors produced by children with DLD is representative of their spelling level in both languages. However, areas of difficulty vary with the language and task, with more morphological errors in French than in English across both tasks and more orthographic errors in English than in French dictated words. The error types produced by children with DLD also differed in the two languages: segmentation and contraction errors were found in French, whilst morphological ending errors were found in English. It is hypothesized that these differences reflect the phonological salience of the units misspelled in both languages. The present study also provides a detailed breakdown of the spelling errors found in both languages for children with DLD and typical peers aged 5–11. Language and literacy development are intricately related. Children build from their knowledge of sounds and words to progressively recognize and represent them in writing. On the one hand, awareness of speech sounds and the ability to manipulate them have been evidenced as an important predictor of later reading and spelling in a range of writing systems . On the g = −1.42  when children with DLD were compared to same-age typical peers, but non-significant when they were compared to younger children matched on language, reading or spelling, suggesting a clear spelling delay in this population. Furthermore, the meta-analysis highlighted that the difference in scores was particularly important in those children identified as having reading or phonological difficulties in addition to their language disorder.It is thus unsurprising that many children with language difficulties also experience literacy difficulties. There is a well-documented comorbidity between Developmental Language Disorder (DLD) and dyslexia, with comorbidity rates ranging from 17 to 71% . In relaAt school entry DLD is reported to affect approximately 7.5% of the population . The tered), progressive (-ing) and noun plural/verb third person (-s), are commonly reported in the spontaneous language of English children with DLD  and noun plural –s are found in the spelling of children with DLD when compared to same-age peers, but results are inconsistent when comparisons are made with younger literacy- or language- matched controls  than in English (66.3%) – see estimation for monosyllabic words by beak, break and head). In comparison, French vowel sounds are relatively consistent in the reading direction , or that a “cédille” is needed in front of -a- or -o- for the letter -c- to make the /s/ sound . They also learn for example that the letter -s- needs to be doubled in order not to become sonorant between two vowels . In English, orthographic constraints in phono-graphemic conventions also exist. For example, English children learn early on that long vowels are often spelled using the -e- letter at the end of CVC words . Furthermore, in both languages, children have to choose between many alternatives in spelling vowels   see . The othEna) see . Taken tEna) see  or to deEna) see . On the s, exceptionally -x), but also for gender (feminine -e). Verbs are inflected for all tenses and persons in French . As an example, the French present for verbs ending in –er  has no less than five different inflections : Je chante(I sing), tu chantes(you sing), il chante(he sings), nous chantons(we sing), vous chantez(you (pl.) sing), ils chantent(they sing). This is known to be a challenge to French spelling and there is a strong emphasis on grammatical spelling early on in French education  and possessive marking . In a few irregular cases plural may provoke a phonological change in the stem as in foot/feet, woman/women, scarf/scarves or stimulus/stimuli. The past tense for verbs is marked by -ed , except for a set of irregular verbs, which also see their stem altered . The present progressive is marked by -ing and the third person present by -s. Inflectional morphology in English is introduced early in the school curriculum, and largely mastered within the first year of schooling. For example, the plural -s is mastered as early as the first semester of grade 1 in English-speaking children , whereas there are many silent and homophone inflections in French  are specialist units within mainstream schools, where children with language disorders receive specialist instruction for some of the curriculum and are included in the mainstream classroom for the rest of their learning. Teachers, speech and language therapists and Special Educational Needs Coordinators  were consulted verbally, and parents were consulted using a brief questionnaire (within the consent form), in order to identify children experiencing language and literacy difficulties within the language units and mainstream Year 3, 4, 5, and 6 classes (ages 8–11).Children were further tested to ascertain their language difficulties using standardized measures. Three measures were taken: sentence repetition, word comprehension and sentence comprehension. Children’s diagnosis of DLD was confirmed and they were included in the DLD sample if they scored −1.28 SD or below in at least two of these measures, or on a composite of all three measures. Children reaching scores −2 SD or below on a standardized test of Non-Verbal Performance (NVP) were excluded. Following this procedure, 17 children with language difficulties were identified within the French sample and 17 in the English sample.A further 17 typically developing children matched on chronological age (CA), and 17 younger children (SA) matched on the raw spelling scores of the Wechsler Individual Achievement Test (WIAT), were identified in each country. These children had NVP, language and spelling scores within the norm for their age range, as reported by parents and teachers and measured on standardized tasks. As indicated in Standardized assessments of language, word reading, phonological awareness and NVP were administered as grouping and control measures. A naturalistic sample of writing was obtained using a narrative task. The narrative Curriculum-Based Measure for Writing (CBM-W) from r = 0.94) and in English (r = 0.96). Cronbach’s Alpha was 0.85 on the French scale, and 0.89 on the English scale, indicating good reliability. The 12 dictated words were chosen for analysis from the French and English version of the WIAT-spelling test , b. All Both experimental tasks were administered in small groups of up to eight children, in one 30-min session. The non-verbal performance test was also administered during this first session, following the test manual’s instructions for group administration Children were then seen individually to assess their language, phonological awareness and reading skills.For the texts, productivity was measured in number of words produced by each child, excluding proper nouns and illegible words. For both tasks, accuracy was measured by dividing the number of words correctly spelled by the number of words attempted.1After measuring accuracy in the texts and dictated words, a qualitative coding of the spelling errors was conducted by the first author and by two trained independent raters who were native speakers of each language. The framework for spelling error analysis was adapted from Productivity and accuracy results are presented first, followed by the qualitative analysis of the spelling errors. These results are always presented for the language comparison first (French vs. English), and then for the subgroup comparisons (CA vs. DLD vs. SA) within each language. Finally, regression models to predict a subset of outcome spelling measures are presented.post hoc tests were run to assess language and subgroup effects on productivity and accuracy measures, in order to account for the presence of outliers and the heterogeneity of variance (ξ) was computed where relevant. ξ-values of 0.10, 0.30, and 0.50 correspond to small, medium, and large effect sizes respectively (Robust ANOVAs and variance . A robusectively . Table 5F(1) = 6.70, p = 0.013, ξ [95% CI] = 0.32 [0.07-0.52]) than French children. On average, English texts were 10 words longer than the French texts. There was no difference in productivity in the word dictation task, with all children attempting all 12 words dictated.In the texts, English children produced more words (F(1) = 50.15, p < 0.001, ξ [95% CI] = 0.79) than French children. On average, English children produced a misspelling every six words of their texts, whilst the French children produced a misspelling every second word. Similarly, in dictation, word accuracy was higher in English than in French (F(1) = 10.03, p = 0.003, ξ [95% CI] = 0.08 [0–0.39]). On average, there was a misspelling in every word attempted in both the English and the French dictated words.English children produced a higher rate of correct words in the texts (F(2) = 39.00, p = 0.001, ξ [95% CI] = 0.71 [0.46–0.86]) and less accurate (F(2) = 53.21, p = 0.001, ξ [95% CI] = 0.65 [0.39–0.89]) texts than their CA peers. On average, children with DLD and SA peers produced a misspelling every two/three words, whilst CA peers produced a misspelling every seven/eight words in their texts. In word dictation, word accuracy was better in the CA than in the DLD and SA groups (F(2) = 169.92, p < 0.001, ξ [95% CI] = 0.99 [0.76–0.99]), in both languages. On average, there was a misspelling in every word attempted in the DLD and SA samples, and one misspelling every three to four words in the CA samples.In both languages, children with DLD and SA peers produced shorter  or dictated words .As shown in W = 245, p < 0.001, r = 0.64). This was the only significant difference . The same result was found in the French dictated words, with more errors in the DLD than in the CA samples .In the French texts, children with DLD produced a higher rate of phonological errors than their CA peers . However, in the dictated words, English children with DLD  and SA peers  produced a higher rate of phonological errors than their CA peers, with no other group differences .In the English texts, the rate of phonological errors did not significantly differentiate any of the subgroups (DLDvsCA: ecept for except) and vowel  and consonant substitutions . See Appendices A, B for the breakdown of error types within the phonological category.In both languages and tasks, phonological errors consisted largely of consonant omissions . However, in the dictated words, the difference in rates of orthographic errors between English and French children approached significance , with more orthographic errors in the English word samples.As shown in W = 229, p = 0.004, r = 0.50) and SA peers  produced a higher rate of orthographic errors than CA peers, but did not differ significantly from one another . By contrast, in the dictated words, only SA peers produced a higher rate of orthographic errors than CA peers , with no other group differences .In the French texts, children with DLD , all other group comparisons being non-significant . A slightly different trend was observed in the dictated words, where English children with DLD  and SA peers  both performed worse than their CA peers.In the English texts, SA children produced a higher rate of orthographic errors than CA peers (rancontre for rencontre) and consonant spellings , regular orthographic patterns  and silent letters . In the English texts, errors on unstressed  and long vowels , regular orthographic patterns  and contextual spelling dominated , especially in the younger and DLD groups. In the dictated words, English children also produced orthographic errors on silent letters  and irregular vowel and consonant spellings . See Appendices C, D for the breakdown of error types within the orthographic category.In the French texts and dictated words, orthographic errors were largely found on irregular vowel . The same result was observed in the dictated words .As shown in W = 189, p = 0.13, r = 0.26; DLDvsSA: W = 127, p = 0.56, r = 0.10; SAvsCA: W = 94.5, p = 0.09, r = 0.29). However, in the dictated words, French children with DLD  and SA peers  produced a higher rate of morphological errors than their CA peers.In the French texts, the rate of morphological errors was not significantly different across any of the groups , but differentiated results in the dictated words. In the dictated words, English children with DLD  and SA peers  also produced a higher rate of morphological errors than their CA peers.The pattern was similar in English, with no significant difference in the rate of morphological errors in the texts across groups , number  and person inflections . In the English DLD and SA samples, the majority of morphological errors were omissions of inflections . The pattern was slightly different in the dictated words, where French children also produced many derivational base errors . In the English dictated words, in addition to inflection omissions, children with DLD and SA also produced errors with contractions , derivational suffixes  and tense marking . See Appendices E, F for the breakdown of error types within the morphological category.In the French texts, children produced a large number of morphological errors on tense . The trend was reversed in the dictated words , where English children produced more semantic errors than their French peers. Note, however, that this error type was marginal in both languages in the dictated words, with error rates flooring close to zero per word attempted.As shown in W = 236, p = 0.002, r = 0.54) but there were no other group differences . However, in the dictated words, no group difference appeared, with the error rate being close to zero across groups .In the French texts, children with DLD produced a higher rate of semantic errors than CA peers . The same was observed in the dictated words .The rate of semantic errors was close to zero in the English texts and did not differentiate any of the groups (DLDvsCA: je ma muse for je m’amusais). In all groups, errors on grammatical homophones were also prominent . These errors were almost absent in English texts. In the dictated words, however, English children, especially in the DLD and SA subgroups produced some errors with grammatical homophones  and word choice . See Appendices G, H for the breakdown of error types within the semantic category.In the French texts, children with DLD and SA produced a large proportion of segmentation errors  in a second step. They were run for outcome measures where significant cross-language differences were found, that is: the number of words produced in the texts (where English children were more productive than French peers), the proportion of words correct in both tasks (where English children were more accurate than French peers); the rate of morphological errors in texts and dictated words and the rate of semantic errors in the texts only (where French children produced more errors than their English peers); the rate of orthographic and semantic errors in the dictated words (where English children produced more errors than their French peers).Number of words produced in the texts was the only continuous outcome with normally distributed residuals and a generalized linear model was applied using the lm function in R . For allNon-verbal performance and phonological awareness correlated strongly with most of the spelling outcomes selected. In English, both measures correlated strongly with the accuracy measures on both tasks, and with the rate of morphological and orthographic spelling errors in the 12 dictated words in particular. In French, they were also strong correlates with the spelling accuracy and productivity measures (in addition to age). In French, phonological awareness was a strong correlate of semantic errors in texts but did not correlate with semantic errors in the dictated words nor with morphological errors in the texts.Stepwise regressions were run to assess the effect of language over and above age, NVP and phonological awareness, for the productivity and accuracy measures where English children performed better than French children: (1) number of words produced in the texts, (2) proportion of correct words in the texts, (3) proportion of correct words in the 12 dictated words. These regressions are presented in R2 = 30.75%).The initial model with age, NVP and phonological awareness explained a significant 18.52% of variance in text productivity. The addition of the language predictor in a second step explained a significant further 12.52% of variance (new model R2 = 47.74%).The initial model with age, NVP and phonological awareness explained 14.73% of variation in the proportion of correct words in the texts. The addition of language in a second step explained a significant further 33.02% (new model R2 = 44.51%).The initial model with age, NVP and phonological awareness explained 24.49% of variation in the proportion of correct words in the 12 dictated words. The addition of language in a second step explained a significant further 20.02%  morphological errors in the texts, (2) morphological errors in the 12 dictated words, (3) semantic errors in the texts. These regressions are presented in R2 = 47.76%).The initial model with age, NVP and phonological awareness explained 1.58% of variation in the rate of morphological errors in the texts. The addition of language in a second step explained a significant further 46.18% (new model R2 = 47.6%).The initial model with age, NVP and phonological awareness explained 22.23% of variation in the rate of morphological errors in the 12 dictated words. The addition of language in a second step explained a significant further 25.37% (new model R2 = 36.94%).The initial model with age, NVP and phonological awareness explained 6.27% of variation in the rate of semantic errors in the 12 dictated words. The addition of language in a second step explained a further 30.67%  orthographic errors in the 12 dictated words, (2) semantic errors in the 12 dictated words. The regression models for these outcome measures are presented in R2 = 36.08%).The initial model with age, NVP and phonological awareness explained 36.15% of variation in the rate of orthographic errors in the 12 dictated words. The addition of language in a second step reduced the model’s prediction coefficient (Pseudo R2 = 47.6%).The initial model with age, NVP and phonological awareness explained 21.2% of variation in the rate of semantic errors in the 12 dictated words. The addition of language in a second step explained a significant further 25.37% . Visual examination of the data  does sugThe current results also provide developmental benchmarks for the assessment of spelling in a population of children with DLD in French and English middle school. Future studies may want to characterize further the spelling profiles of French and English children in early primary and secondary school. This has been done to an extent for adolescents in previous studies , 2014, bing, plural and 3rd person -s and past tense -ed, as also observed in the oral language of English children with DLD (∗les cole for l’école) or in the morphological contraction category .The phonological and morphological difficulties of children with DLD have often been investigated in their early oral language . One aimwith DLD . In our English children with DLD, inflection omission errors are not necessarily found in other languages, at least not in French middle school, arguing against any claim for universality of these particular error types. Secondly, our data question whether the drivers of these specific errors in English are morphological in nature. It has been argued that phonological salience is an important factor to consider when assessing morphological omission errors in the oral language of children with DLD .Overall, the regression analyses supported the role of language found in the quantitative and qualitative errors analyses conducted in sections “Productivity and accuracy within and across languages” and “Qualitative analysis of spelling errors.” Even after accounting for age, NVP and phonological awareness, language was still a significant predictor of text productivity and spelling accuracy in the text and dictated words. English children were more likely to obtain higher scores on these measures, but also more likely than French children to produce semantic errors in the dictated words. By contrast, French children were more likely to produce a higher proportion of morphological and semantic errors in their texts and morphological errors in the dictated words. There was one exception to these confirmatory results: language did not predict the proportion of orthographic errors in the 12 dictated words, over and above age, NVP and phonological awareness. In this model, age was a particularly good predictor of the decrease in the proportion of orthographic errors, suggesting in both languages, continued exposure with written content improves the retention of orthographic patterns, in line with self-teaching accounts .The correlations presented in section “Zero-order correlations between the measures of interest” also provided some insight into the processes involved in different components of spelling in the two languages. Age, NVP and phonological awareness correlated with most of the spelling outcomes considered, in both languages. However, in French, the proportion of semantic errors in the dictated words and morphological errors in the texts was not associated with age or phonological awareness. We interpret this as an indication that these errors are related to spelling skills that were still not mastered in the French older control group . In contrast, large correlations were found between phonological awareness and semantic errors in the texts, and morphological/orthographic errors in the 12 dictated words, indicating phonological awareness plays an important role in representing semantic, orthographic and morphological units in French word spelling. In English, all three control measures correlated with the spelling productivity and accuracy variables and most qualitative measures. However, semantic errors in general and morphological errors in the texts did not correlate very strongly with the predictors. This likely reflects the low rate of such errors in the English sample altogether.Phonological skills have been related to French and English spelling in previous studies , and to Although the present study attempted to draw on a range of linguistic components in the list of words that children were given to spell, it was impossible to match our French and English list of words on all sublexical aspects critical to spelling . Arguably, 12 words is also too small a list to be fully representative of the constraints of each language. Spelling error analysis is a time-consuming process requiring several raters and several rounds of coding, for adequate training and reliability checks. Unfortunately, because of constraints with time and raters’ availability, we had to restrict the analysis to a limited number of words, which we attempted to match across languages. Such attempts are of course imperfect. Future studies may, however, rely on recent developments in the cross-language assessment of language and literacy. One promising tool for future analyses is the Multilanguage Assessment Battery of Early Literacy, recently made available online for a range of languages MABEL,  and whicSimilarly, giving children a free writing task does not allow to capture all the spelling processes that may be at play in spelling for writing. Children may or may not use some of the spelling processes we were aiming to assess. Arguably as well, 5 min is a rather short amount of time for children to generate ideas and produce a text, and it is likely that children’s familiarity with this type of tasks may have affected their productivity and spelling performance on this task. Observations during data collection and discussions with teachers in both French contexts suggest that French children are typically given more time and scaffolding in writing tasks and may have been surprised by such a short and free writing task. Such accounts were not given in the English contexts.Beyond task differences, cross-language comparisons between French and English are complicated by the fact children do not start formal literacy instruction at the same age. Although as a group, the age of the French and English samples did not differ significantly, English children had typically been in formal education for a year longer than their French peers. One cannot rule out the possibility that this difference affected our cross-language comparisons. Socio-economic and instructional factors could also be controlled in future. It is possible that the explicit teaching (or the lack of) of particular aspects of spelling could affect children’s response and the quality of their errors in our spelling tasks.The present study assessed the locus of spelling difficulties in two samples of middle school children with DLD in France and in the United Kingdom. Results suggest a pattern of overall delay in spelling development in children with DLD in both languages, with a range of phonological, orthographic, morphological and semantic errors similar to those of younger peers. They also confirm that the difficulties observed in the early oral language of children with DLD persevere in late primary school in written language, that is difficulties with morphological endings in English and difficulties with pronoun contractions and word segmentation in French. We argue that these specific difficulties in each language might be related to the phonological salience of these grammatical forms. In the general population too, error types were specific to each language assessed, with clear orthographic constraints in English, and morphological constraints in French. Further studies may want to assess children’s spelling at other developmental timepoints and in a broader range of languages contrasted for phono-orthographic transparency and morphological complexity.The datasets generated for this study are available on request to the corresponding author.This study involved human participants and was approved by the ethics committee of UCL Institute of Education. Written informed consent to participate in this study was provided by the participants and by their legal guardian/next of kin.NJ planned, collected the data, and analyzed and wrote for the present study. JD and CM advised and provided feedback at all of these research stages. All the authors contributed to the article and approved the submitted version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Although parental and peer support can influence adolescents’ physical activity (PA), these associations have not been fully examined through a global assessment. This study examined the associations of parental and peer support with PA among adolescents from 74 countries. The Global School-based Student Health Survey data from 250,317 adolescents aged 11–17 years (48.8% girls), collected between 2007 and 2016, were analysed. Adolescents were asked how many days/week they were physically active and about their parental and peer support. Meta-analysis showed that adolescents who had high parental or peer support had higher odds of attaining sufficient PA (odds ratio (OR): 1.40, 95% confidence interval (CI): 1.34–1.46; OR: 1.57, 95% CI: 1.49–1.65, respectively). Pooled estimates of association were significant across all World Health Organization (WHO) regions and country-income categories with the highest estimate from the low-income countries. The Western Pacific region showed the highest association between parental support and adolescents’ PA , while South-East Asia exhibited the highest association between peer support and adolescents’ PA . Country-level estimates of associations are presented. Future studies should use robust assessment of PA and PA-specific parental and peer support with emphasis on qualitative investigation to understand the complexity of the relationships. Physical activity (PA) is essential for the well-being of adolescents and is associated with physical fitness, bone health, and cardio-metabolic biomarkers such as cholesterol, blood pressure, insulin and glucose levels . NeverthParents have a strong influence on the lives of their children and can positively affect adolescents’ PA levels through encouragement, involvement and facilitation . Of all While previous studies showed some relationships between parental support and adolescents’ PA, the role of peer support on adolescents’ PA is not well understood yet. A limited number of studies have reported a positive association between peer influence and adolescents’ PA ,15,16. SAlthough there is evidence to suggest associations between parental and peer support and adolescents’ PA levels, such evidence is based on studies conducted in single countries. Only a handful of multi-country studies conducted on this topic to date ,18 reporThis study was based on publicly available data from countries that participated in the population-based survey of school-going children and adolescents around the world, the Global School-based Student Health Survey (GSHS) . GSHS isFrom all publicly available GSHS data between 2007 and 2016, we selected the datasets that included the key variables pertaining to this analysis. For countries with more than one GSHS dataset, we used the most recent one available. Three countries  were excluded from the analysis due to their small sample size n ≤ 210). The final analytical sample consists of 250,317 adolescents aged 11–17 years from 74 countries, including seven low-income, 25 lower-middle-income, 22 upper-middle-income, and 19 high-income countries, based on the World Bank classification at the time of the survey. Information on Cook Island’s income classification was not available. Of the participating countries, seven were from Africa, 22 from the Americas, 19 from the Eastern Mediterranean, one from Europe, eight from South-East Asia, and 17 from the Western Pacific region. GSHS used a two-stage cluster-sampling design where at the first stage, schools were drawn with probability proportional to their enrolment size and at the second stage, a random selection procedure was used to select classes from the schools. All students in those selected classes were eligible to participate [0. The fiThe GSHS received ethics approval from the Ministry of Education or a relevant Institutional Ethics Review Committee, or both in each of the participating countries. Only those adolescents and their parents who provided written or verbal consent participated. As the current study used retrospective, de-identified, publicly available data, ethics approval was not required for this secondary analysis. Detailed methods of the GSHS have been described on both the US CDC and the WHO websites ,22.PA was assessed with one item: ‘During the past 7 days, on how many days were you physically active for a total of at least 60 min per day?’ The response options were 0 to 7 days. Consistent with the WHO recommendations , we defiParental support was assessed with one item: “During the past 30 days, how often did your parents or guardians understand your problems and worries?”, while peer support was assessed with another item: “During the past 30 days how often were most of the students in your school kind and helpful?”. Possible response options to each of these items were ‘never’, ‘rarely’, ‘sometimes’, ‘most of the time’, and ‘always’. For the regression modelling purpose, the response options were dichotomised: ‘sometimes/rarely/never’ as ‘low levels’ and ‘always/most of the times’ as ‘high levels’ .Age and gender of the participants were included in the survey. The participants were also asked: “During the past 30 days, how often did you go hungry because there was not enough food in your home?” with response options being ‘never’, ‘rarely’, ‘sometimes’, ‘most of the time’, and ‘always’. This food insecurity variable was used as a proxy of socioeconomic status ,24 as thCountry-specific estimates of prevalence of PA, and parental and peer support were computed by taking into account the weighting factor that was applied to each student record to adjust for non-response and the varying probability of selection. Within the GSHS protocol, weighting accounted for the probability of selection of schools and classrooms, non-responding schools and students, and distribution of the population by gender and grade. In examining the association of parental and peer support with PA, a set of covariates was considered including age, gender, BMI, and food insecurity. Possible interactions between gender and parental support, and gender and peer support were tested to see whether gender based analysis was warranted. As the interactions for the overall sample were not statistically significant, the regression modelling was implemented on the overall sample without any stratification by gender, as done elsewhere . A lineaGiven the dichotomous nature of the outcome (PA), binary logistic regression analysis with robust standard errors was used to examine the associations at the country level, by taking into account the sampling weight. This GSHS weighting factor was applied in an identical way to estimate the associations in each of the participating countries. To generate pooled estimates of the association, random effects meta-analysis with the DerSimonian and Laird inverse-variance method were used. Pooled estimates were also derived by country income category, using the World Bank country income classification, collected at the time of the survey for the respective countries, and by WHO regions. metan, a Stata meta-analysis routine, was used to estimate the pooled odds ratios with 95% CI for the estimates. All adjusted estimates of the association parameters are presented in the form of odds ratio (OR) and 95% confidence interval (CI). All statistical analyses were performed using Stata 14.0 SE.The mean age of participating adolescents  was 14.3  years and 48.8% were girls. The vast majority of the participants were from the lower-middle income countries (68.7%), while upper-middle income countries represented 14.7% and low income countries represented 13.5% of the participating adolescents. Over a third (38.2%) of participants were from South-East Asia, followed by 24.3% from Western Pacific and 22.0% from the Eastern Mediterranean region. About 6.1% of adolescents went hungry most of the time or always because there was not enough food in their home, and 44.0% went hungry occasionally. About 15% of adolescents were overweight or obese, while 9.3% were underweight.trend < 0.001) and peer support (ptrend < 0.001) . More than one-third of adolescents reported high levels  of parental support , while high levels of peer support was reported by 43% of adolescents . Overall, compared to boys, slightly higher proportion of girls reported high levels of parental and peer support . High levels of parental and peer support were more prevalent among girls than boys in 69% and 89%, respectively, of the participating countries. The prevalence of sufficient PA among adolescents increased linearly with the increase of levels of parental support (p< 0.001) . About oCountry-wise estimates of association of parental and peer support with sufficient levels of adolescents’ PA are shown in Overall, there was no gender difference in the estimates of associations between parent and peer support and adolescents’ PA, as supported by the insignificant parent-support*gender and peer-support*gender interactions. For parental support, the overall association estimate (OR) was 1.35 (95% CI: 1.26–1.44) for boys and 1.43 (95% CI: 1.33–1.53) for girls. For peer support, the overall association estimate (OR) was 1.53 (95% CI: 1.43–1.63) for boys and 1.60 (95% CI: 1.49–1.72) for girls.The pooled estimates of associations from random effect meta-analyses are presented in To the authors’ knowledge, this is the largest multi-country study examining the associations of parental and peer support with PA of adolescents representing 74 countries across all WHO regions and with various country income levels. After adjusting for age, gender, BMI and food insecurity (as a proxy of socio-economic status), the modelling showed that adolescents with high levels of parental and/or peer support had significantly higher odds of attaining the daily recommended levels of PA. The pooled estimates of association were significant across all WHO regions and country-income groups. The highest pooled estimates of association for both parental and peer support were found in the low-income countries, while South-East Asia region exhibited the highest estimates of association between peer support and adolescents’ PA.trend value. The highest pooled associations between parental support and adolescents’ PA were found in the Western Pacific region and in low-income countries. Parental support has been consistently reported as a positive correlate of adolescents’ PA in previous studies [In the present study, the prevalence of sufficient PA among adolescents increased linearly with the increase of levels of parental support, as demonstrated by the significant p studies ,8,9,10.  studies . Parents studies ,27. A re studies , furtherDuring adolescence, children spend considerable time with their peers and friends, and over time, they become more independent of their parents . During In our study, adolescents’ age was not associated with the levels of PA when considered in the analyses as an adjustment factor. There was no gender difference in the association between parental and peer support, and PA with girls reporting only slightly higher levels, although not statistically significant, of both parental and peer support than boys. In contrast, previous studies conducted in the US, Germany and Scotland reported that compared to boys, girls might receive less peer support for PA, and they might be engaging in more ‘non-physically active’ activities with their peers ,10,14. HStrengths of this study include nationally representative samples of school-going adolescents from 74 countries with diverse socio-cultural and economic context. The GSHS used the same standardised methods such as the type of sample , data collection procedures, and a standardised questionnaire with the same survey items to assess the variables of interest, which facilitated valid assessments of cross-country or regional differences. The statistical modelling of association estimates were adjusted for several potential covariates. The results presented were obtained by using weighted analyses, where the GSHS weighting accounted for the distribution of the population by gender and age.While our study has a number of novel insights, the study findings should be interpreted with several limitations in mind. The GSHS data include only adolescents in schools and, therefore, information from adolescents who were unable to attend school or who had dropped out was not available, which compromises the generalisability of the findings. The degree of complexity in the relationships assessed might be influenced by cultural and/or gendered expectations of sport and recreation or availability of sport facilities, which were not captured in the GSHS. Sample sizes considered in the analyses were disproportionate across the participating counties with a quarter of the data coming from three countries. Parental and peer support were assessed using one item each that were referring to support in general and not specific to support for PA, and as such the support assessed may not fully encapsulate the constructs of parental or peer support under study. Data for this study are self-reported and, therefore, vulnerable to social desirability and recall bias. In addition, other factors  might have contributed to the self-reported perception of support of the survey participants; however, the GSHS did not collect information on these variables. Although GSHS data were collected in countries across all WHO regions, GSHS data were not available for most European countries and several other high-income countries including Australia, New Zealand, Canada and the United States. This study is limited by the cross-sectional design and, as such, causality cannot be established.This study offers global evidence of strong and positive associations between high levels of parental and peer support and sufficient PA of adolescents across the globe. These findings add to the growing evidence of the cross-sectional link between parental and peer support and PA levels of adolescents. Prospective studies with robust assessment of PA and PA-specific parental and peer support that adolescents receive are required to further understand the associations. This study also underscores the need for qualitative explorations of the choices young people make about their engagement in PA.