Most measures of osteomalacia were improved at week 48: osteoid volume/bone, osteoid thickness, and mineralization lag time decreased; osteoid surface/bone surface showed no change. Of 249 fractures/pseudofractures detected across 14 patients at baseline, 33% were fully healed and 13% were partially healed at week 144. Patients reported a reduction in pain and fatigue and an increase in physical health. Two patients discontinued: one to treat an adverse event (AE) of neoplasm progression and one failed to meet dosing criteria . Sixteen serious AEs occurred in seven patients, and there was one death; all serious AEs were considered unrelated to treatment. Nine patients had 16 treatment‐related AEs; all were mild to moderate in severity. In adults with TIO, burosumab exhibited an acceptable safety profile and was associated with improvements in phosphate metabolism and osteomalacia. © 2020 The Authors. Journal of Bone and Mineral Research published by American Society for Bone and Mineral Research..Tumor‐induced osteomalacia (TIO) is caused by phosphaturic mesenchymal tumors producing fibroblast growth factor 23 (FGF23) and is characterized by impaired phosphate metabolism, skeletal health, and quality of life. UX023T‐CL201 is an ongoing, open‐label, phase 2 study investigating the safety and efficacy of burosumab, a fully human monoclonal antibody that inhibits FGF23, in adults with TIO or cutaneous skeletal hypophosphatemia syndrome (CSHS). Key endpoints were changes in serum phosphorus and osteomalacia assessed by transiliac bone biopsies at week 48. This report focuses on 14 patients with TIO, excluding two diagnosed with X‐linked hypophosphatemia post‐enrollment and one with CSHS. Serum phosphorus increased from baseline (0.52 mmol/L) and was maintained after dose titration from week 22 (0.91 mmol/L) to week 144 (0.82 mmol/L,  Most patients have phosphaturic mesenchymal tumors, which are often small and occur in soft tissue or bone, making localization difficult and delaying diagnosis. The excess levels of FGF23 in TIO lead to impaired renal phosphate reabsorption, reduced active vitamin D synthesis, and chronic hypophosphatemia. Clinical manifestations include osteomalacia, fractures, musculoskeletal pain, fatigue, severe myopathy, and reduced health‐related quality of life, which typically result in rapid clinical deterioration of the patient.Tumor‐induced osteomalacia (TIO) is an ultrarare disease caused by tumors secreting fibroblast growth factor 23 (FGF23).1 Most Incomplete resection often results in tumor recurrence with symptoms. Roughly 35% to 40% of tumors cannot be localized. When the tumor cannot be localized and completely resected, supplementation with multiple daily doses of oral phosphate and active vitamin D analogues is required. However, efficacy of supplementation therapy can be limited. Complications of supplementation therapy include frequent gastrointestinal (GI) distress, hypercalcemia, nephrocalcinosis, and tertiary hyperparathyroidism.Complete surgical resection of the causative tumor is curative and the established treatment for TIO.1 Inco In this first report of a long‐term prospective trial in TIO, we present the primary analysis of a phase 2 clinical trial investigating the efficacy and safety of burosumab in adults with TIO.Burosumab is a fully human monoclonal antibody against FGF23. By blocking excess FGF23, burosumab normalized phosphate metabolism, improved bone health, and ameliorated clinical symptoms in both children and adults with X‐linked hypophosphatemia (XLH). Burosumab is approved for treatment of XLH and TIO.8, 9RAS mutations often accompanied by skin lesions and skeletal dysplasia with excess FGF23. Additional key inclusion criteria were fasting serum phosphorus and maximum tubular phosphate reabsorption per unit of glomerular filtration rate (TmP/GFR), both <0.81 mmol/L; intact FGF23 ≥100 pg/mL ; and a corrected serum calcium <10.8 mg/dL. Key exclusion criteria were use of vitamin D analogues or oral phosphate salts within 2 weeks of screening or during the study; use of medication to suppress parathyroid hormone (PTH) within 2 months before screening; and history of malignancy within 5 years of screening, with the exception of phosphaturic mesenchymal tumors or nonmelanoma skin cancers. Additional criteria are in the supplemental materials.Adults (aged ≥18 years) with TIO not curable by surgical excision or cutaneous skeletal hypophosphatemia syndrome (CSHS) were eligible for this trial. CSHS is rare condition caused by somatic ss FGF23.10 Add For structural morphometric analysis, biopsies were stained using Masson Goldner Trichrome.This ongoing, open‐label, single‐arm, phase 2 study (UX023T‐CL201) is investigating the efficacy and safety of burosumab in adults with TIO and CSHS at six US sites. Patients were treated with burosumab subcutaneously every 4 weeks for up to 144 weeks at the time of this report. Dosing started at 0.3 mg/kg and was titrated through week 16, and beyond if needed, to a maximum of 2.0 mg/kg every 4 weeks to achieve a fasting peak serum phosphorus level between 0.81 and 1.29 mmol/L. At baseline and week 48, transiliac bone biopsies—horizontal full‐thickness biopsies of the ilium from a site 2 cm dorsal of the anterior superior iliac spine—were obtained using a needle with an inner diameter of ≥5 mm. The bone biopsy was not required at baseline if a previous bone biopsy taken within 12 months of screening confirmed the diagnosis of osteomalacia, the patients' clinical manifestations have not changed significantly since the time of the previous biopsy/diagnosis, and the tissue collected at that biopsy was made available for testing for this study. Patients received two 3‐day courses of tetracycline‐HCl (or demeclocycline‐HCl) 20 and 8 days before each biopsy for dynamic histomorphometric analysis, as previously described.12 For Key pharmacodynamic endpoints include change from baseline in fasting TmP/GFR, 1,25(OH)2D, and bone‐specific alkaline phosphatase (BALP). A full list of assessments and schedule is in the supplemental materials.Co‐primary endpoints were (i) the proportion of patients with an average fasting serum phosphorus level at the midpoint of the dose interval between baseline and week 24 >0.81 mmol/L; and (ii) change from baseline in parameters of osteomalacia at week 48, as assessed by osteoid thickness, osteoid surface/bone surface, osteoid volume/bone volume, and mineralization lag time. In patients in whom the mineralization defect was profound and, therefore, the uptake of tetracycline label very low, mineralization lag time was calculated using imputation.13 Key99mTc) methyl diphosphonate (MDP) whole‐body bone scan, and fracture healing was assessed by follow‐up 99mTc‐MDP whole‐body bone scans at weeks 24, 48, 96, and 144. Pre‐ and post‐treatment scans were compared by a central reader who was blinded to time point and patient data. Although bone scans are highly sensitive for detecting mineralizing lesions with increased uptake at sites of injury and ongoing repair, they have a low diagnostic specificity and are typically interpreted in the context of the patient's medical condition. In the setting of osteomalacia and TIO, bone scan findings are very informative in providing a comprehensive profile of the underlying skeletal disease. A number of studies have demonstrated the increased sensitivity of bone scans in detecting fractures/pseudofractures compared with standard radiographs, particularly in the setting of osteomalacia. Functional mobility was assessed by the sit‐to‐stand test and the 6‐minute walk test. The 36‐item Short Form Health Survey (SF‐36v2) was used to assess patient‐reported physical and mental health–related quality of life. Patient‐reported pain and fatigue were assessed with the Brief Pain Inventory and the Brief Fatigue Inventory, respectively.Fractures and pseudofractures were identified at baseline by a technetium‐labeled ( disease.14 A n68Ga‐DOTATATE PET/CT scans were added to the protocol for any patients who did not have a tumor identified by other means.Key safety assessments include the incidence and severity of adverse events (AE) and serious adverse events, development of anti‐burosumab antibodies, changes in echocardiograms and electrocardiograms, renal ultrasound nephrocalcinosis scores, fasting serum calcium, plasma intact PTH (iPTH), and 24‐hour urine calcium excretion. Patients with an identifiable tumor undergo CT or MRI scanning, depending on the method of initial identification, every 6 months to monitor tumor size. During the study, ClinicalTrials.gov (NCT02304367).This study was designed, conducted, recorded, and reported in accordance with the principles established by the World Medical Association Declaration of Helsinki Ethical Principles for Medical Research Involving Human Patients. Institutional review boards at each site approved the protocol. Investigators obtained written informed consent from each participant. The study is registered with t test, providing the 95% confidence interval (CI) and p value. For other selected endpoints, the least squares (LS) mean and SE for the change from baseline are provided using the generalized estimating equation (GEE) repeated‐measures analysis, including time as the categorical variable adjusted for baseline measurement in the model with compound symmetry covariance structure. No adjustments for multiplicity were made.Statistical analyses were conducted in SAS version 9.4 . We provide descriptive summaries for efficacy and safety endpoints. Continuous variables are summarized by number of patients, mean, standard error (SE), standard deviation (SD), median, minimum, and maximum. Categorical data are summarized as number or percentage of patients. Changes in histomorphometric endpoints are analyzed using a two‐sided PHEX genetic testing. Four other patients had tumors that had never been located. However, these patients did not undergo PHEX testing because their clinical profile was consistent with TIO . Figures, tables, and text summarize group findings for patients with TIO only. Results for the two patients with X‐linked hypophosphatemia were similar to observations in previous clinical trials. The source of FGF23 in CSHS is unknown and the disease may have a distinct natural history from TIO. Because only one patient with CSHS enrolled in this study, results for this patient are provided separately to allow robust descriptions of both disease states (manuscript describing CSHS patient in preparation).Of the 20 patients screened, 17 were enrolled: 14 had TIO, one had CSHS, and two who enrolled with diagnoses of TIO were subsequently diagnosed with X‐linked hypophosphatemia after enrollment . Finally, one patient with TIO enrolled late, completing all assessments through week 124 at the time of this analysis. Ten patients with TIO completed 144 weeks of treatment; their pharmacodynamic and patient‐reported outcomes are summarized through week 144.2D levels p < .0001; Fig. Seven (50%) patients achieved a mean serum phosphorus above the lower limit of normal 0.81 mmol/L) when the levels at the midpoint of dose intervals were averaged across baseline and week 24 (a co‐primary endpoint). This includes the 16‐week titration period; the mean ± SE serum phosphorus level was 0.85 ± 0.6 mmol/L. At week 22, 12 (86%) patients achieved a fasting serum phosphorus level ≥0.81 mmol/L. Serum phosphorus levels increased at the first post‐baseline assessment (week 1 LS mean change ± SE 0.24 ± 0.77 mmol/L) and were maintained through week 144 ; increases were maintained through week 144.Mean ± SE TmP/GFR level increased from 0.36 ± 0.05 mmol/L at baseline to 0.60 ± 0.05 mmol/L at week 24 Fig. B, refle2D level increased from 68 ± 7 pmol/L at baseline to 103 ± 11 pmol/L at week 24 . After week 24, serum 1,25(OH)2D levels declined toward baseline levels, likely mirroring the normalization in serum phosphorus levels, while remaining within the normal range (47 to 187 pmol/L).Mean ± SE serum 1,25(OH) 24 Fig. C, refleSerum BALP level increased slightly at first and then gradually decreased through the rest of the study, with a mean ± SE of 42.66 ± 5.35 μg/L at baseline, 46.71 ± 6.54 μg/L at week 16, 35.12 ± 5·96 μg/L at week 48, and 25·50 ± 5·33 μg/L at week 144 Fig. . All patients in which mineralization lag time could be evaluated had increased baseline values compared with healthy young adults. However, only 6 of 12 patients (50%) had biopsies with abnormally high osteoid thickness, an important characteristic of osteomalacia on bone histomorphometry.On baseline bone biopsy, 10 of 12 patients (83%) had elevated osteoid volume/bone volume and osteoid surface/bone surface compared with the upper limit of normal for 17.0‐ to 22.9‐year‐old healthy young adults.11 Allp = .0858) . Mineralization lag time decreased from a mean ± SE of 1597.7 ± 419.5 days at baseline (imputation for 8 patients) to 1032.5 ± 711.6 days at week 48 (imputation for 2 patients), reflecting a mean absolute change ± SE of −565.2 ± 650.8 days . Osteoid surface/bone surface showed no change from baseline, with a mean ± SE of 57 ± 9% at baseline and 57 ± 7% at week 48 . Supplemental Table At week 48, a majority of osteomalacia‐related histomorphometric measures improved with burosumab. Osteoid volume/bone volume decreased from a mean ± SE of 17.6 ± 5.9% at baseline to 12.1 ± 4.7% at week 48, reflecting a mean absolute change ± SE of −5.5 ± 2.9%  were fully healed and 56 (23%) were partially healed. At week 144, 81 (33%) were fully healed and 32 (13%) were partially healed ; role physical increased from 33.6 (12.3) to 38.4 ; bodily pain increased from 39.2 (10.5) to 43.3 ; and the physical component summary increased from 32.8 (10.2) to 40.9 . For all measures, higher numbers indicated improved physical functioning. The number of repetitions in the sit‐to‐stand test also increased, with significant improvements found at week 24. The 6‐minute walk test was assessed in a fewer number of patients and only through week 48, demonstrating minimal change. The SF‐36v2 Mental Component Score was within or above the normal range (40 to 60) at baseline and throughout the study.All three domains of the Brief Pain Inventory decreased with burosumab, indicating reductions in pain, with significant reduction in both pain severity and pain interference Table . SimilarSafety is summarized for all patients with TIO who completed at least 144 weeks, and up to 192 weeks, with the exception of one patient with TIO who enrolled late and completed 124 weeks. One patient had an AE of neoplasm progression and discontinued burosumab to undergo chemotherapy Table ; this paAll patients reported at least one AE, with the most frequently occurring AEs typical of TIO  or common in the general population  Table . Nine paPredefined AEs of interest were injection site reactions, hypersensitivity, hyperphosphatemia, ectopic mineralization, and restless leg syndrome. There were 20 AEs of interest in eight patients; all events were mild to moderate in severity. Three patients had eight injection site reactions; all were considered related to burosumab. Two patients had four hypersensitivity events, all of which pertained to rash, were mild in severity, and resolved spontaneously or with topical medication; one event was considered related to burosumab. Two patients had two events of hyperphosphatemia; both were considered related to burosumab. One of these patients had a serum phosphorus level within the normal range at baseline  and experienced a TEAE of hyperphosphatemia on day 16. The second patient had undergone radiation therapy beginning at week 36. This patient experienced a TEAE of hyperphosphatemia on study day 478 (approximately week 68) and required a dose reduction. Three patients had three events of ectopic mineralization , and two patients had restless leg syndrome; all were considered unrelated to burosumab.68Ga‐DOTATATE PET/CT was first performed. All AEs related to tumor progression were considered unrelated to burosumab.There were 16 serious AEs in seven patients; none were considered related to burosumab. Five patients had tumor progression/metastases; one patient had a tooth abscess, sialoadenitis, and rheumatoid arthritis; and one patient had tumor compression, Pickwickian syndrome, acute respiratory failure, cholangitis, pancreatitis, septic shock, and cardiac arrest resulting in death at week 51. Of the six patients with a serious AE related to tumor progression, five had a history of tumor progression before enrollment. Of these five patients with a history of tumor progression, two patients had new metastases identified when p = .0385). Renal ultrasound nephrocalcinosis score, ranging from 0  to 4 (stone formation), was either 0 or 1 throughout the study for all patients. Only two patients tested positive for anti‐drug antibodies at week 120, while all other visits for these two patients and the remaining patients were negative; the presence of anti‐drug antibodies did not impact efficacy results. No neutralizing antibodies were detected at any time.Throughout the study, there were no noteworthy changes in vital signs, echocardiogram and electrocardiogram parameters, or safety labs, including serum and urine calcium, serum parathyroid hormone, creatinine, hematology, and urinalysis ,23 wasFor the patients in this study, mean time since diagnosis was 14 years. During this time, most patients had a history of attempted surgical tumor resection, and all had received prior treatment with vitamin D analogues and/or oral phosphate. In spite of this, most entered the study with multiple fractures/pseudofractures, pain, fatigue, and impaired physical functioning. At baseline bone biopsy, most patients had increased osteoid volume/bone volume, osteoid surface/bone surface, and mineralization lag time, but only six patients had increased osteoid thickness compared with normal reference range. The variability in osteomalacia assessments via bone histomorphometry across the patient population may be the result of previous prolonged treatment with active vitamin D analogues and/or oral phosphate that resulted in partial healing of osteomalacia before study entry. Although osteoid volume/bone volume and osteoid surface/bone surface were assessed as a co‐primary endpoint in this study, it is important to note that both parameters can be elevated in conditions other than osteomalacia and should be interpreted in light of osteoid thickness and mineralization lag time. and in an interim analysis of a phase 2 trial of burosumab in Japanese and Korean patients with TIO. To our knowledge, these are the only other published studies of burosumab in TIO.Burosumab treatment in patients with TIO was associated with normalization of phosphate metabolism, improvement in histomorphometric measures of osteomalacia and BALP, enhanced fracture/pseudofracture healing, decreases in the number of new fractures, reductions in pain and fatigue, and improvements in physical functioning. The improvements in phosphate metabolism, pain, fatigue, and physical functioning occurred within 24 weeks and were maintained through 144 weeks of treatment. Benefits from burosumab treatment demonstrated in patients with TIO in this study were consistent with a case report of burosumab treatment in a patient with TIO, including normalization of serum phosphorus and improvement in pain and physical function,24 and Six patients had an AE of tumor progression, all unrelated to burosumab. All but one of these patients had a history of tumor progression before enrollment, suggesting that changes in tumors during the study may represent the natural course of unresectable or incompletely resected phosphaturic mesenchymal tumors. Burosumab's mechanism of action targets excess FGF23, addressing renal phosphate wasting and impaired vitamin D synthesis with consequent osteomalacia. Although burosumab did not appear to impact the natural course of the underlying disease in this trial, longer‐term studies are needed to understand both the natural history of TIO and any potential effects of burosumab on tumor progression.Burosumab demonstrated an acceptable safety profile, with most AEs mild to moderate in severity and generally reflecting the patients' underlying disease. Incidence of AEs of interest were assessed based on burosumab's known safety profile in X‐linked hypophosphatemia. AEs considered related to burosumab were injection site reactions , hypersensitivity , and hyperphosphatemia , similar to previous burosumab clinical trials.12 Six and was substantially above the range reported in healthy young adults (0.41% to 3.05%). Similarly, mean baseline osteoid thickness, mineralization lag time, and osteoid surface/bone surface were above the reference range, indicating poor skeletal health.Patients had received prior phosphate treatment for a mean of 10.5 years and active vitamin D for a mean of 10.4 years. However, baseline bone biopsies and number of fractures/pseudofractures indicated poor skeletal health. Baseline mean osteoid volume/bone volume (17.6%) was similar to values observed in untreated patients with X‐linked hypophosphatemia (19.1% to 26.1%),28 andAlongside corrections in phosphate metabolism, burosumab substantially improved key histomorphometric measures of osteomalacia in a majority of patients. Concordant with improved osteomalacia, approximately half of the fractures/pseudofractures identified at baseline were fully or partially healed after 96 weeks and there was a reduction in new fractures/pseudofractures. These improvements are in line with results from burosumab trials in patients with X‐linked hypophosphatemia. As expected from improvements in phosphate metabolism, osteomalacia, and fracture healing, patients also reported beneficial changes in pain, fatigue, and physical functioning as early as week 24. Together, these findings suggest that by inhibiting excess FGF23 and restoring phosphate homeostasis, burosumab leads to meaningful improvements in overall bone health and health‐related quality of life in these patients.Because of the rarity of TIO and invasive nature of bone biopsies, a control arm was not included, and baseline values served as a reference to evaluate changes. Still, most patients showed improvements in key histomorphometric parameters; it is also possible that measures of osteomalacia may have continued to improve with longer treatment, as was observed for changes in fracture healing at weeks 96 and 144. Additionally, there were consistent beneficial changes reported in hallmark symptoms of TIO, such as pain, fatigue, and physical functioning. Although this is the largest prospective study in TIO, it is limited by the relatively small sample size. The number of patients and resulting variability may have contributed to the nonsignificant improvements observed in some of the histomorphometric outcomes. Still, there was a significant improvement in osteoid thickness, which is a more reproducible assessment of osteomalacia. Additionally, all other histomorphometric parameters trended favorably, and there was variability in the severity of baseline osteomalacia.In conclusion, data from this trial demonstrate that burosumab restores phosphate homeostasis and improves osteomalacia, fracture healing, and functional mobility, which translates into improvement in health‐related quality of life in patients with TIO. Overall, the results demonstrate a favorable benefit–risk profile of burosumab and offer a new therapeutic option for patients with TIO in whom surgical resection of the underlying tumor is not feasible.SMJdB received grants, personal fees, and non‐financial support from Ultragenyx and grants from Mereo. PDM received grants and participated in a scientific advisory board for Ultragenyx, Amgen, and Radius Health; received grants from Elxion; and is an employee of Colorado Center for Bone Research. TJW received grants and personal fees from Ultragenyx. MP received grants from Ultragenyx. KI received grants, personal fees, and other fees from Ultragenyx. RK has nothing to disclose. FR's lab performed analyses for Ultragenyx on a fee‐for‐service basis, and FR received personal fees from Mereo and Novartis and grants from PreciThera. DL and TC are employees and stockholders of Ultragenyx. MSR is an employee of Ultragenyx. JSM was an employee of Ultragenyx at the time the study was conducted, is an employee and shareholder of Arrowhead, and has a pending patent with Ultragenyx. TOC received grants and personal fees from Ultragenyx and personal fees from Kyowa Kirin and Inozyme. This study was sponsored and funded by Ultragenyx Pharmaceutical Inc. in partnership with Kyowa Kirin International plc. Medical writing support was provided by Catherine Woods (Ultragenyx) and Kerri Hebard‐Massey (Ultragenyx).SMJdB: Conceptualization; investigation; writing‐original draft; writing‐review and editing. PDM: Investigation; writing‐review and editing. TJW: Investigation; writing‐review and editing. MP: Investigation; writing‐review and editing. KI: Investigation; writing‐review and editing. RK: Investigation; writing‐review and editing. FR: Investigation; writing‐review and editing. DL: Conceptualization; formal analysis; investigation; writing‐review and editing. TC: Conceptualization; formal analysis; investigation; writing‐review and editing. MSR: Conceptualization; formal analysis; writing‐original draft; writing‐review and editing. JSM: Conceptualization; writing‐review and editing. TC: Conceptualization; investigation; writing‐original draft; writing‐review and editing.https://publons.com/publon/10.1002/jbmr.4233.The peer review history for this article is available at Supplemental Fig. S1. CONSORT diagram.Supplemental Fig. S2. Pharmacodynamic assessments (mass units).Supplemental Fig. S3. Key safety labs (mass units).Supplemental Table S1. Bone Turnover MarkersSupplemental Table S2. Individual Bone Biopsy AssessmentsSupplemental Table S3. Additional Histomorphometric ParametersSupplemental Results. One patient was enrolled in this study based on inclusionary serum phosphorus levels per testing performed at a local laboratory. However, their serum phosphorus levels were within the normal range per central laboratory testing (data on file), which likely triggered the TEAE of hyperphosphatemia on study day 16. The patient received minimal burosumab dosing during the study  as the patient's serum phosphorus levels did not warrant dosing per protocol‐specified guidelines. Concentrations of burosumab in this subject were significantly lower than in patients who received regular dosing. This patient was discontinued due to minimal burosumab dosing.Click here for additional data file.AppendixS1: Supporting InformationClick here for additional data file.


N = 92; aged 8–9 years; 48 boys); comparing those with no attentional difficulties and severe inattention. We hypothesized that 1) choice would increase reading comprehension and enjoyment 2) choice would increase the reading comprehension and enjoyment of children both with severe inattention and no attentional difficulties 3) choice effects would be significantly greater for children with severe inattention than those with no attentional difficulties. Children participated in a reading intervention that included a Choice  and a No Choice (control) condition. Child inattention was measured via a Virtual Reality Continuous Performance Task  and Teacher Ratings. Choice significantly increased reading comprehension, but not enjoyment compared with no choice. Choice improved the reading comprehension of children with both severe inattention and no attentional difficulties. Choice did not benefit the reading of severely inattentive children more than that of children with no attentional difficulties. These findings underline the educational benefits of choice for young readers both with severe inattention and no attentional difficulties, which are further discussed drawing on existing theory and research.It has been proposed that enhancing motivation supports the learning of children with Attention Deficit Hyperactivity Disorder (ADHD). Less is known if inattentive children with no ADHD diagnosis may similarly benefit, when being motivated to engage in an academic task. Using a repeated-measures design, this study investigated the effects of text choice as an intrinsic motivator on the reading comprehension and enjoyment of Year 4 children attending mainstream primary schools (The online version contains supplementary material available at 10.1007/s10802-021-00835-8. Attention Deficit Hyperactivity Disorder (ADHD) is one of the most common childhood neurodevelopmental conditions characterized by severe degrees of inattention and/or hyperactivity/impulsivity that are inconsistent to the child’s developmental level  and ADHD co-occur in both community and clinical samples  and behavioral interventions (e.g. parent training and positive reinforcement) are designed to reduce diagnosed inattention and/or hyperactivity/impulsivity, rather than target specifically learning  in behavioral tasks  for both neurotypical children and children with ADHD, with these effects being more salient for the latter group , Smith et al.  including choice. In a correlational study with 302 adolescents with and without diagnosed ADHD  than their neurotypical peers . Year 4 children were sought as reading motivation and enjoyment are more likely to decline towards the end of primary phase , data on the virtual reality task (N = 6) and reading data (N = 5) could not be collected due to child absence or technical difficulties. Ninety-two children were finally included in the study. Additional information about the participant characteristics was provided by teachers. The majority of children were of Black ethnic background , others had a White ethnic background , others an Asian ethnic background , others a Mixed ethnic background  and others had any other ethnic background . Of the 92 participating children, 12 children (13%) were eligible to free school meals, 16 children were on pupil premium (17.4%) and 49 children (53.3%) had English as an Additional Language (EAL).Using the G* Power 3.1 software, an a priori analysis showed that a minimum sample size of 42 children was necessary to report medium effects . Cronbach’s alpha was previously reported to be above 0.9 for both test sections ensuring high reliability  were selected as we were interested in the attentional difficulties specifically, rather than hyperactivity/impulsivity. Omission errors occur when the child fails to respond on trials, which require a response. These are indicative of poor sustained attention. RTV has been associated with ADHD, poor word reading, reading fluency and reading comprehension in children with ADHD , r ranging between 0.6 and 0.8 in a mixed sample of 57 children with ADHD  in the presence of realistic classroom distractors and not for clinical purposes  showing high reliability  were rotated and administered across both conditions, counterbalancing the condition order.This study received ethical approval by the Research and Ethics Committee at UCL, Institute of Education. Information letters and opt-in consent forms were sent via teachers to parents/carers before the study. The study began in December 2017 and lasted until January 2019. In the first school visit, children completed the NGRT first and then the MRQ. In the second visit, children of each classroom were randomly assigned to the Choice or No Choice condition. In the first classroom, children participated in the experimental condition (Choice) with the control condition (No Choice) following on a different date (third visit). In the second classroom, children took part in the control condition first with the experimental one taking place after (third visit). Children completed all the tasks individually. The reading tasks were administered in children’s regular classroom during morning sessions that lasted approximately 1 h each. The three visits were between two to seven days apart. Further visits took place in-between the three main visits, during which children completed the AULA task individually.In the Choice  condition, children received two A4 envelopes. Stapled to the front of the envelope they found a different cover page for each story, a different prologue for each story and two different child reviews. The choice was a perceived choice; the actual stories inside the envelopes were the same; only the titles, prologues and reviews were different. Perceived choice enables to control for background knowledge and individual/topic interest. Children had 5 min to read through the stapled material to ensure more meaningful choice. The number of stories was restricted to two as limitless choice could be burdensome and potentially demotivating , the assumption of normality is not necessary . Thus, parametric tests were employed. Descriptive statistics and bivariate correlations among all study variables were initially explored. In order to address Hypothesis 1, we used a repeated measures ANOVA with Choice as the within-subjects variable. For Hypothesis 2 and 3, we followed two analytical methods. First, we applied a whole-sample analysis in order to preserve the continuous nature of the Attention variables, by checking the correlations between the difference scores in Reading comprehension and Enjoyment and the Attention measures to test for any relationships between Attention and Choice. Greater difference scores would indicate that children achieved greater Reading comprehension and Enjoyment in Choice than No Choice condition and vice versa. Use of difference scores could help infer an interaction from the correlation; significant positive correlations between the difference scores in Reading comprehension and Attention variables and between the difference scores in Enjoyment and Attention variables would suggest that there is an interaction effect such that severely inattentive children would benefit more from Choice than No Choice than children with no attentional difficulties. This method aligns with dimensional approaches to ADHD  still met power calculation requirements as indicated by the power analysis (N ≥ 42). Table SD above the mean for Omission errors and more than one SD above the mean for RTV). Such congruence between the statistics reported in our study and previous research provides further support for the reliability of our trichotomization method.After this, three mixed 2 × 3 repeated measures ANOVA tests with a within-subjects variable (Choice) and a trichotomized between- subjects variable  for each of the three attention variables  were employed to test the three hypotheses. Contrary to the median split method, trichotomization is a more refined method that enables to discretise a continuous variable (inattention as measured by Conners 3 and AULA) into three groups based on percentiles and then compare the upper and lower third group  = –0.40, p < 0.01 and a weak negative correlation between the NGRT and Teacher-rated Inattention, r(92) = –0.21, p < 0.05. Therefore, more inattentive children as assessed by AULA were more likely to achieve poor reading scores on the NGRT. Such correlations were not found for RTV. Bivariate correlation analysis showed a weak negative correlation between RTV and MRQ, r(92) = –0.27, p < 0.05. Thus, less motivated children as shown by the MRQ were more likely to experience lapses in attention as measured by AULA. Similar correlations were not found between the Omission errors and MRQ and Teacher-rated Inattention and MRQ. Surprisingly, no correlation was found between the NGRT and MRQ. Children also achieved higher, but not significantly different Reading comprehension scores for Story A across both conditions, M = 9.04, SD = 3.94 compared with Story B, M = 8.42, SD = 3.31, p = 0.122 (two-tailed). Similarly, children achieved higher, but not significantly different Enjoyment scores for Story A across both conditions, M = 39.01, SD = 7.93 compared with Story B, M = 38.22, SD = 6.44, p = 0.319.Table Hypothesis 1: Choice will increase the reading comprehension and enjoyment of children compared with no choice.F = 6.18, p = 0.015, M = 9.22, SD = 3.68 than No Choice condition, M = 8.25, SD = 3.55. Similarly, a repeated measures ANOVA tested whether children reported greater Enjoyment in the Choice than No Choice. There was no significant difference in Enjoyment scores across the conditions, F = 3.48, p = 0.065, A repeated measures ANOVA showed that there was a two-tailed statistically significant difference, ores see .Hypothesis 2: Choice will increase the reading comprehension and enjoyment of children with both severe inattention and no attentional difficulties compared with no choice.Hypothesis 3: There will be an interaction between choice and attention, such that choice will increase particularly the reading comprehension and enjoyment of severely inattentive children than with those with no attentional difficulties.Positive correlations were not reported between difference scores for both Reading comprehension and Enjoyment and Attention , showing that more inattentive children did not achieve greater Reading comprehension and Enjoyment in Choice than No Choice Table .Hypotheses 2 and 3. There was a main effect of Choice, F = 6.17, p = 0.015, F = 5.68, p = 0.005, p = 0.004); however, both groups did better in Choice  compared with No Choice . There was no significant interaction between Choice and Teacher-rated Inattention, F = 0.12, p = 0.891, F = 6.04, p = 0.016, F = 7.74, p = 0.001, p = 0.001). Taken these results together, children with severe attentional difficulties achieved lower Reading comprehension scores than children with no attentional difficulties, however, both groups had better reading comprehension in Choice  compared with No Choice . There was no interaction between Choice and Omission errors, F = 0.89, p = 0.915, F = 6.14, p = 0.015, M = 9.30, SD = 3.84 for children with no attentional difficulties; M = 8.16, SD = 3.74 for children with severe inattention) than No Choice . There was no main effect of RTV, F = 1.83, p = 0.167, F = 1.19, p = 0.310, A mixed 2 × 3 ANOVA was employed with Choice as the within-subjects variable and trichotomized Teacher-rated Inattention as the between-subjects variable to address Choice, F,89 = 6.1Hypotheses 2 and 3  = 3.37, p = 0.070, F = 0.35, p = 0.703, F = 0.06, p = 0.941, F = 3.58, p = 0.062, F = 1.10, p = 0.338, F = 2.90, p = 0.060, F = 3.39, p = 0.069, F = 2.82, p = 0.065, F = 0.41, p = 0.664, A mixed 2 × 3 ANOVA was employed with Choice as the within-subjects variable and trichotomized Teacher-rated Inattention as the between-subjects variable to address We tested the hypotheses that 1) eight- to- nine year old children in mainstream schools would show increased reading comprehension and enjoyment when given a (perceived) choice of a story rather than no choice; 2) choice effects would be present for all children, irrespective of the severity of inattention ; and 3) choice effects would be significantly stronger for children with severe inattention than those with no attentional difficulties. Children participated in a reading intervention with two conditions, a Choice where they selected one out of two stories and a No Choice where they were assigned a story. They completed a virtual reality task designed to assess inattention in a classroom setting and measures of baseline reading ability and motivation. Teachers rated children’s inattention.Hypothesis 1 showed that all children achieved greater reading comprehension, when they had the option to choose their story compared with no choice. These findings replicated Fridkin’s study Testing of p < 1) with children achieving greater enjoyment scores in Choice than No Choice. In theoretical terms, choice has been viewed as a trigger of situational interest, which represents the first phase of interest development . Results remained consistent across all the analyses for each of the different measures of inattention. The partial confirmation of Hypothesis 2 suggests that choice can improve the reading comprehension (not the reading enjoyment) of all children compared with no choice, including those children with attentional difficulties, a risk factor for reading difficulties  and research in ADHD  and baseline reading motivation (MRQ). Similar findings were also reported in Fridkin’s study . These fIn conclusion, this is the first study to explore empirically and report that choice is an important motivational practice that increases the reading comprehension of children with severe inattention and those with no attentional difficulties alike. Choice did not significantly increase enjoyment, although there was a trend with children achieving greater enjoyment scores in Choice than No Choice. Choice did not increase the reading comprehension and enjoyment of the severely inattentive children independently. These findings do not fully support previous studies that found more salient effects of motivational practices (e.g. extrinsic motivators) for the behavior of children with ADHD. These novel findings extend our knowledge about the importance of autonomy-supportive practices, such as choice provision, for the reading of all children in mainstream classrooms. They also provide a starting point to further examine choice effects in young readers with varying attentive profiles  to establish generalizability, with the aim of informing the reading practices of educators. Considering teachers’ high workload, stress and limited freedom over classroom learning due to the exam-oriented character of school education Ofsted, , inclusiSupplementary file1 (DOCX 48 KB)Below is the link to the electronic supplementary material.


Pre‐existing renal dysfunction is an independent risk factor for cardiac surgery‐associated acute kidney injury (AKI). We aimed to investigate whether the improvement of postoperative cardiac function after coronary artery bypass grafting (CABG) surgery would affect the risk of AKI in patients with different levels of baseline renal function.2), non‐CKD (60≤GFR < 90 ml/min/1.73 m2), and CKD (GFR < 60 ml/min/1.73 m2) groups. Improvement in cardiac function was defined as △LVEF (postoperative LVEF–preoperative LVEF) ≥ 10% preoperative LVEF. Patients were further divided into subgroups according to postoperative cardiac function improvement.Data were collected from patients who underwent CABG surgery from January 2018 to April 2019. Patients were divided into normal . For non‐CKD patients with improved cardiac function, the serum creatinine at discharge was significantly lower than its preoperative serum creatinine . Multivariate logistic regression analysis showed that the improvement in cardiac function could reduce the risk for postoperative AKI in non‐CKD patients but not in CKD patients.A total of 1365 patients were enrolled, including 793 (58.1%) in the normal group, 476 (34.9%) in the non‐CKD group, and 96 (7.0%) in the CKD group. The AKI incidence in the normal, non‐CKD, and CKD groups was 22.2%, 28.4%, and 40.6%, respectively. Patients with improved cardiac function in the non‐CKD and CKD groups had significantly lower AKI incidence than those without improved cardiac function , improved cardiac function after CABG surgery can reduce the serum creatinine level and reduce the risk for postoperative AKI.For patients with renal dysfunction and mildly reduced eGFR (60≤GFR < 90 ml/min/1.73 m Patients were excluded if they were <18 years old, underwent urgent or salvage surgery, or underwent maintenance hemodialysis. If patients had more than one surgical procedure during the same hospitalization, we considered only the first procedure. This study was approved by the Ethical Committee of Zhongshan Hospital (No. B2016‐147R).2.22 for ≥3 months, with or without kidney damage. GFR was calculated using the EPI equation.CKD was diagnosed according to the Kidney Disease Improving Global Outcomes criteriaPreoperative left ventricular ejection fraction (LVEF) was measured routinely at hospital admission using transthoracic echocardiography  and calculated using the Simpson apical biplane method. Postoperative LVEF was recorded when no more cardiotonic drugs or vasoactive agents were administered. Improvement in cardiac function was defined as △LVEF (postoperative LVEF–preoperative LVEF) ≥ 10% preoperative LVEF. Complex surgery was CABG combined with other surgeries, such as valves, large vessels, and congenital heart disease. The SCr at discharge was recorded as the final measurement before discharge.2.32), non‐CKD group (60≤GFR < 90 ml/min/1.73 m2), and CKD group (GFR < 60 ml/min/1.73 m2). According to whether the cardiac function improved or not, the three groups were further divided into subgroups as follows: normal & cardiac function improved , normal and cardiac function did not improve , non‐CKD and cardiac function improved (non‐CKD+), non‐CKD and cardiac function did not improve (non‐CKD−), CKD & cardiac function improved (CKD+), and CKD and cardiac function did not improve (CKD−)  and percentages (%) and were analyzed using the χ2 test. Variables with significant differences (p < .05) in the basic characteristics . Continuous and normally distributed variables are expressed as mean ± standard deviation (SD). Groups were compared using a one‐way analysis of variance (ANOVA). Tukey′s pairwise comparisons were used in ANOVA for the adjustment of the family‐wise error rate. Continuous variables that violated the normality assumption were expressed as the median (25%–75% interquartile range) and were analyzed using the Mann–Whitney cs Table  were fir33.1Of 1365 patients who underwent CABG surgery between January 2018 and April 2019, 793 (58.1%) were in the normal group, 476 (34.9%) in the non‐CKD group, and 96 (7.0%) in the CKD group  . The AKI‐RRT incidences in the normal, non‐CKD, and CKD groups were 0.5%, 1.1%, and 6.3%, respectively.The AKI incidence in the normal, non‐CKD, and CKD groups was 22.2%, 28.4%, and 40.6%, respectively Table . Patientp = .002), and SCr at discharge was significantly higher than the preoperative SCr in the CKD− subgroup . There was no significant difference in preoperative SCr and SCr at discharge in the normal+, normal−, non‐CKD−, and CKD+ subgroups , hypertension, decreased preoperative eGFR, complex surgery, CPB duration, APACHE II score on ICU admission, fluid overload, and LCOS, while the improvement of cardiac function can reduce the risk of AKI Table .We found that for CKD patients, age, sex , complex surgery, CPB duration, APACHE II score on ICU admission, fluid overload, and LCOS were independent risk factors for postoperative AKI Table .4In this study, we found that patients with improved cardiac function in the non‐CKD and CKD groups had significantly lower AKI incidence than those without improved cardiac function. For non‐CKD patients with improved cardiac function, the serum creatinine level at discharge was significantly lower than the preoperative serum creatinine level. Multivariate logistic regression analysis showed that the improvement in cardiac function can reduce the risk of postoperative AKI in non‐CKD patients, but not in CKD patients.2.2) and the remainder had mild to severe renal dysfunction.2, only 7.0% of the 1365 patients underwent CABG surgery.Heart and kidney disease commonly coexist in cardiac surgery patients, and the definition of cardio‐renal syndrome has received much attention since it was proposed in the Acute Dialysis Quality Initiative (ADQI) 2008.Studies have shown that preoperative renal dysfunction is a major risk factor for poor prognosis.It is difficult to evaluate the risks and benefits of cardiac surgery in patients with renal dysfunction. On the other hand, ischemia‐reperfusion injury, inflammation, hemolysis, or oxidative stress caused by cardiopulmonary bypass can damage the kidney. However, the predominant pathophysiological mechanisms underlying acute or chronic heart failure leading to renal insufficiency are hemodynamic in nature, including a reduction in cardiac output and effective circulation fluid volume, which cause low renal perfusion, renal ischemia, and increased central venous pressure, which will increase intra‐abdominal pressure, leading to venous congestion.This study provides important findings. First, the rate of patients with improved cardiac function in the normal, non‐CKD, and CKD groups were 67.6%, 60.7%, and 63.5%, respectively, which was quite high. Second, according to the multivariate regression analysis, the improvement of cardiac function can reduce the risk of postoperative AKI in non‐CKD patients, but not in CKD patients. The surgery may not bring advantages to the renal function of CKD patients, possibly because of irreversible pathological changes in the kidney, such as fibrosis and necrosis of the glomeruli. This may explain why the SCr at discharge was significantly higher than the preoperative SCr in the CKD subgroup. Third, the risk of postoperative AKI decreased in patients with renal dysfunction without CKD. In addition, SCr at discharge was significantly lower than preoperative SCr in the non‐CKD+ subgroup. This means that CABG surgery may indirectly improve renal function for patients with mild reduced baseline eGFR. Our study provides new perspectives on the surgical indications for CABG surgery in patients with renal dysfunction. However, this study had some limitations. First, it was a single‐centered retrospective study, which may have bias and requires further confirmation. Second, we were not able to follow up on the long‐term outcomes of cardiac and renal function. Furthermore, volume‐related variables or hemodynamic monitoring were not documented or considered during logistic regression.5Preoperative renal dysfunction is a risk factor for postoperative AKI, and cardiac surgery is often discouraged for these patients. Our present study demonstrated that CABG surgery might indirectly reduce the risk through improved cardiac function, especially in patients with mild renal dysfunction. A multidisciplinary team or nephrologist consultation before surgery may help in the better evaluation and prevention of AKI.The authors declare no conflict of interest.Jiarui Xu, Bo Shen, and Jie Teng were responsible for the conception and design of the study. Jiarui Xuand Xin Chen drafted the manuscript. Jiarui Xu, Yeqing Xie, Jing Lin, Jiawei Yu, Yimei Wang, and Wuhua Jiangwere responsible for data acquisition and analysis. Zhe Luoand Chunsheng Wang provided the patients and participated in manuscript revision. Xiaoqiang Ding, Bo Shen, and Jie Teng read and approved the final version of the manuscript.Supporting information.Click here for additional data file.


Playing music relies on several sensory systems and the motor system, and poses strong demands on control processes, hence, offering an excellent model to study how experience can mold brain structure and function. Although most studies on neural correlates of music expertise rely on cross-sectional comparisons, here we compared within-person changes over time in aspiring professionals intensely preparing for an entrance exam at a University of the Arts to skilled amateur musicians not preparing for a music exam. In the group of aspiring professionals, we observed gray-matter volume decrements in left planum polare, posterior insula, and left inferior frontal orbital gyrus over a period of about 6 months that were absent among the amateur musicians. At the same time, the left planum polare, the largest cluster of structural change, showed increasing functional connectivity with left and right auditory cortex, left precentral gyrus, left supplementary motor cortex, left and right postcentral gyrus, and left cingulate cortex, all regions previously identified to relate to music expertise. In line with the expansion–renormalization pattern of brain plasticity , the aspiring professionals might have been in the selection and refinement period of plastic change. Playing a musical instrument is an intense, multisensory experience. As music itself is a highly complex stimulus and musicians typically devote a lot of time to their training, they offer an excellent model for studying experience-dependent plastic changes in the brain. In our view, brain plasticity is an adaptive process that is triggered by a prolonged mismatch between the functional supply the brain structure can momentarily provide and the experienced demands the environment poses . In the Music expertise has served as a particularly rich and fruitful domain for investigating plastic changes. It involves several sensory systems and the motor system, and it poses high demands on cognitive control processes . Most ofArguably, musicians brains do not only differ structurally from nonmusicians but show also functional differences, such as strengthened functional coupling among relevant regions while performing musical tasks . Indeed,The brain exhibits spontaneous and systematic activity during wakeful rest . ExploitAs summarized above, most studies on neural correlates of music expertise rely on cross-sectional comparisons, rendering conclusions of whether observed group differences were pre-existing or the result of learning de factor impossible. It has been impressively shown, though, that monozygotic twins, that is with identical genes, differing on musical training do indeed exhibit neuroanatomical differences, thereby providing strong support for the causal effects of training . Still, age = 21.92, standard deviation {SD}age = 3.72] who were participating in preparatory courses offered at Berlin music schools to prepare them for an entrance exam at a University of Arts. These participants were either aspiring to study to become a conductor, composer, Tonmeister, or instrumentalist. As a control group, we recruited 17 amateur musicians between 18 and 27 years  with at least 5 years of formal music education who were actively performing music in their daily lives but had no aspirations to perform music professionally. All participants had normal hearing, normal or corrected-to-normal vision, no history of psychological or neurological diseases, and no contraindication to participate in an MR study, such as metallic implants, tinnitus, or claustrophobia. The groups did not differ with respect to age (t(39) < −1.05, P = 0.30) or years of playing a primary instrument (t(38) < 1, P = 0.68 [Missing data for one participant]; aspiring professionals: Myears = 12.04, SDyears = 4.57; amateur musicians: Myears = 12.74, SDyears = 5.97).We recruited a total of 24 young adults between 18 and 31 years [MParticipants were paid up to 200€ for completion of the whole study . The ethical board of the DGPs (Ethikkommission der Deutschen Gesellschaft für Psychologie) approved the study and written consent of all participants was obtained prior to investigation.Participants were invited for behavioral testing as well as MRI assessment between 1 and 5 times, depending on their availability, in the course of about a year, with approximately 10–12 weeks distance between appointments see . ParticiThe BGS was designed by André Werner, a composer and collaborator in this study. It is a listening and transcription task focused on assessing music expertise  with a standard 12-channel head coil. The MR measurement protocol included a T1-weighted magnetization prepared gradient-echo sequence (MPRAGE) of 9.20 min with the following parameters: repetition time (TR) = 2500 ms, echo time (TE) = 4.77 ms, inversion time (TI) = 1100 ms, flip angle = 7°, bandwidth = 140 Hz/pixel, acquisition matrix = 256 × 256 × 192, isometric voxel size = 1 mm3. We used the prescan normalize option and a 3D distortion correction for nonlinear gradients.As structural images, we used a 3-dimensional (3D) T2*-weighted EPI sequence of 8 min sensitive to BOLD contrast . Slices were acquired in an interleaved fashion, aligned to genu splenium of the corpus callosum.Whole brain functional images were collected using a Thttp://dbm.neuro.uni-jena.de/cat/) for SPM12  in Matlab 2017a . Using default parameters, preprocessing of the data for voxel-based morphometry (VBM) involved intrasubject realignment, bias-field and noise removal, skull stripping, segmentation into GM and white matter (WM) and cerebrospinal fluid (CSF), and finally normalization to Montreal Neurological Institute (MNI) space using DARTEL to a 1.5 mm isotropic adult template provided by the CAT12 toolbox . The resulting GM maps were smoothed with a standard Gaussian kernel of 8 mm full-width at half maximum (FWHM). These GM maps represent voxel-wise information on GM probability, which is an estimate of GM volume in an arbitrary unit . This analysis included 23 aspiring professionals and 17 amateur musicians. An absolute GM probability threshold of 0.2 was applied. To control for type-I error, a significant effect was reported when the results met a peak-level threshold of P < 0.005 and when the cluster size exceeded the expected voxels per cluster threshold (k > 259 in this case) in combination with correction for nonisotropic smoothness. The expected voxels per cluster threshold was computed automatically by the CAT12 toolbox according to random field theory and empirically determines the minimum number of voxels that, in combination with a voxel-level threshold, clusters must meet in order to be reported   analysis, focusing on left and right STG, as well as further divisions into bilateral planum temporale, Heschl’s gyrus, and planum polare (taken from the HarvardOxford Atlas ion:262) .The main analysis in this paper focused on differential changes over time in the two groups of musicians by means of a whole-brain flexible factorial design with a focus on the interaction Time × Group. Since not all participants provided data for all time points, we based our statistical analysis on the middle 3 measurement occasions  and only included those participants that contributed data to those 3 time points since this provided us with the highest possible number of participants for a longitudinal analysis in SPM. This resulted in a final sample of 19 aspiring professionals and 15 amateur musicians in this statistical comparison in which we tested for brain regions that display a significant increase or decrease in aspiring professionals compared with amateur musicians over time.P < 0.001 and when the cluster size exceeded the determined expected voxels per cluster threshold (k > 47) in combination with correction for nonisotropic smoothness (as explained above).Again, an absolute GM probability threshold of 0.2 was applied. To control for type-I error, here, a significant effect was reported when the results met a peak-level threshold of http://www.alfnie.com/software), subtracted pretest from posttest values and correlated the difference scores with behavioral performance scores using Pearson’s correlation coefficient.To investigate potential relationships between brain volume changes in the clusters showing a significant Time × Group interaction with behavioral performance, we extracted the data from significant clusters using the REX toolbox   running r values were normalized to z values using Fisher’s z transformation.We then conducted an exploratory analysis by means of DPABI computing “functional connectivity maps with a seed region” consisting of left planum polare in MNI space, taken from the Harvard Oxford atlas . To do sz-transformed correlation values  in the second-level analysis with a focus on a time-by-group interaction, using a family-wise error (FWE) correction for multiple comparisons at P < 0.05 (cluster size k = 20 voxels). We used the REX toolbox to extract the z-transformed correlation coefficient values from within those clusters showing a significant time-by-group interaction.Statistical analysis of the functional connectivity maps was again carried out by means of a whole brain flexible factorial design, again focusing on measurement occasions B, C, and D. We entered the images containing the https://sites.google.com/site/bctnet/)  theory , a toolbbctnet/)  to calcurd Atlas  and edgeWe computed 5 “nodal measures” including degree, path length, global efficiency, local efficiency, and the clustering coefficient. The “degree” refers to the total number of edges connected to a node. In the calculations, the weights of the connections were ignored by binarizing the connectivity matrix so that only edges with nonzero weights were considered connected. “Path length” refers to the average distance from a node to all others. The distance between two nodes is defined as the length of the shortest path between those nodes. In the case of a weighted undirected graph, the length of an edge is a function of its weight. Typically, the edge length is inversely proportional to the edge weight . The “global efficiency” at the nodal level defines the efficiency of the information transfer from one region to the whole network, which assesses the average inverse shortest path length between one node and all other nodes in the network. The “local efficiency” as a nodal measure is calculated as the global efficiency of the node on the subgraph level, created by the node’s neighbors. It reflects the efficiency of the information transfer from each region to the neighboring regions. The “clustering” coefficient at a nodal level is calculated as the fraction of triangles present around a node and is a measure of segregation. It reflects the ability for specialized processing in small groups of nodes and is thus regarded a measure of local connectedness within a network.In addition, we computed 4 “global measures,” namely characteristic path length, global efficiency, local efficiency and clustering coefficient. The “characteristic path length” as a global measure is calculated as the average of the path lengths of all nodes. “Global efficiency” at the global level is the average of the global efficiency of all nodes in the graph and is inversely related to the characteristic path length. “Local efficiency” computed on the global level is the average of the local efficiencies of its nodes and reflects how well the nodes communicate with adjacent nodes. The “clustering coefficient” as a global metric is the average of the clustering coefficients of all nodes.P value of 0.05; https://www.sdmproject.com/utilities/?show=FDR).Statistical significance testing was done by extracting the values of the 3 measurement occasions for local and global measures for each subject from BRAPH and then testing for a time-by-group interaction separately for each nodal and global measure using SPSS, in the end applying a correction for multiple comparisons using the false discovery rate (FDR) algorithm (t(32) = 4.57, P < 0.001, Hedges’ g = 1.58. Furthermore, aspiring professionals showed an increase in performance, whereas amateurs’ performance remained relatively stable, as reflected by a significant time-by-group interaction, F = 8.53, P = 0.001, partial η squared = 0.21  = 2.40, P = 0.02, Hedges’ g = 0.7531) and the left posterior portion of STG (t(38) = 2.37, P = 0.02, Hedges’ g = 0.7419)  see . AnalyseF-scores). All of these clusters were driven by decreases in GM volume in aspiring professional musicians relative to amateur musicians  extending into anterior insula (see ians see B.rTime B (19) = −0.581*, P = 0.009; rTime C (19) = −0.517*, P = 0.023; rTime D (19) = −0.588*, P = 0.008; left posterior insula: rTime B (19) = −0.387, P = 0.102; rTime C (19) = −0.525*, P = 0.021; rTime D (19) = −0.433, P = 0.064; left IFoG: rTime B (19) = −0.558*, P = 0.013; rTime C (19) = −0.634*, P = 0.004; rTime D (19) = −0.589*, P = 0.008). This association was also true across the whole sample (left planum polare: rTime B (34) = −0.580*, P < 0.001; rTime C (34) = −0.523*, P = 0.001; rTime D (34) = −0.599*, P < 0.001; left posterior insula: rTime B (34) = −0.282, P = 0.106; rTime C (34) = −0.398*, P = 0.020; rTime D (34) = −0.373*, P = 0.030; left IFoG: rTime B (34) = −0.586*, P < 0.001; rTime C (34) = −0.620*, P < 0.001; rTime D (34) = −0.620*, P < 0.001). Importantly, no such associations were found within the group of amateur musicians .For the left planum polare and IFoG, the observed decrements in estimates of GM volume in the group of aspiring professionals correlated with general music expertise as assessed by the BGS at measurement occasions B, C, and D see . A similrTime B (33) = −0.434*, P = 0.012; rTime C (33) = −0.354*, P = 0.043; rTime D (33) = −0.468*, P = 0.006; left IFoG: rTime B (33) = −0.519*, P = 0.002; rTime C (33) = −0.559*, P = 0.001; rTime D (33) = −0.561*, P = 0.001, but not in left posterior insula: rTime B (33) = 0.00, P = 0.999; rTime C (33) = −0.162, P = 0.367; rTime D (33) = −0.141, P = 0.433). This means that those individuals showing the highest proficiency in this behavioral test were also the ones that exhibited the most pronounced decrease in GM volume. In contrast, the decrease in estimates of GM volumes did not correlate with improvements in music expertise (rplanum polare (19) = −0.104, P = 0.671; rposterior insula (19) = −161, P = 0.483; rIFoG (19) = −0.171, P = 0.483).Correlations in the total sample continued to differ reliably from zero in planum polare and inferior frontal gyrus after excluding one very high-performing individual who also exhibited the most pronounced structural decrease .At all measurement occasions, we observed significant correlations between individual differences in GM volume decrements and music expertise. In other words, the highest performing individuals exhibited the most pronounced decreases in GM volume in left planum polare, left insula, and left inferior frontal gyrus, thus, show the largest plastic change on the neural level. However, counter to expectations, we did not observe any significant correlations between changes in music expertise and changes in GM volume. One reason for the absence of such a change–change association is the high degree of stability of individual differences in music expertise over time. For instance, in aspiring professionals, we observed the following correlations in music expertise between adjacent measurement occasions (1 maps (We can only speculate about the neurobiological mechanisms that may have caused the observed reductions in GM volume. Synaptic changes including dendritic branching and axon sprouting as well as glial changes come to mind and we and others have elaborated on the exact potential mechanisms before . Future 1 maps .The present study also has some further limitations that need to be mentioned. First, there was no random assignment of participants to groups. Obviously, this caveat is inherent in the studied topic and is not easy to overcome. We have tried to limit this problem by recruiting two groups of participants with comparable years of playing an instrument. Still, there might be pre-existing differences between people who aspire to become professional musicians and people who consider themselves amateur musicians . In addiTo conclude, we found that musicians intensely preparing for the entrance exam to a University of the Arts show reliable reductions in GM volume in regions pertinent to music expertise, whereas a group of amateurs not preparing for an exam did not show such changes. The planum polare, which was the largest GM cluster with volume reductions, showed increasing functional connectivity to other musically relevant regions. This increase in connectivity was also reflected in global metrics of network participation based on graph theory. The present results are consistent with the ESR model of plastic change , which pWe acknowledge financial support by the Max Planck Institute for Human Development. This work was also supported by an intramural grant from the Innovation Fund of the President of the Max Planck Society given to UL.Conflict of interest: None declared.We are grateful for the assistance of the MRI team at the Max Planck Institute for Human Development in Berlin. The authors thank Andreas Brandmaier and Ziyong Lin for setting up the hierarchical SEM for the behavioral task data, Caroline Garcia Forlim for advice on the graph theoretical analyses, as well as all participants and student assistants. Pitch-Study_Supplementary_Material_tgab008Click here for additional data file.


Multivisceral, neurological, hepatic, and renal damage has been witnessed following the use of artemisinin-based combination therapy (ACT) and herbal medicine. These multiple organ damages make us think of muscle damage. The objective was to study the myotoxicity of the combination of ACTs with medicinal plants. Sida acuta (PSA) and plant Enantia polycarpa (PEP) at 10 µg/ml. After 5 days of incubation, the cells were counted by using a hemocytometer with trypan blue solution.  Muscle cells (RD cells) were brought into contact with preparations of antimalarial drugs and/or antimalarial herbs. The following drugs were used: artesunate 100 mg/amodiaquine 270 mg (ASAQ) and artemether 80 mg/lumefantrine 480 mg (AL); plant p < 0.001). There was also a significant difference between the control and artemether/lumefantrine between D2 (p < 0.01) and D4 (p < 0.001) and between the control and the Sida acuta plant, on D2 (p < 0.001), D4 (p < 0.001), and D5 (p < 0.05). In tubes treated with ASAQ and Sida acuta, cell mortality was over 30%. Finally, statistically significant cell destruction in the tubes treated with the combination of antimalarial drugs and traditional plants compared to those of the control was observed from D2 (p < 0.001).  Artesunate/amodiaquine caused a significant drop in the number of muscle cells, compared to the control, between D2 and D4 ( Artemisinin-based combination therapy remains effective and well tolerated. But its combination with medicinal plants induced myotoxic effects. This toxicity would appear to be of the additive type. Further studies should be able to better elucidate the mechanism of this toxicity. The World Health Organization (WHO) recommends the use of therapeutic combinations, especially those based on artemisinin derivatives (ACTs). Nowadays, they are widely used worldwide, mainly in areas of chloroquine resistance and resistance to artemisinin monotherapy . The advThus, these adverse drug reactions which were reported to the pharmacovigilance unit of the Pharmacology Department of the Faculty of Medical Sciences in Abidjan (Cote d'Ivoire) and to the Ivorian National Pharmacovigilance Center were serious and unexpected. They were cases of blackwater fevers, hepatitis, and hepatonephritis with high mortality involving antimalarial drugs, in particular, ACTs . MonomorAqueous plant extracts and drug preparations (ACTs) have been made to be in contact with muscle cells. Muscle cells served as an experimental model.2) on enriched MEM medium. The MEM culture medium is enriched with 10% decomplemented foetal calf serum (FCS), 1% mixture of antibiotics , and 1% of L-glutamine (Sigma Aldrich) for cell growth.The musculocytes or myocytes used were RD muscle cells from rhabdomyosarcoma. These muscle cells were obtained from CDC, Atlanta. They were continuous heteroploid lines, which, due to their rapid growth, were readily available and widely used. The cells were thawed and cultured in T75 culture dishes (75 cmSida acuta (PSA), Malvaceae and Enantia polycarpa (PEP), Annonaceae obtained from the medicinal plant market in Abidjan. Their efficacy had previously been demonstrated [Enantia polycarpa and the leafy stem of Sida acuta were used in our study. Trypan blue from Sigma Aldrich was also used to identify living or dead cells.The antimalarial drugs used were artesunate 100 mg/amodiaquine 270 mg (ASAQ) and artemether 80 mg/lumefantrine 480 mg (AL). The antimalarial plant extracts used were 5 cells/ml was cultured in 2 ml of 10% MEM growth medium in 51 T25 culture tubes (25 cm2) and incubated for 48 h at 36.5 ± 0.5°C under 5% CO₂. Then, the growth medium was emptied.The cells were trypsinized. 0.5.10Enantia polycarpa bark samples were thoroughly washed and dried. These samples were crushed into small pieces and then ground with the use of a suitable grinder to obtain a very fine powder. Enantia polycarpa bark powder (200 g) obtained was added to two liters (2 L) of distilled water. A magnetic stirrer allowed the mixture to be stirred for 24 hours. Then, the resulting solution was filtered three times through cotton wool and Whatman paper. The solution was oven-dried at 40°C. The powder thus obtained constituted the aqueous extract of powdered bark of Enantia polycarpa.Sida acuta was made. Two hundred grams (200 g) of leafy stems of Sida acuta were washed and put in 2 L of distilled water. The mixture was boiled for 15 minutes. The resulting solution was cooled and filtered three times through cotton wool and Whatman paper and then oven-dried at 40°C. The powder obtained was the aqueous extract of the leafy stems of Sida acuta.A preparation of the aqueous extract of the leafy stems of The artesunate 100 mg/amodiaquine 270 mg (ASAQ) and artemether 80 mg/lumefantrine 480 mg (AL) tablets were crushed. The resulting powder was suspended in 2% MEM.μg/ml by means of two-tenth dilutions. Thus, in the T25 culture dishes, 5 ml of the plant and drug preparations were brought into contact with the RD muscle cells. Artemether/lumefantrine, artesunate/amodiaquine, Sida acuta, and Enantia polycarpa were first tested one by one. Then, the products were tested 2 by 2 by combining antimalarials with extracts of medicinal plants. The toxicity of each product was tested in a batch of 5 dishes (5 boxes per product) compared to a batch of 5 negative control dishes (no product was added). Each combined test  was carried out in a batch of 5 dishes and a batch of 5 dishes serving as control or negative control. After inoculation, the dishes were placed in an oven at 36.5 ± 0.5°C under 5% CO₂. Cells were observed on daily basis for 5 days under an inverted fluorescence microscope for cellular carpet confluence. The effect of antimalarials and traditional herbs on muscle cells was measured on daily counting of the number of living and dead cells by using a hemocytometer. Before counting cell, trypan blue was added (dilution factor 2). 30 µL of the mixture (trypan blue + cell suspension) was sampled to fill up the 2 chambers of the hemocytometer by gently touching the edge of the coverslip with the cone. We enumerated separately viable nucleated cells and dead nucleated cells. For authentication, viable or living nucleated cells appear clear, nonblue, and dead nucleated cells appear blue because of damaged cell membrane.A concentration of 1 mg/ml of all the products tested has been prepared. This concentration was reduced to 10 µg/ml. The experiments were carried out in triplicate. In this preliminary study, we could have coupled the first method with Cell Counting Kit-8 (CCK-8). It is a sensitive colorimetric assay for the determination of cell viability in cell proliferation and cytotoxicity assays. It could have allowed us to validate our experience. But, the lack of financial support did not allow us.According to Coulerie , a produ ± SD) of n experiments. Statistical analysis of data was performed by using GraphPad Instat software  and GraphPad Prism software . Statistical analyses were assessed by using one-way or two-way analysis of variance (ANOVA) followed by Bonferroni's posttest when applicable. Statistical significance was considered at p < 0.05.Data were estimated as mean with standard deviation (Mp < 0.001). A significant difference was also noted between the control and artemether/lumefantrine between D2 (p < 0.01) and D4 (p < 0.001), and between the control and the Sida acuta plant, on D2 (p < 0.001), D4 (p < 0.001), and D5 (p < 0.05).∗p < 0.05, ∗∗p < 0.01, and ∗∗∗p < 0.001 versus control.Data are given as means ± SEM of 3 different experiments. Statistical analyses were assessed using two-way analysis of variance (ANOVA) followed by Bonferroni's posttest Sida acuta plant, mortality was also over 30% at D4 and D5. This indicated its cellular toxicity at D4 and D5. Low cell mortality was observed with the plant Enantia polycarpa.p < 0.001) for associations with artesunate/amodiaquine and from D3 (p < 0.001) for combinations with artemether/lumefantrine. The destruction was more massive in the combinations containing artesunate/amodiaquine.We compared the effect of the combination of antimalarial drugs and herbal extracts versus a control on myocytes . All the∗∗∗p < 0,001 versus control.Data are given as means ± SEM of 3 different experiments. Statistical analyses were assessed using two-way analysis of variance (ANOVA) followed by Bonferroni's post-test Sida acuta showed muscle cell toxicity or musculotoxicity. However, in monotherapy artesunate/amodiaquine and the plant Sida acuta appeared to be the most musculotoxic (Artesunate/amodiaquine, artemether/lumefantrine and the plant ulotoxic . MusculoMuscular disorder with artemether-lumefantrine has also been described. Kamagaté et al.  reportedIn combination therapy with plant, artesunate/amodiaquine and artemether/lumefantrine had comparable average musculotoxicity. The plants appeared to enhance the muscle toxicity of conventional antimalarials. Additive effect was observed. This musculotoxicity could be close to the hematologic, nervous, and renal toxicity of the combination of antimalarial drugs and traditional plants. Indeed, in previous studies , 6, it hSida acuta, and combination of medicinal plants with artemisinin-based combination therapy. This toxicity would appear to be additive type. Combination of traditional plants with conventional treatment should then be avoided by patients or carefully monitored. Further studies will elucidate the mechanism of this toxicity by determining blood CPK level and anatomopathological examination.Although in medical practice, ACT for malaria treatment remains effective and well tolerated, the present study showed myotoxic effects of artesunate/amodiaquine,


N = 974) two‐wave survey study with a 4‐week time lag. The results show that anxiety at Time 1 was positively related to stress and physical symptoms at Time 2. Feeling exposed to risk factors related to lower physical health, but was unrelated to stress. Family identification and identification with humankind were both negatively associated with subsequent stress and family identification was negatively associated with subsequent physical symptoms. These findings suggest that for social identities to be beneficial for mental health, they can be embodied as well as symbolic.The COVID‐19 pandemic has triggered health‐related anxiety in ways that undermine peoples’ mental and physical health. Contextual factors such as living in a high‐risk area might further increase the risk of health deterioration. Based on the Social Identity Approach, we argue that social identities can not only be local that are characterized by social interactions, but also be global that are characterized by a symbolic sense of togetherness and that both of these can be a basis for health. In line with these ideas, we tested how identification with one’s family and with humankind relates to stress and physical symptoms while experiencing health‐related anxiety and being exposed to contextual risk factors. We tested our assumptions in a representative sample ( The World Health Organization declared the COVID‐19 outbreak in December 2019 in Wuhan, China, as a worldwide pandemic  which states that identifying and being part of multiple social groups is health beneficial  and/or whether they live close to such high‐risk people. Studies focusing on family caregiving showed health‐declining effects of caring responsibilities, whereby highly burdened caregivers reported the poorest health outcomes . At Time 2, we identified five people who participated twice and only included their first responses leaving us with a sample of N = 1010 at Time 2 (attrition rate: 31.53%). Data collection started a few days after the German government implemented extensive contact restrictions . For the present analyses, we used a sample from Germany. Participants in Germany were recruited via Kantar, an online panel provider and received 1.65 € for their participation per survey. Before completing the online questionnaire, participants had to agree with the informed consent statement. At the end of the first survey, the respondents were asked if they would like to participate in a follow‐up survey four weeks later. A total of 1484 individuals participated in the first survey (26 March – 31 March). We excluded nine cases because seven participants participated more than once. We used only responses of their first completions of the survey which resulted in a sample of 3 = ‘neutral’), (2) their response time was less than 50% of the calculated median of the average response time of the sample  and 59.2% were tested negatively (n = 577).In the final sample, the majority of the participants 61.3%) were employed and 57.1% reported to have children. Only two participants (0.2%) had suffered from and one participant (0.1%) indicated to have been cured of COVID‐19. 40.3% of the participants had not been tested (.3% were SD = 13.76) and gender distributions (52.7% women) of the final sample (N = 974) with the respective distributions of the German population obtained from the Federal Statistical Office . These items were based on the marker item for state anxiety (‘I feel anxious’) in the State‐Trait Anxiety Questionnaire ?’, ‘Are people who are exposed to high‐risk  living in your household or close by?’, ‘Has a family member or close relative/ friend been diagnosed with the coronavirus?’, ‘Do you live in a high‐risk area (with many documented cases of the coronavirus)?’, and ‘Have you recently visited a high‐risk area?’.Building on the five risk factors described before, we asked participants to answer the following questions with M = 9.55  out of 100 (100%) to the aspect ‘recently visited a high‐risk area’. In order to calculate a risk score ranging from 0‐1, the mean weights were divided by 100 and included into the equation. Higher values indicate a higher burden due to the COVID‐19 pandemic. The intraclass correlation coefficient (ICC) was .91 (p < .001), indicating a high inter‐rater reliability . For example, the raters assigned a mean weight of Four items for measuring individual identification , ‘Tension’ (sample item: ‘You feel tensed’), ‘Joy’ , and ‘Demands’ (sample item: ‘You have too many things to do’) can be calculated. As we were interested in the participants’ overall stress experience  was conducted to determine the best‐fitting model for the data. Here, five different confirmatory factor analytical (CFA) models were fitted to the data and systematically compared. Model fit was established by considering both model fit statistics as well as measurement quality  on anxiety, COVID‐19 risk, family identification, and identification with humankind . Stress and physical symptoms were allowed to covary.M = 41.11, SD = 15.63) than those who participated in both surveys , t (810.64) = −11.80, p < .001. However, there were no gender differences between second and first time only participants (2χ (1) = 1.37, p = .242)Participants who only participated in the first survey were significantly younger (t (1434) = −.563, p = .574), family identification (t (1434) = −1.51, p = .13), and identification with humankind (t (1434) = .85, p = .393). However, participants who only participated at Time 1 showed higher COVID‐19 risk scores  = 3.23, p = .001) than participants who participated in both surveys .Regarding the independent variables, there were no differences between second and first time only participants in terms of health‐related anxiety . First‐order factors on stress were constrained to be equal in order to establish convergence. This model was specified to ensure the difference between family identification and identification with humankind.Model 3: Anxiety and physical health were specified as first‐order latent factors with items loading onto their a priori factors. The observed variables for measuring anxiety and stress loaded on a first‐order latent stress anxiety factor. This model was specified to ensure the difference between health‐related anxiety and stress.Model 4: Family identification, identification with humankind, and physical health were specified as first‐order latent factors with items loading onto their a priori factors. Stress was specified as a hierarchical second‐order latent factor, comprising out of four first‐order latent factors .Model 5: Family identification, identification with humankind, anxiety, and physical health were specified as first‐order latent factors with items loading onto their Observed measures were treated as indicators for latent factors. One item of the stress‐scale (‘You feel rested’) was removed due to a non‐significant loading in all models. To enhance model fit for the best‐fitting measurement model, we further permitted the residual error terms of item 4 and item 5 of the anxiety scale and item 7 and item 8 from the physical symptom scale to correlate in all models. The risk score was included directly into the five different models , small residual variances centred around zero, and the absence of multicollinearity between factors  lowest chi‐square‐value, (2) root mean square error of approximation (RMSEA: <0.06), (3) standardized root mean residual (SRMR: <0.08), (4) Tucker‐Lewis Index (TLI: >0.90), (5) comparative fit index (CFI: >0.90) and (6) smaller AIC and BIC values  = 2404.33; p < .001, scaling correction factor for MLR = 1.15, CFI = 0.92; TLI = 0.92; RMSEA = 0.047 ; SRMR = 0.05) fitted the data better than Model 1  and Model 2 , indicating the existence of the four stress subscales tension, worries, joy, and demands and their loading on an overall second‐order stress factor. Additionally, according to the fit indices, Model 5 was superior to Model 3  and Model 4 , supporting the differentiation between family identification and identification with humankind and stress and health‐related anxiety, respectively. Model 5 also showed acceptable levels of measurement quality with all factor loadings exceeding the suggested thresholds , standardized residual variances ranging from .00 to .77, and no indication of multicollinearity between latent factors. Model 5 was therefore retained for further analyses.The model fit statistics for the five models are summarized in Table 2 = 2468.55, scaling correction factor for MLR = 1.15, RMSEA = .05 , CFI = .92, TLI = .91, SRMR = .06). H1 proposed that risk at Time 1 will be positively associated with stress at Time 2 and H2 proposed that risk will be positively associated with physical symptoms at Time 2. Not supporting H1, we did not find a relation between risk and stress . Supporting H2, we found a positive association between risk and physical symptoms . H3 and H4 predicted that health‐related anxiety at Time 1 will be positively related to stress and physical symptoms at Time 2 respectively. Supporting H3 and H4, anxiety was positively associated with stress  and physical symptoms  at Time 2. H5 proposed a negative relation between family identification at Time 1 and stress at Time 2 and H6 proposed a negative relation between family identification at Time 1 and physical symptoms at Time 2. Our results support H5 and H6 as family identification was negatively related to stress  and physical symptoms . Finally, we predicted that identification with humankind at Time 1 would be negatively related with stress (H7) and physical symptoms (H8) at that Time 2. Supporting H7, but not H8, identification with humankind was negatively associated with stress  but not with physical symptoms .The structural path model was estimated based on the best‐fitting measurement model  = 2708.23, scaling correction factor for MLR = 1.15, RMSEA = .05 , CFI = .91, TLI = .91, SRMR = .07). Age was negatively associated with stress  and physical symptoms . However, including age as a covariable did not change our results.As younger people dropped out of the study and did not participate at Time 2, we also run the analysis controlling for participants' age. Model fit was good  but not by larger and more distant groups . Concerning this matter, we are aware that we chose two extreme social groups on the physical distance spectrum. Other critical groups worth studying are communities or neighbourhoods, because they represent some kind of middle ground between family and humankind, and furthermore, community identification improves well‐being  identification with family and identification with humankind are independent factors associated with better mental health, (b) identifying with a proximal group  is more helpful for the individual when dealing with concrete physical symptoms, and (c) the importance of identifying with a large collective in the presence of a worldwide stressor should not be underestimated.everyone struggles with similar negative experiences due to the COVID‐19 pandemic and the need to combat this threat collaboratively, strengthens the perceived identification between people and builds a safer and more secure environment in these challenging times.Thus, rising awareness that The authors declare no conflict of interest.Svenja Frenzel was involved in writing the original draft and performing formal analysis. Svenja Frenzel, Nina M. Junker, Jan A. Häusser, Andreas Mojzisch, Valerie A. Schury und Rolf van Dick were involved in the conceptualization, methodology, and data curation. Nina M. Junker, Jan A. Häusser und Rolf van Dick were involved in funding acquisition and reviewed and edited the manuscript. Llewellyn van Zyl was involved in formal analysis. Lorenzo Avanzi, Aidos Bolatov, S. Alexander Haslam, Ronit Kark, Ines Meyer, Lucas Monzani, Stephen Reicher, Adil Samekin, Niklas K. Steffens, Liliya Sultanova, and Dina Van Dijk were involved in reviewing the manuscript and data curation.