Judging positive emotional states or the trustworthiness of others is important for forming and maintaining social affiliations. Past studies have described alterations in these appraisal processes in Borderline Personality Disorder (BPD), which might have been exacerbated during the Covid-19 pandemic by the requirement to wear face masks. In the present study, we investigated in an online-survey a) whether social judgments are particularly strongly affected in individuals with BPD when they have to judge happiness and trustworthiness in facial stimuli covered by a mask, b) whether appraising a positive emotional state affects trustworthiness appraisals differentially in BPD and healthy individuals and c) whether social judgments are related to how individuals with BPD experience wearing masks during the pandemic.Participants  judged happiness and trustworthiness of faces with calm expression with and without masks. Additionally, data on participants’ confidence in their judgments, the experience of the burden induced by wearing masks, the protective benefits of masks, and compliance to wearing masks were collected.Happiness and trustworthiness were evaluated less confidently and less intense in the BPD group compared to HC. Masks reduced happiness and trustworthiness ratings in both groups. Lower happiness appraisals contributed to lower trustworthiness appraisals except for those with BPD and low levels of symptom severity. Lower trustworthiness ratings were associated with a higher burden, attributing a lower benefit to masks and lower compliance with wearing masks in BPD.Masks do not exacerbate deficits in social judgments. However, lower trustworthiness appraisals in general were linked with more negative evaluations of wearing masks in the BPD group.https://aspredicted.org/f5du7.pdf). For findings of an additionally preregistered research question on the impact of adverse childhood experiences see supplementary material.The aims and hypotheses were preregistered together with the design and planned analyses (The online version contains supplementary material available at 10.1186/s40479-022-00193-x. One of the core symptom domains in Borderline Personality Disorder (BPD) are pervasive interpersonal dysfunctions . StudiesThe face is an important source of information people use to recognise others’ emotional states, and infer complex social judgements, such as others’ trustworthiness. The appraisal of a facial emotion and attributed trustworthiness are closely related. For example, people ascribe a higher trustworthiness to happy faces , 9. ThisIndividuals with a diagnosis of BPD experience positive social signals, such as another person’s smile, less intensively, feel less confident in their evaluation, and tend to misclassify faces with a subtle expression of happiness –15. ThesDuring the Covid-19 pandemic, behavioural restrictions such as wearing masks and social distancing affected everyone’s everyday social life. In particular, wearing a mask places special demands on social encounters: When facial features are partially occluded by masks, especially the recognition of emotional states such as joy is faultier , 26, 27.Being confronted with others wearing masks is not only an additional obstacle on social judgments, but also accentuates the uncertainty people experience during their judgments . SeveralBeyond the influence masks have on trustworthiness ratings by hampering the evaluation of emotional states, peoples’ attitudes towards masks also modulate the effects of masks on social judgments: Attributing protective effects to masks and experiencing a low burden during interactions with people wearing masks were related to smaller changes in appraisals of faces as being less happy and less trustworthy induced by masks . So far,In the present online study, we addressed two topics to contribute to the understanding of trustworthiness impairments in BPD in general, as well as during the Covid-19 pandemic. First, we were interested in the interplay between the appraisal of positive emotional states and trustworthiness and how social judgments such as the evaluation of happiness and trustworthiness are influenced by covering the presented facial stimuli with a face mask in individuals with BPD. We hypothesised that (a) masks influence social judgments to a higher extent in a BPD compared to a HC group. Due to the higher relevance of the mouth region for happiness judgments, we expected that masks result in a stronger decrease in intensity ratings for happiness than trustworthiness ratings. Moreover, we expect that (b) the intensity of a positive emotional state ascribed to a facial stimulus predicts the judgment of trustworthiness in the BPD group to a lower extent than in HC. In regard to the confidence participants experience during social judgments, we expected that (c) masks will reduce confidence in the BPD group to an even higher extent than in the HC group.Second, we were interested in how individuals with BPD experience the burden induced by mask wearing during social encounters in everyday life and whether this burden is related to their social judgments. We expected that (d) individuals of the BPD group experience a higher burden during real-life social contacts due to masks compared with HCs and that a higher burden is related to stronger effects of masks on social judgments and the individuals’ confidence in these judgments. Additionally, we explored the relation between social judgment and attitudes towards masks in regard to their perceived efficiency in protecting from infection, as well as compliance to wearing masks.Due to lockdown regulations at the time of the study, we recruited individuals of the BPD or HC groups of former research projects. At the time of testing, participants presented with a range of current symptom and function levels.The study was conducted between February 13, and April 4, 2021, when Germany was in lockdown under strict measures, which included closing most public facilities, wearing FFP2 or surgical masks in all public spaces and limiting social contact to one person from another household. Due to the lockdown the study was done as an online survey via unipark. Participating in the survey was possible through computers and smartphones.Diagnostics and Statistical Manual of Mental Disorders (DSM-IV) [Participants were recruited from the database of the central project of the KFO 256, a Clinical Research Unit funded by the German Research Foundation dedicated to investigating mechanisms of disturbed emotion processing in BPD . We incl(DSM-IV)  diagnosi(DSM-IV) . For furWe characterised the samples by assessing sociodemographic features, psychopathology, and general trust propensity. We measured BPD symptom severity with the short version of the Borderline Symptom List (BSL-23) , the levKurzskala Interpersonelles Vertrauen (KUSIV-3) [The severity of childhood trauma was based on self-reports measured with the German version  of the sKUSIV-3) . For furnot at all to very much).During the experimental task, each participant assessed how intensely a facial stimulus expressed happiness and trustworthiness (within-subject factor: task) and how confident they were in the judgment. Additionally, we manipulated the visible part of the faces by presenting each face with and without a FFP2 mask (within-subject factor: mask). Participants indicated their responses on a 7-point Likert scale ranging from 1 to 7  from the Interdisciplinary Affective Science Laboratory Face Set . Calm faces have the same valence as happy faces, but a lower level of arousal (see affective circumplex model ). Calm fParticipants rated happiness and trustworthiness together with their confidence in two separate blocks. Each block was split into two sub-blocks, presenting each of the 12 stimulus characters of which six were presented with masks and six without masks. The trials within each sub-block, the order of the sub-blocks within each block, and the types of social judgement were counterbalanced across participants. Please note that while this prevents a differential impact of time-related confounds on task performance, it might also influence the rating in case of asymmetrical transfer effects. The experimental design was adapted from the one used in .not at all to 6 very much). For more details, see supplementary material We asked participants to answer a set of questions related to the experience of wearing masks during the pandemic (adapted from ). QuestiFor further characterisation of the samples, we additionally asked particpants of whether.Social judgements and confidence ratings were analysed in separate 2 × 2 × 2 mixed-ANOVA designs with the repeated-measurement factors mask (without/with FFP2) and task (happiness/trustworthiness) and the between-subject factor group (BPD/HC). Assumptions for ANOVA were tested by tests of normality and inspection of QQ plots. We explored the nature of interaction effects by 2 × 2 sub-designs.To estimate the extent to which the experienced intensity of happiness predicts trustworthiness ratings, we calculated a linear regression analysis with trustworthiness ratings as the dependent variable and happiness ratings and group membership (dummy coded with HCs = 0 and BPD = 1) as predictors.U tests, calculated Spearman correlation coefficients (rs) separately for each group, and compared these coefficients to test for differences in these relationships. In additional exploratory analyses, we conducted corresponding analyses for the protective benefit people ascribed to wearing masks and their compliance to wearing masks. Analyses were performed with SPSS 27 or MATLAB R2019a.To analyse whether the HC and BPD groups differed in the extent to which they experienced masks as a burden during real-life social encounters and whether this experience co-varies with the changes in social judgments related to masks (difference between ratings with and without a mask), we compared both groups using Mann-Whitney https://aspredicted.org/f5du7.pdf). For findings on an additionally preregistered research question on the impact of adverse childhood experiences see The aims and hypotheses were preregistered together with the design and planned analyses (ps > .1). The BPD group reported a higher level of BPD symptoms (BSL-23), BPD features (VEI-BOR) and depressive symptoms (BDI-II), as well as a lower interpersonal trust propensity, compared to the HC group . We analysed the frequency of severity categories of BPD symptoms in both samples following the suggestions by [N = 3) or mild (N = 16) symptom severity and 15 participants with a level of BPD features below the cut-off for clinical significance. In the BPD group, a higher percentage of participants (68.00%) reported to be currently in psychotherapeutic or psychopharmacological treatment compared to the HC group . 47% of the BPD individuals with low to mild symptoms were currently in treatment. According to Corona-related measures, most of the participants had not suffered a confirmed Covid-19 infection themselves  but almost every second person had a close other who had been infected . They reported that they wear masks comparably often as other people around them . For further details, see Table The groups were balanced for age and education  = 22.38, p < .001, ηp2 = .14; Fig. F = 13.00, p = .001, ηp2 = .09; happiness t(140) = 1.98, d = 0.33; trustworthiness t(140) = 5.82, d = 0.98). HC individuals rated trustworthiness higher than happiness, compared with the BPD group  = − 8.80, d = − 1.11; BPD: t(74) = − 2.48, d = − 0.32). Covering a face with a mask led to lower happiness and – to a smaller extent – lower trustworthiness in both groups  = 201.30, p < .001, ηp2 = .59; task × mask: F = 44.71, p = .001, ηp2 = .24; task × mask × group: F = 1.21, p = .274, ηp2 = .01; group × mask: F = 1.67, p = .198, ηp2 = .01). See summary of results, supplementary material, Table SIndividuals with BPD rated faces as less happy and less trustworthy than HCs  = 11.91, p < .001). At trend level, higher BSL-23 scores predicted a stronger drop in intensity ratings for faces covered by a mask  = 3.43, p = .068). For further details, supplementary material Association with BPD symptom severity: To explore the effects of BPD symptom severity on social judgments, we repeated the analysis for the BPD group with the BSL-23 score as covariate. Analyses revealed that ratings of intensity were lower for individuals with higher BSL-23 scores  = 21.21, p < .001).Linear regression analysis revealed that higher happiness ratings predicted higher trustworthiness ratings without evidence for a differential effect in both groups  = 11.65, p < .001) revealed an effect of symptom severity in addition to an interaction between BSL-23 scores and happiness ratings: higher happiness ratings predicted higher trustworthiness ratings depending on higher symptom severity.Association with BPD symptom severity: We explored the effects of BPD symptom severity as modulating factors in the BPD group by adding BSL-23 scores and its interaction with happiness judgments as predictors for trustworthiness judgments. The regression model  = 155.90, p < .001, ηp2 = .53). While there was no difference in the decrease of confidence induced by masks between groups for happiness ratings, the decrease was stronger in the HC group compared with the BPD group for trustworthiness ratings  = 4.63, p = .033, ηp2 = .03; analysis of 2 × 2 ANOVA sub-designs: trustworthiness ratings group × mask: F = 9.00, p = .003, ηp2 = .06, group: F = 4.03, p = .047, ηp2 = .03; happiness ratings group × mask: F = 0.28, p = .600, ηp2 = .002, group: F = 7.70, p = .006, ηp2 = .05, mask: F = 146.49, p < .001, ηp2 < .01). While confidence in judging trustworthiness in faces without masks was lower in the BPD group compared with the HC group (t(140) = 3.09, p = .002, d = 0.52), there was no difference for faces with masks (t(140) = 0.80, p = .424, d = 0.14). For summary of results, see Table SThe confidence in social judgments decreased when faces were covered by a mask compared with faces without a mask .–22.20–22The appraisal of a positive emotional state predicted around 30% of the variance in the appraisal of the more complex social judgment trustworthiness. This confirms the interplay between both types of social judgments described in previous studies , 9, 50. Covering the faces with a mask resulted in a lower confidence during social judgments. However, in contrast to our hypotheses, differences in confidence ratings between groups varied depending on the social judgment. For judging the emotional state, confidence dropped in both groups to a similar extent. For trustworthiness judgments, only the HC group became less confident in the presence of masks, resulting in a comparably low confidence for both groups. Thus, social judgments were related to a higher uncertainty in BPD as shown in previous studies , 31, 32,The importance of first impression trustworthiness appraisals in social life has been shown in many studies . Our datSome limitations of the present study have to be addressed. These include the restricted generalisability of our findings, since only women were included in the current study. Moreover, we included individuals in the BPD group based on the diagnosis of a BPD in the past, independently of whether they currently met the DSM-5 criteria. BSL-23 scores suggested that 4% of the participants reported only low levels of BPD symptoms, implying that our sample also includes individuals currently in symptomatic remission. BPD is a personality disorder characterised by frequent changes between recovery and the reoccurrence of symptoms . HoweverOur data confirm impairments in appraisals of a positive emotional state and trustworthiness in BPD and point to changes in the interplay between these two types of social judgments that might be of particular importance when the acute symptoms of BPD are less intense. However, our data do not confirm that wearing masks during the Covid-19 pandemic affects individuals with BPD to a higher extent than healthy individuals, although there are some hints that this might be the case in individuals with very or extremely high levels of BPD symptoms. Finally, our data reveal the importance of alterations in trustworthiness appraisals, measured by an experimental task, for the evaluation of different facets of wearing masks during the pandemic and maybe most importantly, with the compliance of wearing masks in BPD.Additional file 1. A. Description of Recruitment Procedure. B. Description of the Self-report Questionnaires. C. Stimulus material. D. List of the mask-related Questions. E. Distribution of Levels of BPD Symptom Severity and BPD Features. F. Summary Statistics of 2 × 2 × 2 ANOVA. G. Summary Statistics of 2 × 2 ANOCVA in the BPD sample with BSL-23 covariate. H. Relationships between Social Judgments and Different Facets of Wearing masks. I. Effect of Childhood Abuse and Neglect on Social Judgments and Confidence During Judgements in BPD.


The aim of this study was to evaluate the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of GSK3772847, compared with placebo administered subcutaneously (SC) in healthy participants, including cohorts of Japanese and Chinese participants. This was a single‐center, randomized, placebo‐controlled, double‐blind, single ascending dose study. Following a screening period of up to 28 days, eligible participants were assigned to one of four cohorts receiving a single dose of GSK3772847 70 mg (cohort 1) or 140 mg  or placebo SC. In cohorts 1 and 2, participants were randomly assigned to one of three injection sites , while cohorts 3 and 4 included Japanese and Chinese participants, respectively, assigned to receive GSK3772847 or placebo SC (upper arm). Participants attended follow‐up visits on Days 9, 15, 29, 43, 57, 71, and 85 before final analysis. GSK3772847 was generally well tolerated. Most adverse events (AEs) were mild, resolved without treatment and were considered not related to study treatment by the investigator. There were no serious AEs or deaths during the study. The PK and PD were dose dependent, with negligible differences across injection sites or ethnicities. Target engagement was demonstrated by reduced free soluble interleukin 33 (sIL‐33) concentrations and substantially increased total sIL‐33 concentrations compared with baseline. Subcutaneously administered GSK3772847 was well tolerated in healthy participants, including cohorts of Japanese and Chinese participants, and shows consistent PK and PD across injection sites and ethnicities. AEsadverse eventsALTalanine transaminaseASTaspartate aminotransferaseAUCarea under the plasma‐concentration time curveBMIbody mass indexGCPGood Clinical PracticeICHInternational Conference on HarmonizationIgG2immunoglobulin G2IVintravenousmAbmonoclonal antibodyPDpharmacodynamicsPKpharmacokineticsSAEsserious adverse eventsSCsubcutaneouslysIL‐33soluble interleukin 33TMDDtarget mediated drug disposition1Severe asthma affects approximately 5%–10% of patients with asthma and is associated with frequent asthma exacerbations, decreased health‐related quality of life, and substantial symptom burden.GSK3772847 (formerly CNTO 7160) is a human monoclonal immunoglobulin G2 (IgG2) sigma antibody that binds domain 1 of the cell surface IL‐33R. Three clinical trials have been conducted previously with GSK3772847 using intravenous (IV) administration 22.1This Phase 1, single‐center, randomized, placebo‐controlled, double‐blind, single ascending dose study in healthy participants was conducted in the United States from 21 July 2020 to 21 December 2020. Following a screening period (of up to 28 days), participants who met the eligibility criteria were assigned to one of four cohorts and were randomly allocated within each cohort to receive a single dose of either GSK3772847 or placebo SC  or GSK3772847 140 mg (cohort 2) SC, and six participants to receive placebo SC in each cohort. Participants in cohorts 1 and 2 were also randomized to one of three injection sites . In cohort 3, six Japanese participants were randomly allocated to receive GSK3772847 140 mg SC, and two to receive placebo SC in the upper arm injection site. Finally, in cohort 4, six Chinese participants were randomized to receive GSK3772847 140 mg SC, and two to receive placebo SC in the upper arm injection site. Participants were admitted to the unit the day prior to dosing (Day 0) and were discharged after completion of assessments on Day 6. Participants attended follow‐up visits on Days 9, 15, 29, 43, 57, 71, and 85.The study protocol was reviewed and approved by an institutional review board in accordance with the International Conference on Harmonisation (ICH), Good Clinical Practice (GCP) and relevant country‐specific requirements, all applicable patient privacy requirements, and the guiding principles of the current version of the Declaration of Helsinki. Investigators were trained to conduct the study in accordance with GCP and the study protocol and all patients provided written informed consent prior to study participation. All study staff involved in clinical assessments, including the investigator, sub‐investigators and other site staff, and the participants were blinded to the individual treatments allocated.2.22. Cohort 3 included Japanese participants only, and cohort 4 included Chinese participants only. Participants were excluded if their alanine transaminase (ALT) level was >2× the upper limit of normal or if their bilirubin was >1.5× the upper limit of normal. Participants were also excluded if they had current or chronic history of liver disease, ongoing or recurrent infections, a history of smoking within 6 months of study screening, or clinically significant electrocardiogram ECG findings.Eligible participants were healthy males and females aged between 18 and 50 years, with a body weight of 35–150 kg and a body mass index (BMI) of 18–32 kg/mThe safety population included all randomized participants who received at least one dose of study intervention . The PK population included all randomized participants who received at least one dose of study treatment, and for whom at least one post‐randomization PK sample was obtained, analyzed, and was measurable. The PD population included all randomized participants who received at least one dose of study treatment, and for whom at least one PD sample was obtained, analyzed, and was measurable.2.3Cmax), time to Cmax (tmax) and terminal half‐life (t1/2) of GSK3772847, summarized by cohort and by injection site.The primary safety endpoints were the incidence and frequency of adverse events (AEs) and serious adverse events (SAEs), including injection site reactions, and these were summarized descriptively by treatment group and cohort. Further primary endpoints were PK parameters including, but not limited to, area under the plasma‐concentration time curve (AUC), maximum plasma concentration  in free soluble IL‐33 (sIL‐33); a maximal increase from baseline in total sIL‐33 levels in serum summarized by cohort (and injection site for cohorts 1 and 2); and the incidence and prevalence of anti‐GSK3772847 antibodies and plasma 4β‐hydroxycholesterol/cholesterol (4βOHC/C) ratio (pre‐treatment and following dosing of GSK3772847), summarized by cohort (and injection site for cohorts 1 and 2) over time.Other endpoints included 12‐lead ECGs, clinical laboratory safety tests, vital signs, blood eosinophil levels, free and total sIL‐33 levels in serum, and GSK3772847 levels in the serum, summarized by cohort (and injection site for cohorts 1 and 2) over time. All endpoints were summarized descriptively.2.4GSK3772847 binds domain 1 of transmembrane (IL‐33R) and soluble (sIL‐33R) forms of IL‐33R. Free sIL‐33 and total sIL‐33 concentration in serum were assessed using validated, specific, and sensitive electrochemiluminescent assays .2.5Cmax) with adequate precision  based on comparable monoclonal antibody (mAb) studies. This sample size was also deemed adequate to enable an understanding of the tolerability of GSK3772847 when dosed SC.The sample size was selected to allow estimation of the key PK parameters .2.6http://www.guidetopharmacology.org, the common portal for data from the IUPHAR/BPS Guide to PHARMACOLOGY,Key protein targets and ligands in this article are hyperlinked to corresponding entries in 33.12 (1.493), and mean (SD) body weight, 49.50 kg (4.308), compared with participants from other study cohorts. One participant from cohort 2 withdrew consent on Day 8 due to personal reasons. This participant was replaced with another participant, allocated to the same randomized treatment but with a new randomization number, as specified in the protocol. All 65 participants who entered the study received the study medication as per the study design according to randomization.Patient disposition is shown in Table 3.23.2.1In total, on‐treatment AEs were reported in 13 participants and post‐treatment AEs were reported in eight participants during the study Table . No trenThere were six reported clinical chemistry‐related AEs (ALT increased >33 IU/L and aspartate aminotransferase [AST] increased >32 IU/L) either pre‐dose or during the study. All events were reported as mild intensity, and the events were considered as not related to the study medication by the investigator.There was a serious quality issue identified during the study, which was reported for investigation to the institutional review board. The investigation showed no impact of any clinical significance for any participants; further details can be found in the Supporting Information.3.2.2t) increased in a slightly greater than dose‐proportional manner, with a 2.5‐fold increase in geometric mean for a twofold increase in dose (geometric mean: 4140 h*μg/ml [95% CI 3510–4880] vs. 10 300 [9080–17.0]) and geometric mean apparent terminal half‐life (t1/2) estimates of 243 h [95% CI 224–265] and 293 h [95% CI 256–335] for cohorts 1 and 2, respectively (Table Cmax) of GSK3772847 were approximately dose proportional  between cohorts 1 and 2 were comparable and attained 120 and 130 h post‐dose, respectively.Visual inspection of the median GSK3772847 serum concentration‐time profiles for both dose levels indicated no appreciable difference across injection sites Figure . PK paraly Table . No formt) 13 400 h*μg/ml vs. 11 100 in cohort 2 and 11 300 in Chinese participants; Figure Overall, the geometric mean GSK3772847 serum concentration‐time profiles by cohort for 140 mg SC (upper arm) were comparable, with overlapping confidence intervals Figure . However3.33.3.1A significant decrease in free sIL‐33 levels was seen in GSK3772847 cohorts as compared with placebo cohorts; this decrease was similar across ethnicities in cohorts 2, 3, and 4 over the study duration. The maximum decrease from baseline in free sIL‐33 levels (geometric mean) was >93% with GSK3772847 70 mg SC and >95% with GSK3772847 140 mg SC across all injection sites Figure . The max3.3.2No participant receiving GSK3772847 in cohort 1, 2, or 3 tested positive for anti‐GSK3772847 binding antibodies in the confirmatory assay. One participant from cohort 4 (Chinese) confirmed positive results for anti‐GSK3772847 binding antibodies (titer 80) on Day 57 and Day 85.3.3.3Plasma 4βOHC/C ratio to baseline was essentially unchanged (~1) over the study duration in all cohorts Table .4This was the first study to administer GSK3772847 subcutaneously. GSK3772847 was administered in three injection sites  in healthy volunteers, including cohorts of Chinese and Japanese participants. Both the 70 and 140 mg doses were generally well tolerated with no reported injection site reactions during the study. The majority of AEs were mild, considered unrelated to the study medication, resolved without treatment, and there was no trend related to the injection site. There were six clinical chemistry‐related AEs, which were also considered mild and unrelated to the study treatment. There were no SAEs or deaths.Cmax and AUC (0–t) were higher at the 140 mg SC dose compared with the 70 mg SC dose. Whilst no formal statistical assessment of dose‐proportionality was performed, there does appear to be a reasonable approximation of dose proportionality for Cmax and a slight non‐linearity for AUC, which are consistent with the expected TMDD. Consistent with this effect, target engagement was demonstrated with reduced free sIL‐33 concentrations and substantially increased total sIL‐33 concentrations compared with baseline.Pharmacokinetics parameters were similar across the different injection sites with overlapping confidence intervals, indicating that the location of the injection site does not appear to affect drug availability. As expected, T1/2 and tmax were comparable across 70 and 140 mg doses, with overlapping confidence intervals. PK parameters were also similar across ethnic groups with similar tmax and elimination profiles and overlapping confidence intervals. The median GSK3772847 serum concentration was slightly higher in cohort 3 (Japanese participants) than in cohorts 1, 2, and 4. Given the precedented impact of weight on mAb clearance, the lower mean weight in Cohort 3 is likely to have contributed to the small difference in GSK3772847 serum concentration. Overall, exposures were consistent with the expected 70%–80% for a mAb compared with previous IV administration data.In previous studies, PK and PD modeling suggested an IV administration of GSK3772847 1 mg/kg every 2 weeks would provide adequate systemic drug exposure for effective inhibition of the IL‐33R signaling pathway in 90% of participants.As an endogenous marker for CYP3A4 activity, this study assessed changes in the plasma 4βOHC/C ratio. CYP3A4 is a member of the Cytochrome P450 family of enzymes, which catalyze reactions in the metabolism of a large proportion of drugs and contribute to variation in drug pharmacokinetics.Treatment with mAbs, including GSK3772847, may be associated with the development of antibodies against the therapeutic agent, and participants who develop antibodies to therapeutic proteins may be more likely to experience a hypersensitivity reaction or a decrease in efficacy. During this study, only one participant from cohort 4 had confirmed positive results for anti‐GSK3772847 binding antibodies on Day 57 and Day 85.This was the first study to evaluate the SC dosing of GSK3772847 in healthy volunteers, including cohorts of Japanese and Chinese participants, which assessed the injection site, dose level, and ethnic group impact on PK and PD. Although the number of participants in this study was small, it was sufficiently powered to ensure an adequate understanding of the tolerability of GSK3772847 when dosed subcutaneously and would enable the estimation of the key PK parameters. In summary, GSK3772847 was well tolerated via the SC route, delivered an exposure and target engagement profile consistent with expectations based on data from the IV routeDF, SS, and CN were involved in the conception of the work, and EP, DF, SS, CQZ, and CN contributed to the analysis or interpretation of data. All authors drafted the work or revised it critically for important intellectual content, gave final approval of the version to be published, and agreed to be accountable for all aspects of the work.EP, SS, DF, CQZ, and CN are employees of GSK and hold stocks/shares.The study protocol was reviewed and approved by an institutional review board in accordance with the International Conference on Harmonization Good Clinical Practice and relevant country‐specific requirements, all applicable patient privacy requirements, and the guiding principles of the current version of the Declaration of Helsinki.All patients provided written informed consent prior to study participation.Data S1:Click here for additional data file.


P = 0.046). In the multivariable analysis presence of ILD, age ≥ 60 years and diffusion capacity for carbon monoxide (DLCO) ≤ 65% were negatively associated with survival. The combination of low DLCO and low OxyHem at baseline could predict PH at baseline (sensitivity 76.1%). This study detected for the first time OxyHem ≤ 12.5 g/dl as a prognostic predictor in SSc patients. Further studies are needed to confirm these results.Oxygenated hemoglobin (OxyHem) in arterial blood may reflect disease severity in patients with systemic sclerosis (SSc). The aim of this study was to analyze the predictive value of OxyHem in SSc patients screened for pulmonary hypertension (PH). OxyHem (g/dl) was measured by multiplying the concentration of hemoglobin with fractional oxygen saturation in arterialized capillary blood. Prognostic power was compared with known prognostic parameters in SSc using uni- and multivariable analysis. A total of 280 SSc patients were screened, 267 were included in the analysis. No signs of pulmonary vascular disease were found in 126 patients, while 141 patients presented with mean pulmonary arterial pressure ≥ 21 mmHg. Interstitial lung disease (ILD) was identified in 70 patients. Low OxyHem ≤ 12.5 g/dl at baseline was significantly associated with worse survival ( The severity of organ involvement predicts the outcome in SSc patients3.Systemic sclerosis (SSc) is a rare, autoimmune disease characterized by diffuse fibrosis, inflammation and vasculopathy and remains one of the most complex and lethal diseases among connective tissue disorders1. Consequently, screening and early diagnosis of both the disease and organ involvement are crucial for prognosis.Pulmonary complications, mainly pulmonary arterial hypertension (PAH) and interstitial lung disease (ILD), remain the leading cause of mortality among SSc patients1. Previous studies have already reported the prognostic meaning of impaired oxygen saturation (SaO2) during exercise for survival and disease progression among patients with SSc-ILD5. SaO2 may be influenced by both cardiac and pulmonary comorbidities. Furthermore, anemia has been shown to be a prognostic predictor of survival among patients with SSc6. A combination of these parameters might therefore be beneficial for risk stratification and prognosis.The establishment of risk stratification methods is essential to improve the survival through rapid medical and therapeutic interventions. The majority of available scoring models are yet to be validated2) in arterial capillary blood gas analysis, is a suitable and easy to estimate novel biomarker for the prognosis of patients with chronic obstructive pulmonary disease (COPD)7. OxyHem measured in patients with stable COPD, but also during acute COPD exacerbations was independently associated with higher mortality among those patients8. OxyHem in arterial blood may also be a novel biomarker for the prognosis in patients with SSc.Trudzinski et al. showed that apart from white blood cell count, oxygenated hemoglobin (OxyHem), the product of hemoglobin concentration and fractional oxygen saturation . Furthermore, the study investigated the association of OxyHem with the development of pulmonary vascular disease (PVD) among these patients.9. Out of 267 patients, 46.4% were in World Health Organization functional class (WHO-FC) II, 30.3% in WHO-FC III and 2.6% in WHO-FC IV. The mean 6-min walking distance (6MWD) was 427.7 ± 102.5 m. Comorbidities were identified in 166 patients: 101 (37.8%) suffered from arterial hypertension, 58 (21.7%) had coronary heart disease, one (0.4%) had reported gastric antral vascular ectasia, three (1%) had lymphoma in the past history and 41 (15.4%) were obese, having a body mass index (BMI) > 30 kg/m2.A total of 280 patients with SSc were screened for pulmonary hypertension. From this cohort, 13 patients met exclusion criteria, leading to a final study group of 267 patients . Overall, 94 SSc patients had an OxyHem ≤ 12.5 g/dl and 173 SSc patients OxyHem values above 12.5 g/dl (Table P = 0.001), had mostly lcSSc , a more impaired iron metabolism in terms of lower ferritin levels  in normal range, mean corpuscular volume of erythrocytes (MCV)  and mean corpuscular hemoglobin in erythrocytes . Moreover, they were clinically more limited in terms of WHO-FC (P = 0.001), shorter 6MWD  and greater hemodynamic impairment with a higher pulmonary vascular resistance (PVR) (3.2 ± 2.6 vs. 2.4 ± 1.9 Wood Units (WU), P = 0.018) and mPAP  (Table 1) and total lung capacity (TLC). In the laboratory analysis C-reactive protein (CRP) was higher in the low OxyHem group (P = 0.020) and these patients had significantly lower hemoglobin (Hb) (P < 0.0001). There was no difference in renal function between the two groups (Table The median OxyHem in this cohort was 12.89 g/dl (interquartile range: 151.8). Receiver operating characteristic (ROC) analyses for OxyHem were in line with the cutoff from the literatureP = 0.624) and between patients with dcSSc and lcSSc (P = 0.694).Within the observation period of 3.2 ± 2.6  years 47 patients died (17.6%): 22 due to PH (46.8%), 4 due to PH and/or ILD (8.5%), 3 due to ILD (6.4%), 7 due to cancer (14.9%), one due to pulmonary sepsis (2.1%) and 3 due to left heart disease (6.4%). Two patients underwent lung transplantation due to PH and ILD. In seven cases the cause of death remained unknown (14.9%). The mean estimated overall survival was 7.7 ± 0.3 standard error of the mean years  from baseline. Survival was similar in male and female patients (P = 0.046), age at baseline of ≥ 60 years (P = 0.002), the presence of ILD (P < 0.0001), high PVR ≥ 2 WU (P = 0.002) and low DLCO ≤ 65% predicted (P < 0.001) were significantly associated with worse survival .In the univariable Kaplan–Meier analysis, OxyHem ≤ 12.5 g/dl . Low OxyHem at follow-up was though not associated with hemodynamic status (P = 0.562)  had the highest rate of low OxyHem 41.8%), compared to patients with normal hemodynamics .P = 0.046). ILD, low DLCO, older age were robust prognostic factors associated with survival in the multivariable analysis. Furthermore, low OxyHem in combination with low DLCO at baseline were predictors of PH at baseline and during follow-up . To our knowledge, this is the first study indicating the impact of OxyHem as predictor of survival among SSc patients.This study detected for the first time that SSc patients with an OxyHem level ≤ 12.5 g/dl have a significantly worse survival than patients with an OxyHem level > 12.5 g/dl  showed that oxygen desaturation (SaO2) ≥ 3% at the time of the first follow-up after one year in combination with low DLCO was significantly associated with worse prognosis of PAH20, matching our results linking low OxyHem and low DLCO with early PVD. In this cohort, male sex did not correlate with survival consistent with results from the literature22.In our cohort, OxyHem was associated with pulmonary vasculopathy only at baseline but not at follow-up. This might be caused by initiation of PAH targeted therapy after diagnosis. Hoeper et al. reported that oxygenation was not a prognostic marker for survival among prevalent patients with idiopathic PAH under therapy, which supports our results7. Furthermore, other organ manifestations of SSc, such as gastrointestinal manifestations and renal crisis, could not be considered due to missing data. Although the cohort size of our study is large for such a rare disease, sample size of subgroups was too small to differentiate the impact of OxyHem on survival separately in ILD and PH. Another limitation is that in our cohort blood gas analysis was performed with arterialized capillary blood from the earlobe, which might not be included in standard screening procedures by rheumatologists. However, this method has already shown good correlation with arterial puncture23. The meaning of OxyHem during the course of the disease including follow-up data should be addressed in future studies. Finally, our cohort included only SSc patients referred for screening for PH, which could have led to biased data.This study provides important insights into prognostic predictors and stratification models in SSc patients screened for PH. The screening for PH was performed in an expert center including a thorough diagnostic workup, leading to a well characterized study cohort. OxyHem offers a parameter, which is pathophysiologically important in different organ involvements in SSc such as ILD, PH and cardiac diseases. While it was a significant predictor in the univariable analysis it was outperformed in the multivariable model. This could be due to the limited sample size or the strong effect of ILD on prognosis. Since we only included extensive ILD in our assessment, this could have also biased the results. One of the main limitations of this study is its retrospective character leading to a smaller data set due to missing parameters. Early prognostic markers need to be investigated in future, prospective studies. We also had no control cohort of healthy individuals or other well characterized patients to compare our results to. However, the prognostic value of OxyHem has already been described in COPD patientsThe results of this study revealed that OxyHem may be a new biomarker which could be used for risk stratification in SSc and identification of patients with early PVD and PH, respectively. OxyHem is easy to calculate in daily routine and values ≤ 12.5 g/dl were significantly associated with a worse survival. Moreover, the combination of DLCO ≤ 65% predicted and low OxyHem could predict the development of early PVD in this cohort. Further prospective studies are needed to confirm the results.24 referred to our center for PH at the Thoraxklinik Heidelberg gGmbH at Heidelberg University Hospital, Germany for screening from their rheumatologists between 2008 and 2020 were retrospectively analyzed in this single center, cross-sectional cohort study. All patients fulfilled the SSc classification criteria of the American College of Rheumatology/European League against Rheumatism25 and were followed yearly according to the current recommendations9. Individuals were excluded, if they were underaged, had rheumatic diseases other than SSc, had missing data for the calculation of OxyHem or were unable to provide informed consent. Data of part of this cohort has already been analyzed and published before26. The ethics committee of the Medical Faculty of Heidelberg University  had no objection against the conduct of this study. All patients provided written informed consent for the analysis of the data. The study complied with the Declaration of Helsinki in its current version.SSc patients with dcSSc or lcSSc 2), physical examination, electrocardiogram, PFT with DLCO, blood gas analysis obtained from arterialized capillary blood from earlobe, echocardiography at rest and during exercise, high resolution computed tomography scan of the lungs (HRCT) to investigate the presence of any pulmonary manifestations or diseases, WHO-FC, 6MWD test under standardized conditions27, laboratory examinations including blood count tests, NTproBNP, CRP, analysis for iron deficiency, renal function including glomerular filtration rate, and right heart catheterization at rest and/or during exercise.Data from routinely performed examinations were extracted from the patient's files at the first presentation in the PH center. Patients were referred from their rheumatologists for screening for PH due to unexplained breathlessness and/or suspicion for PH. A detailed clinical work-up was performed in all patients. The routinely performed screening included medical history, recording of comorbidities such as arterial hypertension, coronary heart disease or obesity  measured by RHC9. Signs of early PVD were defined as mPAP ≥ 21 mmHg. PH due to left heart disease was defined by an mPAP ≥ 21 mmHg with a PAWP > 15 mmHg29. PH due to lung disease was based on lung function parameters and in case of ILD HRCT imaging30.The presence of cardiac disease, such as coronary heart disease, and pulmonary manifestations, such as PH or ILD, was documented and, in case of pathology, furtherly examined. ILD was only considered in case of extensive ILD defined as the presence of significant interstitial fibrosis in the HRCT of the lungs (> 20% of the parenchyma) or restrictive pattern in PFT  in case of missing quantification of interstitial fibrosis in the HRCT2 measured during blood gas analysis as described before7.Statistical analyses were performed by a medical statistician (NB). Data are presented as mean ± standard deviation (SD) with 95% confidence interval of the mean. Frequency data are presented as n and %. The concentration of OxyHem, (g/dl) was calculated at baseline by the multiplication of Hb concentration in blood with the SaOSurvival analysis was performed using the Kaplan-Meier and Cox-regression analysis. The first screening visit date was set as baseline for the survival analysis. Death was defined as death due to any cause. Thresholds for dichotomization of parameters were either obtained by the literature of known prognostic predictors or by ROC in case of unknown threshold or in need of threshold adjustment. Clinical parameters were compared with the two-sided student’s t-test for independent samples for patients above versus below the OxyHem threshold. Qualitative data was analyzed using the chi-square test, respectively. This study is of exploratory nature. P-values < 0.05 were considered as statistically significant and were not adapted for multiple testing.31, presence of ILD15, PVR ≥ 2 WU26, DLCO ≤ 65% predicted13. In addition, WBC count was included as it showed significant predictive power aside from OxyHem in the OxyHem discovery cohort7. For the multivariable Cox-regression all parameters listed above were considered.Variables were evaluated by univariable analysis to identify their impact on survival. Parameters were then analyzed with multivariable Cox-regression analysis. OxyHem was compared to known prognostic factors in SSc, which were identified by literature search. These included sex, type of SSc, age ≥ 60 years at baselineSurvival analysis was performed in subsets of patients with signs of cardiovascular disease with either increased PVR ≥ 2 WU, or with mPAP ≥ 25 mmHg. All analyses have been performed using IBM SPSS version 27 .All data were pseudonymized, and the study was approved by the ethics committee of the medical faculty of Heidelberg University Hospital . The study complies with the Declaration of Helsinki in its current version. The patients participating in this study provided written informed consent.


Spectral‐domain optical coherence tomography (OCT) may detect retinal changes as a biomarker in neurodegenerative diseases like manifest Huntington's disease (HD). We investigate macular retinal layer thicknesses in a premanifest HD (pre‐HD) cohort and healthy controls (HC).Pre‐HD mutation carriers underwent standardized ratings and a preset macular OCT scan. Thickness values were determined for each sector of all macular retinal layers, the mean of all sectors and the mean of the inner ring  after segmentation (Heyex segmentation batch). HC were retrospectively included from an existing database. The IR thickness of the ganglion cell layer (GCL), retinal nerve fiber layer (RNFL), GCL + inner plexiform layer (GCIPL), and total retina were included in the exploratory correlation analyses with paraclinical ratings and compared to HC.n = 24 pre‐HD participants  and n = 38 HC . Retinal layer parameters did not correlate with paraclinical ratings. Expected correlations between established HD biomarkers were robust. The IR thicknesses of the GCL, GCIPL, and total retina did not differ between pre‐HD and HC. The IR thickness of the RNFL was significantly higher in pre‐HD participants (pre‐HD: 23.22 μm (standard deviation 2.91), HC: 21.26 μm (1.90), p = .002).The analyses comprised In this cross‐sectional cohort of genetically determined pre‐HD participants, neurodegenerative features were not detected with retinal layer segmentation. Since our pre‐HD collective was more than 16 years before disease onset, OCT may not be sensitive enough to detect early changes. In this study, we investigate optical coherence tomography (OCT) data from pre‐manifest Huntington's disease mutation carriers 16 years prior to disease onset. Comparison to healthy controls and correlation with standardized clinical and paraclinical ratings did not reveal prognostic value or degenerative features. Thus, 16 years before disease onset, OCT may not be sensitive enough to detect early changes. Josef‐Hospital, Ruhr‐University Bochum, by trained personnel  in a room with dimmed artificial light. No pupil dilatation was performed.Data of the control group were collected between September 2016 and July 2017 with SD‐OCT  in the Department of Ophthalmology, Inselspital, by trained personnel and retrospectively used for this study.2.22.2.1Male and female adult participants without clinical HD manifestation, as defined by a diagnostic confidence level below 4, were included , other neurological CNS diseases, chronic diseases with potential effects on the retina  infection, immunodeficiency syndromes, rheumatologic and oncological diseases, traumatic brain injury), premature birth, intake of steroids up to 8 weeks prior to examination, and claustrophobia (MRI).2.2.2From the existing ophthalmological database, we retrospectively included all available participants Table .2.2.3SD‐OCT in pre‐HD was performed by trained technical assistants of the Department of Neurology, Bochum, with Spectralis . The preset high‐speed macula vertical line scan with eye‐tracking measured the thickness (in micrometre) and volume of the macula region (in cubic millimeter). Recordings were made with 61 B‐scans. The distance between the slices was 124 μm. The recorded diameter around the centered fovea was 6 mm. In this area, three circles of 1, 3, and 6‐mm diameter were set. This results in eight sectors plus the centered fovea (C0): inner superior: S1, outer superior: S2, inner temporal: T1, outer temporal: T2, inner inferior: I1, outer inferior: I2, inner nasal: N1, and outer nasal: N2.SD‐OCT of HCs was performed independently of this study in the Department of Ophthalmology, Bern, under comparable conditions with the same device model .Retinal layer segmentation was performed with Heidelberg Eye Explorer (Heyex) Segmentation Batch in an automated fashion with manual correction (in case of minor inaccuracies) or exclusion of scans or sectors in case of insufficient quality . This displayed the following structures: inner limiting membrane (ILM), RNFL, ganglion cell layer (GCL), inner plexiform layer (IPL), inner nuclear layer (INL), outer plexiform layer (OPL), outer nuclear layer (ONL), outer limiting membrane, neural layer, retinal pigment epithelium and basal membrane.All anonymized data were exported to an Excel file for further analysis.2.2.4MRI imaging was performed with a standardized protocol on a 1.5 Tesla scanner using sagittal high‐resolution T1‐weighted 3D MRI data (magnetization prepared rapid gradient echo) for voxel‐based morphometry as described earlier .For participants with left and right eye scans of sufficient quality, the means of both eyes were used for analyses. In individuals with only one available value due to quality selection, the single value was included in the analysis.U‐test with Bonferroni correction for multiple testing of different OCT parameters or Fisher's exact test (for sex distribution).For correlation analyses and comparison to HC, the sum of the inner ring (IR) sectors  of the following layers was used: GCL (primary outcome), RNFL, GCL + IPL layer (GCIPL), and total retina (secondary outcomes). The exploratory unadjusted correlation analysis was calculated for these layers and age, UHDRS motor and cognitive score, caudate volume, DBS, and YTO using Pearson's correlation coefficient. Pre‐HD and HC were compared using the Mann–Whitney All analyses were performed using IBM SPSS statistics, version 25 .2.4Written informed consent was obtained from all participants before enrollment. The examination of pre‐HD participants was conducted at the Department of Neurology, St. Josef‐Hospital, Ruhr‐University Bochum, Germany  and complies with the tenets of the Declaration of Helsinki. The further use of the data in an anonymized fashion was deemed appropriate by the ethics committee after change of the principal investigator to the University of Bern. The HC group was selected from the existing database of the Department of Ophthalmology, Inselspital, University Hospital and the University of Bern, Switzerland . All data were anonymized prior to analysis.33.1n = 24) and HC cohorts (n = 38) are given in Table p = .04).The characteristics of the pre‐HD  for pre‐HD and HC are summarized in Table 3.3The mean IR thicknesses of the retinal layers of interest did not show a significant correlation with age, clinical measures (UHDRS motor and cognitive score), caudate volume, DBS or YTO Table . Caudate3.4p = .002, Table The mean IR thicknesses for the GCL, GCIPL, and total retina did not differ between pre‐HD and HC. A slightly thicker IR RNFL was detected in pre‐HD patients (23.22 (2.91)) as compared to HC (21.26 (1.91), 4This cross‐sectional study distinctly investigated macular retinal layer thicknesses in a unique albeit small pre‐HD cohort. The exploratory correlations did not indicate associations of retinal layer thicknesses with established clinical, MRI and genetic parameters. Yet, among the clinical, MRI and genetic parameters, plausible and expected associations were detected. Despite the premanifest state, caudate volumes correlated with UHDRS motor and cognitive scores, which is in line with earlier findings of subtle changes in the prodromal phase of the disease , grant no. 01GI1601I, and received consulting and speaker's honoraria from Biogen, Bayer, Daiichi Sanykyo, Merck Serono, Novartis, Sanofi, Genzyme and TEVA. C Saft reports personal fees/honoraria from Teva Pharma GmbH, as well as nonfinancial support and other support from ENROLL‐HD study (CHDI), PRIDE‐HD (TEVA), LEGATO (TEVA), and Amaryllis (Pfizer), ASO , RROOF‐HD (Prilenia) for the conducting of studies and grants from Biogen all outside the submitted work and without relevance to the article. A Salmen received speaker honoraria and/or travel compensation for activities with Bristol Myers Squibb, CSL Behring, Novartis and Roche and research support from the Baasch Medicus Foundation and the Swiss MS Society, all not related to this work.https://publons.com/publon/10.1002/brb3.2592The peer review history for this article is available at Supporting information.Click here for additional data file.


Definitive evidence shows sedentary time (ST) is an independent risk factor for chronic disease, irrespective of physical activity. Despite calls to limit youth ST, studies demonstrate a spike in ST at the transition from childhood to adolescence. Identifying periods of the day  during which ST is higher in adolescents vs. children—that is, specifying when within daily routines ST disparities emerge—may be important to inform intervention strategies, as periods of the day correspond with variations in setting and supervision. The purpose of this study was to examine device-assessed ST engagement by period of day and developmental stage in a nationally representative sample of United States youth.N = 2,972 between 6–18 years) from the 2003–2004 and 2005–2006 waves of NHANES reported demographic variables and wore an accelerometer for seven consecutive days to determine ST. Linear regression analyses were applied to study associations between ST and developmental stage (childhood or adolescence) by period of the week and weekend days, while controlling for sex, race/ethnicity, annual family income, and body mass index.Youth  showed that adolescents were more sedentary than children during school, afterschool, and weekday evening periods as well as all the weekend periods. However, during school  and afterschool periods  showed the largest weekly ST disparities by developmental stage. Overall, the during school and after school hours constitute most (during school = 35% and afterschool = 16%) of the weekly ST disparity between children and adolescents.Adjusted linear regressions (Our data provide interventionists with estimates of the potential for ST reduction in each setting and period of the day among US adolescents. Future research should gather information about the barriers and facilitators of ST in adolescents by period of the day to help understand factors driving disparities.The online version contains supplementary material available at 10.1186/s12889-022-14447-4. Sedentary time (ST) in children is associated with adverse health risk factors including obesity, poor cardiometabolic markers , and pooYouth showed lower levels of ST during weekdays compared to weekend days over a two-year period in 970 youth (10 to 13 years of age) in Finland .N = 740, mean age = 10.9 years) of various durations  during each period of the weekday  )  = 587.5, p < 0.0001; b = -8.2 ). During school ST remained significant in the adjusted model  = 118.5, p < 0.0001; b = -7.4 ). This implies that children were less sedentary during school compared to adolescents after adjusting for sex, race/ethnicity, annual family income, and body mass index. Significant covariates of ST during school (see Table p < 0.0001) and body mass index .The unadjusted model indicated that developmental stage was not a significant predictor of ST before school  = 580.8, p < 0.0001; b = -8.9 ). Afterschool ST remained significant in the adjusted model  = 132.2, p < 0.0001; b = -7.8 ), which means that being a child was associated with less ST after school compared to being an adolescent even after including covariates in the model. Significant covariates of ST afterschool (see Table p < 0.0001) as well as being female  and Non-Hispanic Black .A difference of ST afterschool of 8.4 min/hour was observed when comparing children and adolescents. Over the course of a month, these differences constitute an 8-h ST disparity between children and adolescents. In all, the afterschool period accounted for 15.6% of the weekly disparity in ST between children and adolescents. The unadjusted model showed that developmental stage was a significant predictor of afterschool ST  = 702.7, p < 0.0001; b = -8.4 ) and this remained significant after adjustment for covariates  = 106.7, p < 0.0001; b = -7.6 ). This implies children accumulated less ST during the evening compared to adolescents, after adjusting for sex, race/ethnicity, annual family income, and body mass index. Significant covariates of ST during the evening (see Table p = 0.004) and Non-Hispanic Black .ST data during the weekday evening showed a difference of 7.7 min/hour when comparing children to adolescents. Over the course of a month, these differences also constitute an 8-h ST disparity between children and adolescents. In all, the evening period accounted for 14.4% of the weekly disparity in ST between children and adolescents. The unadjusted model showed that developmental stage was a significant predictor of ST during the evening  = 65.0, p < 0.0001; b = -7.7 ). Developmental stage remained a significant predictor of ST during the weekend morning  = 24.6, p < 0.0001; b = -7.1 ) after including covariates in the model. Therefore, being a child was associated with less morning ST compared to adolescents after adjusting for sex, race/ethnicity, annual family income, and body mass index. Significant covariates of ST during the morning (see Table p < 0.0001) and Other Hispanic .Weekend morning ST data revealed a difference of 7.1 min/hour when comparing children to adolescents. Over the course of a month, these differences also constitute a 5-h ST disparity between children and adolescents. In all, the weekend morning period accounted for 8.8% of the weekly disparity in ST between children and adolescents. The adjusted model controlled for sex, race/ethnicity, annual family income, and body mass index. The unadjusted models indicated that developmental stage was a significant predictor of ST during the morning  = 480.8, p < 0.0001; b = -10.1 ). Developmental stage remained a significant predictor of ST during the afternoon  = 92.3, p < 0.0001; b = -8.9 ) after including covariates in the model. Therefore, being a child was associated with less afternoon ST, compared to being an adolescent, after adjusting for sex, race/ethnicity, annual family income, and body mass index. Being a female , and body mass index  were significant covariates of ST during the afternoon  = 310.2, p < 0.0001; b = -9.1 ). Developmental stage remained a significant predictor of ST during the evening  = 60.5, p < 0.0001; b = -8.1 ) after including covariates in the model. Therefore, being a child was associated with less evening ST compared to being an adolescent after adjusting for sex, race/ethnicity, annual family income, and body mass index. Body mass index  was a significant covariate of ST during the evening  and adolescents (mean ST = 533.6 min/day ≈ 8.9 h/day), similar levels of overall ST were observed when compared to previous ST data in US youth which reported that children spend up to 6.0 h/day and adolescents spend up to 8.5 h/day in ST [Within a weekday, the afterschool period showed the largest difference in ST (8.4 min/hour) by developmental stage. However, when the differences at each weekday period were extrapolated, the during school period emerged as the most potentially promising time to reduce ST developmental stage disparities since the daily difference between children and adolescents almost reached one hour (56.7 min/day or 35% difference). On the other hand, the weekend day data by developmental stage revealed that the smallest difference in ST occurred during the weekend morning period (7.1 min/hour) and the largest difference occurred during the weekend afternoon period (9.2 min/hour). Similarly, when the differences at each weekend day period were extrapolated, the afternoon period emerged as the most potentially promising time to reduce these disparities since the daily difference between childhood and adolescence was almost an hour (57.6 min/day or 14% difference). Previous research has shown that if youth substitute 60 min of ST with 60 min of light physical activity , moderatThe accelerometer recorded ST disparities by developmental stage were much larger on weekdays afterschool and during weekend afternoon periods. This may reflect a shift in structured programming between childhood and adolescence. Adolescents are much less likely to be enrolled in structured extracurricular physical activity programs. In adolescence, academic demands also increase and homework responsibilities may displace the physical activity that adolescents tend to participate in during the afternoon hours when they are younger.Evidence supports the potential role of increasing schoolwork demands on ST as children age . A CanadOur weekday findings provided evidence to support our first hypothesis that children would be less sedentary than adolescents during school and afterschool periods. However, it was surprising that developmental stage was a significant predictor of ST during the evening. In terms of the weekday evening difference in ST, the first hours (6:00 p.m. – 7:30 p.m.) of the weekday evening period can be an extension of the afterschool period, in which some youth are still participating in afterschool activities, though perhaps, accessibility to screens and homework demands also play a role here. Similarly, weekend data supported our second hypothesis that children would be less sedentary during the afternoon and evening compared to adolescents. However, the differences during the weekend morning period were unexpected and can be explained, in part, by adolescents’ accessibility to electronic devices that promote ST compared to children’s accessibility to such devices. For instance, some parents ask children to make their bed, take a shower, and have breakfast before starting the day, and if screen time is part of the routine, it is probable that they will engage in screen time under the adult’s supervision.Our findings confirm previous literature stating that adolescents are more sedentary than children during the weekday periods and weekend. In Spain, a cross-sectional study revealed male adolescents spend 255.6 ± 32.3 min/day sedentary compared to male children who spent 192.7 ± 27.4 min/day . A similIt is believed that recreational screen time is a likely contributor to disparities in ST between adolescents and children. With age, parents give children more autonomy and discretion to decide how they use their leisure time. This can promote the use of smartphones, desktop, and laptop computers, which are very accessible to adolescents. Since 2014 – 2015, there has been a 22% increase (from 77 to 95%) in the number of US adolescents who have access to a smartphone and a 3% increase (from 87 to 90%) in those who have access to desktop and laptop computers . Furtherwhy adolescents are more sedentary during each period of the day. Therefore, future studies should be conducted to gather information about the barriers and facilitators of ST in adolescence specific to each period of the weekday and weekend day. The design of the study also does not allow us to determine causality; therefore, we cannot say that too much ST is caused by being an adolescent, though the inverse (ST causes adolescence) is impossible.Although this study is the first to use a US-based nationally representative sample to test differences in ST by developmental stage and periods of the day, it is not exempt of limitations. Thigh-worn accelerometers are more accurate than waist-worn accelerometers for measuring ST (due to their ability to assess participant posture). However, it has been reported that thigh-worn accelerometers reduce wear-time compliance , 32 due The current study’s analyses accounted for the NHANES complex sampling design to account for stratification, clustering, and weighting as well as sex, race/ethnicity, annual family income, and body mass index. Although previous cross-sectional and longitudinal studies have shown adolescents are more sedentary than children, to our knowledge, this is the first study to examine differences by periods of the day in a US sample. Findings confirm adolescents are more sedentary than children during most of the weekday periods  and all weekend day periods , though there is substantial variability in the magnitude of the disparities by period of the day (weekly disparities ranging from 9 to 35%). Evidence suggests that during school and afterschool periods contributed most to sedentary disparities overall, though substantial disparities also exist in periods of the day that correspond with time at home. This provides insight for future interventions, on when and where interventions should seek to reduce ST levels in adolescents.Additional file 1: Table A1. Accelerometer Data Processing Specifications [ications , 36.Additional file 2: Table A2. Description of the Linear Regression Syntax for SAS.Additional file 3: Table A3. Regressions of Sedentary Time on Each Weekday Period on Developmental Stage.Additional file 4: Table A4. Regressions of Sedentary Time During Each Weekend Period on Developmental Stage.


Studies of the association between body mass index (BMI) at diagnosis and treatment outcome in children with acute lymphoblastic leukemia (ALL) have yielded inconsistent results. Hence, we conducted a retrospective study in a large cohort of Chinese children with ALL treated with contemporary protocols.A total of 1437 children  were enrolled in two consecutive clinical trials at the Shanghai Children's Medical Center. The rates of overall survival, event‐free survival, relapse, treatment‐related mortality, and adverse events were compared among patients who were underweight (BMI < 5th percentile), at a healthy weight (5th to 85th percentile), overweight (>85th to <95th percentile), and obese (≥95th percentile).p = 0.02). The treatment‐related mortality rate was higher in the overweight  and obese  groups compared with the underweight (0.0%) and healthy‐weight groups . Multivariable analysis showed that children who were overweight had a higher risk of treatment‐related mortality .At diagnosis, 91 (6.3%) patients were underweight, 1070 (74.5%) were at a healthy weight, 91 (6.3%) were overweight, and 185 (12.9%) were obese. No significant association was found between weight status and 5‐year overall survival, event‐free survival, or relapse in the overall cohort. When analyzed as a continuous variable, a higher BMI Z‐score was associated with treatment‐related mortality , While body weight status was not associated with event‐free survival or overall survival, overweight patients were at higher risk of treatment‐related mortality. We found that overweight/obese children were at higher risk of treatment‐related mortality and developing severe toxicities than underweight or health‐weight children. Our findings reinforce the importance of the normalizing weight during the treatment period to improve survival and treatment outcomes. In the initial study of Children's Oncology Group (COG) of patients enrolled between 1988 and 1995, the 343 obese patient had significantly worse 5‐year event‐free survival (EFS) (72% vs. 77%) than the 3071 nonobese patients.22.1This retrospective study was conducted in a cohort of patients with pediatric ALL who were treated at the Shanghai Children's Medical Center (SCMC) in China. This study was approved by the Research Ethics Board at SCMC. Written informed consent was obtained from the parents or legal guardians of all patients.Children aged 2 to 18 years who were newly diagnosed with ALL between May 1, 2005 and June 30, 2018 were included in the study. Patients who were diagnosed before December 31, 2014 were treated on the SCMC‐ALL‐2005 protocol.Patients younger than 2 years of age at diagnosis were excluded from this study due to the limited diagnostic accuracy of BMI percentile calculation for this age group. Patients lacking data for BMI at diagnosis were also excluded.2.2http://www.pond4kids.org), an online pediatric oncology database developed by St. Jude Children's Research Hospital. The data of patients treated with the CCCG‐ALL‐2015 protocol were retrieved from the Leukemia Registry and Management System of the National Children's Medical Center. Both databases include patient‐specific data, such as clinical diagnosis, adverse events, follow‐up, morbidities and mortality, and information on hospitalization. The databases have been proven to be reliable sources of health administrative data for conducting epidemiological research in China.All study data were retrieved from in‐house electronic databases. The data of patients treated with the SCMC‐ALL‐2005 protocol were retrieved from the Pediatric Oncology Network Database . It is well established that the thresholds for overweight and obesity in children are defined differently in Western and Asian populations.BMI was calculated by dividing the body weight in kilograms by the square of height in meters  was calculated from the date of diagnosis to death from any cause or the last follow‐up.2.5Descriptive statistics  were used to summarize the patient characteristics of the cohort. EFS and OS curves were estimated according to the Kaplan–Meier method, and the log‐rank test was used to compare survival among different BMI groups . Confidence intervals (CIs) for effects of different BMI groups were calculated.The chi‐square test was used to detect differences between BMI categories, stratified by well‐documented risk factors for poorer outcomes in ALL. These factors included older age, higher white blood cell count, CNS involvement, T‐cell immunophenotype, presence of specific cytogenetics abnormalities, MRD by the end of induction and protocol.p value <0.05 (two‐sided test) was considered statistically significant.All statistical analyses were performed using R statistical software version 3.4.4. For all tests, a 33.1p = 0.03).Of the 1492 patients aged 2 to 18 years who were enrolled in the SCMC‐ALL‐2005 or CCCG‐ALL‐2015 protocol, BMI data were available for 1437 (96.3%) patients. Among these 1437 patients, the median age at diagnosis was 5.1 years (range: 2.0–17.9 years), and 62.1% (893/1437) were male. Outcome data were updated on November 30, 2021; the median follow‐up time was 6.3 years . Two‐thirds (64.0%) of the patients were treated on the SCMC‐ALL‐2005 protocol, while the others (36.0%) were treated on the CCCG‐ALL‐2015 protocol. The majority of patients (97.2%) achieved complete remission after induction therapy. At diagnosis, 91 (6.3%) patients were underweight, 1070 (74.5%) were at a healthy weight, 91 (6.3%) were overweight, and 185 (12.9%) were obese. The median Z‐score was 0.2 (range − 5.7 to 5.6). Table 3.2p = 0.10; Figure p = 0.50, Figure p = 0.70; Figure The 5‐year OS was lower in overweight and obese patients  than in the other groups, although the estimates were not significantly different from healthy‐weight  or underweight patients  and marginally poorer EFS . An increase in BMI Z‐score was also associated with a higher hazard of treatment‐related mortality . We did not observe significant association between BMI Z‐score and the 5‐year cumulative risk of relapse .When analyzed as a continuous variable, a higher BMI Z‐score was associated with poorer OS . Within patients with BCR‐ABL1 fusion, the EFS was extremely poor in obese patients (0%), as compared to underweight , healthy‐weight , and overweight  patients (p < 0.001). The OS was also extremely poor in obese patients with BCR‐ABL1 fusion (0%), as compared to underweight , healthy‐weight , and overweight  patients (p < 0.001). All six obese BCR‐ABL1‐positive patients were treated by SCMC‐ALL‐2005 protocol and none of them received tyrosine kinase inhibitor (TKI). Four of them relapsed, one had resistance disease and one died from toxicity. Among other clinical and biological subgroups, there were no significant differences in the 5‐year EFS or OS between healthy‐weight, underweight, overweight, and obese patients p < 0.001), MRD positivity by the end of induction (p < 0.001), and receiving SCMC‐ALL‐2005 protocol treatment (p < 0.001), and male sex (p < 0.001)  Table .3.3Among the 1437 patients, 31 (2.2%) died of toxicities, including 22 infections , three hemorrhages, one intracranial hypertension, one renal failure, and four transplant‐related complications .p = 0.04; Figure p = 0.02) and the SCMC‐ALL‐2005 protocol  were associated with higher treatment‐related mortality  compared with underweight (0.0%) and healthy weight . The infection‐related  and non‐infection‐related mortality rates  were marginally higher in the overweight group, as compared to the healthy‐weight group  was higher in the overweight group than the healthy‐weight group .Only healthy‐weight, overweight, and obese patients were included in the Common Terminology Criteria for Adverse Events grade 4–5 toxicity analysis Table , as ther4Obesity is a well‐established risk factor for mortality and relapse of certain cancers in adults. However, the evidence for the effects of obesity in pediatric leukemia remains inconsistent. This retrospective analysis evaluated the relationship between BMI at diagnosis and treatment outcomes in children with ALL. Our main analysis suggested that while weight status was not associated with survival, children who were overweight were at higher risk of treatment‐related mortality. There was also a significant trend between higher BMI Z‐score and poorer OS, as well as overall mortality. Taken together, our study concurs with the existing literature on the importance of weight control during diagnosis and treatment in children with leukemia.To the best of our knowledge, this is one of the largest studies to examine the impact of weight status on OS, EFS, and mortality in the Asian population. Using BMI growth curves for Chinese children as a reference, the rate of obesity among Chinese children in this study (12.9%) is comparable to that of populations in the United States and Europe (13.0%–20.7%),Overall, BMI groups at diagnosis did not significantly predict poorer OS, EFS, or relapse in our study. Inconsistent results have been reported in the literature. A recent meta‐analysis of 11 studies conducted in high‐income countries reported that pediatric ALL patients with a higher BMI had a 1.35 times higher risk of not achieving EFS than patients with a lower BMI; the association was present across all ages at diagnosis and leukemia phenotypes.BCR/ABL1 mutation. This finding should be interpreted cautiously as the six obese patients with BCR/ABL1 mutation were treated in the earlier era and did not receive TKIs, which is now recognized as an integral treatment for individuals with BCR/ABL1 mutation. It may be possible that the effects of obesity may be more pronounced in patients who are already at risk for poorer survival outcomes due to the presence of specific genotype abnormalities and other risk factors.At baseline, we did not identify differences in presenting features across the BMI groups. However, our stratified analysis suggested that the adverse effects of obesity on survival were more prominent in patients with certain risk factors, particularly B‐cell immunophenotype and After adjusting for clinically relevant factors, we found that patients who were overweight/obese at diagnosis had significantly higher treatment‐related mortality and trended toward lower OS than underweight and healthy‐weight patients. Overweight/obese patients may have immunological abnormalities that increase the likelihood of infection‐related death.Inconsistent findings on the effect of obesity in treatment outcomes may indicate that the pathophysiology of obesity's influence on leukemia is multifactorial and influenced by various factors.Despite having a relatively large, well‐characterized sample with reliable sources of morbidity and mortality data, our findings should be considered in the context of several limitations. First, the patients in the study cohort were recruited from a single pediatric center in a relatively affluent urban city. Thus, it is unlikely to be a representative cohort, as China is a geographically large region with differences in resources between urban and rural areas. Hence, the rates of obesity and underweight, as well as the rate of mortality, are not generalizable to all Chinese children with ALL in the country. Second, this cohort consisted of patients who were diagnosed and treated for ALL from 2005 to 2018; there was a substantial improvement in the quality of medical and supportive care throughout the decade. Furthermore, we also found a significant association between overweight/obese and treatment‐related mortality within the CCCG‐ALL‐2015 protocol but not the earlier SCMC‐ALL‐2005 protocol; this finding suggested that the associations observed in the overall cohort might be driven by the ALL treatment regimens. Although we adjusted for demographic and clinical variables, other confounding factors not captured in this study might affect the association between weight and treatment outcomes. For example, socioeconomic status and behavioral factors, such as dietary intake and physical activity, were not assessed. Studies have also shown that weight management in children is a function of the family system5While BMI status was not associated with EFS or OS in the overall cohort, we observed significant trends between higher BMI Z‐scores and poorer OS, and increased treatment‐related mortality. Chinese children with ALL who were overweight or obese also had a higher risk of treatment‐related mortality and developing severe toxicities. Weight control should be considered at diagnosis and early during treatment to reduce treatment‐related mortality in patients who are overweight/obese at diagnosis. In this regard, normalization of weight during the treatment period was found to mitigate the risk of lower EFS in a COG study.Our findings should be validated in larger multicenter studies to better understand the association between overweight/obesity at diagnosis and pediatric ALL outcomes.Wenting Hu: Formal analysis (lead); writing – original draft . Yin Ting Cheung: Formal analysis (lead); methodology ; writing – original draft . Yanjing Tang: Data curation ; investigation ; validation . Li Hong: Investigation ; methodology ; supervision . Yuan Zhu: Methodology ; resources . Jing Chen: Investigation ; supervision . Zhuo Wang: Investigation ; validation . Min Zhou: Data curation ; validation . Yijin Gao: Methodology ; validation . Jing Chen: Methodology ; supervision . Benshang Li: Investigation ; validation . Huiliang Xue: Investigation ; supervision . Longjun Gu: Investigation ; supervision . Shuhong Shen: Investigation ; supervision . Jingyan Tang: Investigation ; supervision . Ching‐Hon Pui: Methodology ; supervision ; writing – review and editing . Hiroto Inaba: Methodology ; writing – review and editing . Jiaoyang Cai: Formal analysis (lead); methodology ; data curation (lead); writing – review and editing .Table S1Table S2Table S3Table S4Figure S1Click here for additional data file.


To investigate the association between assisted reproductive technology (ART) use and childhood cancer subtype.We deployed a cross‐sectional survey of 1701 parents of children with cancer about their ART use, demographics, and gestational and perinatal factors. Multivariable logistic regression modeled the association between ART use, birthweight and multiple gestation status with childhood cancer, by subtype.p = 0.0020). ART use was also elevated among children with hepatoblastoma, but this relationship appeared to be due to the strong associations between ART use and lower birthweight in our sample. No specific ART modality appeared to drive these associations. In univariate models, multiple gestation was associated with a 2.7‐fold increased odds of hepatoblastoma  and a 1.6‐fold increased odds of neuroblastoma , but these associations were not retained in multivariable models.ART use was highest among children with osteosarcoma relative to children with other cancer types, and this association was statistically significant in multivariable models (OR = 4.4; 95% CI = 1.7–11.3; Associations between ART use and hepatoblastoma risk may be attributable to birthweight, a known hepatoblastoma risk factor. ART use may also be associated with osteosarcoma, independent of birthweight, an association not previously observed in studies limited to cancers diagnosed before adolescence. Evaluating long‐term health outcomes in children conceived by ART, throughout adolescence and potentially into adulthood, appears warranted. Epidemiologic data suggest an increase in U.S. childhood cancer incidence overall, though rates vary across cancer subtypes and few modifiable risk factors for childhood cancer have been identified. A cross‐sectional survey of 1701 parents of children with cancer revealed associations between use of assisted reproductive technology and risk of childhood hepatoblastoma and osteosarcoma. the latter of which has not been previously observed in studies limited to cancers before adolescence. Evaluating long‐term health outcomes in children conceived by ART, throughout adolescence and potentially into adulthood, appears warranted. For example, rates of hepatoblastoma and central nervous system (CNS) tumors increased substantially from 1992–2004.Although numerous genetic factors increase childhood cancer risk, relatively few modifiable risk factors have been conclusively identified. Several pre‐ and perinatal factors have been associated with childhood cancer risk, including in utero exposure to ionizing radiation,The use of assisted reproductive technologies (ART) to conceive is increasingly common – accounting for 1.9% of U.S. births in 2017 – and has previously been associated with elevated childhood cancer risk.My Childhood Cancer: Survey Series cohort. Parents representing >1700 childhood cancer patients provided data on ART utilization, multiple gestation status, birthweight, and other demographic and pre/perinatal factors. We sought to examine whether ART use confers greater risk of specific childhood cancer subtypes, accounting for contributions from other prenatal/perinatal factors.To evaluate the association of ART with childhood subtypes, we performed a cross‐sectional analysis of childhood cancer patients from Alex's Lemonade Stand Foundation's 22.1My Childhood Cancer (MCC): Survey Series explores families' experiences and attitudes from diagnosis, throughout treatment and follow‐up care, and after bereavement (when applicable).MCC survey series. In this cross‐sectional study, we examined responses to the ALSF MCC diagnosis survey completed between August 2012 and April 2019, as prior versions of the survey did not collect data on ART use. Thus, analyses for this study were performed on the subgroup with available ART data (N = 1701 respondents), limiting to one parental respondent per family. Median time from diagnosis to survey completion was 2 years.To explore associations between ART use and childhood cancers, we have partnered with Alex's Lemonade Stand Foundation (ALSF) to conduct an ongoing series of longitudinal surveys of families affected by childhood cancer. Initiated in 2011, the ALSF 2.2MCC: Survey Series registration. Survey respondents were asked “Did [child]’s biological mother receive any medical help in order to become pregnant with [child]?” Responses of “Yes” and “No” were collapsed into an indicator for ART use. Those who responded “Not sure” were excluded. Those who indicated that they received medical help to conceive were asked to answer whether any or all of the following methods of ART were used: IVF, fertility drugs, donor sperm/donor eggs, ICSI, IUI, and GIFT. At the time of data analysis, FET was not a specified ART modality in the survey, but has since been added. We assume that any respondents whose child was conceived via FET would have answered “Yes” to the ART question, and may have additionally endorsed additional ART modalities . The “Yes” and “No” answers to these questions along with the “No” answers to any ART use were collapsed into binary indicators for each ART modality. Respondents who reported use of more than one ART type were included in each specific ART type variable used, but were counted only once in the overall ART use variable. Respondents (94% U.S.‐based) recorded child's birthweight in categories to the nearest pound in the following bins: “3 pounds or less” (≤1.80 kg), “4–5 pounds” (1.81–2.72 kg), “6–9 pounds” (2.73–4.53 kg), “10–11 pounds” (4.54–5.44 kg), “12 pounds or more” (≥5.45 kg), and “Not sure”. Birthweight was modeled as an ordinal variable. A question about whether the child with cancer was a singleton or multiple gestation was collapsed into an indicator for multiparity. Respondent race/ethnicity was collapsed into an indicator for “non‐Hispanic white” versus “American Indian/Alaskan Native,” “Native Hawaiian/Pacific Islander,” “Black/African American,” “Other race,” and “Hispanic or Latino (of any race).” Household income was recorded in the following bins: <$20,000; $20,000–$49,999; $50,000–$74,999; $75,000–$99,999; $100,000–$149,999; ≥$150,000 and modeled as an ordinal variable. Median time from diagnosis to survey completion was 2 years and did not differ across cancer subtype.Childhood cancer type and patient/parental demographics are collected at Dependent variables were specific childhood cancer subtype compared to all other subtypes collapsed, including: Hodgkin's lymphoma, non‐Hodgkin's lymphoma, germ cell tumor, Kidney/Wilms' tumor, hepatoblastoma/liver cancer, neuroblastoma, retinoblastoma, rhabdomyosarcoma, osteosarcoma, Ewing sarcoma, an “all sarcomas” subgroup, ALL, and acute myeloid leukemia (AML). We also included three brain/spinal tumor subgroups: primitive neuroectodermal tumors (PNETs) including medulloblastoma, supratentorial PNETs, and atypical teratoid/rhabdoid tumor (AT/RT); glioma, including astrocytoma/anaplastic astrocytoma, juvenile pilocytic astrocytoma (JPA), diffuse intrinsic pontine glioma (DIPG), glioblastoma; and ependymoma.2.3Independent variables of interest in this analysis included ART use, ART type, birthweight, and multiple gestation status. Survey respondent's race/ethnicity, household income, prematurity (birth prior to 37 weeks gestation), presence of other siblings, delivery mode , maternal age, child's birth year, and years between child's birth and survey completion were included in models as potential confounders. We also included child's sex in models because it could potentially act as a confounder t‐tests for difference. Fisher's exact tests were used when analyzing specific ART types due to small sample sizes. For multivariate analyses, logistic regression was used to examine potential relationships between variables and to control for potential confounders. Our study design, in which a specific cancer subtype is compared to all other childhood cancer subtypes pooled, can reduce differential recall bias since all surveyed parents had a child diagnosed with cancer. Missing data rates for modeled covariates were very low . If data were missing for a modeled covariate, that individual was excluded from the model. For all statistical tests, alpha = 0.05 was used to determine statistical significance. Stata version 16.0 was used for data analysis.Relationships between independent and dependent variables were assessed using chi‐square tests for independence or 3Between August 2012 and April 2019, a total of 1701 respondents from unique families completed the diagnosis survey asking about use of ART to conceive. Median time from diagnosis to survey completion was 2 years (IQR = 1–7). Respondents were largely female, the biologic parent, and identified as non‐Hispanic white. The majority of children were 6–9 pounds at birth (2.72–4.53 kg), singletons, and had siblings at the time of diagnosis (Table p = 0.01) and a 2‐fold increased odds of hepatoblastoma , although this latter association did not reach statistical significance. Multiple gestation was associated with a 2.7‐fold increased odds of hepatoblastoma  and a 1.6‐fold increased odds of neuroblastoma . Children with hepatoblastoma had significantly lower birthweight than children with other cancer types (p < 0.001), while children with germ cell tumors had modestly higher birthweight than children with other cancer types (p = 0.08)  Table .p < 0.001) and with being a multiple gestation (p < 0.001). Multiple gestations were also associated with lower birthweight (p < 0.001). To disentangle these associations, we compared each childhood cancer subtype to all other cancer subtypes collapsed, and report childhood cancer subtype associations for ART use, multiple gestation status, and birthweight from multivariable models additionally adjusted for child sex, race/ethnicity, household income, years between birth and survey completion, gestational age, presence of siblings, delivery mode, maternal age, and child's birth year. In this multivariable model, the association between ART use and osteosarcoma persisted . For hepatoblastoma, however, the magnitude of effect from univariate analyses (OR = 2.03) was strongly attenuated in the multivariable model  , and the magnitude of effect was greatly attenuated in multivariable models accounting for birthweight. Multiparity and low birthweight were significantly associated with hepatoblastoma risk in univariate analyses, corroborating previous studies.,Similar to prior studies, we observed a two‐fold increase in ART use among hepatoblastoma patients compared to children with other cancers. This association was not statistically significant given the modest number of hepatoblastoma patients in our dataset , limiting precision of our effect estimates. Self‐report biases, including recall bias, may be reduced by utilizing certain study design strategies  and by prospectively enrolling participants. For studies which cannot feasibly enroll prospectively, recall bias can be minimized by recruiting participants with recent diagnoses to shorten recall periods, and by accounting for time elapsed between diagnosis and exposure measurement in the analysis stage using adjustment or stratification. Additionally, self‐report bias may be further reduced by employing high‐quality, validated questionnaires which accurately measure a well‐defined exposure, such as ART use. Another limitation to our study is potential confounding due to the unknown relationship between parental infertility itself and risk of cancer in children, as well as limited information on the presence of birth defects and other congenital abnormalities. Finally, ART information was from self‐report and could not be independently validated, but unlike some registry‐based approaches, our data enabled us to examine associations within strata of specific ART modalities.Birth registries often capture ART use unreliably and have historically limited data capture to IVF, thus excluding other forms of ART.Because ART is an increasingly prevalent means of conception, it is important to understand any potential associated risks. Our findings support prior investigations linking ART use to risk of hepatoblastoma, and suggest this association may be attributable to the effect of low birthweight and/or prematurity, an established hepatoblastoma risk factor. Finally, we observed a novel, birthweight‐independent association between ART use and osteosarcoma, emphasizing the need to continue studying ART‐associated cancer risks beyond the first 10 years of life, into adolescence and perhaps continuing throughout adulthood.study conception/design, methodology, and investigation: Gulrajani, Walsh, Landi, Hill, Montes, McGough, Wimberly, Khattab, Semmes, Towry, Hurst, Cohen; supervision/oversight: Hill, Towry, Walsh; funding acquisition: Walsh; data curation: Gulrajani, Hill, Towry, Wimberly; formal analysis: Gulrajani; resources: Towry, Walsh; draft manuscript preparation: Gulrajani. All authors reviewed the results and approved the final version of the manuscript.The authors confirm contribution to the paper as follows: This study was supported by a grant from Alex's Lemonade Stand Foundation (KMW). The funder hosts and advertises the survey portal from which data in this manuscript were collected. The funder had no role in data analysis or interpretation, although an employee of ALSF (LT) is a co‐author of this manuscript in recognition of her significant contributions to constructing and piloting the surveys and her participation in reviewing the final version of the manuscript presented here.The authors have no conflicts of interest to disclose.This study was approved by the Duke University Institutional Review Board (Pro00100771) and did not require informed consent.Table S1Table S2Click here for additional data file.