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Background/Aims Haemophagocytic lymphohistiocytosis (HLH) is a devastating condition caused by uncontrolled activation of the immune system. If left untreated, the condition leads to multi-organ failure and death. Even with treatment, recent UK data has shown a mortality rate of 50%. In 2019, a group of clinicians from University College London Hospital (UCLH) came together with the aim of improving outcomes for patients with HLH. The UCLH HLH multi-disciplinary meeting (MDM) has been running since that time and includes representation from rheumatology, haematology, infectious diseases, tropical medicine, virology, neurology, and critical care. Clinicians from any UK trust are invited to join and present patients. As part of a service evaluation project, we aimed to assess the scope of this meeting with regards to the number, demographics and primary diagnoses of patients discussed and the geographical location of the referring clinical team. Methods This is a retrospective descriptive analysis of all patients discussed at the UCLH HLH MDT from 2nd September 2020 to 20th July 2022. Data were obtained from electronic health records and analysed in Prism version 9.4.1. This work has been registered as a service evaluation project within the Division of Medical Specialities at UCLH. Results 93 patients were discussed. 38 were female. 55 were male. The median age was 38 years. Triggers for HLH were haematological malignancy (38.0%), infection (29.3%) rheumatological (14.1%) primary HLH (6.5%) and unknown (7.6%). In 4 patients, HLH was not felt to be the underlying diagnosis. 40 patients were managed as inpatients at UCLH, 37 of whom were transferred from other trusts. Geographical data were obtained on 81 patients. Patients were referred from all 9 regions of England: London (34), North East (1), North West (2), Yorkshire (2), East Midlands (1), West Midlands (3) South East (11), East of England (11), South West (11) as well as Wales (2), Scotland (2) and Ireland (1). Haemophagocytosis was confirmed on bone marrow biopsy in 66.7% of patients. Mortality data showed that 32 (34%) patients died following their diagnosis. Conclusion A multi-disciplinary approach is essential in the management of HLH. Our data show that patients with HLH are young, have a high mortality and broad range of pathology. The UCLH HLH MDT currently serves a wide geographical area across the UK and UCLH acts as a tertiary referral centre for patients with the condition. Disclosure N.S. Shah: None. M. Hutchinson: None. S. Clark: None. E. Sanchez: None. M. Brown: None. N. Stone: None. A.S. Carr: None. B. Carpenter: None. A. Laurence: None. S.H. Gohil: None. R.S. Tattersall: None. J.J. Manson: None. A. Jones: None.

Background/Aims Objective assessments of disease activity and response to treatment in axial spondyloarthritis (axSpA) remain a challenge. Diffusion-weighted magnetic resonance imaging (DW-MRI) and chemical shift-encoded MRI (CSE-MRI) inform on bone marrow oedema and fat content and could provide more accurate assessments of disease activity and therapeutic response. This study aims to determine the responsiveness and validity of quantitative imaging biomarkers (QIBs) obtained from DW-MRI and CSE-MRI using the partially-automated Bone Edema and Adiposity Characterisation with Histograms (BEACH) tool in patients with axial spondyloarthritis undergoing biologic therapy. Methods Conventional MRI, DWI and CSI was performed on 30 patients with active axSpA at baseline and after 12 - 16 weeks of biologic treatment. Apparent diffusion coefficient (ADC) and proton density fat fraction (PDFF) measures were analysed using the BEACH tool. Conventional MR images were assessed using established visual scoring methods. QIBs were assessed in terms of change after treatment and correlation with clinical and conventional MRI measures of disease activity. Results There were significant reductions for ADC values, while PDFF-scores showed nonsignificant reductions. Responsiveness to therapy was moderate for ADC measures and comparable to established visual scoring methods for bone marrow oedema. ADC and PDFF correlated well with conventional bone marrow oedema and fatty change scores respectively. Inter-observer variability was lower for QIBs compared with conventional visual scores methods. Conclusion ADC measures are sensitive to changes in inflammation in axSpA following biologic therapy and show promise as a biomarker of disease activity in axSpA. Disclosure A. Jones: None. T.J.P. Bray: None. N. Sakai: None. A. Bainbridge: None. C. Ciurtin: None. M.A. Hall-Craggs: None.

Background/Aims Haemophagocytic lymphohistiocytosis (HLH) is a rare systemic inflammatory condition that is characterised by excessive macrophage activation in response to a wide range of triggers, including infections, rheumatological and haematological conditions. HLH is associated with high morbidity and mortality, and treatment requires significant immunosuppression. University College London Hospitals (UCLH) operates an HLH service; we were keen to understand the burden of infective complications in our cohort of patients and establish specific guidelines. Methods A retrospective descriptive analysis was performed of all adults with secondary HLH over a two-year time-frame (1stApril 2019 to 1st April 2021) at UCLH. UCLH has a designated HLH multi-disciplinary team (MDT) supported by rheumatology, infectious diseases, tropical medicine, virology, haematology and critical care. This work was registered as a service evaluation project by the Medical Specialities Division. Data was collated from electronic health records into REDCap, and processed in R version 1.4.1103 and Microsoft Excel by two independent authors. Results 40 patients were identified, with a median age of 37. 14 patients had an identified haematological trigger (35%), 12 an infectious one (30%) and 5 a rheumatological (12.5%). 24 patients (60%) were admitted to intensive care and 13 died during admission (32.5%). 35 patients (87.5%) received steroids at some time during their admission, with 24 (60%) receiving a long course. Four patients (10%) had prolonged neutropaenia during admission. Twenty-four patients (60%) developed an infection during their admission; with 33 bacterial, 7 viral and 12 fungal infections (5 proven, 2 probable and 5 possible) identified. Sixteen patients had >1 infection. Those who did not have a diagnosed infection during their admission were more likely to survive than those who did (93% vs 44%, p = 0.047). The mortality rate of those with fungal infections was 89%, compared to 43% for bacterial and viral infections. Of the 24 patients who received a long course of steroids, 14 (58%) did not receive anti-fungal prophylaxis during their admission and three of these patients were diagnosed with fungal infections during their admission. Of the 4 patients with prolonged neutropenia, 1 (25%) did not receive antifungal prophylaxis and did suffer from a confirmed fungal infection. One patient with confirmed PCP had not previously been taking PCP prophylaxis. Of the seven patients with viral infections, 2 had HSV-1 infections and neither had received anti-viral prophylaxis before their infection start date. Conclusion We demonstrate that a high proportion of patients with HLH develop infective complications, which is associated with increased mortality. Prior to this analysis, the use of antimicrobial prophylaxis was variable. We have since written a specific guideline for the routine use of antimicrobial prophylaxis for patients with HLH, with a view to auditing future care against this guideline. Disclosure P. Saha: None. N. McCann: None. M. Brown: None. N. Stone: None. E. Sanchez: None. B. Carpenter: None. A. Laurence: None. M. Hutchinson: None. A. Jones: None. S.H. Gohil: None. J. Manson: None.

Imaging, and particularly MRI, plays a crucial role in the assessment of inflammation in rheumatic disease, and forms a core component of the diagnostic pathway in axial spondyloarthritis. However, conventional imaging techniques are limited by image contrast being non-specific to inflammation and a reliance on subjective, qualitative reader interpretation. Quantitative MRI methods offer scope to address these limitations and improve our ability to accurately and precisely detect and characterise inflammation, potentially facilitating a more personalised approach to management. Here, we review quantitative MRI methods and emerging quantitative imaging biomarkers for imaging inflammation in axial spondyloarthritis. We discuss the potential benefits as well as the practical considerations that must be addressed in the movement toward clinical translation of quantitative imaging biomarkers.

To date, the American Psychological Association Ethical Standards and Code of Conduct does not include direct guidance about how psychologists should navigate social media. Given the variety of rol...

Background Excessive screen time ($$\ge$$ ≥ 2 h per day) is associated with childhood overweight and obesity, physical inactivity, increased sedentary time, unfavorable dietary behaviors, and disrupted sleep. Previous reviews suggest intervening on screen time is associated with reductions in screen time and improvements in other obesogenic behaviors. However, it is unclear what study characteristics and behavior change techniques are potential mechanisms underlying the effectiveness of behavioral interventions. The purpose of this meta-analysis was to identify the behavior change techniques and study characteristics associated with effectiveness in behavioral interventions to reduce children’s (0–18 years) screen time. Methods A literature search of four databases (Ebscohost, Web of Science, EMBASE, and PubMed) was executed between January and February 2020 and updated during July 2021. Behavioral interventions targeting reductions in children’s (0–18 years) screen time were included. Information on study characteristics (e.g., sample size, duration) and behavior change techniques (e.g., information, goal-setting) were extracted. Data on randomization, allocation concealment, and blinding was extracted and used to assess risk of bias. Meta-regressions were used to explore whether intervention effectiveness was associated with the presence of behavior change techniques and study characteristics. Results The search identified 15,529 articles, of which 10,714 were screened for relevancy and 680 were retained for full-text screening. Of these, 204 studies provided quantitative data in the meta-analysis. The overall summary of random effects showed a small, beneficial impact of screen time interventions compared to controls (SDM = 0.116, 95CI 0.08 to 0.15). Inclusion of the Goals, Feedback, and Planning behavioral techniques were associated with a positive impact on intervention effectiveness (SDM = 0.145, 95CI 0.11 to 0.18). Interventions with smaller sample sizes (n Conclusions Both intervention content and context are important to consider when designing interventions to reduce children’s screen time. As interventions are scaled, determining the active ingredients to optimize interventions along the translational continuum will be crucial to maximize reductions in children’s screen time.

The Strong Black Woman (SBW) schema has been consistently linked to negative mental health outcomes among Black women. However, few have begun to explicate the mechanisms by which the endorsement of the SBW schema may influence mental health outcomes. Accordingly, the current study examined coping styles (social support, disengagement, spirituality, and problem-oriented/engagement) as mediators in the association between endorsement of the SBW schema and depressive symptoms in a sample of Black women. Data from 240 Black women ( Mage = 22.0, SD = 4.0 years) were collected assessing SBW schema endorsement, coping styles, and depressive symptoms. Parallel multiple mediation analysis was conducted using PROCESS Macro. Of the four coping styles examined, disengagement coping partially mediated the association between greater endorsement of the SBW schema and greater depressive symptoms. Study findings add depth to our understanding of the association between the SBW schema and mental health outcomes and lend themselves to research and clinical implications.

Objective Children who fail to meet activity, sleep, and screen‐time guidelines are at increased risk for obesity. Further, children who are Black are more likely to have obesity when compared to children who are White, and children from low‐income households are at increased risk for obesity when compared to children from higher‐income households. The objective of this study was to evaluate the proportion of days meeting obesogenic behavior guidelines during the school year compared to summer vacation by race and free/reduced priced lunch (FRPL) eligibility. Methods Mixed‐effects linear and logistic regressions estimated the proportion of days participants met activity, sleep, and screen‐time guidelines during summer and school by race and FRPL eligibility within an observational cohort sample. Results Children (n = 268, grades = K − 4, 44.1%FRPL, 59.0% Black) attending three schools participated. Children's activity, sleep, and screen‐time were collected during an average of 23 school days and 16 days during summer vacation. During school, both children who were White and eligible for FRPL met activity, sleep, and screen‐time guidelines on a greater proportion of days when compared to their Black and non‐eligible counterparts. Significant differences in changes from school to summer in the proportion of days children met activity (−6.2%, 95CI = −10.1%, −2.3%; OR = 0.7, 95CI = 0.6, 0.9) and sleep (7.6%, 95CI = 2.9%, 12.4%; OR = 2.1, 95CI = 1.4, 3.0) guidelines between children who were Black and White were observed. Differences in changes in activity (−8.5%, 95CI = −4.9%, −12.1%; OR = 1.5, 95CI = 1.3, 1.8) were observed between children eligible versus uneligible for FRPL. Conclusions Summer vacation may be an important time for targeting activity and screen‐time of children who are Black and/or eligible for FRPL.

Introduction The COVID-19 pandemic may have negatively impacted children's weight status owing to the closure of schools, increased food insecurity and reliance on ultraprocessed foods, and reduced opportunities for outdoor activity. Methods In this interrupted time-series study, height and weight were collected from children (n=1,770 children, mean age=8.7 years, 55.3% male, 64.6% Black) and were transformed into BMI z-score in each August/September from 2017 to 2020. Mixed-effects linear regression estimated yearly BMI z-score change before the COVID-19 pandemic year (i.e., 2017–2019) and during the COVID-19 pandemic year (i.e., 2019–2020). Subgroup analyses by sex, race (i.e., Black, White, other race), weight status (overweight or obese and normal weight), and grade (i.e., lower=kindergarten−2nd grade and upper=3rd−6th grade) were conducted. Results Before the COVID-19 pandemic, children's yearly BMI z-score change was +0.03 (95% CI= −0.10, 0.15). Change during the COVID-19 pandemic was +0.34 (95% CI=0.21, 0.47), an acceleration in BMI z-score change of +0.31 (95% CI=0.19, 0.44). For girls and boys, BMI z-score change accelerated by +0.33 (95% CI=0.16, 0.50) and +0.29 (95% CI=0.12, 0.46), respectively, during the pandemic year. Acceleration in BMI z-score change during the pandemic year was observed for children who were Black (+0.41, 95% CI=0.21, 0.61) and White (+0.22, 95% CI=0.06, 0.39). For children classified as normal weight, BMI z-score change accelerated by +0.58 (95% CI=0.40, 0.76). Yearly BMI z-score change accelerated for lower elementary/primary (+0.23, 95% CI=0.08, 0.37) and upper elementary/primary (+0.42, 95% CI=0.42, 0.63) children. Conclusions If similar BMI z-score accelerations occurred for children across the world, public health interventions to address this rapid unhealthy BMI gain will be urgently needed.

To compare sleep parameters produced by the Fitbit Charge 3 (Fitbit) and Actigraph GT9X accelerometer (Actigraph) to polysomnography in children and adolescents.Participants (n = 56, ages 9.2 ± 3.3 years) wore a Fitbit and an Actigraph on their nondominant wrist concurrently with polysomnography during an overnight observation at a children's sleep laboratory. Total sleep time, sleep efficiency, wake after sleep onset, sleep onset, and sleep offset were extracted from the Fitabase and Actilife software packages, respectively, with the Sadeh algorithm. Bland-Altman plots were used to assess the agreement between wearable devices and polysomnography.Seventy-nine percent of participants were diagnosed with OSA. Compared with polysomnography, the Fitbit and the Actigraph underestimated total sleep time by 6.1 minutes (absolute mean bias [AMB] = 27.7 minutes) and 31.5 minutes (AMB = 38.2 minutes), respectively. The Fitbit overestimated sleep efficiency by 3.0% (AMB = 6.3%), and the Actigraph underestimated sleep efficiency by 12.9% (AMB = 13.2%). The Fitbit overestimated wake after sleep onset by 18.8 minutes (AMB = 23.9 minutes), and the Actigraph overestimated wake after sleep onset by 56.1 minutes (AMB = 54.7 minutes). In addition, the Fitbit and the Actigraph underestimated sleep onset by 1.2 minutes (AMB = 13.9 minutes) and 10.2 minutes (AMB = 18.1 minutes), respectively. Finally, the Fitbit and the Actigraph overestimated sleep offset by 6.0 minutes (AMB = 12.0 minutes) and 10.5 minutes (AMB = 12.6 minutes). Linear regression indicated significant trends, with the Fitbit underestimating wake after sleep onset and sleep efficiency at higher values.The Fitbit provided comparable and in some instances better sleep estimates with polysomnography compared to the Actigraph. Findings support the use of multichannel devices to measure sleep in children and adolescents. Additional studies are needed in healthy children over several nights and in free-living settings.

Despite significant advances in cancer precision medicine, a significant hurdle to its broader adoption remains the multitude of variants of unknown significance identified by clinical tumor sequencing and the lack of biologically validated methods to distinguish between functional and benign variants. Here we used functional data on MAP2K1 and MAP2K2 mutations generated in real-time within a co-clinical trial framework to benchmark the predictive value of a three-part in silico methodology. Our computational approach to variant classification incorporated hotspot analysis, three-dimensional molecular dynamics simulation, and sequence paralogy. In silico prediction accurately distinguished functional from benign MAP2K1 and MAP2K2 mutants, yet drug sensitivity varied widely among activating mutant alleles. These results suggest that multifaceted in silico modeling can inform patient accrual to MEK/ERK inhibitor clinical trials, but computational methods need to be paired with laboratory- and clinic-based efforts designed to unravel variabilities in drug response. Significance: Leveraging prospective functional characterization of MEK1/2 mutants, it was found that hotspot analysis, molecular dynamics simulation, and sequence paralogy are complementary tools that can robustly prioritize variants for biologic, therapeutic, and clinical validation. See related commentary by Whitehead and Sebolt-Leopold, p. 4042

The edTPA, a recent example of a teacher candidate assessment, has influenced how teacher education classes are taught and how teacher candidates are learning. We describe three tensions present in...

Funder: Sue and Bob O'Donnell, Summary: Biases introduced in early���stage studies can lead to inflated early discoveries. The risk of generalizability biases (RGBs) identifies key features of feasibility studies that, when present, lead to reduced impact in a larger trial. This meta���study examined the influence of RGBs in adult obesity interventions. Behavioral interventions with a published feasibility study and a larger scale trial of the same intervention (e.g., pairs) were identified. Each pair was coded for the presence of RGBs. Quantitative outcomes were extracted. Multilevel meta���regression models were used to examine the impact of RGBs on the difference in the effect size (ES, standardized mean difference) from pilot to larger scale trial. A total of 114 pairs, representing 230 studies, were identified. Overall, 75% of the pairs had at least one RGB present. The four most prevalent RGBs were duration (33%), delivery agent (30%), implementation support (23%), and target audience (22%) bias. The largest reductions in the ES were observed in pairs where an RGB was present in the pilot and removed in the larger scale trial (average reduction ES ���0.41, range ���1.06 to 0.01), compared with pairs without an RGB (average reduction ES ���0.15, range ���0.18 to ���0.14). Eliminating RGBs during early���stage testing may result in improved evidence.

Many structures and mechanical components are under a combination of loading (stresses) and some kind of corrosive environmental operational condition which is called Stress Corrosion Cracking (SCC). Tubes in cooling water services, geothermal, and nuclear equipment are among the equipment which are subject to SCC. Since the SCC occurs at stresses within the range of typical design stress, it can cause catastrophic failures without a significant indication in structural integrity beforehand. Efficient Nondestructive Inspection (NDI) during the operational life of the structures can prevent such failures by providing accurate information regarding size and characteristics of the SCC flaws. Since majority of SCC defects occur in surface and near surface regions of metallic components, electromagnetic NDI (Eddy Current) is proved to be a promising inspection technique. In this study, Eddy Current Array (ECA) methodology was used for assessment of SCC generated in steel samples in a laboratory setup. ECA as an advanced eddy current NDI uses an array of eddy current coils to provide the scanning image of the inspection area. Prefabricated notches and SCC after a period of load-corrosion application to the samples were detected and characterized. Accuracy and repeatability of the results showed the efficiency of ECA for SCC characterization.

Background COVID-19 school closures pose a threat to children's wellbeing, but no COVID-19-related studies have assessed children's behaviours over multiple years . Objective To examine children's obesogenic behaviours during spring and summer of the COVID-19 pandemic compared to previous data collected from the same children during the same calendar period in the 2 years prior. Methods Physical activity and sleep data were collected via Fitbit Charge-2 in 231 children (7-12 years) over 6 weeks during spring and summer over 3 years. Parents reported their child's screen time and dietary intake via a survey on 2-3 random days/week. Results Children's behaviours worsened at a greater rate following the pandemic onset compared to pre-pandemic trends. During pandemic spring, sedentary behaviour increased (+79 min; 95% CI = 60.6, 97.1) and MVPA decreased (-10 min, 95% CI = -18.2, -1.1) compared to change in previous springs (2018-2019). Sleep timing shifted later (+124 min; 95% CI = 112.9, 135.5). Screen time (+97 min, 95% CI = 79.0, 115.4) and dietary intake increased (healthy: +0.3 foods, 95% CI = 0.2, 0.5; unhealthy: +1.2 foods, 95% CI = 1.0, 1.5). Similar patterns were observed during summer. Conclusions Compared to pre-pandemic measures, children's PA, sedentary behaviour, sleep, screen time, and diet were adversely altered during the COVID-19 pandemic. This may ultimately exacerbate childhood obesity.

Objectives To develop evidence-based recommendations on the use of MRI in the diagnosis of axial SpA (axSpA). Methods A working group comprising nine rheumatologists and nine musculoskeletal radiologists with an interest in axSpA was established, with support from the British Society of Spondyloarthritis (BRITSpA). Two meetings were held. In the first meeting, research questions were formulated. In the second meeting, the results of a systematic literature review designed to inform the recommendations were reviewed. An anonymized Delphi process was used to formulate the final set of recommendations. For each recommendation, the level of evidence and strength of recommendation was determined. The level of agreement was assessed using a 0–10 numerical rating scale. Results Two overarching principles were formulated, as follows: The diagnosis of axSpA is based on clinical, laboratory and imaging features (overarching principle 1), and patients with axSpA can have isolated inflammation of either the sacroiliac joints or the spine (overarching principle 2). Seven recommendations addressing the use of MRI in the assessment of patients with suspected axSpA were formulated, covering topics including recommended sequences, anatomical coverage, acquisition parameters and interpretation of active and structural MRI lesions. The level of agreement for each recommendation was very high (range 8.8–9.8). Conclusion A joint rheumatology and radiology consensus on the acquisition and interpretation of MRI in axSpA diagnosis was achieved, and a research agenda formulated. This consensus should help standardize practice around MRI and ensure a more informed, consistent approach to the diagnosis of axSpA.

Background: Body composition is known to differ across metabolic health and weight phenotypes. Regular exercise improves body composition, yet little is known about differences in exercise response across metabolic health and weight phenotypes. Methods: Normal weight (n=376) and overweight/obese (OWOB) adults (n=456) from the HERITAGE Family Study (56% female, 38% Black) completed a 20-week endurance training program. Four groups based on baseline BMI and metabolic risk were created: metabolically healthy normal weight, MHNW; metabolically unhealthy normal weight, MUNW; metabolically healthy OWOB, MHO; and metabolically unhealthy OWOB, MUO. Unhealthy was defined as having ≥2 metabolic syndrome components. General linear models tested for differences in baseline and change in measures of body composition (fat mass [FM], fat-free mass [FFM], % body fat [%BF], visceral fat) after adjusting for age, sex, and ethnicity (and baseline value in change models). Results: Table 1 shows adjusted mean baseline and change in body composition values by group. Baseline body composition tended to track with weight status, with NW adults having lower FM, %BF, and visceral fat compared to obese adults (p Conclusions: Normal weight adults tended to have better body composition profiles at baseline and larger improvements with exercise compared to obese adults, regardless of metabolic health. Within weight groups, body composition improved regardless of metabolic health status.

Purpose The primary aim of this study was to investigate the extent to which individuals with facial and/or speech differences secondary to a craniofacial anomaly experienced bullying through social media platforms during late school age and adolescence. Method Using an online survey platform, a questionnaire was distributed via several public and private social media groups designated for individuals with craniofacial anomaly and their caregivers. Results The majority of participants ( n = 38; 88.4%) indicated they had been bullied during late school-age and adolescence and that they believed this was due to their facial difference and/or speech disorder ( n = 27; 71.1%). Almost one third indicated they had been victims of cyberbullying during this time ( n = 12; 31.6%) with the most common venues being texting and Facebook. Despite the large percentage of participants who reported being bullied through social media, half ( n = 6) indicated they did not often report these instances of cyberbullying. Conclusions As social media use continues to increase, it appears inevitable that cyberbullying will occur. Particularly vulnerable to both traditional and cyberbullying are individuals with craniofacial anomalies. Because of the specialized training of speech-language pathologists, school-based speech-language pathologists are in a unique position to play a key role in school-wide antibullying efforts and to educate school personnel on ways in which to support the needs of children with craniofacial anomalies both inside and outside of the classroom.

Background/Aims Haemophagocytic lymphohistiocytosis (HLH) is a syndrome characterised by the presence of severe uncontrolled systemic inflammation due the overproduction of inflammatory cytokines and macrophage activation. The majority of adult patients have secondary HLH, triggered by either infection, haematological malignancy or rheumatic disease. Early recognition and initiation of definitive treatment is of vital importance as HLH leads to multi-organ failure and death if left untreated, with mortality of up to 80% in some cohorts. Methods Under-recognition of the disease and vast differences in the management of patients with HLH between specialities have been common problems. To address this, a Rheumatology-led HLH multi-disciplinary team (MDT) meeting was established at University College London Hospital (UCLH) in 2018. The MDT includes physicians from Rheumatology, Infectious Disease, Haematology, Intensive Care, Nephrology and Neurology and feeds into the national HLH group HASC - HLH Across Specialty Collaboration. The MDT is now held bimonthly, discussing between 2 and 4 cases each meeting. The MDT functions as a decision-making tool, while providing consensus on patient management, including collaboration on how to access urgent HLH-directed treatments such as Anakinra for secondary care centres without access. It also serves as a unique learning opportunity for trainees from different disciplines. Results Since the introduction of the MDT the number of patients diagnosed with HLH at ULCH has increased from an average of 6 per year in 2014-2016 to 12 per year in 2018-2020. In the last two years we have seen improved survival from years 2017/18 to 2019/20 (Table 1); survival was approximately 30% in 2017 and 75% in 2019. P018 Table 1:Outcomes of patients diagnosed with HLH (using ICD codes D761 and D762) at University College London Hospital since 2005.YEARALIVEDECEASED200511200601201021201111201220201334201442201525201641201737201839201993202095 Conclusion We believe that the HLH MDT has directly contributed to these improvements by encouraging earlier recognition and subspeciality collaboration. We encourage other sites to adopt a multi-disciplinary approach to managing patients with HLH to promote awareness of the condition and improve patient outcomes. Disclosure D.R. Ludwig: None. J. Manson: None. A. Jones: None. S. Mackenzie: None. N. Mccann: None.

Background Structure may mitigate children's accelerated summer BMI gain and cardiorespiratory-fitness (CRF) loss. Objectives Examine BMI and CRF change during school and summer for year-round and traditional calendar school children. Methods Three schools (N = 2279, 1 year-round) participated in this natural experiment. Children's BMI z-score (zBMI) and CRF (PACER laps) were measured from 2017 to 2019 each May/August. Mixed effects regression estimated monthly zBMI and CRF change during school/summer. Secondary analyses examined differences by weight status and race. Spline regression models estimated zBMI and CRF growth from kindergarten-sixth grade. Results Compared to traditional school, children attending a year-round school gained more zBMI (difference = 0.015; 95CI = 0.002, 0.028) during school, and less zBMI (difference = -0.029; 95CI = -0.041, -0.018), and more CRF (difference = 0.834; 95CI = 0.575, 1.093) monthly during summer. Differences by weight status and race were observed during summer and school. Growth models demonstrated that the magnitude of overall zBMI and CRF change from kindergarten-sixth grade was similar for year-round or traditional school children. Conclusions Contrary to traditional school children zBMI increased during the traditional 9-month school calendar and zBMI decreased during the traditional summer vacation for year-round school children. Structured summer programming may mitigate accelerated summer BMI gain and CRF loss especially for overweight or obese, and/or Black children.

Teachers' Emotion and Identity Work During a Pandemic This piece is a conceptual analysis of the care involved on the part of teachers during the COVID-19 era and the relationship it has to teachers’ identities. Using the author’s stories, we address how fatiguing care is on a normal day, not to mention what is involved during the COVID era. This care, and the emotions involved, is closely tied to teachers’ identities, calling into question how teachers conceptualize their teacherhood during a pandemic. Our hope is that others will consider where they may have misunderstood teachers’ work. We aim to raise awareness of the complexity of teaching and suggest how teacher education can address and support teachers’ needs.

Epithelial tissues line the organs of the body, providing an initial protective barrier as well as a surface for nutrient and drug absorption. Here we identified enzymatic components present in the gastrointestinal epithelium that can serve as selective means for tissue-directed polymerization. We focused on the small intestine, given its role in drug and nutrient absorption, and identified catalase as an essential enzyme with the potential to catalyze polymerization and growth of synthetic biomaterial layers. We demonstrated that the polymerization of dopamine by catalase yields strong tissue adhesion. We characterized the mechanism and specificity of the polymerization in segments of the gastrointestinal tracts of pigs and humans ex vivo. Moreover, we demonstrated proof-of-concept for application of these gastrointestinal synthetic epithelial linings (GSELs) for drug delivery, enzymatic immobilization for digestive supplementation, and nutritional modulation through transient barrier formation in pigs. This catalase-based approach to in situ biomaterial generation may have broad indications for gastrointestinal applications.

This study presents high-quality draft genome assemblies of six bacterial strains isolated from the roots of wheat grown in soil contaminated with cadmium. The results of this study will help to elucidate at the molecular level how heavy metals affect interactions between beneficial rhizobacteria and crop plants.

Background: Pilot/feasibility or studies with small sample sizes may be associated with inflated effects. This study explores the vibration of effect sizes (VoE) in meta-analyses when considering different inclusion criteria based upon sample size or pilot/feasibility status. Methods: Searches were conducted for meta-analyses of behavioral interventions on topics related to the prevention/treatment of childhood obesity from 01-2016 to 10-2019. The computed summary effect sizes (ES) were extracted from each meta-analysis. Individual studies included in the meta-analyses were classified into one of the following four categories: self-identified pilot/feasibility studies or based upon sample size (N≤100, N>100, and N>370 the upper 75th of sample size). The VoE was defined as the absolute difference (ABS) between the re-estimations of summary ES restricted to study classifications compared to the originally reported summary ES. Concordance (kappa) of statistical significance between summary ES was assessed. Fixed and random effects models and meta-regressions were estimated. Three case studies are presented to illustrate the impact of including pilot/feasibility and N≤100 studies on the estimated summary ES.Results: A total of 1,602 effect sizes, representing 145 reported summary ES, were extracted from 48 meta-analyses containing 603 unique studies (avg. 22 avg. meta-analysis, range 2-108) and included 227,217 participants. Pilot/feasibility and N≤100 studies comprised 22% (0-58%) and 21% (0-83%) of studies. Meta-regression indicated the ABS between the re-estimated and original summary ES where summary ES were comprised of ≥40% of N≤100 studies was 0.29. The ABS ES was 0.46 when summary ES comprised of >80% of both pilot/feasibility and N≤100 studies. Where ≤40% of the studies comprising a summary ES had N>370, the ABS ES ranged from 0.20-0.30. Concordance was low when removing both pilot/feasibility and N≤100 studies (kappa=0.53) and restricting analyses only to the largest studies (N>370, kappa=0.35), with 20% and 26% of the originally reported statistically significant ES rendered non-significant. Reanalysis of the three case study meta-analyses resulted in the re-estimated ES rendered either non-significant or half of the originally reported ES. Conclusions: When meta-analyses of behavioral interventions include a substantial proportion of both pilot/feasibility and N≤100 studies, summary ES can be affected markedly and should be interpreted with caution.

Mus musculus is the only known species from which embryonic stem cells (ESC) can be isolated under conditions requiring only leukemia inhibitory factor (LIF). Other species are non-permissive in LIF media, and form developmentally primed epiblast stem cells (EpiSC) similar to cells derived from post-implantation, egg cylinders. To evaluate whether non-permissiveness extends to induced pluripotent stem cells (iPSC), we derived iPSC from the eight founder strains of the mouse Collaborative Cross. Two strains, NOD/ShiLtJ and the WSB/EiJ, were non-permissive, consistent with the previous classification of NOD/ShiLtJ as non-permissive to ESC derivation. We determined non-permissiveness is recessive, and that non-permissive genomes do not compliment. We overcame iPSC non-permissiveness by using GSK3B and MEK inhibitors with serum, a technique we termed 2iS reprogramming. Although used for ESC derivation, GSK3B and MEK inhibitors have not been used during iPSC reprogramming because they inhibit survival of progenitor differentiated cells. iPSC derived in 2iS are more transcriptionally similar to ESC than EpiSC, indicating that 2iS reprogramming acts to overcome genetic background constraints. Finally, of species tested for ESC or iPSC derivation, only some M. musculus strains are permissive under LIF culture conditions suggesting that this is an evolutionarily derived characteristic in the M. musculus lineage.

IntroductionFew treatment options exist for patients with systemic lupus erythematosus (SLE) who fail conventional therapy. Although widely used to treat lupus, the efficacy of B cell depletion therapy using rituximab has not been demonstrated in randomised clinical trials. Following rituximab, elevated levels of serum B cell activating factor (BAFF) have been associated with failure to remit or subsequent lupus relapse. The administration of belimumab, a monoclonal antibody specific for BAFF and approved for lupus therapy, could potentiate the efficacy of rituximab and enable longer periods of disease remission. The aim of this trial is to assess the safety and efficacy of belimumab following rituximab in patients with SLE.Methods and analysisBEAT Lupus is a double-blind, randomised, placebo controlled, phase II clinical trial. Patients with SLE commencing a treatment cycle of rituximab (two 1g infusions, 2 weeks apart) as standard of care will be randomised to receive belimumab or placebo, 4 to 8 weeks following the first rituximab infusion. Belimumab or placebo infusions are administered for 52 weeks. The primary outcome measure is anti-double stranded DNA (anti-dsDNA) antibody levels at 52 weeks. Secondary outcomes include measures of adverse events, lupus disease activity and cumulative steroid dose. The kinetics of B cell repopulation will be assessed in a subgroup of participants. Belimumab administration after rituximab may provide a novel therapeutic pathway for patients with active lupus if safety is demonstrated in this proof of concept study, and lower anti-dsDNA antibodies levels are achieved in those patients treated with belimumab compared with placebo.Ethics and disseminationThe protocol has been reviewed and approved by the Hampstead Research Ethics Committee - London (reference 16/LO/1024). Trial information is available athttps://www.isrctn.com/ISRCTN47873003, and the results of this trial will be submitted for publication in relevant peer-reviewed journals. Key findings will also be presented at national and international conferences.Trial registration numberISRCTN47873; date assigned to the registry: 28 November 2016. The stage is pre-results.

Spondyloarthritis (SpA) encompasses a heterogeneous group of diseases sharing genetic, immunological, clinical and imaging features. Axial spondyloarthritis (axSpA) refers to a subgroup characterised predominately by inflammation of the axial skeleton with subsequent symptoms of chronic (often inflammatory) back pain and sacroiliitis. There is a strong association with the major histocompatibility complex (MHC) class I allele human leukocyte antigen (HLA) B27. In the last decade, there has been significant progress in earlier detection of the disease and the molecular mechanisms involved in its pathogenesis. The subsequent introduction of anti-tumour necrosis factor (TNF) has revolutionised the treatment of patients with axSpA.In this article, we review the current biologic therapies for axSpA, the emergence of biosimilars, predictors of response, primary and secondary failure and new biologics on the horizon.There have been significant advances in the treatment of axSpA. Beyond the clear efficacy of anti-TNF inhibition, IL-17 offers an alternative therapeutic target and there is promise from inhibition of the IL-17/IL-23 pathway and small molecules, such as Janus kinase (JAK) inhibitors. Biosimilars have offered greater affordability and choice within this increasingly growing field of therapeutics.

Introduction In spring 2020, elementary schools closed to minimize the spread of COVID-19. Questionnaire data suggest children’s sleep was impacted during the pandemic, yet device-based data (i.e. accelerometry) on this topic is lacking. The purpose of this study was to examine children’s sleep during the COVID-19 pandemic (i.e. spring and summer 2020) compared to previous data collected from the same children during each of the two previous years (spring and summer 2018 and 2019). Methods 68 children (age = 9.9±1.2 years, 56% Black, 53% male) previously recruited for an observational cohort study wore a Fitbit Charge 2 on their wrist during the spring and summer from 2018-2020 (i.e. six 30-day measurement periods). We used multilevel mixed models to examine how children’s sleep patterns changed during the pandemic accounting for previous trajectory (i.e. 2018 to 2019). Models included age, sex, and race as covariates. Results Children had an average of 84 nights of sleep data across all six 30-day measurement periods. In the spring of the pandemic, children slept 24.6 minutes more (95%CI = 11.6, 37.5) compared to previous springs. During the pandemic summer, they slept 40.0 minutes more (95%CI = 24.6, 58.5) compared to previous summers. Sleep midpoint was 117.1 minutes later (95%CI = 103.6, 130.6) in the spring during the pandemic and 46.0 minutes later (95% CI = 26.9, 65.2) in the summer during the pandemic compared to previous years. Sleep efficiency improved slightly by 1.3% (95% CI = 0.7, 1.9) and 3.6% (95% CI = 2.7, 4.5) in spring and summer, respectively, during the pandemic compared to previous years. Conclusion During the COVID-19 pandemic, children slept longer after accounting for previous developmental trends. Notably, the shift in sleep timing during the pandemic was nearly two hours later in the spring compared to previous years, potentially due to the lack of structure usually provided by school. Later sleep timing is independently associated with poor health behaviors (e.g., nutrition, physical activity, screen time). Future studies should examine if these changes in sleep persist over time and have potential long-term effects on children’s health. Support (if any) R21HD095164 (PI Weaver) & UofSC COVID-19 Research Initiative Grant (PI Armstrong)

Rationally sequencing and combining PD-1/L1-and MAPK-targeted therapies may overcome innate and acquired resistance. Since increased clinical benefit of MAPK inhibitors (MAPKi) is associated with previous immune checkpoint therapy, we compare the efficacies of sequential and/or combinatorial regimens in subcutaneous murine models of melanoma driven by BrafV600, Nras, or Nf1 mutations as well as colorectal and pancreatic carcinoma driven by KrasG12C. Anti-PD-1/L1 lead-in preceding MAPKi combination optimizes response durability by promoting pro-inflammatory polarization of macrophages and clonal expansion of interferon-γhi, and CD8+ cytotoxic and proliferative (versus CD4+ regulatory) Tcells that highly express activation genes. Since therapeutic resistance of melanoma brain metastasis (MBM) limits patient survival, we demonstrate that sequencing anti-PD-1/L1 therapy before MAPKi combination suppresses MBM and improves mouse survival with robust Tcell clonal expansion in both intracranial and extracranial metastatic sites. We propose clinically testing brief anti-PD-1/L1 (± anti-CTLA-4) dosing before MAPKi co-treatment to suppress therapeutic resistance.

Genetic background is known to play a role in the ability to derive pluripotent, embryonic stem cells (ESC), a trait referred to as permissiveness. Previously we have demonstrated that induced pluripotent stem cells (iPSC) can be readily derived from non-permissive mouse strains by addition of serum-based media supplemented with GSK3B and MEK inhibitors, termed 2iS media, three days into reprogramming. Here we describe the derivation of second type of iPSC colony from non-permissive mouse strains that can be stably maintained independently of 2iS media. The resulting cells display transcriptional heterogeneity similar to that observed in ESC from permissive genetic backgrounds derived in conventional serum containing media supplemented with leukemia inhibitor factor. However, unlike previous studies that report exclusive subpopulations, we observe both exclusive and simultaneous expression of naive and primed cell surface markers. Herein, we explore shifts in pluripotency in the presence of 2iS and characterize heterogenous subpopulations to determine their pluripotent state and role in heterogenous iPSCs derived from the non-permissive NOD/ShiLtJ strain. We conclude that heterogeneity is a naturally occurring, necessary quality of stem cells that allows for the maintenance of pluripotency. This study further demonstrates the efficacy of the 2iS reprogramming technique. It is also the first study to derive stable ESC-like stem cells from the non-permissive NOD/ShiLtJ and WSB/EiJ strains, enabling easier and broader research possibilities into pluripotency for these and similar non-permissive mouse strains and species.