bluuebunny/crossref_metadata_2025_split huggingface dataset:
P136 Adverse reaction with intravenous immunoglobulin (IVIG) therapy and management of symptoms: a single centre experience
Authors: Wildman Sabina H. A , Al-Obaidi Muthana 
Published: April 2020

Abstract

Background
IVIG is a therapeutic preparation comprising of pooled blood donated from large numbers of healthy people. There are different preparations of IVIG available. All should have high levels of IgG (&gt;95%) but vary in concentrations, pH, stabilizing agents and IgA content. In inflammatory conditions, IVIG is often used as an adjunct therapy in patients with poor response to first line therapy and in general well tolerated. However adverse reactions can occur and vary in severity from mild constitutional symptoms to aseptic meningitis. The aim of this study was to identify patients who required IVIG within the paediatric rheumatology department at Great Ormond Street Hospital, the underlying diagnosis of these patients and the indication for starting treatment. The study also looked at the number of adverse drug reactions of patients requiring IVIG, the symptoms they presented with and the management of these symptoms.

Methods
A retrospective case review, of patients under the care of the paediatric rheumatology team who received IVIG between July 2013 to August 2018. We collected demographics including, age, sex, diagnosis of patients and indication for commencing IVIG, symptoms of any adverse drug reaction and management of symptoms.

Results
We identified 43 patients who required IVIG over the last 5 years as part of their treatment plan, of which 23 patients had a diagnosis of Juvenile dermatomyositis (JDM). Of the remaining patients 5 had a diagnosis of SLE, 4 with SRP positive mysositis, 2 with necrotising myositis and 2 with atypical systemic onset JIA. The main indication for starting treatment was for active or worsening skin disease, muscle weakness or both. From the 43 patients that required IVIG, 21 patients had an adverse drug reaction and 15/21 patients had a diagnosis of JDM. 5/21 patients had symptoms associated with aseptic meningitis (headache, photophobia and neck stiffness), 2 of which were unable to continue treatment. The remaining 16 patients had milder constitutional symptoms. Symptoms were managed by premedicating patients prior to subsequent IVIG treatment with a combination of paracetamol, chlorphenamine, ondansetron or by reducing the rate of IVIG infusion or reducing the dose of IVIG from 2g/kg to 1g/kg.

Conclusion
We identified from the study, that half the patients requiring IVIG as part of their treatment plan had an adverse drug reaction of which half had a diagnosis of JDM. However, the majority of patients who had an adverse drug reaction had mild constitutional symptoms, relieved by premedication or by adjusting IVIG rate of infusion or dose. Only 2 patients were unable to continue IVIG treatment.

Disclosures
S.H.A. Wildman None. M. Al-Obaidi None.
P144 Validation of the Musculoskeletal Health Questionnaire (MSK-HQ) in patients with musculoskeletal pain in primary care
Authors: Scott Ian C , McCray Gareth , Lancaster Gillian , Foster Nadine E , Hill Jonathan C 
Published: April 2020

Abstract

Background
The Musculoskeletal Health Questionnaire (MSK-HQ) is a recently developed generic patient-reported outcome measure (PROM), evaluating impacts of musculoskeletal (MSK) conditions on patients’ health. Its scores range 0-56; higher scores indicate better health. Its performance (a) in patients with MSK-pain in primary care, and (b) compared to MSK pain-site reference PROMs, is uncertain. We addressed these uncertainties through secondary analysis of a previous primary-care based study, enrolling 524 patients with shoulder, neck, lower back, knee, or multi-site MSK pain managed by GPs, from 8 West Midlands practices.

Methods
The study captured the following self-report questionnaire data at 0 and 6 months: MSK-HQ, EQ-5D-5L, Roland-Morris Disability Questionnaire (back pain), Neck Disability Index (neck pain), Shoulder Pain and Disability Index (shoulder pain), Knee Injury and Outcome Score (knee pain), Short-Form-12 (multisite pain). At 6 months, patients self-rated their global change in MSK pain, from -5 (“very much worse”) to + 5 (“completely recovered”). Receiver operating characteristic curves evaluated the ability of 6-month changes in each PROM to discriminate between patients improving/not improving on global change scores. Minimal Clinically Important Differences (MCID) were calculated (cut-off optimising discriminatory sensitivity/specificity).

Results
Most (60%) reported pain improvements, with mean baseline MSK-HQ scores rising from 29.4 to 37.4 over 6-months. The MSK-HQ had a moderate ability to discriminate between patients improving vs. no change/worsening in MSK pain (area under the curve [AUC] 0.81; 95% CI 0.78-0.85). Its discriminative ability was better than the EQ-5D-3L (AUC 0.68; 95% CI 0.62-0.73) and at least as good as site-specific PROMs (Table). MCID for the 6-month change in MSK-HQ was 5.5 across all patients. Minor variation (&lt;2.0 units) was observed in MSK-HQ MCID across 4/5 pain sites. The MSK-HQ had strong correlations with all PROMs except SF-12 physical/mental component summary scores.

Conclusion
In patients consulting in primary care with MSK pain, the MSK-HQ appears at least as good as existing pain-site specific PROMs at identifying patients self-reporting pain improvements, and superior to the EQ-5D-5L. Our results support the use of the MSK-HQ in this setting.

Disclosures
I.C. Scott None. G. McCray None. G. Lancaster None. N.E. Foster None. J.C. Hill None.
P275 The extent and characteristics of diagnostic delay in axSpA: a systematic review
Authors: Hay Charles A , Ryan Sarah , Packham Jon , Mallen Christian D , Prior James A 
Published: April 2020

Abstract

Background
Axial spondyloarthritis (axSpA) is an inflammatory arthritis predominantly affecting the spine. It is characterised by chronic back pain, stiffness and fatigue. As axSpA progresses it can cause disability, reduction in quality-of-life, depression and impacts on work. Prompt diagnosis is important, but symptoms associated with axSpA are common in the general population resulting in diagnostic delay. The reported diagnostic delay for axSpA varies in the literature, ranging from five to fifteen years. The aim of this review was to ascertain the extent of axSpA diagnostic delay and report on axSpA characteristics associated with diagnostic delay.

Methods
A systematic review was conducted to identify articles reporting diagnostic delay in axSpA. Inclusion criteria were studies including adult axSpA populations, cohort, cross-sectional or case-control design and reporting a median time-period of delay from axSpA symptom onset to final axSpA diagnosis (studies reporting mean delay were excluded due to skewness of data). Data was also extracted which related to delay as a result of specific axSpA characteristics. Narrative synthesis was used to report our findings.

Results
9,848 articles were initially identified. After title, abstract and full-text review, 15 articles reported median diagnostic delay. Of these, 2 were from the UK, 2 from Germany, and 1 each from India, Norway, France, USA, Iran, Turkey, China and Italy. Combined, the total number of participants across eligible papers was 10,661. Though median delay ranged from ≤1 to 8 years, the majority (60%) of articles reported a median delay of between 2-5 years. Regarding the role of specific axSpA characteristics on delay, the most noted causes for delay were lack of extra-articular axSpA symptoms (5.9 vs. 8.7 years of delay for patients with and without extra-articular symptoms respectively) and misdiagnosis. Common misdiagnoses were lumbar disc herniation, rheumatoid arthritis and mechanical back pain (MBP), with the latter being significantly associated with delayed diagnosis (OR 2.83(95% CI 1.16-6.87)). Finally, delay is far from uniform, with a UK study reporting that 30.3% of patients are diagnosed within 2 years, 21% in 3-5 years, 19.9% in 6-10 years, 19.2% after 11-20 years and 9.6% after 20 years.

Conclusion
Though diagnostic delay of axSpA is considerable, affecting long term outcomes in a large number of patients, it is not as long as previously reported by using mean delay, which is more affected by bias (long term delays in small numbers of individuals) than median delay. Further research into the specific barriers and facilitators of delay is required to help reduce this delay in the future.

Disclosures
C.A. Hay None. S. Ryan None. J. Packham None. C.D. Mallen None. J.A. Prior None.
“Biting Our tongues”: Policy Legacies and Memories in the Making of the Syrian Refugee Response in Jordan
Authors: Lenner Katharina 
Published: April 2020

Abstract
This article analyses the significance of policy legacies and policy memories for refugee policy in conflict-neighbouring countries, where most of the world’s displaced live. Drawing on insights from critical policy analysis, it views refugee policy as co-produced by national and international agencies on the basis of previous dynamics that are already the product of an intense history of interaction and translation. This approach is illustrated by analysing two different aspects of refugee policy in Jordan: the process of counting Syrians in the country and the partial integration of Syrians into the formal labour market. Both examples reveal an overarching legacy of accommodation that ties international and host government actors together. Despite sometimes differing over preferred outcomes, the main goals for the various actors involved have been to strike compromises, safeguard organisational interests, and create outward policy success. In order to meet these goals, the agencies involved have learned to tolerate unresolved ambiguities and disregard other inconvenient legacies and memories that would only complicate policy negotiations. Acknowledging this intertwinement of agencies, technologies, and rationales of government is essential for rethinking policy change and responsibility in contexts of mass displacement.
The gray matter volume of the temporoparietal junction varies across cultures: a moderating role of the dopamine D4 receptor gene (DRD4)
Authors: Kitayama Shinobu , Yu Qinggang , King Anthony P , Yoon Carolyn , Liberzon Israel 
Published: April 2020

Abstract
Prior work shows that compared to European Americans, East Asians show an enhanced propensity to take the perspective of another person. In the current work, we tested whether this cultural difference might be reflected in the gray matter (GM) volume of the temporoparietal junction (TPJ), a brain region selectively implicated in perspective taking and mentalizing. We also explored whether the cultural difference in the TPJ GM volume might be moderated by dopamine D4 receptor gene (DRD4) exon 3 variable-number tandem repeat polymorphism. Structural magnetic resonance imaging of 66 European Americans and 66 East Asian-born Asians were subjected to voxel-based morphometry. It was observed that the GM volume of the right TPJ was greater among East Asians than among European Americans. Moreover, this cultural difference was significantly more pronounced among carriers of the 7- or 2-repeat allele of DRD4 than among the non-carriers of these alleles. Our findings contribute to the growing evidence that culture can shape the brain.
Effect of artificial dawn light on cardiovascular function, alertness, and balance in middle-aged and older adults
Authors: Gabel Virginie , Miglis Mitchell , Zeitzer Jamie M 
Published: April 2020

Abstract

Study Objectives
When arising in the morning, many older people experience dizziness and difficulty maintaining proper balance, as the cardiovascular system is not able to compensate to the postural shift (standing) and maintain sufficient blood flow to the brain. Such changes in cardiovascular function are observed in young individuals exposed to a dawn simulation light. In this study, we examined whether exposure to a dawn simulation light could impact cardiovascular function and consequent changes in balance in middle-aged and older adults.

Methods
Twenty-three participants (67.3 ± 8.8 y), 12 of whom reported a history of dizziness in the morning, underwent two overnight stays in our laboratory. During both nights, they slept in complete darkness, except for the last 30 minutes of one of the nights during which a dawn simulation light was used. Continuous blood pressure (BP) and heart rate (HR) were monitored. Subjective and objective alertness, salivary cortisol, and mobile and standing balance were examined upon arising.

Results
Dawn simulation light decreased (33%) the amount of sleep before morning awakening, lowered BP (6.24 mmHg), and increased HR (0.93 bpm). Despite these changes in physiology, there was no significant impact of dawn simulation on subjective or objective alertness, measures of standing or ambulatory balance, morning cortisol awakening response, or cardiovascular function after awakening.

Conclusion
While the dawn simulation did cause an increase in wake and a change in cardiovascular function prior to morning arousal in older adults, we could find no evidence of a functional change in either cardiovascular function or balance upon standing.

Clinical Trial
Registered on Clinicaltrials.gov, #NCT02632318, https://clinicaltrials.gov/ct2/show/NCT02632318
Elucidating CCRK’s function in ciliary assembly and cilium‐dependent signaling
Authors: Eggenschwiler Jonathan T 
Published: April 2020

Our studies are focused on the questions of how ciliary length and ciliary import of cell signaling regulators are controlled. Despite many advances, these questions have yet to be fully answered. One clue as to the mechanistic basis of these processes comes from studies on Cell Cycle‐Related Kinase (CCRK). Work on the Clamydomonas homolog, LF2, indicates that this kinase ensures that flagella are neither too long nor too short, likely mediated by regulated transport of ciliary tubulin (
Craft et al., 2015). We previously showed that mammalian CCRK is similarly required for ciliary length control and that it is needed for cells to achieve appropriate responses to Hedgehog (Hh) signals (
Snouffer et al., 2017). Additional work indicated that CCRK promotes the efficient transport of Hh pathway regulatory factors, such as Smoothened and Gli2, into cilia. However, the manner by which the kinase directs these processes is unknown. One target of CCRK phosphorylation is the ciliary length regulator Intestinal Cell Kinase (ICK); CCRK‐mediated phosphorylation in ICK’s TDY motif promotes ICK activity. Our analysis of Ccrk/Ick double mutants indicates that CCRK must also function via ICK‐independent mechanisms and that ICK promotes functions in the absence of CCRK‐mediated phosphorylation. To gain insight into the ICK‐independent CCRK functions in ciliary length control and ciliary cargo import, we performed phosphoproteomic screens for potential mediators of CCRK function. This screen has pointed to candidate mediators that regulate microfilament and microtubule dynamics. Consistent with a role for CCRK’s action via microfilament dynamics, Ccrk mutant, but not wild‐type, cells showed greatly reduced import of ciliary cargo upon treatment with sub‐threshold doses of the actin polymerization inhibitor Cytochalasin D. Our ongoing work on this mechanism will be presented.Support or Funding InformationThis work was supported by National Institute of Child Health and Human Development grant number R01HD050761 and by the Office of the Vice President of Research at the University of Georgia.
Somatotrope Responses to Acute and Prolonged Loss of Leptin Signaling
Authors: Miles Tiffany K. , Allensworth-James Melody , Moreira Ana Rita Silva , Odle Angela , Haney Anessa C. , Lagasse Alexandra , MacNicol Angus , Childs Gwen V. 
Published: April 2020

In mice and humans, fasting results in a rise of serum growth hormone (GH). In mice, this coincides with increased Gh and growth hormone releasing hormone receptor (Ghrhr) mRNA. Fasting also results in increased serum ghrelin and decreased serum leptin. We have shown that pituitary somatotropes are dependent on circulating leptin to maintain sufficient stores of GH and GHRHR proteins. We hypothesized that the GH rise seen in fasted mice with reduced serum leptin was due to ghrelin‐stimulated pathways. However, a review of the literature revealed a study by Steyn et al. (2011) which demonstrated an acute decline in GH pulses in male mice after 12–18 h of fasting. This study suggests that somatotropes may have time‐dependent responses, with shorter fasting responses driven by the absence of leptin signals.Our fasting study was composed of three groups of male mice: 1) mice fasted for 6, 12, 24, or 48 hours, 2) mice fasted for 24 and 48 hours with 10% glucose in the drinking water, and 3) mice fed ad libitum. Body weight and serum glucose were significantly reduced with all fasting times. After 6 h of fasting, serum leptin levels were reduced from 9625.63 pg/ml (fed controls) to 1798.15 pg/mL with a further reduction to 774.17 pg/ml after 12 h, which was maintained following 24 and 48 h fasting. Ghrelin levels were unchanged with 6, 12 and 24 h fasting but significantly increased by 55.4% with 48 h fasting. Serum GH was unchanged with 6 and 12 h fasting, but was significantly reduced from 7765 pg/ml (fed) to 2253 pg/ml after the 24 h fast (p=0.03 ANOVA). In the 48 h fasted mice, serum GH was significantly increased over fed mice, from 1828 pg/ml (fed) to 10569 pg/ml (p=0.01 ANOVA). There were significant increases in pituitary Ghrhr mRNA after 24 and 48 h fasting and Gh mRNA was increased after 6 and 48 h of fasting. However, GH and GHRHR content were unchanged.This study has uncovered time‐dependent differential responses to fasting by somatotropes in male mice. The reduced serum GH after 24 h correlated well with the reduction in serum leptin. Similarly, the prolonged fasting (48 h) and elevated serum GH correlated well with the rise in ghrelin. The high Gh and Ghrhr mRNA levels corresponds with rising ghrelin levels. Reduced serum GH at 24 h indicates that somatotropes remain dependent on leptin signals for GH secretion. However, with normal GH or GHRHR content, this points to a defect in a signaling pathway needed for secretion that has yet to be determined.Support or Funding InformationNIH grants 5 R01 HD087057‐03 (GVC and AM), 5 R01 HD 093461‐01 (AM and GVC), and 5 R01 DK113776‐02 (GVC and AM). NIGMS grants P20 GM103425 and P30GM11070 (PI Dr. Edgar Garcia‐Rill). NSF funded Southern Regional Education Board Dissertation Award (TKM).
Recruitment of kindlin‐3 to plasma membrane through its PH domain precedes high affinity β2 integrin activation and neutrophil arrest
Authors: Wen Lai , Marki Alex , Roy Payel , McArdle Sara , Sun Hao , Fan Zhichao , Gingras Alexandre R. , Ginsberg Mark H. , Ley Klaus 
Published: April 2020

Leukocytes including neutrophils must adhere to the vascular endothelium in order to respond to injury or infection. Integrin‐mediated neutrophil adhesion starts by arrest from rolling. Activation of integrins involves conformational changes from an inactive bent conformation to an extended conformation (E+) with high affinity for ligand binding (H+). The cytoplasmic protein kindlin‐3 is required for leukocyte adhesion; mutations of kindlin‐3 cause leukocyte adhesion deficiency type III syndrome. However, the molecular mechanism by which kindlin‐3 regulates β2 integrin activation is unknown. Here we measured the spatiotemporal dynamics of kindlin‐3 and β2 integrin conformation changes during neutrophil and HL‐60 cell rolling and arrest under flow. Using high‐resolution quantitative dynamic footprinting (qDF) microscopy and kindlin‐3‐fluorescent protein (FP) fusion proteins, we find that kindlin‐3 is recruited to the plasma membrane prior to induction of the H+ β2 integrin conformation. Deletion of kindlin‐3 or its lipid‐binding pleckstrin homology (PH) domain completely abolished H+ β2 integrin induction. Intravital imaging of bone marrow chimeric mice revealed that EGFP‐tagged kindlin‐3‐expressing neutrophils, but not control kindlin‐3‐deficient neutrophils, arrested in cremaster venules in vivo in response to CXCL1. Our data show that kindlin‐3 is indispensable for the H+ β2 integrin conformation and crucial for integrin‐mediated leukocyte adhesion during inflammation.Support or Funding InformationThis work was supported by grants from the National Institutes of Health, USA (HL078784 to K.L., R01HL145454 to Z.F.), a Postdoctoral Fellowship (19POST34450228 to L.W.) and a Career Development Award (18CDA34110426 to Z.F.) from the American Heart Association, USA.
Mitochondrial RNA‐Chromatin Interactome Regulates Endothelial‐Mesenchymal Transition
Authors: Sriram Kiran , Qi Zhijie , Zhong Sheng , Chen Zhen 
Published: April 2020

Endothelial cells (ECs) play a central role in vascular function and diabetes‐induced endothelial dysfunction leads to the development of cardiovascular diseases. In response to hyperglycemic and inflammatory (high‐glucose + TNFα; HT) stimuli, we found that ECs undergo dysfunction and endothelial‐mesenchymal transition (EndoMT) characterized by upregulation of inflammatory, fibrotic, and mesenchymal genes. To determine whether interaction between regulatory RNAs and chromatin contributes to the induction of EndoMT, we profiled the global changes in RNA‐chromatin interactome in HT‐treated ECs using iMARGI (in‐situ Mapping of RNA‐Genome Interactions). iMARGI revealed extensive chromatin binding of RNAs, particularly at genomic regions containing super enhancers (SEs). SE overlapping SMAD3 (a known regulator of EndoMT) becomes an active SE‐hub, while SMAD3 expression is significantly induced at the single‐cell level with HT treatment. In parallel, iMARGI revealed significant chromatin binding of mitochondrial RNAs with the degree of MT‐RNR2‐binding increasing in a time‐dependent manner with HT treatment. The most enriched SE region for MT‐RNR2‐binding also overlaps with SMAD3. Further preliminary experiments by cell fractionation verified the chromatin‐localized MT‐RNR2‐derived transcripts and their increase in response to HT treatment. Perturbation of mitochondrial function or genetic ablation of mitochondrial transcripts suggests a role for mitochondrial RNAs in regulating EC function and HT‐induced EndoMT. Collectively, our study provides novel insights into the potential involvement of mitochondrial RNAs in retrograde signaling and linking mitochondria to functional genomics important for endothelial regulation and vascular disease.Support or Funding InformationElla Fitzgerald Foundation, NIH grants R00HL122368, R01HL108735, R01HL145170, and NIH 4D Nucleome U01CA200147