bluuebunny/crossref_metadata_2025 huggingface dataset:
TMOD-05. GENETIC AND MOLECULAR PROPERTIES OF LONG-TERM PROLIFERATING TUMORSPHERE -FORMING GLIOMA DERIVED CELLS
Authors: Kijima Noriyuki , kanematsu Daisuke , Shofuda Tomoko , Yoshioka Ema , Yamamoto Atsuyo , Handa Yukako , Fukusumi Hayato , Katsuma Asako , Moriuchi Shusuke , Nonaka Masahiro , Okita Yoshiko , Tsuyuguchi Naohiro , Uda Takehiro , Kawashima Toshiyuki , Fukai Junya , Kodama Yoshinori , Mano Masayuki , Higuchi Yuichiro , Suemizu Hiroshi , Kanemura Yonehiro
Published: November 2021

Long-term proliferating tumorsphere (LTP-TS)-forming glioma derived cells (GDCs) and patient derived xenografts (PDXs) are essential tools for translational research for glioma. However, only small subsets of glioma samples are established as LTP-TS and/or PDXs and little is known about the genetics and molecular properties of LTP-TS -forming GDCs and PDX. In this study, we aim to analyze the characteristics of LTP-TS -forming GDCs and PDXs. We tried primary sphere cultures from 56 glioma patient-derived samples and established 14 LTP-TS -forming GDCs out of 48 glioblastoma samples and no long-term sphere culture was isolated from grade3 and grade 2 gliomas. LTP-TS -forming GDCs had self-renewal ability and possessed certain multipotency. However, they significantly less expressed SOX1 FOXG1 and TUBB3, whereas they expressed LGALS1 significantly higher than normal neural stem/progenitor cells. In addition, we found that LTP-TS -forming GDCs shared the same genetic profiles with original patients’ tumors. Furthermore, we investigated the genetic differences between the glioma tissues which were successfully established as LTP-TS -forming GDCs and those which were not. We found that glioma tissues with TERT promotor mutations and triple CNA (EGFR, CDKN2A, and PTEN loci) are significantly established as LTP-TS -forming GDCs. Lastly, we next investigated in vivo characteristics of glioma PDXs. We have injected glioma PDXs lines into immunodeficient mice and histopathologically analyzed the characteristics of xenografts. Each xenograft well recapitulated histological features of original patients’ tumors and tumor cells remarkably invade through subventricular zone. In conclusion, each LTP-TS -forming GDCs and PDXs had various gene expression profiles, reflecting intratumoral and interpatient heterogeneities of glioma. In addition, TERT promotor mutations and triple CNA significantly correlated with success rate of LTP-TS -forming GDCs. These findings will be of use and advance the preclinical and translational researches of glioma.
TMOD-22. DIFFERENTIAL DRUG SENSITIVITY ANALYSIS IN PAIRED PATIENT-DERIVED CELL LINES OF GLIOBLASTOMA
Authors: Panovska Dena , Shetty Aniket , Derweduwe Marleen , Claeys Annelies , Van der Voordt Marine , Smets Tina , Versele Matthias , Monaco Giovanni , De Moor Bart , Chaltin Patrick , Clement Paul , Ligon Keith , De Vleeschouwer Steven , Sciot Raf , Pey Jon , Antoranz Asier , De Smet Frederik
Published: November 2021

Glioblastoma (GBM) remains the most aggressive adult brain tumour with dismal prognosis. Even when treated by the most optimal standard-of-care modalities, disease progression remains consistently inevitable. Understanding how tumours evolve from a newly diagnosed to a recurrent setting is therefore critical, but research models to functionally test how therapeutic interventions evolve accordingly remain scarce. Here, we describe our efforts to develop paired models including newly diagnosed and recurrent GBM cell lines derived from the same patients. Overall, we collected 50 tumour samples originating from 24 patients at different time points in their treatment scheme. This resulted in the generation of 27 models overall, from which 18 originated from 9 patients at different timepoints. The latter were subsequently investigated extensively. First, using genomic profiling, we consistently observed an increase in mutational burden and chromosomal aberrations in the recurrent samples, while transcriptomic profiling showed that tumour subtypes evolved in a very patient-specific way. A large fraction of the recurrent models showed resistance to temozolomide (TMZ), which coincided with a downregulation of DNA repair (MMR) pathways or mutations. Half of the tested models also acquired resistance to radiation therapy. Next to standard-of-care therapy, we investigated several small molecule inhibitors that are currently in clinical evaluation, which also showed differential sensitivity. Overall, the developed paired cell lines recapitulate the most important features related to tumour recurrence, and offer the opportunity for more elaborate dependency screening efforts.
CNTM-04. Alterations in structural connectomic properties associated with neurocognitive changes following glioma resection
Authors: Noll Kyle , Mitchell Drew , Chen Henry , Wefel Jeffrey , Kumar Vinodh , Hou Ping , Ferguson Sherise , Rao Ganesh , Johnson Jason , Schomer Donald , Prabhu Sujit , Liu Ho-Ling
Published: November 2021

BACKGROUND

Patients with brain tumors often experience decline in neurocognitive functioning (NCF) following surgical tumor resection. Connectomic studies have begun to uncover how abnormalities to underlying cerebral networks contribute to NCF deficits; however, few studies have investigated relationships between pre- to postoperative changes in structural connectomics and NCF.

METHODS

Fifteen right-handed adults with left perisylvian tumors underwent MRI of the brain with diffusion tensor imaging (DTI) and neuropsychological assessment before and after awake tumor resection. Graph theoretical analysis was applied to DTI-derived connectivity matrices to calculate structural network properties. Structural network properties and NCF measures were compared across the pre- to postoperative periods with matched pairs Wilcoxon signed-rank tests. Associations between pre- to postoperative change in network properties and change in NCF were determined with Spearman rank-order correlations (ρ).

RESULTS

Nearly 90% of the sample showed postoperative decline on 1 or more NCF measures. Significant postoperative NCF decline was found across measures of verbal memory, processing speed, executive functioning, receptive language, and the Clinical Trial Battery Composite (CTB COMP) index. Regarding connectomic properties, significant postoperative changes were observed in global and local efficiency, characteristic path length, clustering coefficient, betweenness centrality, and assortativity, with medium effect sizes. Significant associations (ρ = .59 to .62, all p < .05) were observed between changes in aspects of NCF and connectomic properties.

CONCLUSIONS

Decline in NCF was common following resection and some postoperative outcomes were associated with changes in structural connectomic properties following surgery.
CNTM-05. Left hemisphere gliomas induce a plastic bi-hemispheric language network further characterized by lobe specific glioma data
Authors: Ramsey Matthew , Tripathi Shashwat , Saxena Mohit , Tate Matthew
Published: November 2021

Primary brain tumors are among the most burdensome diagnoses patients can receive as they often carry with them externally obvious and significant detriments to motor and speech. The stroke model is severely limited by the inherent nature of the insult to the brain: binary, relatively instantaneous and defined by vascular boundaries. We instead have chosen to study glioma-induced neuroplasticity in patients with gliomas as presentation is over a significantly longer time course with a gradient of insult to language activation areas instead of immediate ablation. Chart review was conducted on 545 patients who completed fMRI imaging from 2013–2019 while completing 1+ of the following language tasks: antonyms, reading comprehension, rhyming, word generation and picture naming. A total of 117 patients’ fMRI scans were included in the final analysis which entailed both a cluster-based analysis in FSL and a 34 gyral, mask-based analysis using FEATquery. Right hemisphere gliomas (RHG) were first established as a reliable control group by averaging anatomically significant voxels across all five language tasks (LT) yielding a core conserved network. Left hemisphere gliomas (LHG) were then directly compared to the RHG language tasks. We found LHG induced global reorganization of the conserved language network with little evidence for direct homologous recruitment of functional structures. Instead, a generalized right hemisphere recruitment is observed with 87% of non-zero masks shifting their laterality index to the right hemisphere. Furthermore, in each of the five LT, the LHG activates fewer total suprathreshold voxels in both the mask and cluster based analyses while having a higher peak intensity within the activated clusters. A preliminary analysis of frontal LHG compared to temporal LHG reveals increased contralateral recruitment in the frontal subgroup with more direct homologous recruitment. This nuanced understanding of existing mechanisms for neuroplasticity can aid in our future intentional manipulation for therapeutic benefit.
FLGS-01. Development of novel topical fluorescent probe for intraoperative rapid detection of glioma
Authors: Tanaka Shota , Kitagawa Yosuke , Kamiya Mako , Shimizu Takenori , Urano Yasuteru , Saito Nobuhito
Published: November 2021

PURPOSE

Fluorescence imaging is an important surgical adjunct in malignant glioma surgery. 5-aminolevulinic acid (5-ALA) has been proven effective for radical tumor resection and extended progression-free survival in a phase III randomized trial and therefore integrated into surgery for malignant glioma. Importantly, however, some limitations still exist in its use, which include false positivity and false negativity as well as inability of re-administration. In this study, we aimed to develop a novel, spray-type fluorescent probe using hydroxymethyl rhodamine green (HMRG) as a fluorescent scaffold.

METHODS

We have previously established a fluorescent probe library comprised of more than 320 kinds of HMRG probes. They have HMRG as a fluorescent scaffold with various types of dipeptides attached to it. Primary probe screening was performed using the homogenized tumor samples from patients with glioblastoma operated at our institution. Secondary screening followed using the selected probes and fresh tumor samples obtained from patients with glioblastoma operated from 2016 until 2018. Diced electrophoresis gel (DEG) assay, two-dimensional gel electrophoresis followed by a multi-well plate-based fluorometric assay, was performed to identify responsible enzymes for the selected probe. Further experiments with inhibitors, real-time PCR, immunohistochemistry, and western blotting were performed for confirmation.

RESULTS

Proline-arginine-HMRG (PR-HMRG) was selected as a candidate probe based upon the above two-step screenings. It achieved 79.4% accuracy in receiver operating characteristic curve analysis. Calpain-1 was found to be responsible to cleave PR-HMRG probe by DEG-proteome analysis. Calpain-1 protein was highly expressed in tumor tissues which reacted to PR-HMRG probe.

CONCLUSIONS

Our innovative screening method was able to find PR-HMRG as a novel fluorescent probe effective for rapid detection of glioblastoma. A preclinical study is planned to assess the efficacy and safety of the selected probe.
ITVT-03. Use of Functional MRI and DTI for Surgical Planning of Maximal Extent of Resection of CNS Tumors - A Single Neurosurgical Center’s Experience
Authors: Lam Fred , Algethami Hanan , Ekkehard Kasper
Published: November 2021

Use of functional neuroimaging capabilities such as fMRI, DTI, MRP, MRS, AS-PET-CT, SPECT, and TMS as noninvasive tools to visualize intrinsic brain and spine morphology in relation to function have developed over the past 30 years. Amongst these imaging modalities, functional magnetic resonance imaging (fMRI) is of particular interest since it follows the physiological coupling between neuronal electrical activity and metabolic structural (cellular) activity as it relates to tissue vascularity and perfusion states. As an adjunct to this modality, MRI-based diffusion tensor imaging (DTI) allows further detailed radiographic assessment of fiber tracts in the brain in relationship to the surgical lesion of interest. In addition, combination of other imaging modalities including MR perfusion and intraoperative tools such as neuronavigation and direct cortical stimulation can help guide the extent of maximal safe resection. Herein we present a case series from our neurosurgical institution of primary intra-axial, extra-axial, supratentorial, and brainstem tumors resected using fMRI and DTI for presurgical planning allowing for maximal safe extent of resection and outcomes.
ITVT-08. Combined use of awake surgery and intraoperative MRI augments extent of resection in eloquent gliomas without neurological impairment
Authors: Jungk Christine , Trong Philip Dao , Eisner Christoph , Haehnel Stefan , Unterberg Andreas
Published: November 2021

Maximizing the extent of resection (EOR) while preserving functional integrity is a mainstay of glioma surgery. Intraoperative MRI (iMRI) helps to augment the EOR. However, in eloquently located gliomas the significance of iMRI is controversial since the EOR is limited by functional rather than image-based boundaries. Thus, we sought to determine the impact of iMRI in our institutional series of awake glioma resections within or adjacent to eloquent (language, motor, sensory) areas since the implementation of a 1.5 Tesla iMRI in 2009. Tumor- and procedure-related data and functional outcome were assessed through medical charts review. The EOR was determined volumetrically on pre-, intra- and postoperative T1 contrast-enhanced (CE) and FLAIR MR images. 131 of 166 awake surgeries (79%) were performed under iMRI-guidance with concurrent language (n=72) and/or motor (n=50) mapping. iMRI was done when functional boundaries were reached (62%), for resection control (28%) or for other reasons (10%). Additional resection after iMRI (AR) was performed in 63 cases (73%); otherwise resection was terminated because the targeted EOR or functional boundaries were reached. New or deteriorated neurological deficits occurred in 20 patients prior and 15 patients post iMRI; however, all but 3 resolved within 6 months. Median EOR significantly increased after AR from 92.6% to 98.4% (∆5.8%; p<0.0001) in CE tumors and from 64.5% to 85.8% (∆21.3%; p<0.0001) in non-enhancing tumors. Remarkably, the reason to perform iMRI (resection control or functional limitations), did not affect the frequency of AR, deficits acquired post iMRI or the increase in EOR after AR. In conclusion, iMRI is a valuable adjunct to maximize the EOR in awake glioma resections without increasing the risk for functional impairment, particularly in non-enhancing tumors. Importantly, iMRI contributes to a maximized EOR even in cases where the resection had to be stopped because functional boundaries were reached.
Postmortem brain donations vs premortem surgical resections for glioblastoma research: viewing the matter as a whole
Authors: Griffin Cassandra P , Paul Christine L , Alexander Kimberley L , Walker Marjorie M , Hondermarck Hubert , Lynam James
Published: November 2021

There have been limited improvements in diagnosis, treatment, and outcomes of primary brain cancers, including glioblastoma, over the past 10 years. This is largely attributable to persistent deficits in understanding brain tumor biology and pathogenesis due to a lack of high-quality biological research specimens. Traditional, premortem, surgical biopsy samples do not allow full characterization of the spatial and temporal heterogeneity of glioblastoma, nor capture end-stage disease to allow full evaluation of the evolutionary and mutational processes that lead to treatment resistance and recurrence. Furthermore, the necessity of ensuring sufficient viable tissue is available for histopathological diagnosis, while minimizing surgically induced functional deficit, leaves minimal tissue for research purposes and results in formalin fixation of most surgical specimens. Postmortem brain donation programs are rapidly gaining support due to their unique ability to address the limitations associated with surgical tissue sampling. Collecting, processing, and preserving tissue samples intended solely for research provides both a spatial and temporal view of tumor heterogeneity as well as the opportunity to fully characterize end-stage disease from histological and molecular standpoints. This review explores the limitations of traditional sample collection and the opportunities afforded by postmortem brain donations for future neurobiological cancer research.
Anatomical and topographical variations in the distribution of brain metastases based on primary cancer origin and molecular subtypes: a systematic review
Authors: Cardinal Tyler , Pangal Dhiraj , Strickland Ben A , Newton Paul , Mahmoodifar Saeedeh , Mason Jeremy , Craig David , Simon Thomas , Tew Ben Yi , Yu Min , Yang Wensha , Chang Eric , Cabeen Ryan P , Ruzevick Jacob , Toga Arthur W , Neman Josh , Salhia Bodour , Zada Gabriel
Published: November 2021

Background

While it has been suspected that different primary cancers have varying predilections for metastasis in certain brain regions, recent advances in neuroimaging and spatial modeling analytics have facilitated further exploration into this field.

Methods

A systematic electronic database search for studies analyzing the distribution of brain metastases (BMs) from any primary systematic cancer published between January 1990 and July 2020 was conducted using PRISMA guidelines.

Results

Two authors independently reviewed 1957 abstracts, 46 of which underwent full-text analysis. A third author arbitrated both lists; 13 studies met inclusion/exclusion criteria. All were retrospective single- or multi-institution database reviews analyzing over 8227 BMs from 2599 patients with breast (8 studies), lung (7 studies), melanoma (5 studies), gastrointestinal (4 studies), renal (3 studies), and prostate (1 study) cancers. Breast, lung, and colorectal cancers tended to metastasize to more posterior/caudal topographic and vascular neuroanatomical regions, particularly the cerebellum, with notable differences based on subtype and receptor expression. HER-2-positive breast cancers were less likely to arise in the frontal lobes or subcortical region, while ER-positive and PR-positive breast metastases were less likely to arise in the occipital lobe or cerebellum. BM from lung adenocarcinoma tended to arise in the frontal lobes and squamous cell carcinoma in the cerebellum. Melanoma metastasized more to the frontal and temporal lobes.

Conclusion

The observed topographical distribution of BM likely develops based on primary cancer type, molecular subtype, and genetic profile. Further studies analyzing this association and relationships to vascular distribution are merited to potentially improve patient treatment and outcomes.
Metabolics risk factors in a New Zealand glioblastoma cohort
Authors: McManus Eileen J , Frampton Chris , Tan Alvin , Phillips Matthew C L
Published: November 2021

Background

Glioblastoma multiforme (GBM) is the most aggressive form of glioma. There is growing recognition that mitochondrial metabolism plays a role in cancer development. Metabolic syndrome is a risk factor for several cancers; however, the prevalence in GBM patients in New Zealand (NZ) is unknown. We hypothesized that patients with GBM would show a higher prevalence of metabolic syndrome compared to the general NZ population and that metabolic syndrome may be associated with worsened overall survival (OS) in GBM.

Methods

We performed a retrospective analysis in 170 patients diagnosed and treated for GBM between 2005 and 2020. Clinical and biochemical data were collected with regard to 5 metabolic criteria. OS was determined from the date of initial surgical diagnosis to the date of death or date of data acquisition.

Results

Of 170 patients, 31 (18.2%) met the diagnostic criteria for metabolic syndrome. The prevalence of metabolic syndrome in our cohort did not significantly differ from that of the general NZ population. However, OS in patients with metabolic syndrome was significantly worse compared to patients without metabolic syndrome (8.0 vs 13.0 months, P = .016). Patients who received a lower dexamethasone dose had significantly better survival outcomes (15.0 vs 5.0 months, P < .01). Differences in OS did not differ by gender or ethnicity.

Conclusions

We have shown that metabolic syndrome is associated with reduced OS in a NZ cohort of GBM patients. This finding further strengthens the possibility that a metabolic pathogenesis may underpin GBM. However, prospective clinical trials are needed.
Evaluating the Diagnostic Paradigm for Group A and Non–Group A Streptococcal Pharyngitis in the College Student Population
Authors: Rich Shannan N , Prosperi Mattia , Klann Emily M , Codreanu Pavel T , Cook Robert L , Turley Melissa K
Published: November 2021

Background

Acute pharyngitis is a frequent illness presenting in outpatient settings. Antibiotics are only recommended for bacterial pharyngitis caused by group A β-hemolytic streptococci (GAS); however, infections with non–group A β-hemolytic streptococci (NGAS) have similar clinical presentations and are common in young adult populations. The objective of this study was to analyze the performance of a current (expert) diagnostic algorithm for GAS pharyngitis, the Centor score, and compare it to alternative models developed to predict GAS and NGAS in a college student population.

Methods

Electronic health records were obtained for all patients who received a streptococcal rapid antigen detection test (RADT) and/or a bacterial throat culture (n = 3963) at a southeastern US university in 2014. Bivariate and multivariable regression models (least absolute shrinkage and selection operator [LASSO] and stepwise-selected) were fitted to assess and compare their diagnostic performances for GAS-positive and NGAS-positive infections.

Results

Prevalence of GAS was 18.8%. In the subset of RADT-negative patients who received bacterial throat cultures (n = 313), growth of NGAS occurred in 34.8%, with group C streptococci the most frequent isolate. Mean Centor score was higher for NGAS (3.2) vs GAS (2.9) infections (P = .0111). The area under the curve (AUC) for GAS prediction was 0.64 using the Centor score and 0.70 using the LASSO model. For NGAS, the most important features were cough, pharyngeal erythema, tonsillar exudate, and gastrointestinal symptoms (AUC = 0.63).

Conclusions

GAS and NGAS pharyngitis were indistinguishable among college students in this study utilizing a commonly applied decision score. Alternative models using additional clinical criteria may be useful for supporting diagnosis of this common illness.
Bloodstream Infection Following Cardiac Valve Repair: A Population-Based Study
Authors: McHugh Jack W , Talha Khawaja M , Baddour Larry M , Fischer Karen M , Crestanello Juan , Arghami Arman , DeSimone Daniel C
Published: November 2021

Background

The aim of this study was to determine the incidence, epidemiology, and associated risk factors of bloodstream infection (BSI) in patients who had previously undergone cardiac valve repair.

Methods

A population-based study that included 7 counties in southeastern Minnesota using the expanded Rochester Epidemiology Project (e-REP) for adults (≥18 years) who underwent valve repair between 1 January 2010 and 31 December 2018 was conducted. Electronic health records were screened for development of BSI and infective endocarditis (IE) from the date of valve repair through 30 July 2020. A 1:4 nested case-control analysis was performed to determine an association, if any, of male sex, Charlson comorbidity index (CCI), and county of residence with BSI.

Results

A total of 335 patients underwent valve repair, of whom 28 (8.3%) developed an index case of BSI, with 14 episodes occurring within 1 year of surgery. The median age of patients with BSI was 70 years, and 79% were male. The crude incidence of BSI was 1671 cases per 100000 person-years and Escherichia coli was the most common pathogen. Case-control analysis demonstrated a significant correlation between CCI and incidence of BSI (P < .001). Only 4 (14.3%) patients developed IE concurrent with the onset of BSI, and no patients developed IE subsequent to BSI.

Conclusions

The crude incidence of BSI following valve repair was higher in our e-REP cohort than previous population-based studies, and half of the BSI cases occurred within 1 year of surgery. Patients with a higher CCI at baseline were at increased risk of subsequent BSI.
PfEMP1-Specific Immunoglobulin G Reactivity Among Beninese Pregnant Women With Sickle Cell Trait
Authors: Lopez-Perez Mary , Viwami Firmine , Seidu Zakaria , Jensen Anja T R , Doritchamou Justin , Ndam Nicaise Tuikue , Hviid Lars
Published: November 2021

Background

Sickle cell trait (HbAS) protects against severe Plasmodium falciparum malaria but not against placental malaria (PM). In this study, P falciparum erythrocyte membrane protein (PfEMP1)-specific antibodies were measured in HbAA and HbAS Beninese pregnant women as a proxy of exposure to specific PfEMP1 variants.

Methods

Plasma samples collected at delivery from 338 HbAA and 63 HbAS women were used to measure immunoglobulin (Ig)G levels to 6 recombinant PfEMP1 proteins and 3 corresponding native proteins expressed on the infected erythrocyte (IE) surface. Immunoglobulin G-mediated inhibition of VAR2CSA+ IEs adhesion to chondroitin sulfate A (CSA) was also tested.

Results

Levels of PfEMP1-specific IgG were similar in the 2 groups, except for native IT4VAR09 on IEs, where IgG levels were significantly higher in HbAS women. Adjusted odds ratios for women with positive IgG to HB3VAR06 and PFD1235w suggest a lower risk of infection with these virulent variants among HbAS individuals. The percentage of IEs binding to CSA did not differ between HbAA and HbAS women, but it correlated positively with levels of anti-VAR2CSA and parity. Women with PM had lower levels of anti-VAR2CSA-specific IgG and lower IgG-mediated inhibition of IE adhesion to CSA.

Conclusions

The findings support similar malaria exposure in HbAA and HbAS women and a lack of HbAS-dependent protection against placental infection among pregnant women.
Extensively Drug-Resistant Typhoid Fever in the United States
Authors: Hughes Michael J , Birhane Meseret G , Dorough Layne , Reynolds Jared L , Caidi Hayat , Tagg Kaitlin A , Snyder Caroline M , Yu Alexander T , Altman Shana M , Boyle Michelle M , Thomas Deepam , Robbins Amy E , Waechter HaeNa A , Cody Irina , Mintz Eric D , Gutelius Bruce , Langley Gayle , Francois Watkins Louise K
Published: November 2021

Cases of extensively drug-resistant (XDR) typhoid fever have been reported in the United States among patients who did not travel internationally. Clinicians should consider if and where the patient traveled when selecting empiric treatment for typhoid fever. XDR typhoid fever should be treated with a carbapenem, azithromycin, or both.
The EU–UK Trade and Cooperation Agreement: lessons learnt
Authors: Bennett Adam , Vines David
Published: November 2021

This paper analyses the Trade and Cooperation Agreement (TCA) between the EU and the UK. We focus on two specific features: rules of origin and non-tariff barriers. The putative purpose of the TCA was to promote free trade between the signatories, and both of the features identified have ‘level-playing-field’ objectives which are designed to promote that purpose. However, both can also be used for covert protectionism against the other party to the agreement. The paper recommends that rules of origin and non-tariff barriers should be recrafted where possible, and there is a description of how this might be done. The aim of such action would be to make transparent the role of these features in preserving a level playing field. Doing this would also make clear that any residual unadulterated rules of origin and non-tariff barriers existed for purely protectionist reasons and jeopardized open borders. Hopefully, the exposure of such protectionism would encourage its dismantlement.
Cis-regulatory sequences in plants: Their importance, discovery, and future challenges
Authors: Schmitz Robert J , Grotewold Erich , Stam Maike
Published: November 2021

The identification and characterization of cis-regulatory DNA sequences and how they function to coordinate responses to developmental and environmental cues is of paramount importance to plant biology. Key to these regulatory processes are cis-regulatory modules (CRMs), which include enhancers and silencers. Despite the extraordinary advances in high-quality sequence assemblies and genome annotations, the identification and understanding of CRMs, and how they regulate gene expression, lag significantly behind. This is especially true for their distinguishing characteristics and activity states. Here, we review the current knowledge on CRMs and breakthrough technologies enabling identification, characterization, and validation of CRMs; we compare the genomic distributions of CRMs with respect to their target genes between different plant species, and discuss the role of transposable elements harboring CRMs in the evolution of gene expression. This is an exciting time to study cis-regulomes in plants; however, significant existing challenges need to be overcome to fully understand and appreciate the role of CRMs in plant biology and in crop improvement.
Intra-Articular Platelet Rich Plasma vs Corticosteroid Injections for Sacroiliac Joint Pain: A Double-Blinded, Randomized Clinical Trial
Authors: Chen Allen S , Solberg Joseph , Smith Clark , Chi Michelle , Lowder Ryan , Christolias George , Singh Jaspal Ricky
Published: November 2021

Objective

Using stringent inclusion criteria, a double-blinded study protocol, and fluoroscopically guided injections, we compare intra-articular sacroiliac joint platelet-rich plasma injections with intra-articular steroids.

Design

Double-blind, randomized controlled trial.

Setting

Two large university-based interdisciplinary spine centers.

Subjects

A total of 26 patients with a positive diagnostic block (>80% relief).

Methods

Subjects who had a positive diagnostic block were randomized to undergo either a fluoroscopically guided intra-articular injection of steroid or a platelet-rich plasma injection. Follow-up was at 1 month, 3 months, and 6 months. Outcomes included level of pain, as indicated on a 0- to 100-mm numeric pain rating scale, and functional disability score, obtained via the Oswestry Disability Index (ODI).

Results

At 1, 3, and 6 months, both groups improved; however, subjects who received steroid injections reported lower pain scores than did subjects who received platelet-rich plasma. Using categorical data, we observed significantly more responders (defined as pain scores that improved by 50% or more from baseline) at 1 and 3 months in the group who received steroids than in the group who received platelet-rich plasma.

Conclusion

Although both groups showed improvements in pain and function, the steroid group had significantly greater response and significantly more responders than did the platelet-rich plasma group.
A systematic review exploring pre-COVID-19 telehealthcare models used in the management of patients with rheumatological disease
Authors: Nelson Alexandra Jayne , Anderson Marina Ellen
Published: November 2021

Objective

The aim was to assess the use of telehealthcare in rheumatology before coronavirus disease 2019 (COVID-19), to which future comparisons of newer interventions adapted during the crisis can be made.

Methods

We performed a registered systematic literature search using MEDLINE, EMBASE, CENTRAL and PubMed databases. All full-length articles comparing telehealthcare delivery models with standard care (face-to-face consultation) in the management of patients with rheumatic conditions were assessed for inclusion.

Results

A total of 4809 studies were identified; 108 studies were suitable for review by full text, and 13 studies were appropriate to be included in this review. Five studies (38%) included patients with RA, four studies (31%) included patients with mixed disease cohorts, two studies (15%) included patients with OA, one study (8%) included patients with JIA, and one study (8%) included patients with FM. Six studies (46%) used telephone consultation, three studies (23%) used mixed method communication, three studies (23%) used videoconferencing, and one study (8%) used website-delivered telecommunication as their method of telehealthcare delivery. Overall, seven studies (54%) identified the telehealthcare intervention to be an effective method of consultation, and six studies (46%) identified the telehealthcare intervention as non-inferior when compared with standard care.

Conclusion

Current evidence for telehealthcare in rheumatology is lacking, and the evidence for effectiveness is limited by methodological bias and clinical heterogeneity of telehealthcare interventions, preventing definitive inferences. Scrutinous assessment of the current telehealthcare interventions used during COVID-19 is required to accommodate recommendations and guideline reviews directed from international working groups.
Understanding flare in axial spondyloarthritis: novel insights from daily self-reported flare experience
Authors: Barnett Rosemarie , Ng Stanley , Sengupta Raj
Published: November 2021

Objectives

Our objective was to explore daily self-reported experiences of axial SpA (axSpA) flare based on data entered into the Project Nightingale smartphone app (www.projectnightingale.org), between 5 April 2018 and 1 April 2020.

Methods

Paired t-tests were conducted for mean_flare_on and mean_flare_off scores for each recorded variable. The mean estimated difference between flare and non-flare values for each variable was calculated with 95% CIs. Mean, S.d. and range were reported for flare duration and frequency. Participants with ≥10 days of data entry were included for affinity propagation cluster analysis. Baseline characteristics and mean flare on vs mean flare off values were reported for each cluster. Welch’s t-test was used to assess differences between clusters.

Results

A total of 143/189 (75.7%) participants recorded at least one flare. Each flare lasted a mean of 4.30 days (S.d. 6.82, range 1–78), with a mean frequency of once every 35.32 days (S.d. 65.73, range 1–677). Significant relationships were identified between flare status and variable scores. Two clusters of participants were identified with distinct flare profiles. Group 1 experienced less severe worsening of symptoms during flare in comparison to group 2 (P < 0.01). However, they experienced significantly longer flare duration (7.2 vs 3.5 days; P < 0.01), perhaps indicating a prolonged, yet less intense flare experience. Groups were similar in terms of flare frequency and clinical characteristics.

Conclusions

Two clusters of participants were identified with distinct flare experiences but similar baseline clinical characteristics. Smartphone technologies capture subtle changes in disease experience not currently considered in clinical practice.
Ultrasound shows swollen joints are the better proxy for synovitis than tender joints in DMARD-naïve early psoriatic arthritis
Authors: Dubash Sayam R , Alabas Oras A , Michelena Xabier , Garcia-Montoya Leticia , De Marco Gabriele , Merashli Mira , Wakefield Richard J , Emery Paul , McGonagle Dennis , Tan Ai Lyn , Marzo-Ortega Helena
Published: November 2021

Objective

To evaluate the relationship between clinical examination/US synovitis in DMARD-naïve early PsA.

Methods

Eligible patients underwent matched clinical/US 44-joint assessment for tender and/or swollen joints (TJ/SJ) and US synovitis [grey scale (GS) ≥ 2 or power Doppler (PD) ≥ 1]. Statistical agreement between TJ/SJ, GS ≥ 2 and PD ≥ 1 was calculated by prevalence-adjusted and bias-adjusted κ (PABAK). To derive probabilities of GS ≥ 2/PD ≥ 1, mixed-effects logistic regression-modelled odds of US synovitis in TJ/SJ were conducted.

Results

In 155 patients, 5616 joints underwent clinical/US examination. Of these joints, 1039 of 5616 (18.5%) were tender, 550 of 5616 (9.8%) were swollen, 1144 of 5616 (20.4%) had GS ≥ 2, and 292 of 5616 (5.2%) had PD ≥ 1. GS ≥ 2 was most prevalent in concomitantly tender and swollen joints [205 of 462 (44%)], followed by swollen non-tender joints [32 of 88 (36.4%)], tender non-swollen joints [148 of 577 (25.7%)] and non-tender non-swollen joints (subclinical synovitis) [759 of 4489 (16.9%)]. Agreement between SJ/PD ≥ 1 was high at the individual joint level (82.6–96.3%, PABAK 0.65–0.93) and for total joints combined (89.9%, PABAK 0.80). SJ/GS ≥ 2 agreement was greater than between TJ/GS ≥ 2 [73.5–92.6% vs 51.0–87.4% (PABAK 0.47–0.85 vs PABAK 0.35–0.75), respectively]. Swelling was independently associated with higher odds of GS ≥ 2 [odds ratio (OR) (95% CI); 4.37 (2.62, 7.29); P < 0.001] but not tenderness [OR = 1.33 (0.87, 2.06); P = 0.192]. Swelling [OR = 8.78 (3.92, 19.66); P < 0.001] or tenderness [OR = 3.38 (1.53, 7.50); P = 0.003] was independently associated with higher odds of PD ≥ 1.

Conclusion

Synovitis (GS ≥ 2 and/or PD ≥ 1) was more likely in swollen joints than in tender joints in DMARD-naïve, early PsA. Agreement indicated that swollen joints were the better proxy for synovitis, adding to greater understanding between clinical and US assessments.
Napping behavior in adults with episodic migraine: a six-week prospective cohort study
Authors: Vgontzas Angeliki , Mostofsky Elizabeth , Hagan Kobina , Rueschman Michael , Mittleman Murray A , Bertisch Suzanne M
Published: November 2021

Study Objectives

Patients with migraine commonly endorse napping as a strategy for headache pain relief, but also experience high rates of sleep disturbance. To elucidate the relationship between napping behavior and migraine, we evaluated the association between napping and headache frequency, severity, and intensity among adults with episodic migraine. We also examined the association between daily napping and that night’s sleep.

Methods

In this six-week prospective cohort study, 97 adults with episodic migraine completed twice-daily headache and sleep electronic diaries and wore a wrist actigraph. We modeled the associations between napping (yes/no) and headaches with conditional logistic regression and daily napping and nighttime sleep with linear regression.

Results

Over 4,353 study days, participants reported 1,059 headache days and 389 days with naps. More than 80% of participants napped during the study, with mean nap duration of 76.7 ± 62.4 min. Naps were more likely to occur on day 2 of headache 35/242 (14.5%) than on nonheadache days 279/3294 (8.5%, OR 2.2 [95% CI 1.4, 3.4]). Mean nap onset time (14:40 ± 3.3 h) was later than headache onset (12:48 ± 5.3 h). In adjusted models, napping was associated with an additional 1.1 (95% CI −1.4, 3.6) headache days/month. Naps were not associated with worse self-reported or objective sleep that night.

Conclusions

Our findings suggest that naps may be an uncommonly used behavioral strategy for prolonged migraine attacks and do not contribute to nightly sleep disturbance. Future studies are needed to examine the acute analgesic effects of daytime napping in patients with migraine.
A Theory of Political Backlash: Assessing the Religious Right’s Effects on the Religious Field
Authors: Braunstein Ruth
Published: November 2021

A growing body of evidence suggests that the rise in religious disaffiliation can be partly attributed to a political backlash against the Religious Right. Yet the concept of “political backlash” remains undertheorized, limiting our ability to evaluate how backlash against the Religious Right has impacted the religious field as a whole. This article develops a general account of how political backlash against a radical actor can impact participants within a given field, distinguishing between broad backlash, narrow backlash, and counter backlash. It then applies this framework to the case of the religious field. An analysis of available evidence suggests that backlash against the Religious Right has had ripple effects beyond the rise of the “nones,” including a rise in “spiritual” identification, positive attention to the “Religious Left,” depoliticization of liberal religion, and purification and radicalization within the Religious Right itself. This article encourages religion scholars to connect dots between trends that have not been understood as related, and deepens our understanding of the relational nature of religious change. More generally, it offers a framework for understanding how backlash against radical actors can shape entire fields.
Intake, nutrient digestibility, rumen parameters, growth rate, carcase characteristics and cannabinoid residues of sheep fed pelleted rations containing hemp (Cannabis sativa L.) stubble
Authors: Krebs Gaye L , De Rosa Daniel W , White Dana M , Blake Bronwyn L , Dods Kenneth C , May Christopher D , Tai Zi X , Clayton E H , Lynch Emma E
Published: November 2021

The feeding value and impact of hemp stubble in the diet of ruminants is unknown. Fifteen Merino castrated male sheep were maintained in individual pens and fed one of three pelletized experimental inclusion diets, as a 0% (Control), 28% (Hemp 1), and 56% (Hemp 2) pellet that delivered a diet meeting the nutrient requirements of the animals. Inclusion of hemp stubble had no effect (P > 0.05) on either DM intake, live weight gain or the feed to gain ratio but positively impacted (P < 0.05) on nutrient digestibility. Hemp stubble inclusion increased the concentration (but not molar proportions) of acetic and butyric acids and increased both the concentrations and molar proportions of iso-butyric, iso-valeric, hexanoic and heptanoic acids, possibly due to increased protein digestibility and/or changes in the composition of rumen cellulolytic bacteria. Tetrahydrocannabinolic acid (THCA) was the only cannabinoid found in plasma in the sheep fed the hemp-containing diets, and this was found at very low concentrations (<16 μg/L). The psychoactive cannabinoid delta-9-tetrahydrocannabinol (Δ 9-THC) was not detected in any plasma samples. THCA was detected in the liver of two sheep fed the Hemp 1 pellets and two sheep fed the Hemp 2 pellets. Cannabidiol (CBD) was detected in the liver of one sheep fed the Hemp 2 pellets (but no liver THCA was detected in this sheep). Δ 9-THC was detected in both the kidney fat and subcutaneous fat of all sheep fed hemp stubble, with the concentrations being higher (P < 0.05) in the sheep fed the Hemp 1 pellets. THCA was also detected in the subcutaneous fat of one of the sheep fed the Hemp 1 pellets. Four of the five sheep fed the Hemp 1 pellet and one of the five sheep fed Hemp 2 pellet had detectable levels of Δ 9-THC in the meat (loin). No other cannabinoids were detected in the meat. Current food standards regulations in Australia prohibit presence of any cannabinoid residues in commercial meat products; thus, determination of a withholding period is required to enable the safe feeding of hemp-stubble to sheep. Further research is also required to gain a greater understanding of the rumen metabolism of cannabinoids.
New Indications and Approvals for Anticancer Drugs
Authors: Aschenbrenner Diane S.
Published: November 2021

Several anticancer drugs have received new indications; new drug approvals; or regular approvals to replace previous accelerated, conditional approvals.
The ICN Global Nursing Leadership Institute: Integrating the SDGs into Leadership and Policy Development
Authors: Rosa William E. , Burnett Camille , Butler Chesanny , Rolle Prescola , Salvage Jane , Wignall Angela , Mason Diana J.
Published: November 2021

This article is one in a series in which contributing authors discuss how the United Nations (UN) Sustainable Development Goals (SDGs) are linked to everyday clinical issues; national public health emergencies; and other nursing issues, such as leadership, shared governance, and advocacy. The 2030 Agenda for Sustainable Development, a 15-year plan of action to achieve the goals, was unanimously adopted by all UN member states in September 2015 and took effect on January 1, 2016. The Agenda consists of 17 SDGs addressing social, economic, and environmental determinants of health and 169 associated targets focused on five themes: people, planet, peace, prosperity, and partnership. The SDGs build on the work of the UN Millennium Development Goals, which were in effect from 2000 to 2015. The current article discusses the International Council of Nurses Global Nursing Leadership Institute and its integration of the SDGs into a global leadership and policy development program.
Family History a Risk for Early-Onset Colorectal Cancer
Authors: Todd Betsy
Published: November 2021

First-degree relatives of people with early-onset colorectal cancer are six times more likely than the general population to be diagnosed with this condition.

First-, second-, and third-degree relatives of people with early-onset colorectal cancer are at higher risk for both early-onset colorectal cancer and colorectal cancer at any age.
The International Council of Nurses
Authors: Todd Betsy
Published: November 2021

Editor's note: From its first issue in 1900 through to the present day, AJN has unparalleled archives detailing nurses' work and lives over more than a century. These articles not only chronicle nursing's growth as a profession within the context of the events of the day, but also reveal prevailing societal attitudes about women, health care, and human rights. Today's nursing school curricula rarely include nursing's history, but it's a history worth knowing. To this end, From the AJN Archives highlights articles selected to fit today's topics and times.
Ethics and Well-Being: The Health Professions and the COVID-19 Pandemic
Authors: Hughes Mark T. , Rushton Cynda H.
Published: November 2021

The COVID-19 pandemic has had a profound impact on health professionals, adding to the moral suffering and burnout that existed prepandemic. The physical, psychological, and moral toll of the pandemic has threatened the well-being and integrity of clinicians. The narrative of self-sacrifice and heroism bolstered people early on but was not sustainable over time. For health professions students, the learning environment changed dramatically, limiting opportunities in direct patient care and raising concerns for meeting training requirements. Learners lost social connections and felt isolated while learning remotely, and they witnessed ethical tensions between patient-centered care and parallel obligations to public health. Worries about transmission of the virus and uncertainty about its management contributed to their moral suffering. Educators adjusted curricula to address the changing ethical landscape. Preparing learners for the realities of their future professional identities requires creation of interprofessional moral communities that provide support and help develop the moral agency and integrity of its members using experiential and relational learning methods. Investing in the well-being and resilience of clinicians, implementing the recommendations of the National Academy of Medicine, and engaging learners and faculty as cocreators of ethical practice have the potential to transform the learning environment. Faculty need to be trained as effective mentors to create safe spaces for exploring challenges and address moral adversity. Ethics education will need to expand to issues related to health systems science, social determinants of health, and public health, and the cultivation of moral sensitivity, character development, professional identity formation, and moral resilience.