bluuebunny/crossref_metadata_2025 huggingface dataset:
A general Bayesian framework for foreground modelling and chromaticity correction for global 21 cm experiments
Authors: Anstey Dominic , de Lera Acedo Eloy , Handley Will
Published: June 2021

The H i 21 cm absorption line is masked by bright foregrounds and systematic distortions that arise due to the chromaticity of the antenna used to make the observation coupling to the spectral inhomogeneity of these foregrounds. We demonstrate that these distortions are sufficient to conceal the 21 cm signal when the antenna is not perfectly achromatic and that simple corrections assuming a constant spatial distribution of foreground power are insufficient to overcome them. We then propose a new physics-motivated method of modelling the foregrounds of 21 cm experiments in order to fit the chromatic distortions as part of the foregrounds. This is done by generating a simulated sky model across the observing band by dividing the sky into N regions and scaling a base map assuming a distinct uniform spectral index in each region. The resulting sky map can then be convolved with a model of the antenna beam to give a model of foregrounds and chromaticity parametrized by the spectral indices of the N regions. We demonstrate that fitting this model for varying N using a Bayesian nested sampling algorithm and comparing the results using the evidence allows the 21 cm signal to be reliably detected in data of a relatively smooth conical log spiral antenna. We also test a much more chromatic conical sinuous antenna and find this model will not produce a reliable signal detection, but in a manner that is easily distinguishable from a true detection.
Multi-resolution characterization of molecular taxonomies in bulk and single-cell transcriptomics data
Authors: Reed Eric R , Monti Stefano
Published: June 2021

As high-throughput genomics assays become more efficient and cost effective, their utilization has become standard in large-scale biomedical projects. These studies are often explorative, in that relationships between samples are not explicitly defined a priori, but rather emerge from data-driven discovery and annotation of molecular subtypes, thereby informing hypotheses and independent evaluation. Here, we present K2Taxonomer, a novel unsupervised recursive partitioning algorithm and associated R package that utilize ensemble learning to identify robust subgroups in a ‘taxonomy-like’ structure. K2Taxonomer was devised to accommodate different data paradigms, and is suitable for the analysis of both bulk and single-cell transcriptomics, and other ‘-omics’, data. For each of these data types, we demonstrate the power of K2Taxonomer to discover known relationships in both simulated and human tissue data. We conclude with a practical application on breast cancer tumor infiltrating lymphocyte (TIL) single-cell profiles, in which we identified co-expression of translational machinery genes as a dominant transcriptional program shared by T cells subtypes, associated with better prognosis in breast cancer tissue bulk expression data.
O-glycoforms of polymeric immunoglobulin A1 in the plasma of patients with IgA nephropathy are associated with pathological phenotypes
Authors: Yu Guizhen , Zhang Yong , Meng Bo , Xie Xinfang , Wang Zi , Ying Wantao , Lv Jicheng , Zhang Hong
Published: June 2021

Background

Immunoglobulin A1 (IgA1) O-glycosylation plays an important role in the pathogenesis of IgA nephropathy (IgAN). However, variations in IgA1 O-glycoforms have not been explored. We aimed to investigate the IgA1 O-glycoforms in the hinge region (HR) of polymeric IgA1 (pIgA1) and then evaluate the association between IgA1 O-glycoforms and crescent formation in IgAN.

Methods

The discovery cohort (Cohort 1) comprised 11 crescentic IgAN patients, 10 noncrescentic IgAN patients and 10 healthy controls and the validation cohort (Cohort 2) comprised 11 crescentic IgAN patients, 9 noncrescentic IgAN patients and 9 healthy controls. A total of 143 IgAN patients with different crescent percentages (Cohort 3) were also included. pIgA1 was purified from the plasma of the participants. The variation in O-glycoforms was evaluated by estimating the molecular weights of IgA1 hinge glycopeptides using reversed-phase liquid chromatography and tandem mass spectrometry under electron-transfer/higher-energy collision dissociation fragmentation mode.

Results

In the discovery cohort (Cohort 1), the number of N-acetylgalactosamine (GalNAc) bound to one HR was lower in IgAN patients. The proportions of GalNAc3 (defined as O-glycans bound to one HR at three sites) and GalNAc4 were highest in crescentic IgAN patients, followed by noncrescentic IgAN patients, and were lowest in healthy controls [GalNAc 3: 9.92 ± 3.37% versus 6.65 ± 1.53% versus 4.05 ± 1.24% (P < 0.001); GalNAc4: 45.91 ± 4.75% versus 41.13 ± 2.95% versus 40.98 ± 2.95% (P = 0.004), respectively]. The proportions of GalNAc5 and GalNAc6 were lowest in crescentic IgAN patients followed by noncrescentic IgAN patients and were highest in healthy controls [GalNAc5: 50.15 ± 4.27% versus 47.92 ± 4.09% versus 45.87 ± 3.79% (P = 0.028); GalNAc6: 6.58 ± 2.53% versus 6.04 ± 1.35% versus 4.65 ± 2.27% (P = 0.034), respectively]. These results were consistent in the validation cohort (Cohort 2). In another cohort with 143 patients with different crescent percentages (Cohort 3), the number of GalNAc in pIgA1 decreased with an increasing percentage of crescents.

Conclusions

The number of GalNAc in IgA1 HRs was lower in IgAN patients, especially in crescentic IgAN patients, and may be associated with a severe IgAN phenotype.
Early Outcomes After Carotid Endarterectomy and Carotid Artery Stenting: A Propensity-Matched Cohort Analysis
Authors: Sastry Rahul A , Pertsch Nathan J , Sagaityte Emilija , Poggi Jonathan A , Toms Steven A , Weil Robert J
Published: June 2021

BACKGROUND

Carotid endarterectomy (CEA) and carotid artery stenting (CAS) represent options to treat many patients with carotid stenosis. Although randomized trial data are plentiful, estimated rates of morbidity and mortality for both CEA and CAS have varied substantially.

OBJECTIVE

To evaluate rates of adverse outcomes after CAS and CEA in a large national database.

METHODS

We analyzed 84 191 adult patients undergoing elective, nonemergent CAS (n = 81 361) or CEA (n = 2830), from 2011 to 2018, in the American College of Surgeons’ National Surgical Quality Improvement Program database. Odds of adverse outcomes (30-d rates of stroke, myocardial infarction (MI), cardiac arrest, prolonged length of stay (LOS), readmission, reoperation, and mortality) were evaluated in propensity-matched (n = 2821) cohorts through logistic regression.

RESULTS

In the propensity-matched cohorts, CAS had increased odds of periprocedural stroke (odds ratio [OR] 1.97, 95% CI 1.32-2.95) and decreased odds of cardiac arrest (OR 0.33, 95% CI 0.13-0.84) and 30-d reoperation (OR 0.59, 95% CI 0.44-0.80) compared to CEA. Relative odds of MI, prolonged LOS, discharge to destination other than home, 30-d readmission, or 30-d mortality were statistically similar. In the unmatched patient population, rates of adverse outcomes with CEA were constant over time; however, for CAS, rates of stroke increased over time. In both the matched and unmatched patient cohorts, patients 70 yr and older had lower rates of post-procedural stroke with CEA, but not with CAS, compared to younger patients.

CONCLUSION

In a propensity-matched analysis of a large, prospectively collected, national, surgical database, CAS was associated with increased odds of periprocedural stroke, which increased over time. Rates of MI and death were not significantly different between the 2 procedures.
Radiation and adjuvant drug-loaded liposomes target glioblastoma stem cells and trigger in-situ immune response
Authors: Pizzocri Marco , Re Francesca , Stanzani Elisabetta , Formicola Beatrice , Tamborini Matteo , Lauranzano Eliana , Ungaro Federica , Rodighiero Simona , Francolini Maura , Gregori Maria , Perin Alessandro , DiMeco Francesco , Masserini Massimo , Matteoli Michela , Passoni Lorena
Published: June 2021

Background

The radio- and chemo-resistance of glioblastoma stem-like cells (GSCs), together with their innate tumor-initiating aptitude, make this cell population a crucial target for effective therapies. However, targeting GSCs is hardly difficult and complex, due to the presence of the blood–brain barrier (BBB) and the infiltrative nature of GSCs arousing their dispersion within the brain parenchyma.

Methods

Liposomes (LIPs), surface-decorated with an Apolipoprotein E-modified peptide (mApoE) to enable BBB crossing, were loaded with doxorubicin (DOXO), as paradigm of cytotoxic drug triggering immunogenic cell death (ICD). Patient-derived xenografts (PDXs) obtained by GSC intracranial injection were treated with mApoE-DOXO-LIPs alone or concomitantly with radiation.

Results

Our results indicated that mApoE, through the engagement of the low-density lipoprotein receptor (LDLR), promotes mApoE-DOXO-LIPs transcytosis across the BBB and confers target specificity towards GSCs. Irradiation enhanced LDLR expression on both BBB and GSCs, thus further promoting LIP diffusion and specificity. When administered in combination with radiations, mApoE-DOXO-LIPs caused a significant reduction of in vivo tumor growth due to GSC apoptosis. GSC apoptosis prompted microglia/macrophage phagocytic activity, together with the activation of the antigen-presenting machinery crucially required for anti-tumor adaptive immune response.

Conclusions

Our results advocate for radiotherapy and adjuvant administration of drug-loaded, mApoE-targeted nanovectors as an effective strategy to deliver cytotoxic molecules to GSCs at the surgical tumor margins, the forefront of glioblastoma (GBM) recurrence, circumventing BBB hurdles. DOXO encapsulation proved in situ immune response activation within GBM microenvironment.
2D mesoporous materials
Authors: Ai Yan , Li Wei , Zhao Dongyuan
Published: June 2021

2D mesoporous materials, combining the unique features of 2D and mesoporous structures, represent a new research direction in materials science. This perspective article highlights the latest progress of 2D mesoporous materials.
Fifty-millimeter abscess in the ileum caused by perforation from anisakiasis successfully treated with conservative therapy without drainage
Authors: Kawanishi Koki , Ikeda Yoshifumi , Furotani Masahiko , Tsuboi Sayaka , Kanno Takayuki , Niwa Toru , Nagaoka Tsunehiro , Tabata Yoshinari , Kitano Masayuki
Published: June 2021

Intestinal anisakiasis is not only a rare but also a difficult to diagnose parasitic disease. The symptoms are not specific and are often severe and abrupt; therefore, patients are sometimes diagnosed as having surgical abdomen. The clinical imaging findings are remarkable, including ascites, enteritis, ileus, eosinophilic granuloma and sometimes perforation. We experienced a case of intestinal anisakiasis diagnosed on the basis of the Anisakis-specific immunoglobulin A level from paired sera and treated successfully with conservative therapy, although ileum perforation was complicated by a 50-mm abscess. Even the large abscess could be treated without drainage in thiscase.
Threshold models improve estimates of molt parameters in datasets with small sample sizes
Authors: Terrill Ryan S , Fong Youyi , Wolfe Jared D , Zellmer Amanda J
Published: June 2021

The timing of events in birds’ annual cycles is important to understanding life history evolution and response to global climate change. Molt timing is often measured as an index of the sum of grown feather proportion or mass within the primary flight feathers. The distribution of these molt data over time has proven difficult to model with standard linear models. The parameters of interest are at change points in model fit over time, and so least-squares regression models that assume molt is linear violate the assumption of even variance. This has led to the introduction of other nonparametric models to estimate molt parameters. Hinge models directly estimate changes in model fit and have been used in many systems to find change points in data distributions. Here, we apply a hinge model to molt timing, through the introduction of a double-hinge (DH) threshold model. We then examine its performance in comparison to current models using simulated and empirical data. Our results suggest that the Underhill–Zucchini (UZ) and Pimm models perform well under many circumstances and appear to outperform the DH model in datasets with high variance. The DH model outperforms the UZ model at low sample sizes of birds in active molt and shorter molt durations and provides more realistic confidence intervals at smaller sample sizes. The DH model provides a novel addition to the toolkit for estimating molt phenology, expanding the conditions under which molt can accurately be estimated.
The Defence of Grace after the 1626 Proclamation
Authors: Hampton Stephen
Published: June 2021

Chapter 4 establishes the ongoing promotion of the Reformed Conformist approach to grace during the 1630s, in the face of an attempt to stifle such opinions by royal proclamation in 1626. Using Ward’s professorial determinations at the Cambridge Commencement, it shows how he ensured that the Reformed vision of grace still held a prominent place within Cambridge and exhibited its compatibility with English Church polity. The chapter also explores Ward’s editorial collaboration with Davenant in the publication of Davenant’s academic works. It underlines that their work ensured that the University press remained a vehicle for Reformed Conformity throughout the 1630s.
Gracious Disciples and Frightened Magistrates
Authors: Westerkamp Marilyn J.
Published: June 2021

This chapter begins with the Quakers in England, the appeal of the Quaker movement in New England, including Hutchinson's followers, and the threat that Quakers posed to the New England magistracy. It examines Hutchinson’s followers in some detail, but the Quaker/ Magistrate conflict is central to the chapter. The response of the governors and clerics mirrored so completely the official responses to the Hutchinsonians that the Quaker crisis becomes a venue through which the same social, political, and ideological issues are encountered and resolved. This is less a second-generation event than the last gasp of the founding generation.
Animals, Energy, Land
Authors: Rowlands Mark
Published: June 2021

This chapter introduces the central themes, and outlines the central argument, of the book. Three dominant environmental threats are identified: climate change, mass extinction, and pestilence. The warming of the planet is accelerating. At the same time, species are becoming extinct at a startling rate. Newly emerging infectious diseases—COVID-19 being the latest off the production line—are becoming more pronounced and problematic. It is argued that our habit of eating animals—and the massive reallocation of biomass that it involves—lies at the heart of all of all three problems, and if we abandon this habit, we can make substantial progress in tackling them. This proposal should be taken seriously on the grounds that it is easier to implement, more effective once implemented, and ultimately more palatable than other options.
Material Culture
Authors: Lally Jagjeet
Published: June 2021

The goods brought into urban emporia and periodic rural markets through caravan trade were not only luxuries for elites (fine horses, for example), but also high-value items consumed in small and affordable quantities (such as silk as well as turquoise or other medicinal, talismanic or apotropaic items) by a broader range of groups. There were also necessities (cloth) and raw materials or productive inputs (raw silk, indigo). This chapter examines the social, cultural and spiritual power deriving from the possession of things, illuminating the role played by goods in processes of self-fashioning, sociability and the expression of changing tastes in ways characteristic of ‘early modernity’ in other global settings.
Reframing Human Rights in a Turbulent Era
Authors: de Búrca Gráinne
Published: June 2021

In a turbulent era, with illiberal nationalism on the rise and international laws and institutions under persistent threat, this book asks what future the international human rights system has. It rejects the claims of those who view human rights law and advocacy as ineffective or worse in challenging injustice. Instead, it presents an experimentalist account of human rights which emphasizes the ongoing engagement between domestic activists and international and domestic institutions and actors in promoting rights-based change. Rather than the monolithic movement depicted in some academic critiques, it discerns a rich and diverse human rights movement which has helped significantly to challenge injustice and advance progressive change in many contexts. Drawing on case studies of gender justice, disability rights, children’s rights and reproductive justice from Pakistan, Argentina and Ireland, the book argues that the human rights movement has made an important difference around the world. It shows that despite daunting contemporary challenges including illiberalism, climate change, inequalities, pandemics and digitalization, human rights advocates and activists are engaged in critical self-reflection, renewal and reform that should enable the human rights movement to engage effectively with these challenges in the future. Indeed, the formidable challenges of our current turbulent era provide powerful reasons to reform, innovate, and strengthen the tools and practices of the human rights movement for the future, rather than abandon it, encourage others to do so, or herald its demise.
A regulatory network driving shoot lignification in rapidly growing bamboo
Authors: Yang Kebin , Li Lichao , Lou Yongfeng , Zhu Chenglei , Li Xueping , Gao Zhimin
Published: June 2021

Woody bamboo is environmentally friendly, abundant, and an alternative to conventional timber. Degree of lignification and lignin content and deposition affect timber properties. However, the lignification regulatory network in monocots is poorly understood. To elucidate the regulatory mechanism of lignification in moso bamboo (Phyllostachys edulis), we conducted integrated analyses using transcriptome, small RNA, and degradome sequencing followed by experimental verification. The lignification degree and lignin content increased with increased bamboo shoot height, whereas phenylalanine ammonia-lyase and Laccase activities first increased and then decreased with shoot growth. Moreover, we identified 11,504 differentially expressed genes (DEGs) in different portions of the 13th internodes of different height shoots; most DEGs associated with cell wall and lignin biosynthesis were upregulated, whereas some DEGs related to cell growth were downregulated. We identified a total of 1,502 miRNAs, of which 687 were differentially expressed. Additionally, in silico and degradome analyses indicated that 5,756 genes were targeted by 691 miRNAs. We constructed a regulatory network of lignification, including 11 miRNAs, 22 transcription factors, and 36 enzyme genes, in moso bamboo. Furthermore, PeLAC20 overexpression increased lignin content in transgenic Arabidopsis (Arabidopsis thaliana) plants. Finally, we proposed a reliable miRNA-mediated “MYB-PeLAC20” module for lignin monomer polymerization. Our findings provide definite insights into the genetic regulation of bamboo lignification. In addition to providing a platform for understanding related mechanisms in other monocots, these insights could be used to develop strategies to improve bamboo timber properties.
Effects of Acupuncture on Postoperative Pain After Total Knee Replacement: Systematic Literature Review and Meta-Analysis
Authors: Ko Hsing Fang , Chen Ching-Hsiu , Dong Kai-Ren , Wu Hsien-Chang
Published: June 2021

Objective

To identify the analgesic effectiveness of acupuncture after total knee replacement by systematic review.

Methods

A search of randomized controlled trials was conducted in five English medical electronic databases and five Chinese databases. Two reviewers independently searched in five English medical electronic databases and five Chinese databases. Two reviewers independently retrieved related studies, assessed the methodological quality, and extracted data with a standardized data form. Meta-analyses were performed with all-time-points meta-analysis.

Results

A total of seven studies with 891 participants were included. The meta-analysis results indicated that acupuncture had a statistically significant influence on pain relief (standardized mean difference = −0.705, 95% CI −1.027 to −0.382, P = 0.000). The subgroup analysis results showed that acupuncture’s effects on analgesia had a statistically significant influence (standardized mean difference= −0.567, 95% CI −0.865 to −0.269, P = 0.000). The main acupuncture points that produced an analgesic effect when they were used after total knee replacement included the Xuehai, Liangqiu, Dubi, Neixiyan, Yanglingquan, and Zusanli points. Electroacupuncture frequency ranged between 2 and 100 Hz.

Conclusions

As an adjunct modality, the use of acupuncture is associated with reduced pain and use of analgesic medications in postoperative patients. In particular, ear acupuncture 1 day before surgery could reduce analgesia .
Movement System Diagnoses for Balance Dysfunction: Recommendations From the Academy of Neurologic Physical Therapy’s Movement System Task Force
Authors: Gill-Body Kathleen M , Hedman Lois D , Plummer Laura , Wolf Leslie , Hanke Timothy , Quinn Lori , Riley Nora , Kaufman Regina , Verma Akanshka , Quiben Myla , Scheets Patricia
Published: June 2021

The movement system was identified as the focus of our expertise as physical therapists in the revised vision statement for the profession adopted by the American Physical Therapy Association in 2013. Attaining success with the profession’s vision requires the development of movement system diagnoses that will be useful in clinical practice, research, and education. To date, only a few movement system diagnoses have been identified and described, and none of these specifically address balance dysfunction. Over the past 2 years, a Balance Diagnosis Task Force, a subgroup of the Movement System Task Force of the Academy of Neurologic Physical Therapy, focused on developing diagnostic labels (or diagnoses) for individuals with balance problems. This paper presents the work of the task force that followed a systematic process to review available diagnostic frameworks related to balance, identify 10 distinct movement system diagnoses that reflect balance dysfunction, and develop complete descriptions of examination findings associated with each balance diagnosis. A standardized approach to movement analysis of core tasks, the Framework for Movement Analysis developed by the Academy of Neurologic Physical Therapy Movement Analysis Task Force, was integrated into the examination and diagnostic processes. The aims of this perspective paper are to (1) summarize the process followed by the Balance Diagnosis Task Force to develop an initial set of movement system (balance) diagnoses; (2) report the recommended diagnostic labels and associated descriptions; (3) demonstrate the clinical decision-making process used to determine a balance diagnosis and develop a plan of care; and (4) identify next steps to validate and implement the diagnoses into physical therapist practice, education, and research.

Impact

The development and use of diagnostic labels to classify distinct movement system problems is needed in physical therapy. The 10 balance diagnosis proposed can aid in clinical decision making regarding intervention.
Correlation between pain severity and levels of anxiety and depression in osteoarthritis patients: a systematic review and meta-analysis
Authors: Fonseca-Rodrigues Diana , Rodrigues André , Martins Teresa , Pinto Joana , Amorim Diana , Almeida Armando , Pinto-Ribeiro Filipa
Published: June 2021

Objectives

Osteoarthritis (OA) is a chronic degenerative musculoskeletal disease that causes articular damage and chronic pain, with a prevalence of up to 50% in individuals >60 years of age. Patients suffering from chronic painful conditions, including OA, also frequently report anxiety or depression. A systematic review and meta-analysis were performed to assess the correlation between pain severity and depressive and anxious symptomatology in OA patients.

Methods

A systematic search was conducted using four databases (PubMed, Medline, Scopus, and Web of Science) from inception up to 14 January 2020. We included original articles evaluating pain severity and anxiety and/or depression severity in OA-diagnosed patients. Detailed data were extracted from each study, including patients’ characteristics and pain, anxiety, and depression severity. When available, the Pearson correlation coefficient between pain and depression severity and pain and anxiety severity was collected, and a meta-analysis of random effects was applied.

Results

This systematic review included 121 studies, with a total of 38 085 participants. The mean age was 64.3 years old, and the subjects were predominantly female (63%). The most-used scale to evaluate pain severity was the Western Ontario and the McMaster Universities Osteoarthritis Index, while for anxiety and depression, the Hospital Anxiety and Depression Scale was the most used. The meta-analysis showed a moderate positive correlation between pain severity and both anxious (r = 0.31, P <0.001) and depressive symptomatology (r = 0.36, P <0.001).

Conclusion

Our results demonstrate a significant correlation between pain and depression/anxiety severity in OA patients, highlighting the need for its routine evaluation by clinicians.
Male Wolffian adnexal tumor: the first report of long-term follow-up after radical surgical treatment
Authors: Milonas Daimantas , Steenkiste Edwin , De Vos Rita , Moerman Philippe , Lerut Evelin , Joniau Steven
Published: June 2021

The male Wolffian tumor is an extremely rare case in male patients. Here, we report a patient with such malignancy and successful radical surgical treatment at 15-year follow-up. The clinicopathological, immunohistochemical, and ultrastructural features are described. The differential diagnosis of this tumor in a male patient is discussed.
Intradermal Band-like Lipomatous Metaplasia Can Be Associated With the Regression of Overlying Skin Neoplasms: A Clinicopathologic Study of 20 Cases
Authors: Takai Toshihiro , Murata Yozo , Goto Keisuke
Published: June 2021

Lipomatous metaplasia has been rarely reported in both neoplastic and inflammatory dermatological disorders. Most neoplastic cases show the lipomatous change within the tumor silhouette, but band-like lipomatous metaplasia in the dermis under tumors has not been well-described. The aim of this study was to reveal the characteristics and relationship of intradermal band-like lipomatous metaplasia and coexisting skin tumors. A total of 20 cases with intradermal band-like lipomatous metaplasia were retrieved from 10,992 archive cases between April 1997 and March 2020 at Hyogo Cancer Center, and subjected to a detailed clinicopathologic analysis. Nine (45%) patients had superficial variant basal cell carcinoma as a coexisting neoplasm. Eight (40%) patients had squamous cell carcinoma, 5 of which were in situ. The remaining 3 (15%) cases were invasive extramammary Paget disease. All 20 cases showed at least one of 3 signs of tumor regression, namely, partial loss of overlying neoplasia, significant inflammatory infiltrate under the tumor, and fibrosis around the tumor. We concluded that intradermal band-like lipomatous metaplasia could be seen in association with the regressing process of cutaneous superficially-spreading neoplasms.
Sporadic and Periodic Interictal Discharges in Critically Ill Children: Seizure Associations and Time to Seizure Identification
Authors: Sansevere Arnold J. , DiBacco Melissa L. , Zhang Bo , Akhondi-Asl Alireza , Libenson Mark H. , Tasker Robert C. , Pearl Phillip L.
Published: June 2021

Purpose:

We evaluated interictal discharges (IEDs) as a biomarker for the time to development of electrographic seizures (ES).

Methods:

Prospective observational study of 254 critically ill children who underwent continuous electroencephalography (cEEG) monitoring. We excluded neonates and patients with known epilepsy or the sole cEEG indication to characterize events. Interictal discharges included sporadic epileptiform discharges and periodic and rhythmic patterns. Sporadic epileptiform discharges were categorized as low frequency (rare [<1/hour] and occasional [≥1/hour but <1/minute]) and high frequency (frequent, [≥1/minute] and abundant [≥1/10 seconds]). Time variables included time from cEEG start to first IED and time between first IED and ES.

Results:

Interictal discharges were present in 33% (83/254) of patients. We identified ES in 20% (50/254), and 86% (43/50) had IEDs. High-frequency sporadic epileptiform discharges (odds ratio [OR], 35; 95% confidence interval [CI], 14.5–88; P < 0.0001) and lateralized periodic discharges (OR, 27; 95% CI, 7.3–100; P < 0.0001) were associated with ES. Mildly abnormal EEG background without IEDs or background asymmetry was associated with the absence of seizures (OR, 0.1; 95% CI, 0.04–0.3; P < 0.0001). Time from cEEG start to first IED was 36 minutes (interquartile range, 3–131 minutes), and time between first IED and ES was 9.6 minutes (interquartile range, 0.6–165 minutes).

Conclusions:

Interictal discharges are associated with ES and are identified in the first 3 hours of cEEG. High-frequency sporadic epileptiform discharges and periodic patterns have the highest risk of ES. Our findings define a window of high seizure risk after the identification of IEDs in which to allocate resources to improve seizure identification and subsequent treatment.
Improved molecular characterization of the Klebsiella oxytoca complex reveals the prevalence of the kleboxymycin biosynthetic gene cluster
Authors: Shibu Preetha , McCuaig Frazer , McCartney Anne L. , Kujawska Magdalena , Hall Lindsay J. , Hoyles Lesley
Published: June 2021

As part of the ongoing studies with clinically relevant

Klebsiella

spp., we characterized the genomes of three clinical GES-5-positive ST138 strains originally identified as Klebsiella oxytoca. bla
OXY gene, average nucleotide identity and phylogenetic analyses showed the strains to be

Klebsiella michiganensis

. Affiliation of the strains to ST138 led us to demonstrate that the current multi-locus sequence typing scheme for

K. oxytoca

can be used to distinguish members of this genetically diverse complex of bacteria. The strains encoded the kleboxymycin biosynthetic gene cluster (BGC), previously only found in

K. oxytoca

strains and one strain of

Klebsiella grimontii

. The finding of this BGC, associated with antibiotic-associated haemorrhagic colitis, in

K. michiganensis

led us to carry out a wide-ranging study to determine the prevalence of this BGC in

Klebsiella

spp. Of 7170 publicly available

Klebsiella

genome sequences screened, 88 encoded the kleboxymycin BGC. All BGC-positive strains belonged to the

K. oxytoca

complex, with strains of four (

K. oxytoca

,

K. pasteurii

,

K. grimontii

,

K. michiganensis

) of the six species of complex found to encode the complete BGC. In addition to being found in

K. grimontii

strains isolated from preterm infants, the BGC was found in

K. oxytoca

and

K. michiganensis

metagenome-assembled genomes recovered from neonates. Detection of the kleboxymycin BGC across the

K. oxytoca

complex may be of clinical relevance and this cluster should be included in databases characterizing virulence factors, in addition to those characterizing BGCs.
Virtual Trials: Causally-validated treatment effects efficiently learned from an observational cancer registry
Authors: Wasserman Asher , Musella Al , Shapiro Mark , Shrager Jeff
Published: June 2021

Randomized controlled trials (RCTs) offer a clear causal interpretation of treatment effects, but are inefficient in terms of information gain per patient. Moreover, because they are intended to test cohort-level effects, RCTs rarely provide information to support precision medicine, which strives to choose the best treatment for an individual patient. If causal information could be efficiently extracted from widely available real-world data, the rapidity of treatment validation could be increased, and its costs reduced. Moreover, inferences could be made across larger, more diverse patient populations. We created a “virtual trial” by fitting a multilevel Bayesian survival model to treatment and outcome records self-reported by 451 brain cancer patients. The model recovers group-level treatment effects comparable to RCTs representing over 3200 patients. The model additionally discovers the feature-treatment interactions needed to make individual-level predictions for precision medicine. By learning from heterogeneous real-world data, virtual trials can generate more causal estimates with fewer patients than RCTs, and they can do so without artificially limiting the patient population. This demonstrates the value of virtual trials as a complement to large randomized controlled trials, especially in highly heterogeneous or rare diseases.
A Multi-center, Prospective, Observational-cohort controlled study of Clinical Outcomes following COVID-19 Convalescent plasma therapy in hospitalized COVID-19 patients
Authors: Chauhan Lakshmi , Pattee Jack , Ford Joshay , Thomas Chris , Lesteberg Kelsey , Richards Eric , Loi Michele , Dumont Larry , Annen Kyle , Berg Mary , Zirbes Mercedes , Miller Amanda , Jenkins Timothy C. , Bennett Tellen D. , Monkowski Daniel , Boxer Rebecca S. , Beckham J. David
Published: June 2021

Background

The SARS-CoV2 pandemic has caused high inpatient mortality and morbidity throughout the world. COVID19 convalescent plasma has been utilized as a potential therapy for patients hospitalized with COVID19 pneumonia. This study evaluated the outcomes of hospitalized COVID19 patients treated with COVID19 convalescent plasma in a prospective, observational multicenter trial.

Methods

From April 2020 through August 2020, hospitalized COVID19 patients at 16 participating hospitals in Colorado were enrolled and treated with COVID19 convalescent plasma (CCP) and compared to hospitalized patients with COVID19 who were not treated with convalescent plasma. Plasma antibody levels were determined following the trial given that antibody tests were not approved at the initiation of the trial. CCP-treated and untreated COVID19 hospitalized patients were matched using propensity scores followed by analysis for length of hospitalization and inpatient mortality.

Results

542 total hospitalized COVID19 patients were enrolled at 16 hospitals across the region. A total of 468 hospitalized COVID19 patients were entered into propensity score matching with 188 patients matched for analysis in the CCP-treatment and control arms. Fine-Gray models revealed increased length of hospital stay in CCP-treated patients and no change in inpatient mortality compared to controls. In subgroup analysis of CCP-treated patients within 7 days of admission, there was no difference in length of hospitalization and inpatient mortality.

Conclusions

These data show that treatment of hospitalized COVID19 patients with CCP did not significantly improve patient hospitalization length of stay or inpatient mortality.
What can we learn from COVID-19 data by using epidemic models with unidentified infectious cases?
Authors: Griette Quentin , Demongeot Jacques , Magal Pierre
Published: June 2021

Background

The COVID-19 epidemic, which started in late December 2019 and rapidly spread throughout the world, was accompanied by an unprecedented release of reported case data. Our objective is to propose a fresh look at this data by coupling a phenomenological description to the epidemiological dynamics.

Methods

We use a phenomenological model to describe and regularize the data. This model can be matched by a single mathematical model reproducing the epidemiological dynamics with a time-dependent transmission rate. We provide a method to compute this transmission rate and reconstruct the changes in the social interactions between people as well as changes in host-pathogen interactions. This method is applied to the cumulative case data of 8 different geographic areas.

Findings

We reconstruct the transmission rate from the data, therefore we are in position to understand the contribution of the dynamical effects of social interactions (contacts between individuals) and the contribution of the dynamics of the epidemic. We deduce from the comparison of several instantaneous reproduction numbers that the social effects are the most important in the dynamic of COVID-19. We obtain an instantaneous reproduction number that stays below 3.5 from early beginning of the epidemic.

Conclusion

The instantaneous reproduction number staying below 3.5 implies that it is sufficient to vaccinate 71% of the population in each state or country considered in our study. Therefore assuming the vaccines will remain efficient against the new variants, and to be more confident it is sufficient to vaccinate 75 − 80% to get rid of COVID-19 in each state or country.

Funding

This research was funded by the Agence Nationale de la Recherche in France (Project name: MPCUII (PM) and (QG))
Time-resolved multivariate pattern analysis of infant EEG data
Authors: Ashton Kira , Zinszer Benjamin D. , Cichy Radoslaw M. , Nelson Charles A. , Aslin Richard N. , Bayet Laurie
Published: June 2021

Time-resolved multivariate pattern analysis (MVPA), a popular technique for analyzing magneto- and electro-encephalography (M/EEG) neuroimaging data, quantifies the extent and time-course by which neural representations support the discrimination of relevant stimuli dimensions. As EEG is widely used for infant neuroimaging, time-resolved MVPA of infant EEG data is a particularly promising tool for infant cognitive neuroscience. MVPA methods have recently been applied to common infant imaging methods such as EEG and fNIRS. In this tutorial, we provide and describe code to implement time-resolved, within-subject MVPA with infant EEG data. A pipeline for time-resolved MVPA based on linear SVM classification is described and implemented with accompanying code in both Matlab and Python. Results from a test dataset indicated that in both infants and adults this method reliably produced above chance classification accuracy. Extensions of the core pipeline are presented including both geometric- and accuracy-based representational similarity analysis, implemented in Python. Common choices of implementation are presented and discussed. As the amount of artifact-free EEG data contributed by each participant is lower in studies of infants than in studies of children and adults, we also explore and discuss the impact of varying participant-level inclusion thresholds on resulting MVPA findings in these datasets.
Unconventional conservation reveals structure-function relationships in the synaptonemal complex
Authors: Kursel Lisa E. , Cope Henry D. , Rog Ofer
Published: June 2021

Functional requirements constrain protein evolution, commonly manifesting in conserved primary amino acid sequence. Here, we extend this idea to secondary structural features by tracking their conservation in essential meiotic proteins with highly diverged sequences. The synaptonemal complex (SC) aligns parental chromosome pairs and regulates exchanges between them. In electron micrographs of meiocytes from all eukaryotic clades, the SC appears as a ~100 nm-wide ladder-like structure with regular striations. Despite the conserved ultrastructure and functions, the proteins that make up the SC are highly divergent in sequence. Here we found that, within the Caenorhabditis genus, SC proteins are significantly more diverged than other proteins. However, SC proteins have highly conserved protein length and coiled-coil domain structure. The same unconventional conservation signature holds true for SC proteins in Drosophila and mammals, suggesting it could be a universal feature of SC proteins. We used this evolutionary signature to identify a novel SC protein in the nematode Pristionchus pacificus, Ppa-SYP-1, which has no significant homology to any protein outside of Pristionchus. Our work suggests that the length and relative arrangement of coiled-coils play a key role in the structure and function of the SC. Furthermore, our analysis implies that expanding sequence analysis beyond measures of per-site identity or similarity can enhance our understanding of protein evolution and function.

Short abstract

Functional requirements constrain protein evolution, commonly manifesting in a conserved amino acid sequence. Here, we extend this idea to secondary structural features by tracking their conservation in essential meiotic proteins with highly diverged sequences. The synaptonemal complex (SC) is a ~100 nm-wide ladder-like meiotic structure present in all eukaryotic clades, where it aligns parental chromosomes and regulates exchanges between them. Despite the conserved ultrastructure and functions of the SC, SC proteins are highly divergent within Caenorhabditis. However, SC proteins have highly conserved length and coiled-coil domain structure. We found the same unconventional conservation signature in Drosophila and mammals, and used it to identify a novel SC protein in Pristionchus pacificus, Ppa-SYP-1. Our work suggests that coiled-coils play wide-ranging roles in the structure and function of the SC, and more broadly, that expanding sequence analysis beyond measures of per-site similarity can enhance our understanding of protein evolution and function.
Fyn kinase inhibition using AZD0530 improves recognition memory and reduces depressive-like behaviour in an experimental model of Parkinson’s disease
Authors: Guglietti Bianca , Carr Laura , Ellul Benjamin , Mustafa Sanam , Corrigan Frances , Collins-Praino Lyndsey E
Published: June 2021

Fyn kinase has recently been established as a major upstream regulator of neuroinflammation in PD. This study aimed to determine if inhibition of Fyn kinase could lead to reduced neuroinflammation and improvements in motor and non-motor impairments in an early-stage model of PD. An experimental model of PD was produced using intra-striatal injection (4µl) of the neurotoxin 6-OHDA (5µg/µl). Sprague Dawley rats (n=42) were given either vehicle, 6mg/kg or 12mg/kg of Fyn kinase inhibitor (AZD0530) daily for 32 days via oral gavage and tested on a battery of tasks assessing motor, cognitive and neuropsychiatric outcomes. AZD 0530 administration led to improvement in volitional locomotion and recognition memory, as well as a reduction in depressive-like behaviour. Pathologically, an inflammatory response was observed; however, there were no significant differences in markers of neuroinflammation between treatment groups. Taken together, results indicate a potential therapeutic benefit for use of Fyn kinase inhibition to treat non-motor symptoms of PD, although mechanisms remain to be elucidated.

HIGHLIGHTS

Fyn kinase has recently been proposed as a major upstream regulator of microglial activation in Parkinson’s disease (PD).

This study was the first to evaluate the effects of Fyn kinase inhibition in a rodent model of PD.

Fyn kinase inhibition using the Fyn kinase inhibitor AZD 0530 was capable of improving volitional locomotion and recognition memory and reducing depressive-like behaviour in a rodent model of PD.

Interestingly, while increases in microglial activation were observed in this rodent model of PD, AZD 0530 did not significantly reduce this activation.

This suggests that the behavioural improvements associated with Fyn kinase inhibition may occur independently of neuroinflammation and may be attributable to other brain mechanisms, including actions on NMDA or 5-HT6 receptors.
The Cost of Untracked Diversity in Brain-Imaging Prediction
Authors: Benkarim Oualid , Paquola Casey , Park Bo-yong , Kebets Valeria , Hong Seok-Jun , de Wael Reinder Vos , Zhang Shaoshi , Thomas Yeo B.T. , Eickenberg Michael , Ge Tian , Poline Jean-Baptiste , Bernhardt Boris , Bzdok Danilo
Published: June 2021

Brain-imaging research enjoys increasing adoption of supervised machine learning for singlesubject disease classification. Yet, the success of these algorithms likely depends on population diversity, including demographic differences and other factors that may be outside of primary scientific interest. Here, we capitalize on propensity scores as a composite confound index to quantify diversity due to major sources of population stratification. We delineate the impact of population heterogeneity on the predictive accuracy and pattern stability in two separate clinical cohorts: the Autism Brain Imaging Data Exchange (ABIDE, n=297) and the Healthy Brain Network (HBN, n=551). Across various analysis scenarios, our results uncover the extent to which cross-validated prediction performances are interlocked with diversity. The instability of extracted brain patterns attributable to diversity is located preferentially to the default mode network. Our collective findings highlight the limitations of prevailing deconfounding practices in mitigating the full consequences of population diversity.
The chemical synthesis of knob domain antibody fragments
Authors: Macpherson Alex , Birtley James R. , Broadbridge Robert J. , Brady Kevin , Tang Yalan , Joyce Callum , Saunders Kenneth , Bogle Gregory , Horton John , Kelm Sebastian , Taylor Richard D. , Franklin Richard J. , Selby Matthew D. , Laabei Maisem , Wonfor Toska , Hold Adam , Vadysirisack Douangsone , Shi Jiye , van den Elsen Jean , Lawson Alastair D.G.
Published: June 2021

Cysteine-rich knob domains found in the ultralong complementarity determining regions of a subset of bovine antibodies, are capable of functioning autonomously as 3-6 kDa peptides. While they can be expressed recombinantly in cellular systems, in this paper we show that knob domains are also readily amenable to chemical synthesis, with a co-crystal structure of a chemically synthesised knob domain in complex with antigen showing structural equivalence to the biological product. For drug discovery, following immunisation of cattle, knob domain peptides can be synthesised directly from antibody sequence data, combining the power and diversity of the bovine immune repertoire with the ability to rapidly incorporate non-biological modifications. We demonstrate that, through rational design with non-natural amino acids, paratope diversity can be massively expanded, in this case improving the efficacy of an allosteric peptide. As a potential route to further improve stability, we also performed head-to-tail cyclisation, exploiting the unusual proximity of the N- and C-termini to synthesise functional, fully cyclic antibody fragments. Lastly, we highlight the stability of knob domains in plasma and, through pharmacokinetic studies, use palmitoylation as a route to extend the plasma half-life of knob domains in vivo. This study presents an antibody-derived medicinal chemistry platform, with protocols for solid-phase synthesis of knob domains; together with characterisation of their molecular structures, in vitro pharmacology and pharmacokinetics.