bluuebunny/crossref_metadata_2025 huggingface dataset:
Rapid screening and detection of inter-type viral recombinants using phylo-k-mers
Authors: Scholz Guillaume E , Linard Benjamin , Romashchenko Nikolai , Rivals Eric , Pardi Fabio
Published: November 2020

Motivation

Novel recombinant viruses may have important medical and evolutionary significance, as they sometimes display new traits not present in the parental strains. This is particularly concerning when the new viruses combine fragments coming from phylogenetically distinct viral types. Here, we consider the task of screening large collections of sequences for such novel recombinants. A number of methods already exist for this task. However, these methods rely on complex models and heavy computations that are not always practical for a quick scan of a large number of sequences.

Results

We have developed SHERPAS, a new program to detect novel recombinants and provide a first estimate of their parental composition. Our approach is based on the precomputation of a large database of ‘phylogenetically-informed k-mers’, an idea recently introduced in the context of phylogenetic placement in metagenomics. Our experiments show that SHERPAS is hundreds to thousands of times faster than existing software, and enables the analysis of thousands of whole genomes, or long-sequencing reads, within minutes or seconds, and with limited loss of accuracy.

Availability and implementation

The source code is freely available for download at https://github.com/phylo42/sherpas.

Supplementary information

Supplementary data are available at Bioinformatics online.
Recent diversification in the high Andes: unveiling the evolutionary history of the Ecuadorian hillstar,Oreotrochilus chimborazo(Apodiformes: Trochilidae)
Authors: Bonaccorso Elisa , Rodríguez-Saltos Carlos A , Freile Juan F , Peñafiel Nicolás , Rosado-Llerena Laura , Oleas Nora H
Published: November 2020

Studying the genetic signatures of evolutionary diversification in young lineages is among the most promising approaches for unveiling the processes behind speciation. Here, we focus on Oreotrochilus chimborazo, a high Andean species of hummingbird that might have experienced rapid diversification in the recent past. To understand the evolution of this species, we generated a dataset of ten microsatellite markers and complementary data on morphometrics, plumage variation and ecological niches. We applied a series of population and coalescent-based analyses to understand the population structure and differentiation within the species, in addition to the signatures of current and historical gene flow, the location of potential contact zones and the relationships among lineages. We found that O. chimborazo comprises three genetic groups: one corresponding to subspecies O. c. chimborazo, from Chimborazo volcano and surroundings, and two corresponding to the northern and southern ranges of subspecies O. c. jamesonii, found from the extreme south of Colombia to southern Ecuador. We inferred modest levels of both contemporary and historical gene flow and proposed the location of a contact zone between lineages. Also, our coalescent-based analyses supported a rapid split among these three lineages during the mid-to-late Holocene. We discuss our results in the light of past and present potential distributions of the species, in addition to evolutionary trends seen in other Andean hummingbirds.
Pollination in thecampo rupestre: a test of hypothesis for an ancient tropical mountain vegetation
Authors: Monteiro Beatriz Lopes , Camargo Maria Gabriela Gutierrez , Loiola Priscilla De Paula , Carstensen Daniel Wisbech , Gustafsson Simone , Morellato Leonor Patricia Cerdeira
Published: November 2020

The campo rupestre is a Neotropical OCBIL (old, climatically buffered infertile landscape), a grassy-shrub vegetation with high species richness and endemism, characterized by rocky outcrops surrounded by grasslands distributed in South American ancient mountaintops. We tested one OCBIL prediction: the prevalence of long-distance pollinators ensuring cross-pollination across the archipelago-like landscapes of the campo rupestre. We described the pollination systems and tested whether their frequency differed across vegetation types and elevation, focusing on long-distance systems. We performed non-systematic and systematic surveys of plants and plant-pollinator interactions across the elevation gradient and vegetation types. We also reviewed the literature on campo rupestre pollination and applied an accuracy criterion to infer 11 pollination systems. The bee system was split into large bee (long-distance) and small bee (shorter distances) to test the prevalence of long-distance pollination systems. We surveyed 413 pollinator species, mostly bees (220) and flies (69). Among the 636 plant species studied, the bee pollination system was dominant (56%), followed by wind and hummingbird. Wind, small-bee and fly pollination systems increased with elevation, and small-bee and wind pollination systems prevailed in grasslands. Large-bee and hummingbird long-distance pollination systems remained unchanged with elevation and were more frequent in the highly isolated rocky outcrops corroborating the OCBIL theory.
Ecomorphological divergence and trophic resource partitioning in 15 syntopic Indo-Pacific parrotfishes (Labridae: Scarini)
Authors: Nicholson Georgina M , Clements Kendall D
Published: November 2020

Adaptive diversification is a product of both phylogenetic constraint and ecological opportunity. The species-rich parrotfish genera Scarus and Chlorurus display considerable variation in trophic cranial morphology, but these parrotfishes are often described as generalist herbivores. Recent work has suggested that parrotfish partition trophic resources at very fine spatial scales, raising the question of whether interspecific differences in cranial morphology reflect trophic partitioning. We tested this hypothesis by comparing targeted feeding substrata with a previously published dataset of nine cranial morphological traits. We sampled feeding substrata of 15 parrotfish species at Lizard Island, Great Barrier Reef, Australia, by following individuals until focused biting was observed, then extracting a bite core 22 mm in diameter. Three indices were parameterized for each bite core: substratum taphonomy, maximum turf height and cover of crustose coralline algae. Parrotfish species were spread along a single axis of variation in feeding substrata: successional status of the substratum taphonomy and epilithic and endolithic biota. This axis of trophic variation was significantly correlated with cranial morphology, indicating that morphological disparity within this clade is associated with interspecific partitioning of feeding substrata. Phylogenetic signal and phylomorphospace analyses revealed that the evolution of this clade involved a hitherto-unrecognized level of trophic diversification.
Bird watching on the asphalt
Authors: Lees A J
Published: November 2020

Attempting to make a diagnosis from a collection of baffling symptoms is comparable to the challenge of identifying an unusual bird that refuses to stay still. Andrew Lees describes how bird watching and a love of natural history helped turn him not only into a noticer, but ultimately into a neurologist.
Transcranial magnetic stimulation reveals diminished homoeostatic metaplasticity in cognitively impaired adults
Authors: Sundman Mark H , Lim Koeun , Ton That Viet , Mizell Jack-Morgan , Ugonna Chidi , Rodriguez Rudolph , Chen Nan-Kuei , Fuglevand Andrew J , Liu Yilin , Wilson Robert C , Fellous Jean-Marc , Rapcsak Steven , Chou Ying-Hui
Published: November 2020

Homoeostatic metaplasticity is a neuroprotective physiological feature that counterbalances Hebbian forms of plasticity to prevent network destabilization and hyperexcitability. Recent animal models highlight dysfunctional homoeostatic metaplasticity in the pathogenesis of Alzheimer’s disease. However, the association between homoeostatic metaplasticity and cognitive status has not been systematically characterized in either demented or non-demented human populations, and the potential value of homoeostatic metaplasticity as an early biomarker of cognitive impairment has not been explored in humans. Here, we report that, through pre-conditioning the synaptic activity prior to non-invasive brain stimulation, the association between homoeostatic metaplasticity and cognitive status could be established in a population of non-demented human subjects (older adults across cognitive spectrums; all within the non-demented range). All participants (n = 40; age range, 65–74, 47.5% female) underwent a standardized neuropsychological battery, magnetic resonance imaging and a transcranial magnetic stimulation protocol. Specifically, we sampled motor-evoked potentials with an input/output curve immediately before and after repetitive transcranial magnetic stimulation to assess neural plasticity with two experimental paradigms: one with voluntary muscle contraction (i.e. modulated synaptic activity history) to deliberately introduce homoeostatic interference, and one without to serve as a control condition. From comparing neuroplastic responses across these experimental paradigms and across cohorts grouped by cognitive status, we found that (i) homoeostatic metaplasticity is diminished in our cohort of cognitively impaired older adults and (ii) this neuroprotective feature remains intact in cognitively normal participants. This novel finding suggests that (i) future studies should expand their scope beyond just Hebbian forms of plasticity that are traditionally assessed when using non-invasive brain stimulation to investigate cognitive ageing and (ii) the potential value of homoeostatic metaplasticity in serving as a biomarker for cognitive impairment should be further explored.
Cognitive profiles in persons with depressive disorder and Alzheimer’s disease
Authors: Lanza Claudia , Sejunaite Karolina , Steindel Charlotte , Scholz Ingo , Riepe Matthias W
Published: November 2020

Alzheimer’s disease and depressive disorder are frequent in old age. Both may be associated with depressed mood and cognitive impairment. Therefore, finding a strategy to clarify the diagnosis underlying subjective complaints of impaired cognition and depressed mood in older persons is of utmost interest. We conducted a cross-sectional retrospective observational clinical cohort study using patient records from 2014 to 2018. From 3758 patients, we included patients aged 60 years and older with a Mini-Mental-Status Examination score of 24 and above. Final analysis included all patients in whom Alzheimer’s disease biomarker analysis was performed (cerebrospinal fluid markers of Alzheimer’s disease or positron emission tomography imaging; n = 179) and patients with depressive disorder in whom Alzheimer’s disease was ruled out by analysis of biomarkers suggestive of Alzheimer’s disease (n = 70). With case–control matching for age, education and gender, performance of patients with Alzheimer’s disease was worse in acquisition, consolidation and recall of verbal information and false-positive answers. None of the results, however, sufficed to differentially diagnose individual patients with Alzheimer’s disease or depressive disorder. With more severe symptoms of depression, patients with biomarker-verified Alzheimer’s disease performed worse in executive testing but were not additionally impaired in verbal episodic memory performance. We conclude that distinguishing between Alzheimer’s disease and depressive disorder is unreliable on clinical grounds and behavioural testing alone. Diagnosing the cause of subjective complaints about deteriorating cognitive function or depressed mood requires additional biomarker assessment, whereas cognitive assessment is needed to define appropriate targets of symptomatic treatment in patients with Alzheimer’s disease and depressive disorder.
Extended antibiotic therapy for the prevention of relapsing and recurrent peritonitis in peritoneal dialysis patients: a randomized controlled trial
Authors: Szeto Cheuk-Chun , Ng Jack Kit-Chung , Wing-Shing Fung Winston , Chan Gordon Chun-Kau , Cheng Phyllis Mei-Shan , Lai Ka-Bik , Pang Wing-Fai , Chow Kai-Ming , Leung Chi-Bon , Li Philip Kam-Tao
Published: November 2020

Background

Relapsing and recurrent peritonitis episodes are major causes of technique failure in peritoneal dialysis (PD). We examined the efficacy of extended antibiotic therapy for the prevention of relapsing and recurrent peritonitis.

Methods

From February 2016 to November 2018 we recruited 254 PD patients who fulfilled the diagnostic criteria for PD peritonitis. They were randomized to a standard group, with the duration of intraperitoneal (IP) antibiotic treatment following the International Society for Peritoneal Dialysis (ISPD) guideline according to the causative microorganisms, and an extended group, with 1 extra week of IP antibiotics. The primary endpoint was relapsing, recurrent or repeat peritonitis episodes within 6 months.

Results

The primary endpoint developed in 36 and 29 patients of the extended and standard groups, respectively (28.3% versus 22.8%; P = 0.34). The rate of complete cure, without relapsing, recurrent or repeat peritonitis within 6 months, was 63.8 and 69.3% for the extended and standard groups, respectively (P = 0.35). Repeat peritonitis episodes were more common in the extended than the standard group (15.0% versus 5.5%; P = 0.013).

Conclusions

In patients with PD-related peritonitis, extending the antibiotic therapy for 1 extra week beyond the ISPD protocol should not be recommended. Extending the treatment does not reduce the risk of relapsing or recurrent peritonitis episodes but rather is associated with a higher risk of repeat peritonitis episodes.
Role of nodal skip metastasis in patients with mid-thoracic oesophageal squamous cell carcinoma: a propensity score matching study
Authors: Xu Zhi-Jie , Zhuo Ze-Guo , Song Tie-Niu , Alai Gu-Ha , Shen Xu , Yao Peng- , Lin Yi-Dan
Published: November 2020

OBJECTIVES

Nodal skip metastasis (NSM) is a common phenomenon in mid-thoracic oesophageal squamous cell carcinoma (MT-OSCC); however, the prognostic implications of NSM in patients with MT-OSCC remain unclear.

METHODS

This retrospective study enrolled 300 patients with MT-OSCC who underwent radical oesophagectomy and who had pathologically confirmed lymph node metastasis from January 2014 to December 2016. The patients were divided into 2 groups according to the presence or absence of NSM. Propensity score matching was applied to minimize patient selection bias. The impact of NSM on overall survival (OS) was assessed by Kaplan–Meier and multiple Cox proportional hazards analyses. The median follow-up time was 57 months.

RESULTS

The NSM rate in the entire cohort was 22.0% (66/300). Pathological N (pN) stage (P < 0.001) and sex (P = 0.001) were identified as significant independent risk factors for NSM. NSM was more frequent in pN1 compared with pN2 patients (87.9% vs 12.1%, P < 0.001) and no NSM was found in pN3. NSM(+) patients had better prognoses than NSM(−) patients (Kaplan–Meier; 3-year OS, 62.1% vs 34.1%, P < 0.001). Propensity score matching produced 51 matched pairs, and the 3-year OS was still better in the NSM(+) compared with the NSM(−) group (66.7% vs 40.0%, P = 0.025). Multivariable Cox analysis confirmed NSM(+) as an independent factor favouring OS in patients with MT-OSCC.

CONCLUSIONS

NSM usually occurs at pN1 stage in patients with MT-OSCC, and is associated with a favourable prognosis.
Mixed evidence for the compression of morbidity hypothesis for smoking elimination—a systematic literature review
Authors: Dieteren Charlotte M , Faber Timor , van Exel Job , Brouwer Werner B F , Mackenbach Johan P , Nusselder Wilma J
Published: November 2020

Background

There is debate around the composition of life years gained from smoking elimination. The aim of this study was to conduct a systematic review of the literature to synthesize existing evidence on the effect of smoking status on health expectancy and to examine whether smoking elimination leads to compression of morbidity.

Methods

Five databases were systematically searched for peer-reviewed articles. Studies that presented quantitative estimates of health expectancy for smokers and non-/never-smokers were eligible for inclusion. Studies were searched, selected and reviewed by two reviewers who extracted the relevant data and assessed the risk of bias of the included articles independently.

Results

The search identified 2491 unique records, whereof 20 articles were eligible for inclusion (including 26 cohorts). The indicators used to measure health included disability/activity limitations (n=9), health-related quality of life (EQ-5D) (n=2), weighted disabilities (n=1), self-rated health (n=9), chronic diseases (n=6), cardiovascular diseases (n=4) and cognitive impairment (n=1). Available evidence showed consistently that non-/never-smokers experience more healthy life years throughout their lives than smokers. Findings were inconsistent on the effect of smoking on the absolute number of unhealthy life years. Findings concerning the time proportionally spent unhealthy were less heterogeneous: nearly all included articles reported that non-/never-smokers experience relatively less unhealthy life years (e.g. relative compression of morbidity).

Conclusions

Support for the relative compression of morbidity due to smoking elimination was evident. Further research is needed into the absolute compression of morbidity hypothesis since current evidence is mixed, and methodology of studies needs to be harmonized.
Chlamydia pneumoniaeandMycoplasma pneumoniaein children with cystic fibrosis: impact on bacterial respiratory microbiota diversity
Authors: Pittet Laure F , Bertelli Claire , Scherz Valentin , Rochat Isabelle , Mardegan Chiara , Brouillet René , Jaton Katia , Mornand Anne , Kaiser Laurent , Posfay-Barbe Klara , Asner Sandra A , Greub Gilbert
Published: November 2020

Objectives: The contribution of intracellular and fastidious bacteria in Cystic fibrosis (CF) pulmonary exacerbations, and progressive lung function decline remains unknown. This project aimed to explore their impact on bacterial microbiota diversity over time in CF children. Methods: Sixty-one children enrolled in the MUCOVIB multicentre prospective cohort provided 746 samples, mostly nasopharyngeal swabs, throat swabs and sputa which were analysed using culture, specific real-time qPCRs and 16S rRNA amplicon metagenomics. Results:  Chlamydia pneumoniae (n = 3) and Mycoplasma pneumoniae (n = 1) were prospectively documented in 6.6% of CF children. Microbiota alpha-diversity in children with a documented C. pneumoniae was highly variable, similarly to children infected with Staphylococcus aureus or Pseudomonas aeruginosa. The transition from routine follow-up visits to pulmonary exacerbation (n = 17) yielded variable changes in diversity indexes with some extreme loss of diversity. Conclusions: The high rate of C. pneumoniae detection supports the need for regular screenings in CF patients. A minor impact of C. pneumoniae on the microbial community structure was documented. Although detected in a single patient, M. pneumoniae should also be considered as a possible aetiology of lung infection in CF subjects.
Optimal Contribution Selection in Highly Fecund Species With Overlapping Generations
Authors: Hamilton Matthew G
Published: November 2020

Optimal contributions approaches to parental selection in closed breeding populations aim to maximize genetic gains, while restraining long-term inbreeding. The adoption of optimal contribution selection (OCS) in highly fecund outcrossing species presents a number of challenges not applicable to species of low fecundity (e.g., livestock) for which they were developed. This is particularly true if overlapping-generations or rolling-front breeding strategies are applied, in which case the number of individuals per family in juvenile (i.e., sexually immature) age groups is not necessarily known but is likely to be large. In these circumstances, conventional OCS procedures must be modified or a large number of dummy individuals defined, making computations onerous. Here, an approach to OCS is presented that involves the use of “between-family relationship matrices” instead of “between-individual relationship matrices.” The method is applicable to breeding programs involving highly fecund outcrossing species with overlapping generations, including circumstances where the number of juveniles per family is unknown but large.
Factors that mold the nuclear landscape of HIV-1 integration
Authors: Bedwell Gregory J , Engelman Alan N
Published: November 2020

The integration of retroviral reverse transcripts into the chromatin of the cells that they infect is required for virus replication. Retroviral integration has far-reaching consequences, from perpetuating deadly human diseases to molding metazoan evolution. The lentivirus human immunodeficiency virus 1 (HIV-1), which is the causative agent of the AIDS pandemic, efficiently infects interphase cells due to the active nuclear import of its preintegration complex (PIC). To enable integration, the PIC must navigate the densely-packed nuclear environment where the genome is organized into different chromatin states of varying accessibility in accordance with cellular needs. The HIV-1 capsid protein interacts with specific host factors to facilitate PIC nuclear import, while additional interactions of viral integrase, the enzyme responsible for viral DNA integration, with cellular nuclear proteins and nucleobases guide integration to specific chromosomal sites. HIV-1 integration favors transcriptionally active chromatin such as speckle-associated domains and disfavors heterochromatin including lamina-associated domains. In this review, we describe virus-host interactions that facilitate HIV-1 PIC nuclear import and integration site targeting, highlighting commonalities among factors that participate in both of these steps. We moreover discuss how the nuclear landscape influences HIV-1 integration site selection as well as the establishment of active versus latent virus infection.
Tumor edge-to-core transition promotes malignancy in primary-to-recurrent glioblastoma progression in a PLAGL1/CD109-mediated mechanism
Authors: Li Chaoxi , Cho Hee Jin , Yamashita Daisuke , Abdelrashid Moaaz , Chen Qin , Bastola Soniya , Chagoya Gustavo , Elsayed Galal A , Komarova Svetlana , Ozaki Saya , Ohtsuka Yoshihiro , Kunieda Takeharu , Kornblum Harley I , Kondo Toru , Nam Do-Hyun , Nakano Ichiro
Published: November 2020

Background

Glioblastoma remains highly lethal due to its inevitable recurrence. Most of this recurrence is found locally, indicating that postsurgical tumor-initiating cells (TICs) accumulate at the tumor edge. These edge-TICs then generate local recurrence harboring new core lesions. Here, we investigated the clinical significance of the edge-to-core (E-to-C) signature generating glioblastoma recurrence and sought to identify its central mediators.

Methods

First, we examined the association of E-to-C-related expression changes to patient outcome in matched primary and recurrent samples (n = 37). Specifically, we tested whether the combined decrease of the edge-TIC marker PROM1 (CD133) with the increase of the core-TIC marker CD109, representing E-to-C transition during the primary-to-recurrence progression, indicates poorer patient outcome. We then investigated the specific molecular mediators that trigger tumor recurrence driven by the E-to-C progression. Subsequently, the functional and translational significance of the identified molecule was validated with our patient-derived edge-TIC models in vitro and in vivo.

Results

Patients exhibiting the CD133low/CD109high signature upon recurrence representing E-to-C transition displayed a strong association with poorer progression-free survival and overall survival among all tested patients. Differential gene expression identified that PLAGL1 was tightly correlated with the core TIC marker CD109 and was linked to shorter patient survival. Experimentally, forced PLAGL1 overexpression enhanced, while its knockdown reduced, glioblastoma edge-derived tumor growth in vivo and subsequent mouse survival, suggesting its essential role in the E-to-C-mediated glioblastoma progression.

Conclusions

E-to-C axis represents an ongoing lethal process in primary glioblastoma contributing to its recurrence, partly in a PLAGL1/CD109-mediated mechanism.
Associations Between Tenofovir Diphosphate in Dried Blood Spots, Impaired Physical Function, and Fracture Risk
Authors: Abdo Mona , Coyle Ryan P , Seifert Sharon M , Castillo-Mancilla Jose R , Jankowski Catherine M , Mawhinney Samantha , Anderson Peter L , Erlandson Kristine M
Published: November 2020

Background

In this study, we evaluate associations between cumulative antiretroviral adherence/exposure, quantified using tenofovir diphosphate (TFV-DP) in dried blood spots (DBS), and human immunodeficiency virus (HIV)-related aging factors.

Methods

This is a cross-sectional analysis of younger (ages 18–35) and older (ages ≥60) persons with HIV (PWH) taking TFV disoproxil fumarate. Tenofovir diphosphate concentrations were quantified in DBS. Linear and logistic regression models were used to evaluate associations between TFV-DP and bone mineral density (BMD), physical function, frailty, and falls.

Results

Forty-five PWH were enrolled (23 younger, 22 older). Every 500 fmol/punch (equivalent to an increase in ~2 doses/week) increase in TFV-DP was associated with decreased hip BMD (−0.021 g/cm2; 95% confidence interval [CI], −0.040 to −0.002; P = .03). Adjusting for total fat mass, every 500 fmol/punch increase in TFV-DP was associated with higher odds of Short Physical Performance Battery impairment (score ≤10; adjusted odds ratio [OR], 1.6; 95% CI, 1.0–2.5; P = .04). Every 500 fmol/punch increase in TFV-DP was associated with slower 400-meter walk time (14.8 seconds; 95% CI, 3.8–25.8; P = .01) and remained significant after adjusting for age, lean body mass, body mass index (BMI), and fat mass (all P ≤ .01). Every 500 fmol/punch increase in TFV-DP was associated with higher odds of reporting a fall in the prior 6 months (OR, 1.8; 95% CI, 1.1–2.8; P = .02); this remained significant after adjusting for age, lean body mass, BMI, and total fat mass (all P < .05).

Conclusions

Higher TFV-DP levels were associated with lower hip BMD, poorer physical function, and greater risk for falls, a concerning combination for increased fracture risk.
Mycobacterium Mucogenicum Bacteremia and Nodular Soft Tissue Infection in a Person Who Uses Tap Water to Inject Drugs
Authors: Boodman Carl , Smith Catherine , von Kuster Ken , Lagacé-Wiens Philippe , Wuerz Terence
Published: November 2020

The ongoing North American epidemic of intravenous opioid and methamphetamine use increases the occurrence of bacteremia from environmental organisms. In this study, we report a case of Mycobacterium mucogenicum bacteremia and associated nodular soft tissue infection in a person who uses tap water to inject drugs.
Having a co-morbidity predicts worse outcome in early rheumatoid arthritis despite intensive treatment: a post hoc evaluation of the pragmatic randomized controlled CareRA trial
Authors: Stouten Veerle , Westhovens René , De Cock Diederik , Van der Elst Kristien , Pazmino Sofia , Bertrand Delphine , Joly Johan , Verschueren Patrick
Published: November 2020

Objectives

To quantify the prevalence of co-morbidities in patients with early RA and determine their prognostic value for effectiveness outcomes in a randomized trial.

Methods

We included patients from the 2-year pragmatic randomized CareRA trial, who had early RA (diagnosis < 1 year), were DMARD naïve and then treated-to-target with different remission induction schemes. Prevalence of co-morbidities was registered at baseline and the Rheumatic Diseases Comorbidity Index (RDCI; range 0–9) was calculated. We tested the relation between baseline RDCI and outcomes including disease activity (DAS28-CRP), physical function (HAQ index), quality of life (SF-36 domains) and hospitalizations over 2 years, using linear mixed models or generalized estimating equations models.

Results

Of 379 included patients, 167 (44%) had a RDCI of minimum 1. RDCI scores of 1, 2 or ≥3 were obtained in 65 (17%), 70 (19%), and 32 (8%) participants, respectively. The most frequent co-morbidity was hypertension (22%). Patients with co-morbidities had significantly higher HAQ (β = 0.215; 95% CI: 0.071, 0.358), DAS28-CRP (β = 0.225; 95% CI: 0.132, 0.319) and lower SF-36 physical component summary scores (β =−3.195; 95% CI: −4.844, −1.546) over 2 years than patients without co-morbidities, after adjusting for possible confounders including disease activity and randomized treatment. Patients with co-morbidities had over time lower chances of achieving remission (OR = 0.724; 95% CI: 0.604, 0.867) and a higher risk of hospitalization (OR = 3.725; 95% CI: 2.136, 6.494).

Conclusion

At disease onset, almost half of RA patients had at least one clinically important co-morbidity. Having co-morbidities was associated with worse functionality and disease activity outcomes over 2 years, despite intensive remission induction treatment.

Trial registration

Clinical trials NCT01172639.
Testing the contiguity of the sleep and fatigue relationship: a daily diary study
Authors: Harris Andrea L , Carmona Nicole E , Moss Taryn G , Carney Colleen E
Published: November 2020

Study Objectives

There is mixed evidence for the relationship between poor sleep and daytime fatigue, and some have suggested that fatigue is simply caused by lack of sleep. Although retrospective measures of insomnia and fatigue tend to correlate, other studies fail to demonstrate a link between objectively disturbed sleep and fatigue. The current study prospectively explored the relationship between sleep and fatigue among those with and without insomnia disorder.

Methods

Participants meeting Research Diagnostic Criteria for insomnia disorder (n = 33) or normal sleepers (n = 32) completed the Consensus Sleep Diary (CSD) and daily fatigue ratings for 2 weeks. Baseline questionnaires evaluated cognitive factors including unhelpful beliefs about sleep and rumination about fatigue. Hierarchical linear modeling tested the within- and between-participant relationships between sleep quality, total sleep time, and daily fatigue ratings. Mediation analyses tested if cognitive factors mediated the relationship between insomnia and fatigue.

Results

Self-reported nightly sleep quality significantly predicted subsequent daily fatigue ratings. Total sleep time was a significant predictor of fatigue within, but not between, participants. Unhelpful sleep beliefs and rumination about fatigue mediated the relationship between insomnia and fatigue reporting.

Conclusions

The results suggest that perception of sleep plays an important role in predicting reports of daytime fatigue. These findings could be used in treatment to help shift the focus away from total sleep times, and instead, focus on challenging maladaptive sleep-related cognitions to change fatigue perception.
Exploring utility of genomic epidemiology to trace origins of highly pathogenic influenza A/H7N9 in Guangdong
Authors: Bai Ru , Sikkema Reina S , Munnink Bas B Oude , Li Cong Rong , Wu Jie , Zou Lirong , Jing Yi , Lu Jing , Yuan Run Yu , Liao Ming , Koopmans Marion , Ke Chang-Wen
Published: November 2020

The first highly pathogenic (HP) influenza A/H7N9 was reported in Guangdong in January 2017. To investigate the emergence and spread of HP A/H7N9 in Guangdong province, we sequenced 297 viruses (58 HP A/H7N9, 19 low pathogenic (LP) A/H7N9, and 220 A/H9N2) during 2016–2017. Our analysis showed that during the fifth wave, three A/H7N9 lineages were co-circulating in Guangdong: the local LP Pearl River Delta (PRD) lineage (13%), the newly imported LP Yangtze River Delta (YRD) lineage (23%), and the HP YRD lineage (64%). Previously circulating YRD-lineage LP during the third wave evolved to the YRD-lineage HP A/H7N9 in Guangdong. All YRD-lineage LP detected during the fifth wave most likely originated from newly imported viruses into Guangdong. Genotype comparison of HP A/H7N9 suggests limited outward spread of HP A/H7N9 to other provinces. The distribution of HP A/H7N9 cleavage site variants on live poultry markets differed from that found in humans, suggesting a V1-type cleavage site may facilitate human infections.
Septoria Nodorum Blotch of Wheat: Disease Management and Resistance Breeding in the Face of Shifting Disease Dynamics and a Changing Environment
Authors: Downie Rowena C. , Lin Min , Corsi Beatrice , Ficke Andrea , Lillemo Morten , Oliver Richard P. , Phan Huyen T. T. , Tan Kar-Chun , Cockram James
Published: November 2020

The fungus Parastagonospora nodorum is a narrow host range necrotrophic fungal pathogen that causes Septoria nodorum blotch (SNB) of cereals, most notably wheat (Triticum aestivum). Although commonly observed on wheat seedlings, P. nodorum infection has the greatest effect on the adult crop. It results in leaf blotch, which limits photosynthesis and thus crop growth and yield. It can also affect the wheat ear, resulting in glume blotch, which directly affects grain quality. Reports of P. nodorum fungicide resistance, the increasing use of reduced tillage agronomic practices, and high evolutionary potential of the pathogen, combined with changes in climate and agricultural environments, mean that genetic resistance to SNB remains a high priority in many regions of wheat cultivation. In this review, we summarize current information on P. nodorum population structure and its implication for improved SNB management. We then review recent advances in the genetics of host resistance to P. nodorum and the necrotrophic effectors it secretes during infection, integrating the genomic positions of these genetic loci by using the recently released wheat reference genome assembly. Finally, we discuss the genetic and genomic tools now available for SNB resistance breeding and consider future opportunities and challenges in crop health management by using the wheat–P. nodorum interaction as a model.
NonClasGP-Pred: robust and efficient prediction of non-classically secreted proteins by integrating subset-specific optimal models of imbalanced data
Authors: Wang Chao , Wu Jin , Xu Lei , Zou Quan
Published: November 2020

Non-classically secreted proteins (NCSPs) are proteins that are located in the extracellular environment, although there is a lack of known signal peptides or secretion motifs. They usually perform different biological functions in intracellular and extracellular environments, and several of their biological functions are linked to bacterial virulence and cell defence. Accurate protein localization is essential for all living organisms, however, the performance of existing methods developed for NCSP identification has been unsatisfactory and in particular suffer from data deficiency and possible overfitting problems. Further improvement is desirable, especially to address the lack of informative features and mining subset-specific features in imbalanced datasets. In the present study, a new computational predictor was developed for NCSP prediction of gram-positive bacteria. First, to address the possible prediction bias caused by the data imbalance problem, ten balanced subdatasets were generated for ensemble model construction. Then, the F-score algorithm combined with sequential forward search was used to strengthen the feature representation ability for each of the training subdatasets. Third, the subset-specific optimal feature combination process was adopted to characterize the original data from different aspects, and all subdataset-based models were integrated into a unified model, NonClasGP-Pred, which achieved an excellent performance with an accuracy of 93.23 %, a sensitivity of 100 %, a specificity of 89.01 %, a Matthew’s correlation coefficient of 87.68 % and an area under the curve value of 0.9975 for ten-fold cross-validation. Based on assessment on the independent test dataset, the proposed model outperformed state-of-the-art available toolkits. For availability and implementation, see: http://lab.malab.cn/~wangchao/softwares/NonClasGP/.
Association of Toll-like receptor 7 variants with life-threatening COVID-19 disease in males
Authors: Fallerini Chiara , Daga Sergio , Mantovani Stefania , Benetti Elisa , Pujol Aurora , Picchiotti Nicola , Schluter Agatha , Planas-Serra Laura , Troya Jesús , Baldassarri Margherita , Fava Francesca , Ludovisi Serena , Castelli Francesco , Quiros-Roldan Maria Eugenia , Vaghi Massimo , Rusconi Stefano , Siano Matteo , Bandini Maria , Furini Simone , Mari Francesca ,   GEN-COVID Multicenter Study, Renieri Alessandra , Mondelli Mario U. , Frullanti Elisa
Published: November 2020

Background

COVID-19 clinical presentation ranges from asymptomatic to fatal outcome. This variability is due in part to host genome specific mutations. Recently, two families in which COVID-19 segregates like an X-linked recessive monogenic disorder environmentally conditioned by SARS-CoV-2 have been reported leading to identification of loss-of-function variants in TLR7.

Objective

We sought to determine whether the two families represent the tip of the iceberg of a subset of COVID-19 male patients.

Methods

We compared male subjects with extreme phenotype selected from the Italian GEN-COVID cohort of 1178 SARS-CoV-2-infected subjects (<60y, 79 severe cases versus 77 control cases). We applied the LASSO Logistic Regression analysis, considering only rare variants on the young male subset, picking up TLR7 as the most important susceptibility gene.

Results

Rare TLR7 missense variants were predicted to impact on protein function in severely affected males and in none of the asymptomatic subjects. We then investigated a similar white European cohort in Spain, confirming the impact of TRL7 variants. A gene expression profile analysis in peripheral blood mononuclear cells after stimulation with TLR7 agonist demonstrated a reduction of mRNA level of TLR7, IRF7, ISG15, IFN-□ and IFN-γ in COVID-19 patients compared with unaffected controls demonstrating an impairment in type I and II INF responses.

Conclusion

Young males with TLR7 loss-of-function mutations and severe COVID-19 in the two reported families represent only a fraction of a broader and complex host genome situation. Specifically, missense mutations in the X-linked recessive TLR7 disorder may significantly contribute to disease susceptibility in up to 4% of severe COVID-19.

Clinical Implication

In this new yet complex scenario, our observations provide the basis for a personalized interferon-based therapy in patients with rare TLR7 variants.

CAPSULE SUMMARY

Our results in large cohorts from Italy and Spain showed that X-linked recessive TLR7 disorder may represent the cause of disease susceptibility to COVID-19 in up to 4% of severely affected young male cases.
Validation and implementation of a direct RT-qPCR method for rapid screening of SARS-CoV-2 infection by using non-invasive saliva samples
Authors: Brotons Pedro , Perez-Argüello Amaresh , Launes Cristian , Torrents Francesc , Saucedo Jesica , Claverol Joana , Garcia-Garcia Juan Jose , Rodas Gil , Fumado Vicky , Jordan Iolanda , Gratacos Eduard , Bassat Quique , Muñoz-Almagro Carmen
Published: November 2020

Background

There is an urgent need to curb COVID-19 pandemic through early identification of asymptomatic but infectious cases. We aimed to validate and implement an optimised screening method for detection of SARS-CoV-2 RNA combining use of self-collected raw saliva samples, single-step heat-treated virus inactivation and RNA extraction, and direct RT-qPCR.

Methods and findings

The study was conducted in Sant Joan de Deu University Hospital (Barcelona, Spain), including: i) analytical validation against standard RT-qPCR in saliva samples; ii) diagnostic validation against standard RT-qPCR using paired saliva-nasopharyngeal samples obtained from asymptomatic teenagers and young and older adults in a youth sports academy; and iii) high throughput pilot screening of asymptomatic health workers and other staff in the study site.

The proposed method had comparable analytical performance to standard RT-qPCR in saliva. Diagnostic validation included saliva samples self-collected with supervision by 173 participants during 9-12 weeks and nasopharyngeal samples collected from them. At baseline, all participants (100.0%) were negative for SARS-CoV-2 in both paired saliva-nasopharyngeal samples. In the following weeks, standard RT-qPCR yielded 23 positive results in nasopharyngeal samples whereas paired saliva specimens yielded 22 (95.7%) positive and one inconclusive result.

A total of 2,709 participants engaged in the pilot screening, with high rate of participation (83.4% among health workers). Only 17 (0.6%) of saliva samples self-collected by participants in an unsupervised manner were invalid. Saliva was positive in 24 (0.9%) out of 2,692 valid specimens and inconclusive in 27 (1.0%). All 24 saliva-positive participants and 4 with saliva inconclusive results were positive by standard RT-qPCR in nasopharyngeal samples. The pilot showed potential for rapid analytical workflow (up to 384 batched samples can be processed in <2 hours).

Conclusion

Direct RT-qPCR on self-collected raw saliva is a simple, rapid, and accurate method with potential to be scaled up for enhanced SARS-CoV-2 community-wide screening.
Tripterygium glycosides as a potential treatment for CAR-T induced cytokine release syndrome: implication of monocyte depletion
Authors: Xu Zuqiong , Tian Fang , Chen Biqing , Kong Xiangtu , Dai Xingbin , Cao Jiang , Jiang Pengjun , Tan Jianxin , Lu Lu , Wang Xiachang , Lv Qi , Kang Di , Xu Miao , Hu Yingying , Yang Aiping , Wang Qian , Yang Zhong-Fa , Sun Xuemei , Ma Leyuan , Hu Lihong , Zhu Xuejun
Published: November 2020

Background

Cytokine release syndrome (CRS) is a potentially life-threatening complication of chimeric antigen receptor T (CAR-T) cell therapy. Recent studies indicated critical roles of macrophages and monocytes in CAR-T induced CRS. Here, we report rapid dissipation of CAR-T induced CRS in two patients after receiving Tripterygium glycosides (TG). Effects of triptolide, the major active component of TG, on macrophages and monocytes were examined in animal models.

Methods

Two patients with CRS after CAR-T cell therapy (for hematological malignancy) received TG (50 mg, p.o.). Flow cytometry analysis and single cell RNA sequencing (scRNAseq) were conducted to examine the effects of TG on immune cells. Potential effects of triptolide were also examined ex vivo using patient-derived monocytes, as well as in mice.

Findings

Rapid alleviation of fever and cytokine storm was observed within 72 hours after TG treatment. Blood concentration of triptolide ranged from 21 to 154 ng/mL during treatment. Flow cytometry and scRNAseq showed selective depletion of monocytes with minimal impact on CAR-T cells in both patients. In ex vivo experiments with patient-derived monocytes, triptolide dramatically inhibited the synthesis of pro-inflammatory cytokines (e.g., IL-6, IL-10, and IP-10). Triptolide also rapidly and selectively depleted peritoneal concanavalin A activated macrophages and monocytes in mice.

Interpretation

TG could be a promising treatment for CAR-T induced CRS, as well as other diseases with similar mechanisms, e.g., hemophagocytic lymphohistiocytosis and COVID-19. Our preliminary findings require further verification with properly designed clinical trials.
Meningioma epigenetic grouping reveals biologic drivers and therapeutic vulnerabilities
Authors: Choudhury Abrar , Magill Stephen T. , Eaton Charlotte D. , Prager Briana C. , Chen William C. , Seo Kyounghee , Lucas Calixto-Hope G. , Villanueva-Meyer Javier E. , Lam Tai-Chung , Pu Jenny Kan-Suen , Li Lai-Fung , Leung Gilberto Ka-Kit , Vasudevan Harish N. , Liu S. John , Chan Jason W. , Qiu Zhixin , Zhang Michael Y. , Martin Michael V. , Susko Matthew S. , Braunstein Steve E. , Oberheim Bush Nancy Ann , Schulte Jessica , Butowski Nicholas , Sneed Penny K. , Berger Mitchel S. , Perry Arie , Phillips Joanna J. , Solomon David A. , Costello Joseph F. , McDermott Michael W. , Rich Jeremy N. , Raleigh David R.
Published: November 2020

Meningiomas arising from the meningothelial central nervous system lining are the most common primary intracranial tumors, and a significant cause of neurologic morbidity and mortality1. There are no effective medical therapies for meningioma patients2,3, and new treatments have been encumbered by limited understanding of meningioma biology. DNA methylation profiling provides robust classification of central nervous system tumors4, and can elucidate targets for molecular therapy5. Here we use DNA methylation profiling on 565 meningiomas integrated with genetic, transcriptomic, biochemical, and single-cell approaches to show meningiomas are comprised of 3 epigenetic groups with distinct clinical outcomes and biological features informing new treatments for meningioma patients. Merlin-intact meningiomas (group A, 34%) have the best outcomes and are distinguished by a novel apoptotic tumor suppressor function ofNF2/Merlin. Immune-enriched meningiomas (group B, 38%) have intermediate outcomes and are distinguished by immune cell infiltration,HLAexpression, and lymphatic vessels. Hypermitotic meningiomas (group C, 28%) have the worst outcomes and are distinguished by convergent genetic mechanisms misactivating the cell cycle. Consistently, we find cell cycle inhibitors block meningioma growth in cell culture, organoids, xenografts, and patients. Our results establish a framework for understanding meningioma biology, and provide preclinical rationale for new therapies to treat meningioma patients.
Peptide microarray based analysis of antibody responses to SARS-CoV-2 identifies unique epitopes with potential for diagnostic test development
Authors: Holenya Pavlo , Lange Paul Joris , Reimer Ulf , Woltersdorf Wolfram , Panterodt Thomas , Glas Michael , Wasner Mark , Eckey Maren , Drosch Michael , Hollidt Jörg-Michael , Naumann Michael , Kern Florian , Wenschuh Holger , Lange Robert , Schnatbaum Karsten , Bier Frank F.
Published: November 2020

Humoral immunity to the Severe Adult Respiratory Syndrome (SARS) Coronavirus (CoV)-2 is not fully understood yet but may be a crucial factor of immune protection. The possibility of antibody cross-reactivity between SARS-CoV-2 and other human coronaviruses (HCoVs) would have important implications for immune protection but also for the development of specific diagnostic ELISA tests. Using peptide microarrays, n=24 patient samples and n=12 control samples were screened for antibodies against the entire SARS-CoV-2 proteome as well as the Spike (S), Nucleocapsid (N), VME1 (V), R1ab, and Protein 3a (AP3A) of the HCoV strains SARS, MERS, OC43 and 229E. While widespread cross-reactivity was revealed across several immunodominant regions of S and N, IgG binding to several SARS-CoV-2-derived peptides provided statistically significant discrimination between COVID-19 patients and controls. Selected target peptides may serve as capture antigens for future, highly COVID-19-specific diagnostic antibody tests.