bluuebunny/crossref_metadata_2025_split huggingface dataset:
Genetically related micafungin-resistant Candida parapsilosis blood isolates harbouring novel mutation R658G in hotspot 1 of Fks1p: a new challenge?
Authors: Arastehfar Amir , Daneshnia Farnaz , Hilmioglu-Polat Süleyha , Ilkit Macit , Yasar Melike , Polat Furkan , Metin Dilek Yeşim , Dokumcu Ülküm Zafer , Pan Weihua , Hagen Ferry , Boekhout Teun , Perlin David S , Lass-Flörl Cornelia 
Published: November 2020

Abstract

Background
Echinocandin resistance rarely occurs in clinical Candida parapsilosis isolates and the underlying mechanism is unknown.

Objectives
To determine the prevalence of echinocandin resistance and the underlying mechanism for a large collection of C. parapsilosis blood isolates and to determine whether the echinocandin-resistant isolates were clonally related.

Methods
C. parapsilosis blood isolates (n = 213) were subjected to antifungal susceptibility testing (CLSI M27), for micafungin, anidulafungin, amphotericin B and, if appropriate, caspofungin. Hotspot (HS) 1 and HS2 of FKS1 were sequenced for all isolates (n = 213) and microsatellite typing was performed for echinocandin-resistant isolates.

Results
All isolates were susceptible to amphotericin B and two isolates were intermediate to anidulafungin (MIC = 4 mg/L), while micafungin resistance was noted in four isolates (MIC &gt;8 mg/L); three of which were also fluconazole resistant and therefore were MDR. Interestingly, micafungin-resistant isolates, but not those intermediate to anidulafungin, carried novel mutation R658G in HS1 of Fks1p; three of which also harboured Y132F+K143R in Erg11. The first isolate (MICR1) was recovered in November 2017 from a patient admitted to paediatric gastroenterology who showed therapeutic failure under caspofungin treatment. MICR2–MICR4 were collected during 2018–19 and were recovered from three echinocandin-naive paediatric-surgery patients; the isolates shared the same genotype.

Conclusions
Herein, for the first time (to the best of our knowledge), we identified micafungin-resistant C. parapsilosis blood isolates harbouring a novel mutation in HS1 of FKS1, which was likely attributable to in vitro micafungin resistance and in vivo caspofungin therapeutic failure. The acquisition of micafungin-resistant C. parapsilosis isolates in echinocandin-naive patients likely implicates clonal expansion, as supported by the close genetic relatedness of MICR2–MICR4.
A case report of an incidental finding of congenital oesophageal diverticulum in a patient presenting with stridor
Authors: Limbu Raju , Brar Sabrina , Modayil Prince 
Published: November 2020

Abstract
Congenital oesophageal diverticulum is incredibly rare and has not commonly been published in the literature. Oesophageal diverticulum can be asymptomatic; however, symptoms such as dysphagia, regurgitation and chest discomfort may be present. We describe the case of a paediatric patient presenting with biphasic stridor, respiratory distress and cyanosis at birth, who was found to have a supraglottic cyst and later the presence of an oesophageal diverticulum shown on ultrasound imaging. There has been one other case reported in the literature of an oesophageal diverticulum presenting with stridor, and we therefore believe this is one of only two cases to illustrate this atypical presentation of congenital oesophageal diverticulum. It highlights the importance of a meticulous multidisciplinary team approach to patient care, as well as conducting appropriate investigations to aid early diagnosis to improve patient outcomes.
Systematic velocity drifts of methanol masers associated with G9.62+0.20E
Authors: MacLeod G C , Chibueze J O , Sanna A , Paulsen J D , Houde M , van den Heever S P , Goedhart S 
Published: November 2020

ABSTRACT
The source G9.62+0.20E surprises again! Several of the associated 6.7- and 12.2-GHz methanol masers are experiencing contemporaneous and systematic velocity drifts. Both 6.7- and 12.2-GHz methanol features blueward of v = +1.2 km s−1 are blue shifting while those redward are red shifting. A best-fitting rotating Keplerian disc with a central mass of ∼12 M⊙, radii Rinner = 5 au and Router = 5000 au, and at an inclination angle of 22○ either precessing and/or experiencing infall explains these systematic velocity drifts. Also three more distinct 6.7-GHz methanol maser features are found to vary periodically; two very weak and one obviously periodic only after 2003. Evidence of periodicity is seen as early as 1992. Time lags are confirmed but the cause is unclear. It is possible this source will surprise again.
How to Make a Rodent Giant: Genomic Basis and Tradeoffs of Gigantism in the Capybara, the World’s Largest Rodent
Authors: Herrera-Álvarez Santiago , Karlsson Elinor , Ryder Oliver A , Lindblad-Toh Kerstin , Crawford Andrew J 
Published: November 2020

AbstractGigantism results when one lineage within a clade evolves extremely large body size relative to its small-bodied ancestors, a common phenomenon in animals. Theory predicts that the evolution of giants should be constrained by two tradeoffs. First, because body size is negatively correlated with population size, purifying selection is expected to be less efficient in species of large body size, leading to increased mutational load. Second, gigantism is achieved through generating a higher number of cells along with higher rates of cell proliferation, thus increasing the likelihood of cancer. To explore the genetic basis of gigantism in rodents and uncover genomic signatures of gigantism-related tradeoffs, we assembled a draft genome of the capybara (Hydrochoerus hydrochaeris), the world’s largest living rodent. We found that the genome-wide ratio of nonsynonymous to synonymous mutations (ω) is elevated in the capybara relative to other rodents, likely caused by a generation-time effect and consistent with a nearly neutral model of molecular evolution. A genome-wide scan for adaptive protein evolution in the capybara highlighted several genes controlling postnatal bone growth regulation and musculoskeletal development, which are relevant to anatomical and developmental modifications for an increase in overall body size. Capybara-specific gene-family expansions included a putative novel anticancer adaptation that involves T-cell-mediated tumor suppression, offering a potential resolution to the increased cancer risk in this lineage. Our comparative genomic results uncovered the signature of an intragenomic conflict where the evolution of gigantism in the capybara involved selection on genes and pathways that are directly linked to cancer.
HK022 bacteriophage Integrase mediated RMCE as a potential tool for human gene therapy
Authors: Elias Amer , Kassis Hala , Elkader Suha Abd , Gritsenko Natasha , Nahmad Alessio , Shir Hodaya , Younis Liana , Shannan Atheer , Aihara Hideki , Prag Gali , Yagil Ezra , Kolot Mikhail 
Published: November 2020

AbstractHK022 coliphage site-specific recombinase Integrase (Int) can catalyze integrative site-specific recombination and recombinase-mediated cassette exchange (RMCE) reactions in mammalian cell cultures. Owing to the promiscuity of the 7 bp overlap sequence in its att sites, active ‘attB’ sites flanking human deleterious mutations were previously identified that may serve as substrates for RMCE reactions for future potential gene therapy. However, the wild type Int proved inefficient in catalyzing such RMCE reactions. To address this low efficiency, variants of Int were constructed and examined by integrative site-specific recombination and RMCE assays in human cells using native ‘attB’ sites. As a proof of concept, various Int derivatives have demonstrated successful RMCE reactions using a pair of native ‘attB’ sites that were inserted as a substrate into the human genome. Moreover, successful RMCE reactions were demonstrated in native locations of the human CTNS and DMD genes whose mutations are responsible for Cystinosis and Duchene Muscular Dystrophy diseases, respectively. This work provides a steppingstone for potential downstream therapeutic applications.
Brain network motif topography may predict emergence from disorders of consciousness: a case series
Authors: Nadin Danielle , Duclos Catherine , Mahdid Yacine , Rokos Alexander , Badawy Mohamed , Létourneau Justin , Arbour Caroline , Plourde Gilles , Blain-Moraes Stefanie 
Published: November 2020

Abstract
Neuroimaging methods have improved the accuracy of diagnosis in patients with disorders of consciousness (DOC), but novel, clinically translatable methods for prognosticating this population are still needed. In this case series, we explored the association between topographic and global brain network properties and prognosis in patients with DOC. We recorded high-density electroencephalograms in three patients with acute or chronic DOC, two of whom also underwent an anesthetic protocol. In these two cases, we compared functional network motifs, network hubs and power topography (i.e. topographic network properties), as well as relative power and graph theoretical measures (i.e. global network properties), at baseline, during exposure to anesthesia and after recovery from anesthesia. We also compared these properties to a group of healthy, conscious controls. At baseline, the topographic distribution of nodes participating in alpha motifs resembled conscious controls in patients who later recovered consciousness and high relative power in the delta band was associated with a negative outcome. Strikingly, the reorganization of network motifs, network hubs and power topography under anesthesia followed by their return to a baseline patterns upon recovery from anesthesia, was associated with recovery of consciousness. Our findings suggest that topographic network properties measured at the single-electrode level might provide more prognostic information than global network properties that are averaged across the brain network. In addition, we propose that the brain network’s capacity to reorganize in response to a perturbation is a precursor to the recovery of consciousness in DOC patients.
T-Cell Immune Surveillance in Allogenic Stem Cell Transplant Recipients: Are Whole Blood–Based Assays Ready to Challenge ELISPOT?
Authors: Lauruschkat Chris D , Page Lukas , Etter Sonja , Weis Philipp , Gamon Florian , Kraus Sabrina , Einsele Hermann , Wurster Sebastian , Loeffler Juergen 
Published: November 2020

Abstract
We compared the feasibility of 4 cytomegalovirus (CMV)- and Aspergillus-reactive T-cell immunoassay protocols in allogenic stem cell transplant recipients. While enzyme-linked immunospot performed best overall, logistically advantageous whole blood–based assays performed comparably in patients with less severe lymphocytopenia. CMV-induced interferon-gamma responses correlated strongly across all protocols and showed high concordance with serology.
Structure- and sequence-based design of synthetic single-domain antibody libraries
Authors: Sevy Alexander M , Chen Ming-Tang , Castor Michelle , Sylvia Tyler , Krishnamurthy Harini , Ishchenko Andrii , Hsieh Chung-Ming 
Published: November 2020

Abstract
Single-domain antibody fragments known as VHH have emerged in the pharmaceutical industry as useful biotherapeutics. These molecules, which are naturally produced by camelids, share the characteristics of high affinity and specificity with traditional human immunoglobulins, while consisting of only a single heavy chain. Currently, the most common method for generating VHH is via animal immunization, which can be costly and time-consuming. Here we describe the development of a synthetic VHH library for in vitro selection of single domain binders. We combine structure-based design and next-generation sequencing analysis to build a library with characteristics that closely mimic the natural repertoire. To validate the performance of our synthetic library, we isolated VHH against three model antigens (soluble mouse PD-1 ectodomain, amyloid-β peptide, and MrgX1 GPCR) of different sizes and characteristics. We were able to isolate diverse binders targeting different epitopes with high affinity (as high as 5 nM) against all three targets. We then show that anti-mPD-1 binders have functional activity in a receptor blocking assay.
A meta-analysis of accelerometer sleep outcomes in healthy children based on the Sadeh algorithm: the influence of child and device characteristics
Authors: van Kooten Jojanneke A M C , Jacobse Sofie T W , Heymans Martijn W , de Vries Ralph , Kaspers Gertjan J L , van Litsenburg Raphaële R L 
Published: November 2020

Abstract

Study Objectives
Children often experience sleep problems, with a negative impact on mood, behavior, cognitive function, and other aspects of mental and physical health. Accelerometers are widely used to assess sleep, but general reference values for healthy children do not yet exist. The aim of this meta-analysis was to determine mean values for wake after sleep onset (WASO), sleep efficiency (SE), total sleep time (TST) and sleep onset latency (SOL), and to determine the effect of child and accelerometer-characteristics.

Methods
A search included studies with healthy children, 0–18 years, reporting WASO, SE, TST, and/or SOL, calculated with the Sadeh algorithm. Meta-analyses with random effects produced pooled estimate means per outcome. Meta-regression analyses determined the effect of age, sex, placement site and accelerometer type.

Results
Eighty-three studies (9,068 participants) were included. Pooled means were 63 min (95% CI 57 to 69) for WASO, 88% (95% CI 87 to 89) for SE, 477 min (95% CI 464 to 491) for TST and 19 min (95% CI 17 to 22) for SOL. Heterogeneity was high (95%–99%). TST decreased with age and there was an age-effect on SOL. SE differed between wrist and ankle (used in age 0–24 months) placement, and between piezoelectric and MEMS-type accelerometers. No differences were found between boys and girls, although this number of studies was small.

Conclusions
We found differences in almost all investigated outcomes and heterogeneity was high. Therefore, we advise to use a study-specific control sample until more robust reference values are available. Future research should narrow the methodological heterogeneity and produce larger datasets, needed to establish these reference values.
Effect of microbial feed additives on growth performance, microbial protein synthesis, and rumen microbial population in growing lambs
Authors: Direkvandi Ehsan , Mohammadabadi Tahereh , Salem Abdelfattah Z M 
Published: November 2020

Abstract
Arabi lambs (n =28; body weight = 24 ± 3.7 kg; average age = 120 ± 8 days) were used to investigate the effect of microbial additives on growth performance, microbial protein synthesis and rumen microbial population of fattening lamb based on completely randomized design. Four treatments were studied: (1) control (without additive; CON); (2) Lactobacillus fermentum and L. plantarum (FP); (3) Saccharomyces cerevisiae (SC) plus FP (SCFP); and (4) Megasphaera elsdenii plus SCFP (MSCFP). Lambs were inoculated before morning feeding (daily oral dosed) with a 50 mL microbial suspension as follows: FP, 50 mL bacterial suspension containing 4.5 × 108 colony-forming unit per day (cfu/d) of L. plantarum and L. fermentum (in ratio 50:50); SCFP, 50 mL microbial suspension containing 4.5 × 108 cfu/d FP and 1.4 × 1010 cfu/d SC; MSCFP, 50 mL microbial suspension containing 4.5 × 108 cfu/d Me, 4.5 × 108 cfu/d FP and 1.4 × 1010 cfu/d SC. Feed intake and body weight of lambs were not affected by microbial additives. Average daily gain and feed efficiency were increased on day 0 to 21. The highest concentration of uric acid, total excreted purine derivatives (PD), microbial N, microbial CP, and metabolizable protein were in MSCFP lambs. The ruminal population of Ruminococcus albus and Ruminococcus flavefaciens was higher in MSCFP and SCFP than CON and FP lambs. The highest and the lowest abundance of M. elsdenii and methanogen respectively was observed in lambs fed on microbial additives. The tendency to improve growth performance vs. CON may be due to improvements in microbial protein synthesis and microbial populations, especially fiber-degrading bacteria. The decrease in the population of methanogens as a result of the use of microbial additives is another positive result.
Management of primary vasculitides with biologic and novel small molecule medications
Authors: Serling-Boyd Naomi , Wallace Zachary S. 
Published: November 2020

Purpose of review
Vasculitides can affect small, medium and/or large vessels, leading to end-organ damage, decreased quality of life and death. Glucocorticoids remain the backbone of treatment for systemic vasculitis but are associated with numerous toxicities. In recent years, the efficacy of glucocorticoid-sparing biologic and novel small molecule therapies has been demonstrated.

Recent findings
In giant cell arteritis, tocilizumab was superior to glucocorticoid monotherapy in maintenance remission and cumulative glucocorticoid exposure and is now approved for the treatment of giant cell arteritis. In addition to the previously demonstrated efficacy of rituximab for remission induction in antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis, recent trials have also demonstrated its superiority for remission maintenance compared to alternative approaches. Mepolizumab is superior to standard of care alone with regard to remission rates and glucocorticoid-sparing effect in refractory eosinophilic granulomatosis with polyangiitis. Avacopan has shown significant promise in ANCA-associated vasculitis as part of a glucocorticoid-free induction regimen in a recently completed phase 3 trial. Use of biologics in rarer vasculitides remains guided by reports from small case series.

Summary
Biologics and other novel therapies have an increasingly important role in the management of systemic vasculitis. Additional studies are needed to define their optimal use and to guide their use in more rare forms of vasculitis.
Plate Versus Lag Screw Only Fixation of Unstable Ankle Fractures Involving the Fibula in Adolescent Patients
Authors: Paez Conner J. , Lurie Benjamin M. , Bomar James D. , Upasani Vidyadhar V. , Pennock Andrew T. 
Published: November 2020

Background:
Plate fixation has been the traditional technique for fracture repair of unstable ankle injuries with an associated lateral malleolus fracture. Recently, biomechanical and clinical data have demonstrated lag screw only fixation to be an effective alternative to plate fixation in the adult population. This comparison has yet to be studied in the adolescent or pediatric population. The objective of this study was to compare lag screw only fixation with traditional plating for lateral malleolus fractures in adolescents.

Methods:
A retrospective review was conducted of 83 adolescents with unstable oblique lateral malleolus fractures treated at a single pediatric level-1 trauma center between 2011 and 2019 with a minimum clinical follow-up until fracture union. Patients were divided into 2 surgical groups: (1) plate fixation (n=51) or (2) lag screw fixation (n=32). Radiographic and clinical outcomes and complications were measured in both groups.

Results:
All patients in both groups achieved our primary outcome measure of fracture union without loss of reduction. The mean surgical time for subjects treated with a plate was 15 minutes longer (64 vs. 49 min) (P=0.001) and these patients were 3.8 times more likely to have symptomatic implants (P<0.044) than subjects treated with screws. Approximately 50% of the cohort was available by phone for patient-reported outcomes at a mean follow-up of 50 months. The mean Single Assessment Numerical Evaluation scores, Foot and Ankle Ability Measure Activities of Daily Living scores, Foot and Ankle Ability Measure sports scores, and return to sports rates were similar (92 vs. 93, 98.2 vs. 98.1, 93.2 vs. 94.0, 95% vs. 86%, respectively; P>0.05) between the 2 treatment methods.

Conclusions:
Lag screw only fixation is a safe and effective procedure for noncomminuted, oblique fibula fractures in the adolescent population as demonstrated by equivalent fracture healing rates without loss of reduction and similar outcome scores. Given these comparable results with the additional benefits of shorter surgical time and less symptomatic implants, lag screw only fixation should be considered as a viable treatment alternative to traditional lateral plating in the adolescent population.

Level of Evidence:
Level III.
Part-time Abduction Bracing in Infants With Residual Acetabular Dysplasia: Does Compliance Monitoring Support a Dose-dependent Relationship?
Authors: Swarup Ishaan , Talwar Divya , Sankar Wudbhav N. 
Published: November 2020

Introduction:
Residual acetabular dysplasia is often seen after successful Pavlik treatment or during follow-up for infants with risk factors for developmental dysplasia of the hip. A previous study supported the effectiveness of part-time abduction bracing for treating this residual dysplasia. However, the relationship between time in the brace and acetabular improvement was not established given the lack of compliance data. The purpose of this prospective study was to validate the effect of part-time bracing on acetabular dysplasia and determine if a dose-dependent relationship exists.

Methods:
Eligibility criteria included infants ~6 months of age with an AP pelvic radiograph demonstrating acetabular dysplasia, defined as an acetabular index (AI) ≥30 degrees. After obtaining informed consent, a rigid abduction orthosis was prescribed with a thermal compliance sensor. Patients were instructed to wear the brace for nights/naps and follow-up at 1 year of age for repeat radiograph. AIs were measured by the senior author who was blinded to the compliance data. Hours of wear were compared with changes in AI over the study period using descriptive statistics and a generalized estimating equation model.

Results:
Our series consisted of 26 infants (36 hips) with a mean age at enrollment of 5.9 months (range, 4.9 to 7.9); 84.6% were female individuals. At a mean follow-up of 6 months (range, 5.1 to 8.2), average wear time/day was 11.5 hours (range, 1.3 to 21.7), and total time in brace averaged 1698 hours (range, 218 to 3244 hours). The mean improvement in AI over the study period was 4.8 degrees (95% confidence interval, 3.9-5.5 degrees). The authors found a significant correlation between average hours of brace wear per day and improvement in AI (r=0.36, P<0.05), a relationship that remained significant in our multivariate model after adjusting for confounders.

Conclusions:
Part-time abduction bracing is effective for treating residual dysplasia, with the degree of improvement in AI correlating with hours of brace wear per day. Given this dose-dependent relationship, the optimal hours of wear may depend on the severity of residual dysplasia and the tolerance of the child and family to bracing.