bluuebunny/crossref_metadata_2025 huggingface dataset:
Relative incidence of thrombotic thrombocytopenic purpura and haemolytic uraemic syndrome in clinically suspected cases of thrombotic microangiopathy
Authors: Schönermarck Ulf , Ries Wolfgang , Schröppel Bernd , Pape Lars , Dunaj-Kazmierowska Malgorzata , Burst Volker , Mitzner Steffen , Basara Nadezda , Starck Michael , Schmidbauer Daniel , Mellmann Alexander , Dittmer Rita , Jeglitsch Michael , Haas Christian S
Published: May 2019

Background

Data are lacking on the relative incidence of thrombotic thrombocytopenic purpura (TTP), haemolytic uraemic syndrome (HUS) caused by Shiga toxin–producing Escherichia coli (STEC) and atypical HUS (aHUS) in patients presenting with thrombotic microangiopathies (TMAs).

Methods

This was a prospective, cross-sectional, multicentre and non-interventional epidemiological study. Patients fulfilling criteria for TMAs (platelet consumption, microangiopathic haemolytic anaemia and organ dysfunction) were included in the study. The primary objective was to assess the relative incidence of TTP, STEC-HUS, aHUS and ‘other’ physician-defined diagnoses. The secondary objective was to develop an algorithm to predict a severe deficiency in ADAMTS13 (a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13) activity (≤10%) using routine laboratory parameters. A post hoc classification using the recent Kidney Disease: Improving Global Outcomes diagnostic criteria was then undertaken to further classify patient groups.

Results

aHUS was diagnosed with a relative incidence of 61%, whereas TTP, STEC-HUS and ‘other’ were diagnosed in 13, 6 and 20% of patients, respectively. In the post hoc analysis, 27% of patients with a TMA were classified as ‘primary aHUS’ and 53% as ‘secondary aHUS’. Multivariate analysis revealed that severe deficiency in ADAMTS13 activity (≤10%) was unlikely to underlie TMA if platelet and serum creatinine were above threshold values of 30 × 109/L and 1.8 mg/dL, respectively (negative predictive value of 92.3 and 98.1, respectively, if one or both values were above the threshold).

Conclusions

In this study, aHUS was the most common single diagnosis among patients presenting with a TMA. In the absence of an ADAMTS13 activity result, platelet count and serum creatinine may aid in the differential diagnosis.
Esophageal contractility increases and gastroesophageal reflux does not worsen after lung transplantation
Authors: Posner Shai , Finn Raymond T , Shimpi Rahul A , Wood Richard K , Fisher Deborah , Hartwig Matthew G , Klapper Jacob , Reynolds John , Niedzwiecki Donna , Parish Alice , Leiman David A
Published: May 2019

Gastroesophageal reflux and esophageal dysmotility are common in patients with advanced lung disease and are associated with allograft dysfunction after lung transplantation. The effect of transplantation on reflux and esophageal motility is unclear. The aim of this study was to describe the changes in esophageal function occurring after lung transplantation. A retrospective cohort study was performed on lung transplant candidates evaluated at a tertiary care center between 2015 and 2016. A total of 76 patients who underwent lung transplantation had high-resolution manometry and ambulatory pH-metry before and after transplant. Demographic data, esophageal function testing results, and clinical outcomes such as pulmonary function testing were collected and analyzed using appropriate statistical tests and multivariable regression. Of the 76 patients, 59 (78%) received a bilateral transplant. There was a significant increase in esophageal contractility posttransplant, with an increase in median distal contractile integral from 1470 to 2549 mmHg cm s (P < 0.01). There were 19 patients with Jackhammer esophagus posttransplant, including 15 patients with normal motility pretransplant. Nine patients with ineffective or fragmented peristalsis pretransplant had normal manometry posttransplant. Abnormal pH-metry was observed in 35 (46%) patients pretransplant and 29 (38%) patients posttransplant (P = 0.33). Patients with gastroesophageal reflux disease posttransplant had less improvement in pulmonary function at one year, as measured by forced expiratory volume (P = 0.04). These results demonstrate that esophageal contractility increases significantly after lung transplantation, with an associated change in motility classification. In comparison, gastroesophageal reflux does not worsen, but is associated with worse pulmonary function, posttransplant.
Novel approaches to the management of chronic systolic heart failure: future directions and unanswered questions
Authors: Reddy Yogesh N V , Borlaug Barry A , O’Connor Christopher M , Gersh Bernard J
Published: May 2019

Despite improvements in outcomes in the last few decades for heart failure (HF) with reduced ejection fraction (HFrEF), there still remains a need for novel therapies as many patients incompletely recover with existing therapies and progress to advanced HF. In this review, we will discuss recent advances in the management of HFrEF with a focus on upcoming therapies that hold the greatest promise for clinical use. We will discuss novel pharmacological therapies and areas of uncertainty with existing therapies. We will also discuss the potential utility and controversy surrounding novel interventions for HF such as percutaneous mitral valve repair, atrial fibrillation ablation, and other emerging interventions with positive signals for benefit in HFrEF. Finally, we will summarize the current state of stem cell and gene therapy for HFrEF and future directions.
Short-term Calorie Restriction and 17α-Estradiol Administration Elicit Divergent Effects on Proteostatic Processes and Protein Content in Metabolically Active Tissues
Authors: Miller Benjamin F , Pharaoh Gavin A , Hamilton Karyn L , Peelor Fredrick F , Kirkland James L , Freeman Willard M , Mann Shivani N , Kinter Michael , Price John C , Stout Michael B
Published: May 2019

17α-Estradiol (17α-E2) is a “non-feminizing” estrogen that extends life span in male, but not female, mice. We recently reported that 17α-E2 had robust beneficial effects on metabolic and inflammatory parameters in aged male mice. However, it remains unclear if 17α-E2 also delays other “hallmarks” of aging, particularly maintaining proteostasis. Here, we used isotope labeling methods in older mice to examine proteostatic mechanisms. We compared weight-matched mild calorie restricted (CR) and 17α-E2 treated male mice with the hypothesis that 17α-E2 would increase protein synthesis for somatic maintenance. 17α-E2 had no effect on protein synthesis or DNA synthesis in multiple tissues, including white adipose tissue. Conversely, mild short-term CR decreased DNA synthesis and increased the protein to DNA synthesis ratio in multiple tissues. Examination of individual protein synthesis and content did not differentiate treatments, although it provided insight into the regulation of protein content between tissues. Contrary to our hypothesis, we did not see the predicted differences in protein to DNA synthesis following 17α-E2 treatment. However, mild short-term CR elicited differences consistent with both lifelong CR and other treatments that curtail aging processes. These data indicated that despite similar maintenance of body mass, 17α-E2 and CR treatments elicit distinctly different proteostatic outcomes.
The Assessment of Scales of Frailty and Physical Performance Improves Prediction of Major Adverse Cardiac Events in Older Adults with Acute Coronary Syndrome
Authors: Campo Gianluca , Maietti Elisa , Tonet Elisabetta , Biscaglia Simone , Ariza-Solè Albert , Pavasini Rita , Tebaldi Matteo , Cimaglia Paolo , Bugani Giulia , Serenelli Matteo , Ruggiero Rossella , Vitali Francesco , Formiga Francesc , Sanchis Juan , Galvani Marcello , Minarelli Monica , Lucchi Giulia Ricci , Ferrari Roberto , Guralnik Jack , Volpato Stefano
Published: May 2019

Background

The number of older adults admitted to hospital for acute coronary syndrome (ACS) has increased worldwide. The aim of this study was to determine which scale of frailty or physical performance provides incremental improvements in risk stratification of older adults after ACS.

Methods

A prospective cohort of 402 older (≥70 years) ACS patients were enrolled. Data about baseline characteristics, Global Registry of Acute Coronary Events (GRACE), and Thrombolysis in Myocardial Infarction (TIMI) risk scores were collected. Before hospital discharge, seven scales of frailty and physical performance were measured. The 1-year occurrence of adverse events (cardiac death, reinfarction, and cerebrovascular accident [MACCE] and all-cause mortality) was recorded.

Results

Out of the 402 patients, 43 (10.5%) had a MACCE and 35 (8.7%) died. Following adjustment for confounding factors, scales of frailty and physical performance were associated with adverse events. Among the scales, the addition of short physical performance battery (SPPB) produced the highest incremental value over the initial model generated by baseline characteristics both for MACCE (ΔC-statistic 0.043, p = .04; integrated discrimination improvement (IDI) 0.054, p = .001; net reclassification improvement (NRI) 0.752, p < .001) and all-cause mortality (ΔC-statistic 0.063, p = .02; IDI 0.061, p < .001; NRI 1.022, p < .001). The addition of SPPB scale on top of GRACE or TIMI risk scores led to a considerable improvement in the prediction of MACCE and all-cause mortality (about 15% and 20%, respectively).

Conclusions

The assessment of the physical performance with SPPB scale before hospital discharge increases the ability to predict adverse events in older ACS patients and may be useful in the clinical decision-making process.

Clinical trial registration

www.clinicaltrials.gov NCT02386124.
Mechanism and chain specificity of RNF216/TRIAD3, the ubiquitin ligase mutated in Gordon Holmes syndrome
Authors: Seenivasan Ramkumar , Hermanns Thomas , Blyszcz Tamara , Lammers Michael , Praefcke Gerrit J K , Hofmann Kay
Published: May 2019

Gordon Holmes syndrome (GDHS) is an adult-onset neurodegenerative disorder characterized by ataxia and hypogonadotropic hypogonadism. GDHS is caused by mutations in the gene encoding the RING-between-RING (RBR)-type ubiquitin ligase RNF216, also known as TRIAD3. The molecular pathology of GDHS is not understood, although RNF216 has been reported to modify several substrates with K48-linked ubiquitin chains, thereby targeting them for proteasomal degradation. We identified RNF216 in a bioinformatical screen for putative SUMO-targeted ubiquitin ligases and confirmed that a cluster of predicted SUMO-interaction motifs (SIMs) indeed recognizes SUMO2 chains without targeting them for ubiquitination. Surprisingly, purified RNF216 turned out to be a highly active ubiquitin ligase that exclusively forms K63-linked ubiquitin chains, suggesting that the previously reported increase of K48-linked chains after RNF216 overexpression is an indirect effect. The linkage-determining region of RNF216 was mapped to a narrow window encompassing the last two Zn-fingers of the RBR triad, including a short C-terminal extension. Neither the SIMs nor a newly discovered ubiquitin-binding domain in the central portion of RNF216 contributes to chain specificity. Both missense mutations reported in GDHS patients completely abrogate the ubiquitin ligase activity. For the R660C mutation, ligase activity could be restored by using a chemical ubiquitin loading protocol that circumvents the requirement for ubiquitin-conjugating (E2) enzymes. This result suggests Arg-660 to be required for the ubiquitin transfer from the E2 to the catalytic cysteine. Our findings necessitate a re-evaluation of the previously assumed degradative role of RNF216 and rather argue for a non-degradative K63 ubiquitination, potentially acting on SUMOylated substrates.
Fine particulate air pollution and adult hospital admissions in 200 Chinese cities: a time-series analysis
Authors: Tian Yaohua , Liu Hui , Liang Tianlang , Xiang Xiao , Li Man , Juan Juan , Song Jing , Cao Yaying , Wang Xiaowen , Chen Libo , Wei Chen , Gao Pei , Hu Yonghua
Published: May 2019

Background

The association between short-term exposure to ambient fine particulate matter (PM2.5) and morbidity risk in developing countries is not fully understood. We conducted a nationwide time-series study to estimate the short-term effect of PM2.5 on hospital admissions in Chinese adults.

Methods

Daily counts of hospital admissions for 2014–16 were obtained from the National Urban Employee Basic Medical Insurance database. We identified more than 58 million hospitalizations from 0.28 billion insured persons in 200 Chinese cities for subjects aged 18 years or older. Generalized additive models with quasi-Poisson regression were applied to examine city-specific associations of PM2.5 concentrations with hospital admissions. National-average estimates of the association were obtained from a random-effects meta-analysis. We also investigated potential effect modifiers, such as age, sex, temperature and relative humidity.

Results

An increase of 10 μg/m3 in same-day PM2.5 concentrations was positively associated with a 0.19% (95% confidence interval: 0.07–0.30) increase in the daily number of hospital admissions at the national level. PM2.5 exposure remained positively associated with hospital admissions on days when the daily concentrations met the current Chinese Ambient Air Quality Standards (75 μg/m3). Estimates of admission varied across cities and increased in cities with lower PM2.5 concentrations (p = 0.044) or higher temperatures (p = 0.002) and relative humidity (p = 0.003). The elderly were more sensitive to PM2.5 exposure (p < 0.001).

Conclusions

Short-term exposure to PM2.5 was positively associated with adult hospital admissions in China, even at levels below current Chinese Ambient Air Quality Standards.
High prevalence of a globally disseminated hypervirulent clone, Staphylococcus aureus CC121, with reduced vancomycin susceptibility in community settings in China
Authors: Shen Ping , Zhou Kai , Wang Yu , Song Jingjie , Liu Yang , Zhou Yanzi , Xiao Yonghong
Published: May 2019

Objectives

Most vancomycin-intermediate Staphylococcus aureus (VISA) and heterogeneous VISA (hVISA) are derived from hospital-associated MRSA due to treatment failure; however, the prevalence of hVISA/VISA in community settings remains unclear.

Methods

Four hundred and seventy-six community-associated isolates were collected between 2010 and 2011 during national surveillance for antimicrobial resistance in 31 county hospitals across China. Drug susceptibility evaluation and mecA detection were performed by using broth microdilution and PCR analysis, respectively. hVISA/VISA were identified by using macro-Etest and a modified population analysis profile (PAP)-AUC method. The genetic features of all hVISA/VISA isolates were genotyped.

Results

Among 476 isolates, MRSA and MSSA accounted for 19.7% (n = 94) and 80.3% (n = 382), respectively. Two VISA and 36 hVISA isolates were identified by PAP-AUC testing. The VISA isolates and 29 of the hVISA isolates were MRSA. The proportion of hVISA/VISA was significantly higher in MRSA (30.9%) than in MSSA (1.8%). The hVISA/VISA isolates were assigned to 18 STs classified into seven clonal complexes (CCs). CC121 (n = 12) followed by ST239 (n = 11) was the most prevalent hVISA/VISA clone. All ST239-hVISA/VISA were MRSA, while 12 CC121-hVISA isolates included 6 MSSA and 6 MRSA isolates. SCCmec III was predominant among MRSA-hVISA/VISA isolates. agr I and agr IV were detected in ST239 and CC121, respectively. All except two strains were positive for Panton–Valentine leucocidin genes.

Conclusions

To the best of our knowledge, this is the first report of CC121 as a prevalent hVISA clone in community settings, highlighting the necessity of surveillance and stricter infection control measures for this globally disseminated lineage.
Prices, Policing and Policy: The Dynamics of Crime Booms and Busts
Authors: Kirchmaier Tom , Machin Stephen , Sandi Matteo , Witt Robert
Published: May 2019

In many historical episodes, criminal activity displays booms and busts. One clear example is the case of metal crime in the United Kingdom (and elsewhere) where, in the face of big increases in value driven by world commodity prices, thefts rose very sharply in the 2000s, after which they fell. This paper studies the respective roles of prices, policing and policy in shaping this crime boom and bust. Separate study of each reveals metal crime being driven up via sizeable and significant metal crime–price elasticities and driven down by changes in policing and policy. A regression-based decomposition analysis confirms that all three of the hypothesised factors considered in the paper - prices, policing and policy - were empirically important in the different stages of metal theft's boom and bust.
The Politics of CEOs
Authors: Cohen Alma , Hazan Moshe , Tallarita Roberto , Weiss David
Published: May 2019

This article studies the political preferences of chief executive officers (CEOs) of public companies. We use Federal Election Commission records to compile a comprehensive database of the political contributions made by more than 3800 individuals who served as CEOs of Standard & Poor’s 1500 companies between 2000 and 2017. We find a substantial preference for Republican candidates. We identify how this pattern is related to the company’s industry, region, and CEO gender. In addition, we show that companies led by Republican CEOs tend to be less transparent to investors with respect to their political spending. Finally, we discuss the policy implications of our analysis.
Promoting Sustainable Living among College Students: Key Programming Components
Authors: Wynveen Brooklynn J , Meyer Andrew R , Wynveen Christopher J
Published: May 2019

Research has made clear that sustainable living behaviors are an integral aspect of natural-resource management and conservation. Because of their numbers, influence, and tendency toward nonsustainable practices and behaviors, college students represent a key target population for messages of sustainable living. Accordingly, we collaborated with college-aged populations at a local evangelical church to develop and conduct an intervention aimed at promoting sustainable living within this population. This intervention was part of a larger project aimed at: (1) fostering participation in sustainable living educational programming among nonenvironmentally motivated individuals; and (2) obtaining behavior change commitments from those participants. Our findings suggest three key components for enhancing the effectiveness of such programming: (1) present curriculum in small group formats; (2) use a discussion-based format; and (3) appeal to existing values, priorities, and motivations of participants.
A Developmental Cascade from Prenatal Stress to Child Internalizing and Externalizing Problems
Authors: Hentges Rochelle F , Graham Susan A , Plamondon Andre , Tough Suzanne , Madigan Sheri
Published: May 2019

Objective

This study utilized a developmental cascade approach to test alternative theories about the underlying mechanisms behind the association of maternal prenatal stress and child psychopathology. The fetal programming hypothesis suggests that prenatal stress affects fetal structural and physiological systems responsible for individual differences in child temperament, which further increases risk for internalizing and externalizing problems. Interpersonal models of stress transmission suggest that maternal stress influences child mental health via early parenting behaviors. We also examined a continuation of stress hypothesis, in which prenatal stress predicts child mental health via the continuation of maternal stress in the postpartum period.

Methods

Participants were 1,992 mother–child pairs drawn from a prospective pregnancy cohort. Mothers reported on their perceived stress, anxiety, and depression during pregnancy and at 4-month postpartum. Birthweight was assessed via medical records of birthweight. At 4-month postpartum, hostile-reactive parenting behaviors were assessed. Child temperamental negative affect was measured at age 3. Child internalizing and externalizing problems were assessed at age 5.

Results

Prenatal stress was associated with both internalizing and externalizing problems via postnatal stress and child temperament. Prenatal stress was also associated with externalizing behaviors via increased hostile-reactive parenting. After accounting for postnatal factors, prenatal stress continued to have a direct effect on child internalizing, but not externalizing, symptoms.

Conclusion

Results provide support for the fetal programming, interpersonal stress transmission, and continuation of stress models. Findings highlight the need for prenatal preventative programs that continue into the early postnatal period, targeting maternal stress and parenting behaviors.
ETHOS – an Effective Theory of Structure Formation: detecting dark matter interactions through the Lyman-α forest
Authors: Bose Sownak , Vogelsberger Mark , Zavala Jesús , Pfrommer Christoph , Cyr-Racine Francis-Yan , Bohr Sebastian , Bringmann Torsten
Published: May 2019

We perform a series of cosmological hydrodynamic simulations to investigate the effects of non-gravitational dark matter (DM) interactions on the intergalactic medium (IGM). In particular, we use the Ethos framework to compare statistics of the Lyman-α forest in cold dark matter (CDM) with an alternative model in which the DM couples strongly with a relativistic species in the early universe. These models are characterized by a cut-off in the linear power spectrum, followed by a series of ‘dark acoustic oscillations’ (DAOs) on sub-dwarf scales. While the primordial cut-off delays the formation of the first galaxies, structure builds up more rapidly in the interacting DM model compared to CDM. We show that although DAOs are quickly washed away in the non-linear clustering of DM at z ≲ 10, their signature can be imprinted prominently in the Lyman-α flux power spectrum at z > 5. On scales larger than the cut-off (k ∼ 0.08 s km−1 for the specific model considered here), the relative difference to CDM is reminiscent of a warm dark matter (WDM) model with a similar initial cut-off; however, the redshift evolution on smaller scales is distinctly different. The appearance and disappearance of DAOs in the Lyman-α flux spectrum provides a powerful way to distinguish interacting DM models from WDM and, indeed, variations in the thermal history of the IGM that may also induce a small-scale cut-off.
Spatial statistics in star-forming regions: testing the limits of randomness
Authors: Retter B , Hatchell J , Naylor Tim
Published: May 2019

Observational studies of star formation reveal spatial distributions of young stellar objects (YSOs) that are ‘snapshots’ of an ongoing star formation process. Using methods from spatial statistics it is possible to test the likelihood that a given distribution process could produce the observed patterns of YSOs. The aim of this paper is to determine the usefulness of the spatial statistics tests Diggle’s G function (G), the ‘free-space’ function (F), Ripley’s K, and O-ring for application to astrophysical data. The spatial statistics tests were applied to simulated data containing 2D Gaussian clusters projected on random distributions of stars. The number of stars within the Gaussian cluster and number of background stars were varied to determine the tests’ ability to reject complete spatial randomness (CSR) with changing signal-to-noise. The best performing test was O-ring optimized with overlapping logarithmic bins, closely followed by Ripley’s K. The O-ring test is equivalent to the two-point correlation function. Both F and G (and the minimum spanning tree, of which G is a subset) performed significantly less well, requiring a cluster with a factor of two higher signal-to-noise in order to reject CSR consistently. We demonstrate the tests on example astrophysical datasets drawn from the Spitzer Gould's Belt Survey catalogue.
HD 226766: a hierarchical SB3 system with two twin Am stars
Authors: Catanzaro G , Gangi M , Giarrusso M , Munari M , Leone F
Published: May 2019

In this paper, we present a detailed revision of the orbital parameters and the first quantitative abundance analysis of the spectroscopic triple system HD 226766. By means of a simultaneous fit of the radial velocities of all the three components, we derived precise orbital parameters for the system, in particular inner pair has P(d)  =  31.9187 ± 0.0001, e  =  0.28 ± 0.01, and MA/MB  = 1.03 ± 0.03, while the C component orbits around the inner pair with a period of P(d)  =  1615 ± 59 in a very eccentric orbit (e  =  0.54 ± 0.11). From the fit of the Hβ and Hα profiles, we determined the effective temperatures and surface gravities of each component of the inner pair: Teff  =  8600 ± 500 K and log g  =  3.8 ± 0.2 for HD 226766 A and Teff  =  8500 ± 400 K and log g  =  4.0 ± 0.2 for HD 226766 B. In the hypothesis that component C is a main sequence star (log g  =  4.0) we derived Teff  =  8000 ± 500 K. Rotational velocities have been estimated by modeling the profiles of metallic lines: v sin i  =  13 ± 1 km s−1 for inner pair and v sin i  =  150 ± 20 km s−1 for the C component. We find that the inner pair is heterogeneous from the point of view of the chemical composition: both stars are very similar and show chemical anomalies typical of Am stars. With some hypothesis about the masses of the components, we estimated the orbital inclination angle for the inner binary, i = (47 ± 1)○, and for the outer orbit, i = (54 ± 19)○.
Elucidation of Codon Usage Signatures across the Domains of Life
Authors: Novoa Eva Maria , Jungreis Irwin , Jaillon Olivier , Kellis Manolis
Published: May 2019

Because of the degeneracy of the genetic code, multiple codons are translated into the same amino acid. Despite being “synonymous,” these codons are not equally used. Selective pressures are thought to drive the choice among synonymous codons within a genome, while GC content, which is typically attributed to mutational drift, is the major determinant of variation across species. Here, we find that in addition to GC content, interspecies codon usage signatures can also be detected. More specifically, we show that a single amino acid, arginine, is the major contributor to codon usage bias differences across domains of life. We then exploit this finding and show that domain-specific codon bias signatures can be used to classify a given sequence into its corresponding domain of life with high accuracy. We then wondered whether the inclusion of codon usage codon autocorrelation patterns, which reflects the nonrandom distribution of codon occurrences throughout a transcript, might improve the classification performance of our algorithm. However, we find that autocorrelation patterns are not domain-specific, and surprisingly, are unrelated to tRNA reusage, in contrast to previous reports. Instead, our results suggest that codon autocorrelation patterns are a by-product of codon optimality throughout a sequence, where highly expressed genes display autocorrelated “optimal” codons, whereas lowly expressed genes display autocorrelated “nonoptimal” codons.
Ancestral Admixture Is the Main Determinant of Global Biodiversity in Fission Yeast
Authors: Tusso Sergio , Nieuwenhuis Bart P S , Sedlazeck Fritz J , Davey John W , Jeffares Daniel C , Wolf Jochen B W
Published: May 2019

Mutation and recombination are key evolutionary processes governing phenotypic variation and reproductive isolation. We here demonstrate that biodiversity within all globally known strains of Schizosaccharomyces pombe arose through admixture between two divergent ancestral lineages. Initial hybridization was inferred to have occurred ∼20–60 sexual outcrossing generations ago consistent with recent, human-induced migration at the onset of intensified transcontinental trade. Species-wide heritable phenotypic variation was explained near-exclusively by strain-specific arrangements of alternating ancestry components with evidence for transgressive segregation. Reproductive compatibility between strains was likewise predicted by the degree of shared ancestry. To assess the genetic determinants of ancestry block distribution across the genome, we characterized the type, frequency, and position of structural genomic variation using nanopore and single-molecule real-time sequencing. Despite being associated with double-strand break initiation points, over 800 segregating structural variants exerted overall little influence on the introgression landscape or on reproductive compatibility between strains. In contrast, we found strong ancestry disequilibrium consistent with negative epistatic selection shaping genomic ancestry combinations during the course of hybridization. This study provides a detailed, experimentally tractable example that genomes of natural populations are mosaics reflecting different evolutionary histories. Exploiting genome-wide heterogeneity in the history of ancestral recombination and lineage-specific mutations sheds new light on the population history of S. pombe and highlights the importance of hybridization as a creative force in generating biodiversity.
A long noncoding RNA cluster-based genomic locus maintains proper development and visual function
Authors: Wang Fei , Ren Dalong , Liang Xiaolin , Ke Shengwei , Zhang Bowen , Hu Bing , Song Xiaoyuan , Wang Xiangting
Published: May 2019

Long noncoding RNAs (lncRNAs) represent a group of regulatory RNAs that play critical roles in numerous cellular events, but their functional importance in development remains largely unexplored. Here, we discovered a series of previously unidentified gene clusters harboring conserved lncRNAs at the nonimprinting regions in brain (CNIBs). Among the seven identified CNIBs, human CNIB1 locus is located at Chr 9q33.3 and conserved from Danio rerio to Homo sapiens. Chr 9q33.3-9q34.11 microdeletion has previously been linked to human nail-patella syndrome (NPS) which is frequently accompanied by developmental and visual deficiencies. By generating CNIB1 deletion alleles in zebrafish, we demonstrated the requirement of CNIB1 for proper growth and development, and visual activities. Furthermore, we found that the role of CNIB1 on visual activity is mediated through a regulator of ocular development-lmx1bb. Collectively, our study shows that CNIB1 lncRNAs are important for zebrafish development and provides an lncRNA cluster-mediated pathophysiological mechanism for human Chr 9q33.3-9q34.11 microdeletion syndrome.
Proteomic analysis of meningiomas reveals clinically distinct molecular patterns
Authors: Papaioannou Michail-Dimitrios , Djuric Ugljesa , Kao Jennifer , Karimi Shirin , Zadeh Gelareh , Aldape Kenneth , Diamandis Phedias
Published: May 2019

Background

Meningiomas represent one of the most common brain tumors and exhibit a clinically heterogeneous behavior, sometimes difficult to predict with classic histopathologic features. While emerging molecular profiling efforts have linked specific genomic drivers to distinct clinical patterns, the proteomic landscape of meningiomas remains largely unexplored.

Methods

We utilize liquid chromatography tandem mass spectrometry with an Orbitrap mass analyzer to quantify global protein abundances of a clinically well-annotated formalin-fixed paraffin embedded (FFPE) cohort (n = 61) of meningiomas spanning all World Health Organization (WHO) grades and various degrees of clinical aggressiveness.

Results

In total, we quantify 3042 unique proteins comparing patterns across different clinical parameters. Unsupervised clustering analysis highlighted distinct proteomic (n = 106 proteins, Welch’s t-test, P < 0.01) and pathway-level (eg, Notch and PI3K/AKT/mTOR) differences between convexity and skull base meningiomas. Supervised comparative analyses of different pathological grades revealed distinct patterns between benign (grade I) and atypical/malignant (grades II‒III) meningiomas with specific oncogenes enriched in higher grade lesions. Independent of WHO grade, clinically aggressive meningiomas that rapidly recurred (<3 y) had distinctive protein patterns converging on mRNA processing and impaired activation of the matrisome complex. Larger sized meningiomas (>3 cm maximum tumor diameter) and those with previous radiation exposure revealed perturbed pro-proliferative (eg, epidermal growth factor receptor) and metabolic as well as inflammatory response pathways (mitochondrial activity, interferon), respectively.

Conclusions

Our proteomic study demonstrates that meningiomas of different grades and clinical parameters present distinct proteomic profiles. These proteomic variations offer potential future utility in helping better predict patient outcome and in nominating novel therapeutic targets for personalized care.
Strategies to Mitigate Toxicities From Stereotactic Body Radiation Therapy for Spine Metastases
Authors: Schaub Stephanie K , Tseng Yolanda D , Chang Eric L , Sahgal Arjun , Saigal Rajiv , Hofstetter Christoph P , Foote Matthew , Ko Andrew L , Yuh William T C , Mossa-Basha Mahmud , Mayr Nina A , Lo Simon S
Published: May 2019

Improvements in systemic therapy are translating into more patients living longer with metastatic disease. Bone is the most common site of metastasis, where spinal lesions can result in significant pain impacting quality of life and possible neurological dysfunction resulting in a decline in performance status. Stereotactic body radiation therapy (SBRT) of the spine has emerged as a promising technique to provide durable local control, palliation of symptoms, control of oligoprogressive sites of disease, and possibly augment the immune response. SBRT achieves this by delivering highly conformal radiation therapy to allow for dose escalation due to a steep dose gradient from the planning target volume to nearby critical organs at risk. In our review, we provide an in-depth review and expert commentary regarding seminal literature that defined clinically meaningful toxicity endpoints with actionable dosimetric limits and/or clinical management strategies to mitigate toxicity potentially attributable to SBRT of the spine. We placed a spotlight on radiation myelopathy (de novo, reirradiation after conventional external beam radiation therapy or salvage after an initial course of spinal SBRT), plexopathy, vertebral compression fracture, pain flare, esophageal toxicity, myositis, and safety regarding combination with concurrent targeted or immune therapies.
Resection of Myxopapillary Ependymoma of the Filum Terminale: 2-Dimensional Operative Video
Authors: Mastorakos Panagiotis , Lynes John , Maggio Dominic , Quezado Martha M , Nduom Edjah K
Published: May 2019

We present the case of a 48-yr-old female who presented with persistent thigh pain and was found to have a heterogeneous mass caudal to the conus most consistent with a myxopapillary ependymoma. We performed L2-3 laminectomies for tumor resection. For this procedure, we used intraoperative ultrasound as well as neuromonitoring. This video illustrates the gross pathology of a myxopapillary ependymoma, effective circumferential blunt and sharp dissection of the cauda equina from the tumor, and identification, preparation, and sectioning of the filum terminale. This case also underlines the challenges of removing a large myxopapillary ependymoma when motor nerve rootlets are encapsulated in the tumor. In this case, we were obligated to enter the tumor capsule ventrally in order to dissect away cauda equina nerves passing through the tumor. The patient consented to be part of our research study
Flat-lining or seething beneath the surface? Two decades of changing economic inequality in the UK
Authors: Obolenskaya Polina , Hills John
Published: May 2019

This paper analyses what happened to economic inequalities in the United Kingdom in the two decades from 1995–6. In aggregate, inequality changes were unremarkable, especially by comparison with sharp increases in the 1980s. However, over the first decade economic outcomes improved across population groups, while over the second near-stagnation accompanied continuing high inequality. We show that the apparent stability of inequality in this period masked the way in which the nature and depth of economic inequalities changed after the economic crisis, leading to substantial differences between and within groups defined in different ways. Pervasively, younger adults lost out in the second decade compared to older ones. When population groups are defined in other ways (such as region, housing tenure, or ethnicity) patterns are more complex, but with the worst-off in particular groups often being ‘left behind’.
Court-imposed fines as a feature of the homelessness-incarceration nexus: a cross-sectional study of the relationship between legal debt and duration of homelessness in Seattle, Washington, USA
Authors: Mogk Jessica , Shmigol Valerie , Futrell Marvin , Stover Bert , Hagopian Amy
Published: May 2019

Background

Legal system involvement is a policy-driven risk factor for homelessness. Legal financial obligations (LFOs), such as court fees, fines and restitution, can endanger the financial security of those ensnared in the criminal justice system. In this study we measured the effect of incarceration and LFOs on duration of homelessness in Seattle, WA, USA.

Methods

To analyze the relationship between incarceration, debt and duration of homelessness, we interviewed 101 adults experiencing homelessness and living in city-sanctioned encampments and tiny house villages in Seattle, WA in 2017–18. We collected personal housing history, presence and amount of debt, and measures of legal system involvement.

Results

Our respondents experienced homelessness an average of 41 months during the current episode. Nearly two-thirds reported being convicted of a crime, and 78% had been incarcerated. More than 25% reported owing current legal fines. Individuals with legal fine debt experienced 22.9 months of additional homelessness after considering the effects of race, age, and gender.

Conclusion

We confirmed a strong association between homelessness and legal trouble. Among high-income countries, the USA has the highest rates of legal system involvement and the highest rates of homelessness; the relationship between the two may be connected.
Subglottic stenosis and endobronchial disease in granulomatosis with polyangiitis
Authors: Quinn Kaitlin A , Gelbard Alexander , Sibley Cailin , Sirajuddin Arlene , Ferrada Marcela A , Chen Marcus , Cuthbertson David , Carette Simon , Khalidi Nader A , Koening Curry L , Langford Carol A , McAlear Carol A , Monach Paul A , Moreland Larry W , Pagnoux Christian , Seo Philip , Specks Ulrich , Sreih Antoine G , Ytterberg Steven R , Merkel Peter A , Grayson Peter C
Published: May 2019

Objectives

To describe tracheobronchial disease in patients with granulomatosis with polyangiitis (GPA) and evaluate the utility of dynamic expiratory CT to detect large-airway disease.

Methods

Demographic and clinical features associated with the presence of subglottic stenosis (SGS) or endobronchial involvement were assessed in a multicentre, observational cohort of patients with GPA. A subset of patients with GPA from a single-centre cohort underwent dynamic chest CT to evaluate the airways.

Results

Among 962 patients with GPA, SGS and endobronchial disease were identified in 95 (10%) and 59 (6%) patients, respectively. Patients with SGS were more likely to be female (72% vs 53%, P < 0.01), younger at time of diagnosis (36 vs 49 years, P < 0.01), and have saddle-nose deformities (28% vs 10%, P < 0.01), but were less likely to have renal involvement (39% vs 62%, P < 0.01). Patients with endobronchial disease were more likely to be PR3-ANCA positive (85% vs 66%, P < 0.01), with more ENT involvement (97% vs 77%, P < 0.01) and less renal involvement (42% vs 62%, P < 0.01). Disease activity in patients with large-airway disease was commonly isolated to the subglottis/upper airway (57%) or bronchi (32%). Seven of 23 patients screened by dynamic chest CT had large-airway pathology, including four patients with chronic, unexplained cough, discovered to have tracheobronchomalacia.

Conclusion

SGS and endobronchial disease occur in 10% and 6% of patients with GPA, respectively, and may occur without disease activity in other organs. Dynamic expiratory chest CT is a potential non-invasive screening test for large-airway involvement in GPA.
Arthritis self-efficacy beliefs and functioning among osteoarthritis and rheumatoid arthritis patients: a meta-analytic review
Authors: Jackson Todd , Xu Ting , Jia Xiaojun
Published: May 2019

Objectives

The Arthritis Self-Efficacy Scale (ASES) is a widely used self-report measure of beliefs reflecting confidence in one’s capacity to function despite pain and control pain or other symptoms of arthritis. Despite evidence linking higher ASES scores to lower levels of impairment, pain and emotional distress, numerous modest, non-significant associations have also been observed. In this meta-analysis, we evaluated overall associations between ASES scores and adjustment in RA and OA samples as well as potential moderators that may explain the heterogeneity in these associations.

Method

Data from 48 samples that met all 10 inclusion criteria (N = 9222 patients) were subject to analyses.

Results

ASES scores had significant medium average effect sizes with functional impairment, pain severity and emotional distress but substantial heterogeneity was evident for each association. ASES–impairment associations were moderated by the diagnosis, ASES version and ASES subscale content: significantly larger effect sizes were found for studies that included RA patients, used the original 20-item ASES and assessed subscale content reflecting the pursuit of daily activities despite pain (i.e. functional self-efficacy) than for studies based exclusively on OA patients, the eight-item ASES and ASES pain control and other symptom subscales. Relations of ASES scores with pain severity and emotional distress were moderated by ASES version and subscale content, respectively.

Conclusion

The ASES has significant overall associations with key areas of functioning. Moderator analyses of the measure provide empirically grounded suggestions for optimal use of the ASES within OA and RA patient samples.
Increased infection risk in Addison’s disease and congenital adrenal hyperplasia: a primary care database cohort study
Authors: Tresoldi Alberto S. , Sumilo Dana , Perrins Mary , Toulis Konstantinos A. , Prete Alessandro , Reddy Narendra , Wass John A.H. , Arlt Wiebke , Nirantharakumar Krishnarajah
Published: May 2019

Context

Mortality and infection-related hospital admissions are increased in patients with primary adrenal insufficiency (PAI). However, the risk of primary care-managed infections in patients with PAI is unknown.

Objective

To estimate infection risk in PAI due to Addison’s disease (AD) and congenital adrenal hyperplasia (CAH) in a primary care setting.

Design

Retrospective cohort study using UK data collected from 1995 to 2018.

Main outcome measures

Incidence of lower respiratory tract infections (LRTIs), urinary tract infections (UTIs), gastrointestinal infections (GIIs), and prescription counts of antimicrobials in adult PAI patients compared to unexposed controls.

Results

A diagnosis of PAI was established in 1580 AD patients (mean age 51.7 years) and 602 CAH patients (mean age 35.4 years). All AD patients and 42% of CAH patients were prescribed glucocorticoids, most frequently hydrocortisone in AD (82%) and prednisolone in CAH (50%). AD and CAH patients exposed to glucocorticoids, but not CAH patients without glucocorticoid treatment, had a significantly increased risk of LRTIs (adjusted incidence rate ratio AD 2.11 [95% confidence interval 1.64-2.69], CAH 3.23 [1.21-8.61]), UTIs (AD 1.51 [1.29-1.77], CAH 2.20 [1.43-3.34]), and GIIs (AD 3.80 [2.99-4.84], CAH 1.93 [1.06-3.52]). This was mirrored by increased prescription of antibiotics (AD 1.73 [1.69-1.77], CAH 1.77 [1.66-1.89]) and antifungals (AD 1.89 [1.74-2.05], CAH 1.91 [1.50-2.43]).

Conclusions

There is an increased risk of infections and antimicrobial use in PAI in the primary care setting at least partially linked to glucocorticoid treatment. Future studies will need to address whether more physiological glucocorticoid replacement modes could reduce this risk.

Précis

Using data from 1580 AD patients and 602 CAH patients collected in a UK primary care database from 1995 to 2018, we identified increased risk of infections and antimicrobial prescription counts.
Strategies for building computing skills to support microbiome analysis: a five-year perspective from the EDAMAME workshop
Authors: Shade Ashley , Dunivin Taylor K. , Choi Jinlyung , Teal Tracy K. , Howe Adina C.
Published: May 2019

Here, we report our educational approach and learner evaluations of the first five years of the Explorations in Data Analysis for Metagenomic Advances in Microbial Ecology (EDAMAME) workshop, held annually at Michigan State University’s Kellogg Biological Station from 2014-2018. We hope this information will be useful for others who want to organize computing-intensive workshops and encourage quantitative skill development among microbiologists.

Importance

High-throughput sequencing and related statistical and bioinformatic analyses have become routine in microbiology in the past decade, but there are few formal training opportunities to develop these skills. A week-long workshop can offer sufficient time for novices to become introduced to best computing practices and common workflows in sequence analysis. We report our experiences in executing such a workshop targeted to professional learners (graduate students, post-doctoral scientists, faculty, and research staff).
Awake hippocampal-prefrontal replay mediates spatial learning and decision making
Authors: Shin Justin D. , Tang Wenbo , Jadhav Shantanu P.
Published: May 2019

Spatial learning requires remembering and choosing paths to goals. Hippocampal place cells replay spatial paths during immobility in reverse and forward order, offering a potential mechanism. However, how replay mediates both goal-directed learning and memory-guided decision making is unclear. We therefore continuously tracked replay in the same hippocampal-prefrontal ensembles throughout learning of a spatial alternation task. We found that during pauses between behavioral trajectories, awake reverse and forward hippocampal replay consistently mediated an internal cognitive search of all available past and future possibilities, and exhibited opposing learning gradients for prediction of past and future behavioral paths, respectively. Coordinated hippocampal-prefrontal replay mediated recall of correct past paths and selection of future choices leading to reward based on the hippocampal cognitive search, executing spatial working memory rules. Our findings reveal a learning shift from hippocampal reverse-replay-based retrospective evaluation to forward-replay-based prospective planning, with prefrontal filtering of memory-guided paths for learning and decision-making.