bluuebunny/crossref_metadata_2025 huggingface dataset:
The evolution of subject-verb agreement in Eastern Tukanoan
Authors: Chacon Thiago Costa , Michael Lev
Published: July 2018

This article describes the evolution of past/perfective subject-verb agreement morphology in the Tukanoan family, reconstructing relevant aspects of Proto-Tukanoan verbal morphology and delineating the subsequent diachronic development of verbal subject agreement morphology in the Eastern branch of the family. We argue that suffixes that cumulatively expone past/perfective and person, number, and gender (png) subject agreement resulted from the fusion of post-verbal demonstratives/pronouns expressingpnginformation with suffixes expressing past/perfectivetaminformation. We propose that differentpngagreement categories developed at successive stages in the diversification of the family, with third person masculine singular subject agreement emerging before otherpngcategories, followed by animate plural agreement, then finally by the development of third person feminine agreement. The result in Eastern Tukanoan was a cross-linguistically unusual agreement system that contrasts four agreement categories: (i) first and second person singular and third person inanimate (singular and plural); (ii) third person animate masculine singular; (iii) third person animate feminine singular; and (iv) third animate plural.
Kinship in three Tamangic varieties
Authors: Hildebrandt Kristine A. , Bond Oliver , Dhakal Dubi Nanda
Published: July 2018

We examine kinship terms in three closely related Tamangic varieties: Manange, Nar, and Phu. Using Proto-Tamangic and Proto Tibeto-Burman reconstructions, we track cognate forms as well as structural innovations. Our account allows a first examination of lexico-semantic aspects of Phu, an under-documented representative of the Nar-Phu complex. While Nar-Phu is usually treated as a single language, considerable differences exist in the organization of all three kinship term systems. Kinship terms are considered to be conservative, basic vocabulary and thus indicative of close within-family relationships, but our study shows that even closely related varieties can show considerable differences in kin nomenclature.
Transitivity markers in West Himalayish
Authors: Widmer Manuel
Published: July 2018

The present paper describes a transitivity distinction that is attested in some Tibeto-Burman (TB) languages of the West Himalayish (WH) subgroup. The relevant distinction is encoded by a set of dedicated markers that occur between verb stems and inflectional endings and group verbs into transitivity classes. The paper first offers a synchronic description of transitivity classes in the WH language Bunan, discussing their formal realization and functional motivation. Subsequently, the relevant transitivity classes are discussed from a historical-comparative perspective. It is argued that the transitivity distinction developed when an object agreement marker was reanalyzed as a marker of transitive verbs. The paper thus offers new perspectives on transitivity in TB from both a synchronic and a diacronic point of view, and adduces evidence for a hitherto underscribed reanalysis from “object agreement marker” > “marker of transitive verbs”.
Licensing conditions on null generic subjects in Spanish
Authors: Maddox Matthew L.
Published: July 2018

Holmberg’s (2005, 2010) Null Generic Subject Generalization (NGSG) states that only partial null subject languages allow null generic third-singular subjects while consistent null subject languages (cNSLs) like Spanish only have referential pro due to a D-feature in T. Novel data from Spanish contradicts this. Following Frascarelli (2007), I analyze the licensing of null generic subjects as topic-identification with generic uno. The Special Morphology Condition on the NGSG, which stipulates that generic pro is allowed in cNSLs when licensed by special morphology, cannot account for uno. Thus, we may dispense with the postulation of a D-feature in T in cNSLs. I propose a revised set of licensing conditions on pro in null-subject languages.
Causativization of verbs of directed motion in Romance languages
Authors: Pineda Anna
Published: July 2018

The purpose of this paper is to shed light on a particular behavior displayed by verbs of inherently directed motion, the availability of a causative transitive alternate, and how this phenomenon interacts with the presence of clitic se in the intransitive variant. Data from Catalan, Aragonese and Italian varieties, none of which have received much attention in the literature, will prove crucial for our proposal. We adopt an inter-Romance perspective and a nanosyntactic approach to lexicalization in order to refine the correlation Jiménez-Fernández and Tubino (2014, 2017) find for Spanish, where inherently directional motion verbs are claimed to be more easily causativized (entrar el coche ‘go in the car’) in varieties where the use of se in the intransitive forms is also more frequent (Juan se entró ‘Juan se went in’).
Resumed phrases (are always moved, even with in-island resumption)
Authors: Sportiche Dominique
Published: July 2018

On the basis of the properties of resumption in colloquial spoken French, I conclude that resumption of a phrase by a pronominal element always involve run of the mill movement of this phrase, whether the resumptive pronoun is inside an island or not. I propose that such movement can take place in two steps, the first being one of the Left Dislocation options, which feeds a variety of possible second steps (e.g., wh-movement or Clitic Left Dislocation).
Cognate noun constructions in Early Modern English
Authors: Lavidas Nikolaos
Published: July 2018

This paper examines cognate noun constructions (CNCs) (e.g. smile a disarming smile) in Early Modern English, particularly in the first complete English translation of the Bible from the original Greek and Hebrew by William Tyndale. Tyndale’s translation is produced during a period of significant expansion of CNCs in English. It is argued that CNCs in Tyndale are a marker of a particular English biblical register which involves archaic (early) English properties (cognate nouns in PPs) rather than a new tendency for cognate direct objects or the result of a translation effect alone. In other words, it is shown that Tyndale’s translation follows archaic/early English rules, thus deviating both from the new tendency for cognate direct objects and from the source text. This archaic characteristic of CNCs with cognate nouns in PPs instantiates a general tendency in Tyndale’s translation to use archaisms – as evidenced, for instance, in his dispreference of auxiliaries.
Learning structural motif representations for efficient protein structure search
Authors: Liu Yang , Ye Qing , Wang Liwei , Peng Jian
Published: July 2018

Motivation

Given a protein of unknown function, fast identification of similar protein structures from the Protein Data Bank (PDB) is a critical step for inferring its biological function. Such structural neighbors can provide evolutionary insights into protein conformation, interfaces and binding sites that are not detectable from sequence similarity. However, the computational cost of performing pairwise structural alignment against all structures in PDB is prohibitively expensive. Alignment-free approaches have been introduced to enable fast but coarse comparisons by representing each protein as a vector of structure features or fingerprints and only computing similarity between vectors. As a notable example, FragBag represents each protein by a ‘bag of fragments’, which is a vector of frequencies of contiguous short backbone fragments from a predetermined library. Despite being efficient, the accuracy of FragBag is unsatisfactory because its backbone fragment library may not be optimally constructed and long-range interacting patterns are omitted.

Results

Here we present a new approach to learning effective structural motif presentations using deep learning. We develop DeepFold, a deep convolutional neural network model to extract structural motif features of a protein structure. We demonstrate that DeepFold substantially outperforms FragBag on protein structural search on a non-redundant protein structure database and a set of newly released structures. Remarkably, DeepFold not only extracts meaningful backbone segments but also finds important long-range interacting motifs for structural comparison. We expect that DeepFold will provide new insights into the evolution and hierarchical organization of protein structural motifs.

Availability and implementation

https://github.com/largelymfs/DeepFold
The Terabase Search Engine: a large-scale relational database of short-read sequences
Authors: Wilton Richard , Wheelan Sarah J , Szalay Alexander S , Salzberg Steven L
Published: July 2018

Motivation

DNA sequencing archives have grown to enormous scales in recent years, and thousands of human genomes have already been sequenced. The size of these data sets has made searching the raw read data infeasible without high-performance data-query technology. Additionally, it is challenging to search a repository of short-read data using relational logic and to apply that logic across samples from multiple whole-genome sequencing samples.

Results

We have built a compact, efficiently-indexed database that contains the raw read data for over 250 human genomes, encompassing trillions of bases of DNA, and that allows users to search these data in real-time. The Terabase Search Engine enables retrieval from this database of all the reads for any genomic location in a matter of seconds. Users can search using a range of positions or a specific sequence that is aligned to the genome on the fly.

Availability and implementation

Public access to the Terabase Search Engine database is available at http://tse.idies.jhu.edu.

Supplementary information

Supplementary data are available at Bioinformatics online.
iSwathX: an interactive web-based application for extension of DIA peptide reference libraries
Authors: Noor Zainab , Wu Jemma X , Pascovici Dana , Mohamedali Abidali , Molloy Mark P , Baker Mark S , Ranganathan Shoba
Published: July 2018

Large-scale peptide mass spectrometry (MS)/MS reference libraries are essential for the comprehensive analysis of data-independent acquisition (DIA) MS datasets, providing a comprehensive set of spectra for identification and quantification of proteins. We have developed a novel web-based R-package (iSwathX) for combining reference libraries that is compatible with different DIA analysis software. This open-source web GUI automates the process of normalization and combination of spectral libraries and provides a user-friendly method for performing library format conversions, analysis and visualizations, with no need for programing familiarity.

Availability and implementation

iSwathX is freely accessible at https://biolinfo.shinyapps.io/iSwathX with the R-package and Shiny source code available from GitHub (https://github.com/znoor/iSwathX).

Supplementary information

Supplementary data are available at Bioinformatics online.
Addressing the gender-knowledge gap in glucose-6-phosphate dehydrogenase deficiency: challenges and opportunities
Authors: Domingo Gonzalo J , Advani Nicole , Satyagraha Ari W , Sibley Carol H , Rowley Elizabeth , Kalnoky Michael , Cohen Jessica , Parker Michael , Kelley Maureen
Published: July 2018

Glucose-6-phosphate dehyrdgoenase (G6PD) deficiency is a common X-linked genetic trait, with an associated enzyme phenotype, whereby males are either G6PD deficient or normal, but females exhibit a broader range of G6PD deficiencies, ranging from severe deficiency to normal. Heterozygous females typically have intermediate G6PD activity. G6PD deficiency has implications for the safe treatment for Plasmodium vivax malaria. Individuals with this deficiency are at greater risk of serious adverse events following treatment with the only curative class of anti-malarials, 8-aminoquinolines, such as primaquine. Quantitative diagnostic tests for G6PD deficiency are complex and require sophisticated laboratories. The commonly used qualitative tests, do not discriminate intermediate G6PD activities. This has resulted in poor understanding of the epidemiology of G6PD activity in females and its corresponding treatment ramifications. New simple-to-use quantitative tests, and a momentum to eliminate malaria, create an opportunity to address this knowledge gap. While this will require additional resources for clinical studies, adequate operational research, and appropriate pharmacovigilance, the health benefits from this investment go beyond the immediate intervention for which the G6PD status is first diagnosed.
Pediatric Histoplasmosis in an Area of Endemicity: A Contemporary Analysis
Authors: Ouellette Christopher P , Stanek Joseph R , Leber Amy , Ardura Monica I
Published: July 2018

A high index of suspicion for histoplasmosis is required for its diagnosis. A combination of tests, including serology, urine and blood antigen measurements, and culture, should be performed to optimize the diagnostic yield in pediatric patients suspected of having histoplasmosis.
Global Effects of Focal Brain Tumors on Functional Complexity and Network Robustness: A Prospective Cohort Study
Authors: Hart Michael G , Romero-Garcia Rafael , Price Stephen J , Suckling John
Published: July 2018

BACKGROUND

Neurosurgical management of brain tumors has entered a paradigm of supramarginal resections that demands thorough understanding of peritumoral functional effects. Historically, the effects of tumors have been believed to be local, and long-range effects have not been considered.

OBJECTIVE

To test the hypothesis that tumors affect the brain globally, producing long-range gradients in cortical function.

METHODS

Resting-state functional magnetic resonance imaging (fMRI) data were acquired from 11 participants with glioblastoma and split into discovery and validation datasets in a single-center prospective cohort study. Fractal complexity was computed with a wavelet-based estimator of the Hurst exponent. Distance-related effects of the tumors were tested with a tumor mask-dilation technique and parcellation of the underlying Hurst maps.

RESULTS

Fractal complexity demonstrates a penumbra of suppression in the peritumoral region. At a global level, as distance from the tumor increases, this initial suppression is balanced by a subsequent overactivity before finally normalizing. These effects were best fit by a quadratic model and were consistent across different network construction pipelines. The Hurst exponent was correlated with graph theory measures of centrality including network robustness, but graph theory measures did not demonstrate distance-dependent effects.

CONCLUSION

This work provides evidence supporting the theory that focal brain tumors produce long-range gradients in function. Consequently, the effects of focal lesions need to be interpreted in terms of the global changes on functional complexity and network architecture rather than purely in terms of functional localization. Determining whether peritumoral changes represent potential plasticity may facilitate extended resection of tumors without functional cost.
Survival impact of prolonged postoperative radiation therapy for patients with glioblastoma treated with combined-modality therapy
Authors: Yusuf Mehran B , Gaskins Jeremy , Amsbaugh Mark J , Woo Shiao , Burton Eric
Published: July 2018

Background

Though conventionally fractionated chemoradiation (CRT) is well tolerated by selected patients with newly diagnosed glioblastoma (GBM), adverse health-related and nonhealth-related factors can lead to unplanned interruptions in treatment. The effects of prolonged time to completion (TTC) of radiation therapy (RT) on overall survival (OS) for these patients are unclear.

Methods

The National Cancer Database (NCDB) was queried for all adult patients with newly diagnosed GBM undergoing surgical resection followed by adjuvant CRT with conventionally fractionated RT (6000-6600 cGy in 30-33 fractions) from 2005 to 2012. TTC was defined as the interval from first to last fraction of RT. Recursive partitioning analysis (RPA) was used to determine a threshold for TTC of adjuvant RT. Cox proportional hazards modeling was used to identify covariates associated with OS.

Results

A total of 13489 patients were included in our cohort. Patients who completed adjuvant RT within the RPA-defined threshold of 46 days from initiation of RT (median OS: 14.0 months, 95% confidence interval (CI) 13.7 to 14.3 months) had significantly improved OS compared to patients with TTC of 47 days or greater (median OS: 12.0 months, 95% CI 11.4 to 12.6 months, P < .001). Delays in completing adjuvant RT were relatively common, with 15.0% of patients in our cohort having a TTC of RT of 47 days or greater.

Conclusions

Delays in completing adjuvant RT were associated with a worse survival outcome. Any unnecessary delays in completing adjuvant RT should be minimized while ensuring the safe delivery of therapy.
The Presence and Success of National-Level Parties in Local and Regional Elections
Authors: Rahat Gideon , Kenig Ofer
Published: July 2018

The chapter addresses patterns of stability and change in the strength of national-level parties at the local and at the regional levels. It starts with a discussion of the importance of the presence and performance of national-level parties at subnational level. The indicators that are used to assess such trends examine the performance of local parties and independents at the local level and changes in the gap between national party votes at the regional and national levels. A general trend of decline in the power of national parties at the local and regional levels is identified. But it is far from being a unified trend in terms of magnitude. There are countries where stability is evident, and a few where there is an increase in partyness at these levels.
Loss of lipin 1‐mediated phosphatidic acid phosphohydrolase activity in muscle leads to skeletal myopathy in mice
Authors: Schweitzer George G. , Collier Sara L. , Chen Zhouji , Mccommis Kyle S. , Pittman Sara K. , Yoshino Jun , Matkovich Scot J. , Hsu Fong-Fu , Chrast Roman , Eaton James M. , Harris Thurl E. , Weihl Conrad C. , Finck Brian N.
Published: July 2018

Lipin 1 regulates glycerolipid homeostasis by acting as a phosphatidic acid phosphohydrolase (PAP) enzyme in the triglyceride‐synthesis pathway and by regulating transcription factor activity. Mutations in human lipin 1 are a common cause of recurrent rhabdomyolysis in children. Mice with constitutive whole‐body lipin 1 deficiency have been used to examine mechanisms connecting lipin 1 deficiency to myocyte injury. However, that mouse model is confounded by lipodystrophy not phenocopied in people. Herein, 2 muscle‐specific mouse models were studied: 1) Lpin1 exon 3 and 4 deletion, resulting in a hypomorphic protein without PAP activity, but which preserved transcriptional coregulatory function; and 2) Lpin1 exon 7 deletion, resulting in total protein loss. In both models, skeletal muscles exhibited a chronic myopathy with ongoing muscle fiber necrosis and regeneration and accumulation of phosphatidic acid and, paradoxically, diacylglycerol. Additionally, lipin 1–deficient mice had abundant, but abnormal, mitochondria likely because of impaired autophagy. Finally, these mice exhibited increased plasma creatine kinase following exhaustive exercise when unfed. These data suggest that mice lacking lipin 1–mediated PAP activity in skeletal muscle may serve as a model for determining the mechanisms by which lipin 1 deficiency leads to myocyte injury and for testing potential therapeutic approaches.—Schweitzer, G. G., Collier, S. L., Chen, Z., McCommis, K. S., Pittman, S. K., Yoshino, J., Matkovich, S. J., Hsu, F.‐F., Chrast, R., Eaton, J. M., Harris, T. E., Weihl, C. C., Finck, B. N. Loss of lipin 1–mediated phosphatidic acid phosphohydrolase activity in muscle leads to skeletal myopathy in mice. FASEB J. 33, 652–667 (2019). www.fasebj.org
Klippel-Feil Syndrome With Auxiliary Anterior Cervical Meningomyelocele and Thoracic Syringomyelia
Authors: Alam Mehtab , Haq Ayaz ul , Shah Muzaffar , Haqqani Usman , Ullah Sajjad
Published: July 2018

Study Design.

Case report.

Objective.

Since this is the first ever case of a male patient with Klippel-Feil syndrome (KFS) with anterior cervical meningomyelocele and syringomyelia. All four previously reported cases were female patients. This makes this case unique.

Summary of Background Data.

KFS with auxiliary anterior cervical meningomyelocele is a rare entity. To the best of our knowledge so far only four cases are reported.

Methods.

A 22-year-old male patient was presented to neurology outpatient department with 2-year history of left hand paresthesia and progressive weakness. The diagnostic evaluation showed KFS with auxiliary anterior cervical meningomyelocele and thoracic syringomyelia.

Results.

Patient was sent to neurosurgery department for intervention. After discussing the possible risks and complications of intervention he opted for conservative therapy and declined the surgery.

Conclusion.

The paucity of data is the key reason for any recommended protocol for management of such patients but the available literature recommends neurosurgical intervention in symptomatic patients.

Level of Evidence: 5
New perspectives in the therapeutic approach of peripheral T-cell lymphoma
Authors: Gisselbrecht Christian , Sibon David
Published: July 2018

Purpose of review

Peripheral T-cell lymphoma (PTCL) is a heterogeneous group of mature T-cell and natural killer (NK)-cell neoplasms in the WHO 2016 classification. Patient prognosis is poor when treated with CHOP, and there is an unmet need for new drugs. Several agents have been developed for PTCL, and their use is the subject of this review.

Recent findings

Phase 2 studies demonstrated the activity of new drugs in Relapsed/refractory PTCL. Only four compounds were approved by the food and drug administration: romidepsin and belinostat, which are epigenetic modifiers, the antifolate agent pralatrexate, the immuno-conjugate brentuximab vedotin. New combinations have been tested, but the results were disappointing. Given the latest progress in biology, targeted agents are evaluated in different subtypes of PTCL. Relapsed anaplastic large-cell lymphoma exhibits improved prognosis with the approved anti-CD30 drug conjugate brentuximab vedotin. Localized nasal NK/T is treated with radiotherapy and nonanthracycline chemotherapy with L-asparaginase. Recently, immune checkpoint inhibitors demonstrated activity in NK/T lymphoma and can be used in elderly patients.

Treatment remains a challenge for PTCL, and several targeted drugs provide new approaches. Progress will be made incrementally in the different subtypes. One of the critical situations facing new drugs is the ability to run robust clinical trials in rare diseases.
Forty-year Seasonality Trends in Occurrence of Myocardial Infarction, Ischemic Stroke, and Hemorrhagic Stroke
Authors: Skajaa Nils , Horváth-Puhó Erzsébet , Sundbøll Jens , Adelborg Kasper , Rothman Kenneth J. , Sørensen Henrik Toft
Published: July 2018

Background:

The occurrence of myocardial infarction (MI), ischemic stroke, and hemorrhagic stroke has decreased in recent years, but trends in seasonal occurrence remain unclear.

Methods:

Using Danish healthcare databases, we identified all patients with a first-time MI, ischemic stroke, or hemorrhagic stroke during the study period (1977–2016). We summarized monthly cases for each disease separately and computed the peak-to-trough ratio as a measure of seasonal occurrence of one cycle. To examine trends over time in seasonal occurrence, we computed the peak-to-trough ratio for each of the 40 years. We also quantified the amount of bias arising from random error in peak-to-trough ratios.

Results:

Before consideration of bias, the peak-to-trough ratio of summarized monthly cases was 1.11 (95% confidence interval [CI] = 1.10, 1.12) for MI, 1.08 (95% CI = 1.07, 1.09) for ischemic stroke, and 1.12 (95% CI = 1.10, 1.14) for hemorrhagic stroke. The peak-to-trough ratio of MI occurrence increased from 1.09 (95% CI = 1.04, 1.15) in 1977 to 1.16 (95% CI = 1.09, 1.23) in 1999. The trend then remained stable. The peak-to-trough ratio of ischemic stroke occurrence declined continuously during the study period, dropping from 1.12 (95% CI = 1.02, 1.24) in 1977 to 1.06 (95% CI = 1.00, 1.12) in 2016. The peak-to-trough ratio of hemorrhagic stroke occurrence remained stable over time. However, after adjusting for potential bias, time trends in peak-to-trough ratios were almost flat.

Conclusions:

We found no substantial seasonality for MI, ischemic stroke, or hemorrhagic stroke occurrence during 1977−2016. Modest peak-to-trough ratios should be interpreted after considering bias induced by random variation.
TOPICAL DORZOLAMIDE FOR CYSTOID MACULAR EDEMA IN BIETTI CRYSTALLINE RETINAL DYSTROPHY
Authors: Khojasteh Hassan , Roohipoor Ramak , Riazi-Esfahani Hamid , Ghasempour Mehrbod
Published: July 2018

Purpose:

To report a case of Bietti crystalline retinal dystrophy with cystoid macular edema (CME) that was successfully treated with topical carbonic anhydrase inhibitor.

Methods:

A 35-year-old otherwise healthy woman, with a known case of Bietti crystalline retinal dystrophy, presented with progressive visual impairment in her right eye for 3 months. The best-corrected visual acuity was 20/50 in the right eye and 20/25 in the left eye. On the basis of the multimodal imaging findings, the patient was diagnosed with Bietti crystalline retinal dystrophy with unilateral CME. Carbonic anhydrase inhibitor therapy twice a day was initiated.

Results:

Three months later, visual acuity improved to 20/25 in the right eye, and CME had resolved based on spectral domain ocular coherence tomography findings, although the CME reoccurred after discontinuation of the drug. Three months after resuming the therapy, the best-corrected visual acuity improved back to 20/25.

Conclusion:

Cystoid macular edema is one of the main causes of central visual worsening in patients with Bietti crystalline retinal dystrophy. This complication may be resolved with topical carbonic anhydrase inhibitor, resulting in improved anatomical and visual outcomes.
Hepatotoxicity of Inflammatory Bowel Disease Medications
Authors: Shamberg Lucy , Vaziri Haleh
Published: July 2018

Various medications used to treat inflammatory bowel diseases have been implicated to cause hepatotoxicity. These include sulfasalazine, 5-aminosalicylic acids, fluoroquinolones, metronidazole, thiopurines, methotrexate, anti–tumor necrosis factor agents, and alpha-4 integrin inhibitors. Various types of liver injury have been reported in association with these medications including hypersensitivity reaction, hepatocellular or cholestatic disease, nodular regenerative hyperplasia, liver fibrosis/cirrhosis, portal hypertension and autoimmune liver injury. The revised Roussel Uclaf Causality Assessment Method (RUCAM) provides a scoring system to determine the likelihood of whether a drug caused liver injury. Unfortunately some of the reported liver injuries in association with these treatments have not undergone RUCAM assessment. Therefore, although some of the reports used in this review article show an association between a medication and the reported liver injury, they may not necessarily show causation. In this article, we address methods of monitoring to detect these injuries. We also discuss the prognosis and recommended management plans when liver injury occurs.
Incidence, Admission Rates, and Economic Burden of Adult Emergency Visits for Chronic Pancreatitis
Authors: Garg Sushil K. , Singh Dupinder , Sarvepalli Shashank , Bazerbachi Fateh , Puthanveedu Nitin D. , Obaitan Itegbemie , Haffar Samir , Goyal Hemant , Sanaka Madhusudhan R.
Published: July 2018

Introduction:

Chronic pancreatitis (CP) is a common reason for emergency department (ED) visits, but little research has examined ED use by patients with CP.

Materials and Methods:

The Nationwide Emergency Department Sample (2006 to 2012) was interrogated to evaluate trends in adult ED visits for a primary diagnosis of CP (International Classification of Disease, 9th revision, Clinical Modification code: 577.1), the rates of subsequent hospital admission, and total charges. A survey logistic regression model was used to determine factors associated with hospitalization from the ED.

Results:

We identified 253,753 ED visits with a primary diagnosis of CP. No significant trends in annual incidence were noted. However, the ED-to-hospitalization rates decreased by 3% per year (P<0.001) and mean ED charges after adjusting for inflation increased by 11.8% per year (P<0.001). Higher Charlson comorbidity index, current smoker status, alcohol use, and biliary-related CP were associated with hospitalization. In hospitalized patients, length of stay decreased by 2.2% per year (P=0.003) and inpatient charges increased by 2.9% per year (P=0.004).

Conclusions:

Patient characteristics associated with higher risk of hospitalization from the ED deserve further attention.
Adverse outcomes of long-term use of proton pump inhibitors: a systematic review and meta-analysis
Authors: Islam Md.Mohaimenul , Poly Tahmina N. , Walther Bruno A. , Dubey Navneet K. , Anggraini Ningrum Dina N. , Shabbir Syed-Abdul , (Jack) Li Yu-Chuan
Published: July 2018

The association between the long-term use of proton pump inhibitors (PPIs) and the risks of various diseases remains controversial. Therefore, the primary objective of this study was to quantify the associations as presented in the literature and to also provide this information to healthcare professionals and patients about their potentially adverse effects. In July 2016, we searched through Medline (PubMed), Embase, and the Cochrane Library from inception using common keywords. We included observational studies that provided risk estimates on the long-term use of PPIs and their adverse effects. Overall, 43 studies were included in the systematic review, of which 28 studies were also included in the random effect meta-analysis. Odds of community-acquired pneumonia, hip fracture, and colorectal cancer were 67% [odds ratio (OR)=1.67; 95% confidence interval (CI): 1.04–2.67], 42% (OR=1.42; 95% CI: 1.33–1.53), and 55% (OR=1.55; 95% CI: 0.88–2.73) higher in patients with long-term PPIs use compared with patients who did not use PPIs. Although the use of PPIs provides short-term health benefits, their prolonged use is associated with minor and also potentially major adverse health outcomes. Hence, we strongly recommend that the prescription of PPIs should be done with caution to improve the medication’s efficacy and patients’ safety.
Is the WHO Creating Unnecessary Confusion Over Breast Milk Substitutes?
Authors: Forsyth Stewart
Published: July 2018

A recent statement by WHO that “breast milk substitutes should be understood to include any milks …that are specifically marketed for feeding infants and young children up to the age of 3 years” differs significantly from the definition in the International Code which states “a breast milk substitute is any food being marketed or otherwise presented as a partial or total replacement for breast milk, whether or not suitable for that purpose.” The new interpretation, which lacks consultation and endorsement, is also ambiguous, with the boundaries between breast milk substitutes and complementary foods being blurred during the first 3 years of life. The logical definitions of breast milk substitutes and complementary foods contained within the Code should be maintained and inappropriate promotion of foods and fluids for infants and young children should be addressed through effective regulation of composition and labelling standards.
Redesigning Hospital Diabetes Education
Authors: Smith Kelly M. , Baker Kelley M. , Bardsley Joan K. , McCartney Patricia , Magee Michelle
Published: July 2018

Background:

Methods to deliver diabetes education are needed to support patient safety and glycemic control in the transition from hospital to home.

Purpose:

This study examined barriers and facilitators of integrating web-based, iPad-delivered diabetes survival skills education (DSSE) into the nursing inpatient unit workflow.

Methods:

Nurses, nurse managers, and patient care technicians (PCTs) from 3 medical-surgical and 2 behavioral health units participated in semistructured interviews and focus groups.

Results:

Four themes emerged: educational program and content; platform usability; tablet feasibility (eg, theft prevention, infection control, and charging); and workflow considerations. Behavioral health unit-specific concerns were also identified. Findings indicated that nurses and PCTs were eager to find approaches to deliver DSSE.

Conclusions:

Implementation of a web-based DSSE program for inpatients needs adaptation to overcome challenges at the patient, care team, and process levels.
Low-Fidelity Code Blue Simulation on the Orthopaedic Unit
Authors: Ryzner Diane M. , Kujath Amber S.
Published: July 2018

Orthopaedic nurses care for a range of patients with comorbid conditions, but because of the implementation of Rapid Response Teams, rarely do orthopaedic patients experience cardiac or respiratory arrest. Rapid Response Teams decrease emergent arrest situations on nursing units by intervening to treat clinical deterioration or move patients to a higher level of care prior to cardiac or respiratory arrest. Orthopaedic nurses still need to be prepared to act emergently with basic life support skills, which are only renewed every 2 years. Review of actual code blue events and the implementation of low-fidelity code blue simulation may improve comfort levels and performance of basic life support skills. The purpose of this article is to describe how educators designed a low-fidelity mandatory annual code blue simulation exercise for nurses to help increase confidence when faced with the rare cardiac or respiratory arrest emergency. The low-fidelity code blue simulation has been repeated annually and has been an effective exercise for orthopaedic nurses.
Fatal Transorbital Intracranial Penetrating Injury Due to a Bicycle Brake Handle
Authors: Sathish K , Chaudhari Vinod Ashok , Murthy Abilash Srinivasa
Published: July 2018

Transorbital intracranial injuries are uncommon and mostly accidental in nature. These injuries are usually associated with high mortality. The key to preventing this mortality involves an early diagnosis of intracranial injuries and immediate and appropriate management. Any delay can pose a serious risk to the patient’s life. A case of a 55-year-old man who had experienced an accidental self-fall while riding a bicycle is presented. Initially, he was treated at a primary health center. He was referred to the tertiary care institute due to unavailability of ancillary investigation at the primary health center. He was declared dead on arrival at the casualty in the tertiary institute. On autopsy, it was observed that the injury above the right side of the upper eyelid was penetrating the right side roof of the orbit and the right cerebral cortex and brainstem. The highlighting feature of the case is that, despite the fatal penetrating brain injury, the eyeball did not sustain any major injury.
Rethinking Regenerative Medicine From a Transplant Perspective (and Vice Versa)
Authors: Orlando Giuseppe , Murphy Sean V. , Bussolati Benedetta , Clancy Marc , Cravedi Paolo , Migliaccio Giovanni , Murray Patricia
Published: July 2018

No field in health sciences has more interest than organ transplantation in fostering progress in regenerative medicine (RM) because the future of no other field more than the future of organ transplantation will be forged by progress occurring in RM. In fact, the most urgent needs of modern transplant medicine, namely, more organs to satisfy the skyrocketing demand and immunosuppression-free transplantation, cannot be met in full with current technologies and are at risk of remaining elusive goals. Instead, in the past few decades, groundbreaking progress in RM is suggesting a different approach to the problem. New, RM-inspired technologies among which decellularization, 3-dimensional printing and interspecies blastocyst complementation, promise organoids manufactured from the patients' own cells and bear potential to render the use of currently used allografts obsolete. Transplantation, a field that has traditionally been immunology-based, is therefore destined to become a RM-based discipline. However, the contours of RM remain unclear, mainly due to the lack of a universally accepted definition, the lack of clarity of its potential modalities of application and the unjustified and misleading hype that often follows the reports of clinical application of RM technologies. All this generates excessive and unmet expectations and an erroneous perception of what RM really is and can offer. In this article, we will (1) discuss these aspects of RM and transplant medicine, (2) propose a definition of RM, and (3) illustrate the state of the art of the most promising RM-based technologies of transplant interest.
Deep Profiling of the CD8+ T-cell Compartment Identifies Activated Cell Subsets and Multifunctional Responses Associated With Control of Cytomegalovirus Viremia
Authors: Ferreira Victor H. , Kumar Deepali , Humar Atul
Published: July 2018

Background.

Human cytomegalovirus (HCMV) is a common opportunistic pathogen in transplant recipients. Patterns of viremia and reactivation are influenced by the host immune response, including CD8+ T cells. However, the cellular deficits or phenotypic differences that account for differential outcomes during HCMV viremia are incompletely understood.

Methods.

Peripheral blood mononuclear cells were collected from 20 transplant recipients (10 viremia controllers and 10 noncontrollers) at onset of HCMV viremia and 4 weeks postonset. We used mass cytometry to perform in-depth characterization of cell surface and intracellular CD8+ T cell markers and to compare frequencies of these cells between groups.

Results.

Deep profiling identified 2 central memory T cell subsets at onset and 5 terminally differentiated memory T (TEMRA) cell subsets at 4 weeks that were associated with control of HCMV viremia, in addition to 6 TEMRA subsets at onset and 4 weeks associated with relapsing or remitting HCMV viremia. In general, CD8+ T-cell clusters associated with poorly controlled HCMV viremia lacked markers of activation or terminal differentiation including CD38, CD69, CD25, CD57, and HLA-DR. We also measured the production of 8 HCMV-specific effector molecules (TNFα, IFNγ, interleukin 2, granzyme B, perforin, macrophage inflammatory protein 1β, interleukin 10, and CD107a) in CD8+ T cells. Viremia controllers had greater diversity of HCMV-specific multifunctional responses at both time points, including significantly higher frequencies of HCMV-specific TNFα+IFNγ+ CD8+ T cells at onset. These multifunctional cells had a phenotype consistent with activated TEM/TEMRA cells.

Conclusions.

Uncontrolled CMV viremia is associated with specific clusters of memory T-cell subsets and lower frequencies of HCMV-specific multifunctional CD8+ T cells.
DNA Methylation Explains a Subset of Placental Gene Expression Differences Based on Ancestry and Altitude
Authors: Gundling William E. , Pantham Priyadarshini , Illsley Nicholas P , Echalar Lourdes , Zamudio Stacy , Wildman Derek E.
Published: July 2018

Objectives: The most pronounced effect of high altitude (>2700m) on reproductive outcomes is reduced birth weight. Indigenous Bolivians (Andean Native Americans) residing for generations at high altitudes have higher birth weights relative to more recent migrants of primarily European ancestry. Previous research demonstrated that the placenta is a key contributor to the preservation of Andean birth weight at high altitude. Our current research investigated how gene expression and epigenetics contributes to the conservation of birth weight at high altitude by examining mRNA expression and DNA methylation differences between placentas of Andeans and those of European ancestry residing at high and low altitude.

Methods: Genome-wide mRNA expression and DNA methylation of villous placenta tissue was quantified utilizing microarray technology. Subjects were of Andean and European ancestry and resident at high (3600m) or low (400m) altitudes. Differentially expressed genes (DEGs) associated with altitude or ancestry were identified (FDR<0.1, |fold change|>1.25). To predict which DEGs could be regulated by methylation we tested for correlation between gene expression and methylation values.

Results: 69 DEGs associated with altitude (n=36) or ancestry (n=34) were identified. Altitude-associated DEGs included members of the AP-1 transcription factor family. Ancestry-associated DEGs were implicated in inflammatory pathways and associated with pro-angiogenic macrophages. More ancestry-associated DEGs correlated significantly (n=17) (FDR<0.1) with promoter or gene body methylation (p=0.0242) when compared to altitude associated DEGs (n=8).

Conclusions:Compared to altitude-associated DEGs, methylation regulates more ancestry-associated DEGs, potentially allowing for rapid modification in the expression of inflammatory genes to attract pro-angiogenic macrophages as a means of promoting placental capillary growth in Andeans, regardless of altitude.
Dynamics of Cas10 Govern Discrimination between Self and Nonself in Type III CRISPR-Cas Immunity
Authors: Wang Ling , Mo Charlie Y. , Wasserman Michael R. , Rostøl Jakob T. , Marraffini Luciano A. , Liu Shixin
Published: July 2018

Adaptive immune systems are required to accurately distinguish between self and nonself in order to defend against invading pathogens while avoiding autoimmunity. Type III CRISPR-Cas systems employ guide RNAs that recognize complementary RNA molecules to trigger the degradation of both the target transcript and its template DNA. These systems can broadly eliminate foreign targets with multiple mutations, but still effectively curb immunity against the host. The molecular basis for these unique features remains unknown. Here we use single-molecule fluorescence microscopy to study the interaction between a type III-A ribonucleoprotein complex and various RNA substrates. We find that Cas10—the DNase effector of the complex—displays rapid conformational fluctuations on foreign RNA targets, but is locked in a static configuration on self RNA. Single-stranded DNA promotes Cas10’s occupancy at a selected set of conformational states, which is also sensitively modulated by target mutations and predictive of CRISPR interference activity. These findings highlight the central role of the internal dynamics of CRISPR-Cas complexes in self/nonself discrimination and target specificity.
The genome of the jellyfish Clytia hemisphaerica and the evolution of the cnidarian life-cycle
Authors: Leclère Lucas , Horin Coralie , Chevalier Sandra , Lapébie Pascal , Dru Philippe , Peron Sophie , Jager Muriel , Condamine Thomas , Pottin Karen , Romano Séverine , Steger Julia , Sinigaglia Chiara , Barreau Carine , Artigas Gonzalo Quiroga , Ruggiero Antonella , Fourrage Cécile , Kraus Johanna E. M. , Poulain Julie , Aury Jean-Marc , Wincker Patrick , Quéinnec Eric , Technau Ulrich , Manuel Michaël , Momose Tsuyoshi , Houliston Evelyn , Copley Richard R.
Published: July 2018

Jellyfish (medusae) are a distinctive life-cycle stage of medusozoan cnidarians. They are major marine predators, with integrated neurosensory, muscular and organ systems. The genetic foundations of this complex form are largely unknown. We report the draft genome of the hydrozoan jellyfish Clytia hemisphaerica and use multiple transcriptomes to determine gene use across life-cycle stages. Medusa, planula larva and polyp are each characterised by distinct transcriptome signatures reflecting abrupt life cycle transitions, and all deploy a mixture of phylogenetically old and new genes. Medusa specific transcription factors, including many with bilaterian orthologs, associate with diverse neurosensory structures. Compared to Clytia, the polyp-only hydrozoan Hydra has lost many of the medusa-expressed transcription factors, despite similar overall rates of gene content and sequence evolution. Absence of expression and gene loss among Clytia orthologs of genes patterning the anthozoan aboral pole, secondary axis and endomesoderm support simplification of planulae and polyps in Hydrozoa, including loss of bilateral symmetry. Consequently, although the polyp and planula are generally considered the ancestral cnidarian forms, in Clytia the medusa maximally deploys ancestral cnidarian–bilaterian transcription factor gene complexity.
PIP4Ks Suppress Insulin Signaling Through a Catalytic-Independent Mechanism
Authors: Wang Diana G. , Paddock Marcia N. , Lundquist Mark R. , Sun Janet Y. , Mashadova Oksana , Amadiume Solomon , Bumpus Timothy W. , Hodakoski Cindy , Hopkins Benjamin D. , Fine Matthew , Hill Amanda , Jonathan Yang T. , Baskin Jeremy M. , Dow Lukas E. , Cantley Lewis C.
Published: July 2018

Insulin stimulates conversion of phosphatidylinositol-4,5-bisphosphate (PI(4,5)P2) to phosphatidylinositol-3,4,5-trisphosphate (PI(3,4,5)P3), which mediates downstream cellular responses. PI(4,5)P2is produced by phosphatidylinositol-4-phosphate 5-kinases (PIP5Ks) and byphosphatidylinositol-5-phosphate 4-kinases (PIP4Ks). Here we show that deletion of the three genes that encode PIP4Ks (PIP4K2A, PIP4K2BandPIP4K2C)in vitroresults in a paradoxical increase in PI(4,5)P2and a subsequent increase in insulin-stimulated production of PI(3,4,5)P3. Surprisingly, reintroduction of either wild-type or kinase-dead forms of the PIP4Ks restored cellular PI(4,5)P2levels and insulin stimulation of the PI3K pathway. These effects are explained by an increase in PIP5K activity upon deletion of PIP4Ks, which we demonstrate can suppress PIP5K activityin vitrothrough a direct binding interaction. Collectively, our work reveals an important non-catalytic function of PIP4Ks in suppressing PIP5K-mediated PI(4,5)P2synthesis and insulin-dependent conversion to PI(3,4,5)P3by PI3K enzymes and suggests that pharmacological depletion of PIP4K enzymes using emerging degrader technologies could represent a novel strategy for stimulating insulin signaling.
Antibiotic treatment protocols revisited: The challenges of a conclusive assessment by mathematical modeling
Authors: Uecker Hildegard , Bonhoeffer Sebastian
Published: July 2018

Hospital-acquired bacterial infections lead to prolonged hospital stays and increased mortality. The problem is exacerbated by antibiotic resistant strains that delay or impede effective treatment. To ensure a successful therapy and to manage antibiotic resistance, treatment protocols that draw on several different antibiotics might be used. This includes the administration of drug cocktails to individual patients (“combination therapy”) but also the random assignment of drugs to different patients (“mixing”) and a regular switch in the default drug used in the hospital from drug A to drug B and back (“cycling”). For the past 20 years, mathematical models have been used to assess the prospects of antibiotic combination therapy, mixing, and cycling. But while tendencies in their ranking across studies have emerged, the picture remains surprisingly inconclusive and incomplete. In this article, we review existing modeling studies and demonstrate by means of examples how methodological factors complicate the emergence of a consistent picture. These factors include the choice of the criterion by which the effects of the protocols are compared, the model implementation, and its analysis. We thereafter discuss how progress can be made and suggest future modeling directions.