bluuebunny/crossref_metadata_2025_split huggingface dataset:
A National Strategy to Diagnose Coronavirus Disease 2019–Associated Invasive Fungal Disease in the Intensive Care Unit
Authors: White P Lewis , Dhillon Rishi , Cordey Alan , Hughes Harriet , Faggian Federica , Soni Shuchita , Pandey Manish , Whitaker Harriet , May Alex , Morgan Matt , Wise Matthew P , Healy Brendan , Blyth Ian , Price Jessica S , Vale Lorna , Posso Raquel , Kronda Joanna , Blackwood Adam , Rafferty Hannah , Moffitt Amy , Tsitsopoulou Alexandra , Gaur Soma , Holmes Tom , Backx Matthijs 
Published: August 2020

Abstract

Background
Fungal coinfection is a recognized complication of respiratory virus infections, increasing morbidity and mortality, but can be readily treated if diagnosed early. An increasing number of small studies describing aspergillosis in coronavirus disease 2019 (COVID-19) patients with severe respiratory distress are being reported, but comprehensive data are lacking. The aim of this study was to determine the incidence, risk factors, and impact of invasive fungal disease in adult COVID-19 patients with severe respiratory distress.

Methods
An evaluation of a national, multicenter, prospective cohort evaluation of an enhanced testing strategy to diagnose invasive fungal disease in COVID-19 intensive care patients. Results were used to generate a mechanism to define aspergillosis in future COVID-19 patients.

Results
One-hundred and thirty-five adults (median age: 57, M/F: 2.2/1) were screened. The incidence was 26.7% (14.1% aspergillosis, 12.6% yeast infections). The overall mortality rate was 38%; 53% and 31% in patients with and without fungal disease, respectively (P = .0387). The mortality rate was reduced by the use of antifungal therapy (mortality: 38.5% in patients receiving therapy vs 90% in patients not receiving therapy (P = .008). The use of corticosteroids (P = .007) and history of chronic respiratory disease (P = .05) increased the likelihood of aspergillosis.

Conclusions
Fungal disease occurs frequently in critically ill, mechanically ventilated COVID-19 patients. The survival benefit observed in patients receiving antifungal therapy implies that the proposed diagnostic and defining criteria are appropriate. Screening using a strategic diagnostic approach and antifungal prophylaxis of patients with risk factors will likely enhance the management of COVID-19 patients.
Valerie Gillies: Inscriptions in the Wind
Authors: Severin Laura 
Published: August 2020

Abstract
This article focuses on Valerie Gillies’s contribution to women’s poetry through an examination of her 2016 exhibition, A Garden of Time and Silence, with textile artist Anna S. King, at Dawyck Botanic Gardens in the Scottish Borders. While Gillies is an acclaimed print-page poet, this piece represents her skill at alternative uses of poetry. Throughout her career, Gillies has employed collaborative multimedia art to engage in contemporary political discussion, often on the environment, in order to challenge, more directly than is possible with print text, poetry’s gendered assumptions.
Standardized exercise training is feasible, safe, and effective in pulmonary arterial and chronic thromboembolic pulmonary hypertension: results from a large European multicentre randomized controlled trial
Authors: Grünig Ekkehard , MacKenzie Alison , Peacock Andrew J , Eichstaedt Christina A , Benjamin Nicola , Nechwatal Robert , Ulrich Silvia , Saxer Stéphanie , Bussotti Maurizio , Sommaruga Marinella , Ghio Stefano , Gumbiene Lina , Palevičiūtė Eglė , Jurevičienė Elena , Cittadini Antonio , Stanziola Anna A , Marra Alberto M , Kovacs Gabor , Olschewski Horst , Barberà Joan-Albert , Blanco Isabel , Spruit Martijn A , Franssen Frits M E , Vonk Noordegraaf Anton , Reis Abílio , Santos Mário , Viamonte Sofia Gonçalves , Demeyer Heleen , Delcroix Marion , Bossone Eduardo , Johnson Martin 
Published: August 2020

Abstract

Aims
This prospective, randomized, controlled, multicentre study aimed to evaluate efficacy and safety of exercise training in patients with pulmonary arterial (PAH) and chronic thromboembolic pulmonary hypertension (CTEPH).

Methods and results
For the first time a specialized PAH/CTEPH rehabilitation programme was implemented in 11 centres across 10 European countries. Out of 129 enrolled patients, 116 patients (58 vs. 58 randomized into a training or usual care control group) on disease-targeted medication completed the study [85 female; mean age 53.6 ± 12.5 years; mean pulmonary arterial pressure 46.6 ± 15.1 mmHg; World Health Organization (WHO) functional class II 53%, III 46%; PAH n = 98; CTEPH n = 18]. Patients of the training group performed a standardized in-hospital rehabilitation with mean duration of 25 days [95% confidence interval (CI) 17–33 days], which was continued at home. The primary endpoint, change of 6-min walking distance, significantly improved by 34.1 ± 8.3 m in the training compared with the control group (95% CI, 18–51 m; P &lt; 0.0001). Exercise training was feasible, safe, and well-tolerated. Secondary endpoints showed improvements in quality of life (short-form health survey 36 mental health 7.3 ± 2.5, P = 0.004), WHO-functional class (training vs. control: improvement 9:1, worsening 4:3; χ2 P = 0.027) and peak oxygen consumption (0.9 ± 0.5 mL/min/kg, P = 0.048) compared with the control group.

Conclusion
This is the first multicentre and so far the largest randomized, controlled study on feasibility, safety, and efficacy of exercise training as add-on to medical therapy in PAH and CTEPH. Within this study, a standardized specialized training programme with in-hospital start was successfully established in 10 European countries.
Age-Related Changes in Audiovisual Simultaneity Perception and Their Relationship With Working Memory
Authors: Chen Yi-Chuan , Yeh Su-Ling , Tang Pei-Fang 
Published: August 2020

Abstract

Objectives
Perceiving simultaneity of a visual and an auditory signal is critical for humans to integrate these multisensory inputs effectively and respond properly. We examined age-related changes in audiovisual simultaneity perception, and the relationships between this perception and working memory performances with aging.

Methods
Audiovisual simultaneity perception of young, middle-aged, and older adults was measured using a simultaneity judgment (SJ) task, in which a flash and a beep were presented at 1 of 11 stimulus-onset asynchronies (SOAs). Participants judged whether these two stimuli were perceived simultaneously. Precision of simultaneity perception, the SOA corresponding to the point of subjective simultaneity (PSS), and response errors at each SOA were estimated using model fitting. The precision and PSS are associated with multisensory perception per se, whereas the response error reflects executive ability when performing the SJ task. Visual working memory of the same middle-aged and older adults was measured using the Cambridge Neuropsychological Test Automated Battery (CANTAB) beforehand.

Results
Compared to young adults’ performances, middle-aged and older adults showed a decreased precision, a shift of PSS toward the visual-leading SOAs, and increased response errors at the visual-leading SOAs. Among these changes, only the increased response errors correlated with worse spatial recognition memory in middle-aged and older adults.

Discussion
Age-related decrements in audiovisual simultaneity perception start from middle age and are manifested in both perceptual and executive parameters. Furthermore, higher-order executive ability is plausibly a common cause for age-related degenerations in the audiovisual simultaneity perception and visual working memory.
Improving Local Service Delivery to Prevent Falls in Community-Dwelling Older Adults: Translating Research to Practice
Authors: Gagen Travis M , Bulzacchelli Maria T 
Published: August 2020

AbstractUnintentional falls are the leading cause of both fatal and nonfatal injuries among Americans 65 years of age and older and place an enormous burden on the health care system. As the population continues to age, preventing falls will be increasingly important for reducing morbidity, mortality, and medical costs. Evidence-based fall prevention interventions for older adults exist, but widespread adoption of these interventions is needed. Local health departments, Area Agencies on Aging, first responders, and health care professionals can all play important roles in implementing fall prevention programs. This article presents a conceptual model for local delivery of fall prevention programs for community-dwelling older adults. This model can serve as a guide for translating existing fall prevention research into practice.
Conserved UBE3A subcellular distribution between human and mice is facilitated by non-homologous isoforms
Authors: Zampeta F Isabella , Sonzogni Monica , Niggl Eva , Lendemeijer Bas , Smeenk Hilde , de Vrij Femke M S , Kushner Steven A , Distel Ben , Elgersma Ype 
Published: August 2020

Abstract
The human UBE3A gene, which is essential for normal neurodevelopment, encodes three Ubiquitin E3 ligase A (UBE3A) protein isoforms. However, the subcellular localization and relative abundance of these human UBE3A isoforms are unknown. We found, as previously reported in mice, that UBE3A is predominantly nuclear in human neurons. However, this conserved subcellular distribution is achieved by strikingly distinct cis-acting mechanisms. A single amino-acid deletion in the N-terminus of human hUBE3A-Iso3, which is homologous to cytosolic mouse mUBE3A-Iso2, results in its translocation to the nucleus. This singe amino-acid deletion is shared with apes and Old World monkeys and was preceded by the appearance of the cytosolic hUBE3A-Iso2 isoform. This hUBE3A-Iso2 isoform arose after the lineage of New World monkeys and Old World monkeys separated from the Tarsiers (Tarsiidae). Due to the loss of a single nucleotide in a non-coding exon, this exon became in frame with the remainder of the UBE3A protein. RNA-seq analysis of human brain samples showed that the human UBE3A isoforms arise by alternative splicing. Consistent with the predominant nuclear enrichment of UBE3A in human neurons, the two nuclear-localized isoforms, hUBE3A-Iso1 and -Iso3, are the most abundantly expressed isoforms of UBE3A, while hUBE3A-Iso2 maintains a small pool of cytosolic UBE3A. Our findings provide new insight into UBE3A localization and evolution and may have important implications for gene therapy approaches in Angelman syndrome.
Pharmacokinetic and pharmacodynamic analysis of baloxavir marboxil, a novel cap-dependent endonuclease inhibitor, in a murine model of influenza virus infection
Authors: Ando Yoshinori , Noshi Takeshi , Sato Kenji , Ishibashi Toru , Yoshida Yuki , Hasegawa Takahiro , Onishi Motoyasu , Kitano Mitsutaka , Oka Ryoko , Kawai Makoto , Yoshida Ryu , Sato Akihiko , Shishido Takao , Naito Akira 
Published: August 2020

Abstract

Background
Baloxavir acid, the active form of the orally available prodrug baloxavir marboxil, is a novel cap-dependent endonuclease inhibitor of influenza virus. Baloxavir marboxil has been shown to rapidly reduce virus titres compared with oseltamivir in clinical studies.

Objectives
We investigated the relationship between pharmacokinetic (PK) parameters and antiviral activity of baloxavir acid based on virus titre reduction in lungs of infected mice.

Methods
BALB/c mice infected with a sub-lethal dose of influenza A(H1N1), A(H1N1)pdm09, A(H3N2) or type B virus were treated on day 5 with oral baloxavir marboxil (0.5–50 mg/kg q12h), subcutaneous baloxavir acid (0.25–8 mg/kg/day), oseltamivir phosphate (5 or 50 eq mg/kg q12h) or other antivirals for 1 day. Lung virus titres were assessed 24 h after initial antiviral dosing. PK testing was performed at up to 24 h post-dosing of baloxavir marboxil or baloxavir acid in A/WSN/33-infected mice and the PK/pharmacodynamic (PD) relationship was evaluated for baloxavir acid.

Results
Oral baloxavir marboxil administration showed dose-dependent virus titre reductions in lungs of mice infected with the different types/subtypes of influenza viruses 24 h post-dosing. Baloxavir marboxil at 15 mg/kg q12h resulted in ≥100-fold and ≥10-fold reductions in influenza A and B virus titres, respectively, compared with oseltamivir phosphate. PK/PD analysis showed that the plasma concentration at the end of the dosing interval (Cτ) or the plasma concentration at 24 h after initial dosing (C24) was the PK parameter predicting the virus titres at 24 h post-dosing of baloxavir acid.

Conclusions
PK/PD analysis of baloxavir acid based on virus titre reduction in this mouse model could be helpful in predicting and maximizing virological outcomes in clinical settings.
Multiple structural states of Ca2+-regulated PET hydrolase, Cut190, and its correlation with activity and stability
Authors: Senga Akane , Numoto Nobutaka , Yamashita Mitsuaki , Iida Akira , Ito Nobutoshi , Kawai Fusako , Oda Masayuki 
Published: August 2020

Abstract
An enzyme, Cut190, from a thermophilic isolate, Saccharomonospora viridis AHK190 could depolymerize polyethylene terephthalate (PET). The catalytic activity and stability of Cut190 and its S226P/R228S mutant, Cut190*, are regulated by Ca2+ binding. We previously determined the crystal structures of the inactive mutant of Cut190*, Cut190*S176A, in complex with metal ions, Ca2+ and Zn2+, and substrates, monoethyl succinate and monoethyl adipate. In this study, we determined the crystal structures of another mutant of Cut190*, Cut190**, in which the three C-terminal residues of Cut190* are deleted, and the inactive mutant, Cut190**S176A, in complex with metal ions. In addition to the previously observed closed, open and engaged forms, we determined the ejecting form, which would allow the product to irreversibly dissociate, followed by proceeding to the next cycle of reaction. These multiple forms would be stable or sub-stable states of Cut190, regulated by Ca2+ binding, and would be closely correlated with the enzyme function. Upon the deletion of the C-terminal residues, we found that the thermal stability increased while retaining the activity. The increased stability could be applied for the protein engineering of Cut190 for PET depolymerization as it requires the reaction above the glass transition temperature of PET.
A logic of blockchain updates
Authors: Brünnler Kai , Flumini Dandolo , Studer Thomas 
Published: August 2020

Abstract
Blockchains are distributed data structures that are used to achieve consensus in systems for cryptocurrencies (like Bitcoin) or smart contracts (like Ethereum). Although blockchains gained a lot of popularity recently, there are only few logic-based models for blockchains available. We introduce $\mathsf{BCL}$, a dynamic logic to reason about blockchain updates, and show that $\mathsf{BCL}$ is sound and complete with respect to a simple blockchain model.
Synthesis, chirality-dependent conformational and biological properties of siRNAs containing 5′-(R)- and 5′-(S)-C-methyl-guanosine
Authors: Mikami Atsushi , Erande Namrata , Matsuda Shigeo , Kel’in Alexander , Woods Lauren Blair , Chickering Tyler , Pallan Pradeep S , Schlegel Mark K , Zlatev Ivan , Egli Martin , Manoharan Muthiah 
Published: August 2020

Abstract
Various chemical modifications have been identified that enhance potency of small interfering RNAs (siRNAs) and that reduce off-target effects, immune stimulation, and toxicities of metabolites of these therapeutic agents. We previously described 5′-C-methyl pyrimidine nucleotides also modified at the 2′ position of the sugar. Here, we describe the synthesis of 2′-position unmodified 5′-(R)- and 5′-(S)-C-methyl guanosine and evaluation of these nucleotides in the context of siRNA. The (R) isomer provided protection from 5′ exonuclease and the (S) isomer provided protection from 3′ exonuclease in the context of a terminally modified oligonucleotide. siRNA potency was maintained when these modifications were incorporated at the tested positions of sense and antisense strands. Moreover, the corresponding 5′ triphosphates were not substrates for mitochondrial DNA polymerase. Models generated based on crystal structures of 5′ and 3′ exonuclease oligonucleotide complexes with 5′-(R)- and 5′-(S)-C-methyl substituents attached to the 5′- and 3′-terminal nucleotides, respectively, provided insight into the origins of the observed protections. Structural properties of 5′-(R)-C-methyl guanosine incorporated into an RNA octamer were analysed by X-ray crystallography, and the structure explains the loss in duplex thermal stability for the (R) isomer compared with the (S) isomer. Finally, the effect of 5′-C-methylation on endoribonuclease activity has been explained.
NEO100 enables brain delivery of blood‒brain barrier impermeable therapeutics
Authors: Wang Weijun , Marín-Ramos Nagore I , He Haiping , Zeng Shan , Cho Hee-Yeon , Swenson Stephen D , Zheng Long , Epstein Alan L , Schönthal Axel H , Hofman Florence M , Chen Ligang , Chen Thomas C 
Published: August 2020

Abstract

Background
Intracarotid injection of mannitol has been applied for decades to support brain entry of therapeutics that otherwise do not effectively cross the blood–brain barrier (BBB). However, the elaborate and high-risk nature of this procedure has kept its use restricted to well-equipped medical centers. We are developing a more straightforward approach to safely open the BBB, based on the intra-arterial (IA) injection of NEO100, a highly purified version of the natural monoterpene perillyl alcohol.

Methods
In vitro barrier permeability with NEO100 was evaluated by transepithelial/transendothelial electrical resistance and antibody diffusion assays. Its mechanism of action was studied by western blot, microarray analysis, and electron microscopy. In mouse models, we performed ultrasound-guided intracardiac administration of NEO100, followed by intravenous application of Evan’s blue, methotrexate, checkpoint-inhibitory antibodies, or chimeric antigen receptor (CAR) T cells.

Results
NEO100 opened the BBB in a reversible and nontoxic fashion in vitro and in vivo. It enabled greatly increased brain entry of all tested therapeutics and was well tolerated by animals. Mechanistic studies revealed effects of NEO100 on different BBB transport pathways, along with translocation of tight junction proteins from the membrane to the cytoplasm in brain endothelial cells.

Conclusion
We envision that this procedure can be translated to patients in the form of transfemoral arterial catheterization and cannulation to the cerebral arteries, which represents a low-risk procedure commonly used in a variety of clinical settings. Combined with NEO100, it is expected to provide a safe, widely available approach to enhance brain entry of any therapeutic.
Depression Partially Mediates the Association of Adverse Childhood Experiences with Pain Intensity in Patients with Chronic Pelvic Pain Syndrome: Results from a Cross-Sectional Patient Survey
Authors: Piontek Katharina , Apfelbacher Christian , Ketels Gesche , Brünahl Christian , Löwe Bernd 
Published: August 2020

Abstract

Objective
Adverse childhood experiences (ACEs), such as emotional and physical maltreatment, are linked to chronic pelvic pain syndrome (CPPS) in adults. Psychological factors are important in understanding CPPS. We aimed to determine the nature and frequency of ACEs in male and female patients with CPPS and to investigate whether somatic symptoms and psychological comorbidities mediate the relationship of ACE severity with pain intensity.

Design
Cross-sectional study.

Setting
Interdisciplinary outpatient clinic for CPPS in Hamburg, Germany.

Subjects
Individuals with CPPS (n = 234) who were 18 to 84 years of age.

Methods
Using a self-administered questionnaire, we assessed the history of ACEs (ACE Scale), pain intensity (McGill Pain Questionnaire), somatic symptoms (Patient Health Questionnaire–15]), depression (Patient Health Questionnaire–9), and anxiety (Generalized Anxiety Disorder Scale). Parallel mediation analysis was conducted to examine whether the association of ACE severity with pain intensity is mediated by somatic symptoms, depression, and anxiety.

Results
Emotional abuse and neglect were reported more than twice as often as physical abuse and neglect (37.2% vs 17.1%). Depression partially mediated the association of ACE severity with pain intensity in the whole study population. In sex-stratified analyses, different patterns of associations were observed, but somatic symptoms predicted pain intensity in both sexes.

Conclusions
Emotional maltreatment was highly prevalent, supporting an increased consideration of psychological factors in CPPS and indicating the need to screen for ACEs in patients with CPPS. Findings further suggest that depression and somatic symptoms may be important targets for therapeutic interventions in patients with CPPS who have a history of childhood adversity.
Peripheral Nerve Stimulation: A New Treatment for Meralgia Paresthetica
Authors: Langford Brendan , Mauck William D 
Published: August 2020

Abstract

Background
Meralgia paresthetica is a condition caused by entrapment of the lateral femoral cutaneous nerve that leads to paresthesia along the anterolateral portion of the thigh. Because of advancements in neuromodulation, peripheral nerve stimulation (PNS) has been considered a new treatment option for meralgia paresthetica. Newer PNS technology targets peripheral nerves directly yet in a minimally invasive manner. We report a case in which a PNS device provided more than 12 months of complete pain relief in a patient with meralgia paresthetica and helped the patient avoid a neurolysis procedure.

Case Presentation
A 57-year-old male presented to clinic with a 6-year history of “painful numbness [and] burning” along the right lateral thigh. He rated his pain as 8 out of 10, which decreased to a rating of 2 out of 10 with the use of gabapentin, but unwanted side effects motivated him to seek alternative treatment. On the basis of his history, physical exam, and imaging results, he was diagnosed with meralgia paresthetica. He was offered neurolysis; however, after seeing a pain specialist, he agreed to the implantation of a SPRINT peripheral nerve stimulator. After the implantation procedure, his pain reduced to 0 out of 10, and his quality of life improved, with better sleep and less somnolence. The device was removed after 60 days, as planned. He continued to have complete resolution of pain at 12 months after the date of device implantation.

Conclusion
With recent advancements, PNS can be used to treat meralgia paresthetica in an effective yet minimally invasive manner. As newer PNS technology becomes more familiar to physicians and pain specialists, it is likely to be used as a mainstay treatment for meralgia paresthetica.
The Yield Spread and Bond Return Predictability in Expansions and Recessions
Authors: Andreasen Martin M , Engsted Tom , Møller Stig V , Sander Magnus 
Published: August 2020

Abstract
This paper uncovers that expected excess bond returns display a positive correlation with the slope of the yield curve (i.e., yield spread) in expansions but a negative correlation in recessions. We use a macro-finance term structure model with different market prices of risk in expansions and recessions to show that a very accommodating monetary policy in recessions is a key driver of this switch in return predictability.