bluuebunny/crossref_metadata_2025_split huggingface dataset:
The C2 domain of the ubiquitin ligase Rsp5 is required for ubiquitination of the endocytic protein Rvs167 upon change of nitrogen source
Authors: Tanahashi Ryoya , Afiah Tira Siti Nur , Nishimura Akira , Watanabe Daisuke , Takagi Hiroshi 
Published: October 2020

ABSTRACT
Ubiquitination is a key signal for endocytosis of proteins on the plasma membrane. The ubiquitin ligase Rsp5 of Saccharomyces cerevisiae, which contains an amino-terminal membrane-binding C2 domain, three substrate-recognizing tryptophan-tryptophan (WW) domains and a carboxyl-terminal catalytic homologous to the E6-AP carboxyl terminus (HECT) domain, can ubiquitinate plasma membrane proteins directing them for endocytosis. Here, we examined the roles of the C2 domain in endocytosis for the downregulation of the general amino acid permease Gap1, which is one of nitrogen-regulated permeases in S. cerevisiae. First, we constructed several rsp5 mutants producing Rsp5 variants without the C2 domain or with amino acid changes of membrane-binding lysine residues. These mutants showed defects in endocytosis of Gap1 in response to a preferred nitrogen source. Intriguingly, we found that ubiquitination of Gap1 in these mutant cells was highly similar to that in wild-type cells during endocytosis. These results indicate that the C2 domain is essential for endocytosis but not for ubiquitination of substrates such as Gap1. Moreover, genetic and biochemical analyses showed that the endocytic protein Rvs167 was ubiquitinated via Rsp5 and the C2 domain was required for efficient ubiquitination in response to a preferred nitrogen source. Here, we propose a mechanism for the C2 domain-mediated endocytosis of plasma membrane permeases.
Systematic recovery of instrumental timing and phase errors using interferometric surface-waves retrieved from large-N seismic arrays
Authors: Weemstra Cornelis , de Laat Janneke I , Verdel Arie , Smets Pieter 
Published: October 2020

SUMMARYInstrumental timing and phase errors are a notorious problem in seismic data acquisition and processing. These can be frequency independent, for example due to clock drift, but may also be frequency dependent, for example due to imperfectly known instrument responses. A technique is presented that allows both types of errors to be recovered in a systematic fashion. The methodology relies on the time-symmetry usually inherent in time-averaged cross-correlations of ambient seismic noise: the difference between the arrival time of the direct surface-wave at positive time and the arrival time of the direct surface-wave at negative time is quantified. Doing this for all eligible receiver–receiver pairs of a large-N seismic array, including one or more receivers devoid of instrumental timing errors, the instrumental timing errors of all incorrectly timed receivers can be determined uniquely. Most notably, this is accomplished by means of a weighted least-squares inversion. The weights are based on the receiver–receiver distances and decrease the adverse effect of inhomogeneities in the noise illumination pattern on the recovered instrumental timing errors. Inversion results are furthermore optimized by limiting the inversion to receiver couples that (i) exceed a specific receiver–receiver distance threshold and (ii) whose time-averaged cross-correlations exceed a specific signal-to-noise ratio threshold. Potential frequency dependence of the timing errors is incorporated by means of an iterative, frequency-dependent approach. The proposed methodology is validated using synthetic recordings of ambient seismic surface-wave noise due to an arbitrary non-uniform illumination pattern. The methodology is successfully applied to time-averaged cross-correlations of field recordings of ambient seismic noise on and around the Reykjanes peninsula, SW Iceland.
Disclaimers in European Patent Applications
Authors: Barycki Michał 
Published: October 2020

Abstract
A European patent application may be amended by, among others, deleting a part of the claimed subject matter under established conditions or by the incorporation of an undisclosed or disclosed disclaimer. Disclaimers are a useful tool in order to maintain the balance between the practical needs of applicants and the interests of third parties in legal clarity and completeness. The incorporation of disclaimers may not extend beyond the content of the European patent application as filed and the protection it confers. The purpose of this paper is to illustrate how an applicant can introduce a negative technical feature into the patent application in the light of the extensive judicial practice of the Technical and Enlarged Boards of Appeal of the European Patent Office. The author has analysed the criteria for disclaimers set out in decisions G 1/03, G 2/10 and G 1/16 in accordance with the general notion of patent law and requirements of patentability. Additionally, this problem was also characterized in the light of the judicial practice of national courts and legislations of the EU Member States.
Surgical treatment of pleural empyema in Coronavirus disease 19 patients: the Southern Switzerland experience
Authors: Tessitore Adele , Patella Miriam , Giuliani Mauro , Theologou Thomas , Freguia Stefania , Minerva Eleonora Maddalena , Rugel Gregor , Cafarotti Stefano 
Published: October 2020

Abstract
We report the first surgical series of patients developing pleural empyema after severe bilateral interstitial lung disease in confirmed severe acute respiratory syndrome coronavirus 2 infection. The empyema results in a complex medical challenge that requires combination of medical therapies, mechanical ventilation and surgery. The chest drainage approach was not successful to relieve the symptomatology and to drain the excess fluid. After multidisciplinary discussion, a surgical approach was recommended. Even though decortication and pleurectomy are high-risk procedures, they must be considered as an option for pleural effusion in Coronavirus disease-positive patients. This is a life-treating condition, which can worsen the coronavirus disease manifestation and should be treated immediately to improve patient’s status and chance of recovery.
Causal effects of physical activity and sedentary behaviour on health deficits accumulation in older adults
Authors: García-Esquinas Esther , Ortolá Rosario , Martínez-Gómez David , Damián Javier , Prina Matthew , Rodríguez-Artalejo Fernando , Pastor-Barriuso Roberto 
Published: October 2020

Abstract

Background
Increasing physical activity (PA) and reducing sedentary behaviour (SB) have been associated with healthy ageing, but their effects when adjusted for reverse causation and selection bias remain unclear.

Methods
A deficits accumulation (DA) index based on the number and severity of 51 health deficits (0–100%) was calculated at baseline and three biannual follow-up visits, in a representative cohort of 3 228 community-dwelling older adults in Spain. Average differences in DA index by previous recreational PA, household PA, mentally-active SB and passive SB were estimated using marginal structural models with inverse probability of exposure and censoring weights.

Results
Compared with participants with previous recreational PA of 10–19.9 metabolic equivalent hours/week (MET-hours/week), average differences in DA index (95% confidence intervals) were 0.19 (−1.09, 1.48), 0.69 (−0.23, 1.61), −0.66 (−1.34, 0.02), −0.87 (−1.59, −0.13) and −0.55 (−1.37, 0.28) for 0, 0.1–9.9, 20–29.9, 30–39.9 and ≥40 MET-hours/week, respectively (P for trend = 0.006). Household PA showed no effect on subsequent DA after adjusting for reverse causation. Women, but not men, who spent 7–14.9, 15–20.9 and ≥21 h/week on mentally active SB had DA decreases of 0.09 (−1.00, 1.19), 1.08 (−0.28, 2.45) and 2.17 (0.58, 3.75), respectively, compared with 1–6.9 h/week (P for trend = 0.005); whereas women who spent 3–3.9, 4–4.9 and ≥5 h/day on passive SB showed DA increases of 0.41 (−0.52, 1.35), 1.35 (0.13, 2.57) and 2.13 (0.78, 3.47), respectively, compared with 2–2.9 h/day (P for trend = 0.001).

Conclusions
The proposed methodology allows estimation of the causal effects of PA and SB on ageing, by simulating a random assignment in which all subjects have the same probability of exposure.
The effect of angiotensin-converting enzyme levels on COVID-19 susceptibility and severity: a Mendelian randomization study
Authors: Butler-Laporte Guillaume , Nakanishi Tomoko , Mooser Vincent , Renieri Alessandra , Amitrano Sara , Zhou Sirui , Chen Yiheng , Forgetta Vincenzo , Richards J Brent 
Published: October 2020

Abstract

Background
There has been uncertainty about the safety or benefit of angiotensin-converting enzyme (ACE) inhibitors during the COVID-19 pandemic. We used Mendelian randomization using genetic determinants of serum-ACE levels to test whether decreased ACE levels increase susceptibility to SARS-CoV-2 infection or COVID-19 severity, while reducing potential bias from confounding and reverse causation in observational studies.

Methods
Genetic variants strongly associated with ACE levels, which were nearby the ACE gene, were identified from the ORIGIN trial and a separate genome-wide association study (GWAS) of ACE levels from the AGES cohort. The ORIGIN trial included 4147 individuals of European and Latino ancestries. Sensitivity analyses were performed using a study of 3200 Icelanders. Cohorts from the COVID-19 Host Genetics Initiative GWAS of up to 960 186 individuals of European ancestry were used for COVID-19 susceptibility, hospitalization and severe-disease outcome.

Results
Genetic variants were identified that explain between 18% and 37% of variance in ACE levels. Using genetic variants from the ORIGIN trial, a standard-deviation decrease in ACE levels was not associated with an increase in COVID-19 susceptibility [odds ratio (OR): 1.02, 95% confidence interval (CI): 0.90, 1.15], hospitalization (OR: 0.86, 95% CI: 0.68, 1.08) or severe disease (OR: 0.74, 95% CI: 0.51, 1.06). Using genetic variants from the AGES cohort, the result was similar for susceptibility (OR: 0.98, 95% CI: 0.89, 1.09), hospitalization (OR: 0.86, 95% CI: 0.66, 1.11) and severity (OR: 0.75, 95% CI: 0.50, 1.14). Multiple-sensitivity analyses led to similar results.

Conclusion
Genetically decreased serum ACE levels were not associated with susceptibility to, or severity of, COVID-19 disease. These data suggest that individuals taking ACE inhibitors should not discontinue therapy during the COVID-19 pandemic.
Impact of Immune Reconstitution-Induced Hepatic Flare on Hepatitis B Surface Antigen Loss in Hepatitis B Virus/Human Immunodeficiency Virus-1 Coinfected Patients
Authors: Yoshikawa Shiori , Yoshio Sachiyo , Yoshida Yuichi , Tsutsui Yuriko , Kawai Hironari , Yamazoe Taiji , Mori Taizo , Osawa Yosuke , Sugiyama Masaya , Iwamoto Masashi , Watashi Koichi , Kawaguchi Takumi , Akita Tomoyuki , Tanaka Junko , Kikuchi Yoshimi , Mizokami Masashi , Oka Shinichi , Kanto Tatsuya , Gatanaga Hiroyuki 
Published: October 2020

Abstract

Background
Hepatitis B surface antigen (HBsAg) loss is an ideal goal for chronic hepatitis B patients. Antiretroviral therapy (ART) in hepatitis B virus/human immunodeficiency virus-1 (HBV/HIV-1)–coinfected patients can lead to hepatic flare (HF) caused by immune reconstitution-induced inflammatory syndrome (IRIS). Here, we investigated the impact of IRIS-HF on HBsAg loss.

Methods
This was a retrospective study of 58 HBV/HIV-1–coinfected subjects HBsAg-positive for ≥6 months before ART initiation and followed for ≥1 year (median 9.9 years) after ART initiation. We examined humoral factors in sera from healthy volunteers, HIV-monoinfected patients, and HBV/HIV-1–coinfected patients with IRIS-HF or acute hepatitis B infection.

Results
During ART, HBsAg loss was observed in 20 of 58 HBV/HIV-1–coinfected patients (34.5%). Of the 58 patients, 15 (25.9%) developed IRIS-HF within 12 months of ART initiation. HBsAg loss was more frequent among patients who developed IRIS-HF (11/15, 73.3%) than those who did not (9/43, 20.9%). Multivariate analysis showed IRIS-HF was an independent predictor of subsequent HBsAg loss. Younger age and higher baseline HBV DNA titer were associated with IRIS-HF. Elevation of sCD163, not CXCL9, CXC10, CXCXL11, or CXCL13, was observed at IRIS-HF.

Conclusions
IRIS-HF was associated with HBsAg loss in HBV/HIV-1–coinfected patients.
Prolonged Severe Acute Respiratory Syndrome Coronavirus 2 Replication in an Immunocompromised Patient
Authors: Baang Ji Hoon , Smith Christopher , Mirabelli Carmen , Valesano Andrew L , Manthei David M , Bachman Michael A , Wobus Christiane E , Adams Michael , Washer Laraine , Martin Emily T , Lauring Adam S 
Published: October 2020

Abstract
We describe a case of chronic coronavirus disease 2019 (COVID-19) in a patient with lymphoma and associated B-cell immunodeficiency. Viral cultures and sequence analysis demonstrate ongoing replication of infectious severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) for at least 119 days. The patient had 3 admissions related to COVID-19 over a 4-month period and was treated twice with remdesivir and convalescent plasma with resolution of symptoms. The patient’s lack of seroconversion and prolonged course illustrate the importance of humoral immunity in resolving SARS-CoV-2 infection. This case highlights challenges in managing immunocompromised hosts, who may act as persistent shedders and sources of transmission.
Impact of an antimicrobial stewardship programme on reducing broad-spectrum antibiotic use and its effect on carbapenem-resistantAcinetobacter baumannii(CRAb) in hospitals in Jordan
Authors: Yusef Dawood , Hayajneh Wail A , Bani Issa Ali , Haddad Rami , Al-Azzam Sayer , Lattyak Elizabeth A , Lattyak William J , Gould Ian , Conway Barbara R , Bond Stuart , Conlon-Bingham Geraldine , Aldeyab Mamoon A 
Published: October 2020

AbstractObjectivesTo evaluate the impact of an antimicrobial stewardship programme (ASP) on reducing broad-spectrum antibiotic use and its effect on carbapenem-resistant Acinetobacter baumannii (CRAb) in hospitalized patients.MethodsThe study was a retrospective, ecological assessment in a tertiary teaching hospital over 6 years (January 2014 to December 2019). The intervention involved the implementation of an ASP in February 2018, which remains in effect today. This ASP consists of several components, including education, antibiotic guidelines, antibiotic restriction policy with prior approval, audit of compliance to the restriction policy and feedback. Restricted antibiotics were imipenem/cilastatin, ertapenem, meropenem, vancomycin, teicoplanin, tigecycline, colistin, amikacin, piperacillin/tazobactam, levofloxacin and ciprofloxacin. The intervention was evaluated by time-series methods.ResultsStatistically significant decreases in the level of antibiotic use, after the introduction of the ASP, were observed for the following antibiotics: imipenem/cilastatin (P = 0.0008), all carbapenems (P = 0.0001), vancomycin (P = 0.0006), colistin (P = 0.0016) and third-generation cephalosporins (P = 0.0004). A statistically significant decrease in the slope, after the introduction of the ASP, for ertapenem (P = 0.0044) and ciprofloxacin (P = 0.0117) was observed. For piperacillin/tazobactam, there was a significant increasing trend (P = 0.0208) before the introduction of the ASP. However, this increased trend was halted post-introduction of the ASP (P = 0.4574). The introduction of the ASP was associated with a significant impact on reducing the levels of CRAb (P = 0.0237).ConclusionsThe introduced antimicrobial stewardship interventions contributed to a reduction in the use of several broad-spectrum antibiotics, reversed the trends of increasing use of other antibiotics and were associated with a significant reduction in CRAb.
Electronic health records and clinician burnout: A story of three eras
Authors: Johnson Kevin B , Neuss Michael J , Detmer Don Eugene 
Published: October 2020

AbstractObjectiveThe study sought to provide physicians, informaticians, and institutional policymakers with an introductory tutorial about the history of medical documentation, sources of clinician burnout, and opportunities to improve electronic health records (EHRs). We now have unprecedented opportunities in health care, with the promise of new cures, improved equity, greater sensitivity to social and behavioral determinants of health, and data-driven precision medicine all on the horizon. EHRs have succeeded in making many aspects of care safer and more reliable. Unfortunately, current limitations in EHR usability and problems with clinician burnout distract from these successes. A complex interplay of technology, policy, and healthcare delivery has contributed to our current frustrations with EHRs. Fortunately, there are opportunities to improve the EHR and health system. A stronger emphasis on improving the clinician’s experience through close collaboration by informaticians, clinicians, and vendors can combine with specific policy changes to address the causes of burnout.Target audienceThis tutorial is intended for clinicians, informaticians, policymakers, and regulators, who are essential participants in discussions focused on improving clinician burnout. Learners in biomedicine, regardless of clinical discipline, also may benefit from this primer and review.ScopeWe include (1) an overview of medical documentation from a historical perspective; (2) a summary of the forces converging over the past 20 years to develop and disseminate the modern EHR; and (3) future opportunities to improve EHR structure, function, user base, and time required to collect and extract information.
First Evidence of Western Bean Cutworm (Lepidoptera: Noctuidae) Overwintering in the Province of Québec (Canada)
Authors: Saguez Julien , Neau Mathieu , Rieux Christine , Vallières-Murray Maryse , Petrauskas Priscila , Mathieu Stéphanie , Duval Brigitte , Auger Yves , Fréchette Isabelle 
Published: October 2020

Abstract
The western bean cutworm, Striacosta albicosta (Smith), is considered a major corn pest in North America. In 2009, it started invading the province of Québec (northeastern Canada). To our knowledge, there has been no evidence that this pest could overwinter in this province. In the falls of 2017 and 2018, storage totes containing mature western bean cutworm larvae were placed in the soil in three agricultural regions, in Québec, where western bean cutworm invasions are frequent and crop damage is often significant. The goal was to evaluate if western bean cutworm could resist the province’s winter conditions. The storage totes were removed from the soil at different dates to estimate winter survival. Emergence cages were installed over the totes in the spring of the following year to determine whether western bean cutworm could complete its life cycle. In the spring of 2019, car shelters were also installed at two different sites to evaluate natural moth emergences in fields in which numerous mature western bean cutworm larvae and damage were reported in 2018. Western bean cutworm moth emergences occurred in both cases. These experiments constitute the first documented evidence that western bean cutworm can overwinter and complete its life cycle in Québec’s cold climate. It also represents the northernmost overwintering survival for this species ever documented in North America. The western bean cutworm’s ability to overwinter in Québec will have important implications for corn producers. Pest monitoring and management programs in the province of Québec will need to be adapted accordingly.
Postmarketing observational study of pazopanib in patients with metastatic soft tissue sarcoma in Japan
Authors: Teshima Yasutomo , Nomura Satoshi , Fukasawa Nobuaki 
Published: October 2020

Abstract

Background
This study evaluated the safety and efficacy of pazopanib in patients with metastatic soft tissue sarcoma in routine clinical use in Japan.

Methods
It was a multicentre, centrally registered and uncontrolled observational study in patients who received pazopanib for metastatic soft tissue sarcoma, with an observation period of 1 year after the start of drug administration. The study was conducted at 378 investigational sites in Japan from September 2012 to September 2019. Progression-free survival (PFS) and overall survival (OS) were the efficacy endpoints of the study.

Results
A total of 1970 patients were enrolled. Of these, 680 with finalized study forms were included in the analysis. Overall, 649 patients were included in the safety analysis set, and 569 were included in the efficacy analysis set. Most of the patients (81.97%) experienced at least one adverse drug reaction (ADR); 22.34% of patients reported serious ADRs and 34.98% of patients experienced grade ≥ 3 ADRs in the safety set. Hypertension (40.37%) and hepatic dysfunction (26.50%) were the two most common ADRs. A total of 262 deaths were reported, of which 12 were due to ADRs. The median PFS was 3.09 months, whereas the median OS was not reached at the end of the 1-year observation period.

Conclusions
The safety and efficacy profiles in this postmarketing observational study were consistent with prior data and registration clinical trials. No new safety signals were observed while treating patients with metastatic soft tissue sarcoma with pazopanib.
A multi-institutional survey of the quality of life after treatment for uterine cervical cancer: a comparison between radical radiotherapy and surgery in Japan
Authors: Kaneyasu Yuko , Fujiwara Hisaya , Nishimura Tetsuo , Sakurai Hideyuki , Kazumoto Tomoko , Ikushima Hitoshi , Uno Takashi , Tokumaru Sunao , Harima Yoko , Gomi Hiromichi , Toita Takafumi , Kita Midori , Noda Shin-ei , Takahashi Takeo , Kato Shingo , Ohkawa Ayako , Tozawa-Ono Akiko , Ushijima Hiroki , Hasumi Yoko , Hirashima Yasuyuki , Niibe Yuzuru , Nakagawa Tomio , Akita Tomoyuki , Tanaka Junko , Ohno Tatsuya ,   the Working Group of the Gynecological Tumor Committee of the Japanese Radiation Oncology Study Group (JROSG)
Published: October 2020

Abstract
This study aimed to research the post-treatment quality of life (QOL) between radiotherapy (RT)- and operation (OP)-treated early cervical cancer survivors, using separate questionnaires for physicians and patients. We administered an observational questionnaire to patients aged 20–70 years old with Stages IB1–IIB cervical cancer who had undergone RT or OP and without recurrence as outpatients for ≥6 months after treatment. We divided 100 registered patients equally into two treatment groups (n = 50 each). The average age was 53 and 44 years in the RT and OP groups, respectively. The RT group included 34 and 66% Stage I and II patients, respectively, whereas the OP group included 66 and 34% Stage I and II patients, respectively. The OP group included 58% of patients with postoperative RT. Combination chemotherapy was performed in 84 and 48% of patients in the RT and OP groups, respectively. On the physicians’ questionnaire, we observed significant differences in bone marrow suppression (RT) and leg edema (OP). On the patients’ questionnaire, significantly more patients had dysuria and leg edema in the OP group than in the RT group, and severe (Score 4–5) leg edema was significantly higher in the post-operative RT group than in the OP only group. The frequency of sexual intercourse decreased after treatment in both groups. On the patients’ questionnaire, there were no significant differences between the two groups regarding sexual activity. These findings are useful to patients and physicians for shared decision-making in treatment choices. The guidance of everyday life and health information including sexual life after treatment is important.