bluuebunny/crossref_metadata_2025_split huggingface dataset:
MutateX: an automated pipeline for in silico saturation mutagenesis of protein structures and structural ensembles
Authors: Tiberti Matteo , Terkelsen Thilde , Degn Kristine , Beltrame Ludovica , Cremers Tycho Canter , da Piedade Isabelle , Di Marco Miriam , Maiani Emiliano , Papaleo Elena 
Published: February 2022

Abstract
Mutations, which result in amino acid substitutions, influence the stability of proteins and their binding to biomolecules. A molecular understanding of the effects of protein mutations is both of biotechnological and medical relevance. Empirical free energy functions that quickly estimate the free energy change upon mutation (ΔΔG) can be exploited for systematic screenings of proteins and protein complexes. In silico saturation mutagenesis can guide the design of new experiments or rationalize the consequences of known mutations. Often software such as FoldX, while fast and reliable, lack the necessary automation features to apply them in a high-throughput manner. We introduce MutateX, a software to automate the prediction of ΔΔGs associated with the systematic mutation of each residue within a protein, or protein complex to all other possible residue types, using the FoldX energy function. MutateX also supports ΔΔG calculations over protein ensembles, upon post-translational modifications and in multimeric assemblies. At the heart of MutateX lies an automated pipeline engine that handles input preparation, parallelization and outputs publication-ready figures. We illustrate the MutateX protocol applied to different case studies. The results of the high-throughput scan provided by our tools can help in different applications, such as the analysis of disease-associated mutations, to complement experimental deep mutational scans, or assist the design of variants for industrial applications. MutateX is a collection of Python tools that relies on open-source libraries. It is available free of charge under the GNU General Public License from https://github.com/ELELAB/mutatex.
Advanced graph and sequence neural networks for molecular property prediction and drug discovery
Authors: Wang Zhengyang , Liu Meng , Luo Youzhi , Xu Zhao , Xie Yaochen , Wang Limei , Cai Lei , Qi Qi , Yuan Zhuoning , Yang Tianbao , Ji Shuiwang 
Published: February 2022

AbstractMotivationProperties of molecules are indicative of their functions and thus are useful in many applications. With the advances of deep-learning methods, computational approaches for predicting molecular properties are gaining increasing momentum. However, there lacks customized and advanced methods and comprehensive tools for this task currently.ResultsHere, we develop a suite of comprehensive machine-learning methods and tools spanning different computational models, molecular representations and loss functions for molecular property prediction and drug discovery. Specifically, we represent molecules as both graphs and sequences. Built on these representations, we develop novel deep models for learning from molecular graphs and sequences. In order to learn effectively from highly imbalanced datasets, we develop advanced loss functions that optimize areas under precision–recall curves (PRCs) and receiver operating characteristic (ROC) curves. Altogether, our work not only serves as a comprehensive tool, but also contributes toward developing novel and advanced graph and sequence-learning methodologies. Results on both online and offline antibiotics discovery and molecular property prediction tasks show that our methods achieve consistent improvements over prior methods. In particular, our methods achieve #1 ranking in terms of both ROC-AUC (area under curve) and PRC-AUC on the AI Cures open challenge for drug discovery related to COVID-19.Availability and implementationOur source code is released as part of the MoleculeX library (https://github.com/divelab/MoleculeX) under AdvProp.Supplementary informationSupplementary data are available at Bioinformatics online.
Autophagy modulation in multiple sclerosis and experimental autoimmune encephalomyelitis
Authors: Shen Donghui , Liu Kang , Wang Hongyan , Wang Haifeng 
Published: February 2022

AbstractMultiple sclerosis (MS), a white matter demyelinating disease of the central nervous system (CNS), is characterized by neuroinflammatory and neurodegenerative. Experimental autoimmune encephalomyelitis (EAE) is a commonly used animal model for investigating pathogenic mechanisms of MS, representing the destruction of the blood-brain barrier (BBB), the activation of T cells, and the infiltration of myeloid cells. An increasing number of studies have documented that autophagy plays a critical role in the pathogenesis of both MS and EAE. Autophagy maintains CNS homeostasis by degrading the damaged organelles and abnormal proteins. Furthermore, autophagy is involved in inflammatory responses by regulating the activation of immune cells and the secretion of inflammatory factors. However, the specific mechanisms of autophagy involved in MS and EAE are not completely understood. In this review, we will summarize the complex mechanisms of autophagy in MS and EAE, providing potential therapeutic approaches for the management of MS.
Verbal production dynamics and plasticity: functional contributions of language and executive control systems
Authors: Gurunandan Kshipra , Carreiras Manuel , Paz-Alonso Pedro M 
Published: February 2022

Abstract
Bilingual language production requires both language knowledge and language control in order to communicate in a target language. Learning or improving a language in adulthood is an increasingly common undertaking, and this has complex effects on the cognitive and neural processes underlying language production. The current functional magnetic resonance imaging (fMRI) experiment investigated the functional plasticity of verbal production in adult language learners, and examined the dynamics of word retrieval in order to dissociate the contributions of language knowledge and executive control. Thirty four adults who were either intermediate or advanced language learners, underwent MRI scanning while performing verbal fluency tasks in their native and new languages. A multipronged analytical approach revealed (i) time-varying contributions of language knowledge and executive control to verbal fluency performance, (ii) learning-related changes in the functional correlates of verbal fluency in both the native and new languages, (iii) no effect of learning on lateralization, and (iv) greater functional coupling between language and language control regions with greater second language experience. Collectively, our results point to significant functional plasticity in adult language learners that impacts the neural correlates of production in both the native and new languages, and provide new insight into the widely used verbal fluency task.
Reduced Serological Response to COVID-19 Vaccines in Patients with IBD is Further Diminished by TNF Inhibitor Therapy; Early Results of the VARIATION study [VAriability in Response in IBD Against SARS-COV-2 ImmunisatiON]
Authors: Doherty Jayne , Morain Neil O , Stack Roisin , Girod Parker , Tosetto Miriam , Inzitiari Rosanna , Sheridan Juliette , Cullen Garret , McDermott Edel , Buckley Maire , Horgan Gareth , Mulcahy Hugh , Ryan Elizabeth J , Daghfal David , Doran Peter , Morain Colm O , Doherty Glen A 
Published: February 2022

Abstract

Background and Aims
Evidence suggests patients with inflammatory bowel disease [IBD] receiving TNF antagonists have attenuated response to vaccination against COVID-19. We sought to determine the impact of IBD and of various medications for treatment of IBD on antibody responses to vaccination against COVID-19.

Methods
Patients with IBD [n = 270] and healthy controls [HC, n = 116] were recruited prospectively, and quantitative antibody responses were assessed following COVID-19 vaccination. The impact of IBD and of medications for treatment of IBD on vaccine response rates was investigated.

Results
Of HC, 100% seroconverted following complete vaccination with two vaccine doses; 2% of patients with IBD failed to seroconvert. Median anti-spike protein [SP] immunoglobulin [Ig]G levels following complete vaccination in our IBD cohort was significantly lower than among HC [2613 AU/mL versus 6871 AU/mL, p ≤0.001]. A diagnosis of IBD was independently associated with lower anti-SP IgG levels [β coefficient -0.2, p = 0.001]. Use of mRNA vaccines was independently associated with higher anti-SP IgG levels [β coefficient 0.25, p ≤0.001]. Patients with IBD receiving TNF inhibitors had significantly lower anti-SP IgG levels [2445 AU/mL] than IBD patients not receiving TNF inhibitors [3868 AU/mL, p ≤0.001]. Patients with IBD not receiving TNF inhibitors still showed attenuated responses compared with HC [3868 AU/mL versus 8747 AU/mL, p = 0.001].

Conclusions
Patients with IBD have attenuated serological responses to SARS-CoV-2 vaccination. Use of anti-TNF therapy negatively affects anti-SP IgG levels further. Patients who do not seroconvert following vaccination are a particularly vulnerable cohort. Impaired responses to vaccination in our study highlight the importance of booster vaccination programmes for patients with IBD.
Case report of the broad spectrum of late complications in an adult patient with univentricular physiology palliated by the Fontan circulation
Authors: Nederend Marieke , Egorova Anastasia D , Vliegen Hubert W , Roest Arno A W , Ruijter Bastian N , Korteweg Tijmen , Ninaber Maarten K , Zeppenfeld Katja , Hazekamp Mark G , Kiès Philippine , Jongbloed Monique R M 
Published: February 2022

Abstract

Background
At the most severe end of the spectrum of congenital heart disease are patients with an univentricular physiology. They comprise a heterogeneous group of congenital heart malformations that have the common characteristic that the cardiac morphology is not equipped for sustaining a biventricular circulation.

Case summary
Here, we present a case of an adult patient after Fontan palliation, illustrative of the complex clinical course and the broad spectrum of complications that can be encountered during follow-up, highlighting the need for a multidisciplinary approach in the clinical care for these patients.

Discussion
During the surgical Fontan procedure, the inferior vena cava is connected to the pulmonary circulation, after prior connection of the superior vena cava to the pulmonary arterial circulation. The resulting cavopulmonary connection, thus lacking a subpulmonic ventricle, provides non-pulsatile passive flow of oxygen-poor blood from the systemic venous circulation into the lungs, and the functional monoventricle pumps the oxygen-rich pulmonary venous return blood into the aorta. With an operative mortality of &lt;5% and current 30-year survival rates up to 85%, the adult population of patients with a Fontan circulation is growing. This increase in survival is, however, inevitably accompanied by long-term complications affecting multiple organ systems, resulting in decline in cardiovascular performance.

Conclusion
For optimal treatment, the evaluation in a multidisciplinary team is mandatory, using the specific expertise of the team members to timely detect and address late complications and to support quality of life.
Treatment and intention-to-treat propensity score analysis to evaluate the impact of video-assisted thoracic surgery on 90-day mortality after anatomical resection for lung cancer
Authors: Recuero-Díaz Jose Luis , Royo-Crespo Iñigo , Gómez de-Antonio David , Call Sergi , Aguinagalde Borja , Gómez-Hernández María Teresa , Hernández-Ferrández Jorge , Sánchez-Lorente David , Sesma-Romero Julio , Rivo Eduardo , Moreno-Mata Nicolás , Embun Raul 
Published: February 2022

Abstract

OBJECTIVES
The aim of this study was to know the treatment effect of video-assisted thoracic surgery (VATS) on 90-day mortality after anatomical lung resection based on a nationwide cohort.

METHODS
This is a multicentre prospective cohort of 2721 anatomical resections for lung cancer from December 2016 to March 2018. Treatment and intention-to-treat (ITT) analyses were performed after inverse probability score weighting and different propensity score matching algorithms. Covariate balance was assessed by standardized mean differences. The estimators reported were the average treatment effect, the average treatment effect on the treated and odds ratios after conditional logistic models with 95% confidence intervals. The unconfoundedness assumption was evaluated by sensitivity analysis for average treatment effect (c-dependence) and average treatment effect on the treated (Γ).

RESULTS
VATS was the initial approach in 1911 patients (70.2%), though 273 cases (14.3%) had to be converted to thoracotomy. Ninety-day mortality rates were: treatment analysis (VATS 1.16% vs open 3.9%, P &lt; 0.001), ITT analysis (VATS 1.78% vs open 3.36%, P = 0.012). After inverse probability score weighting and propensity score matching, in the treatment analysis, VATS meant absolute risk reductions between 2.25% and 2.96% and relative risk reductions between 65% and 70% [OR = 0.34 (95% confidence interval 0.15–0.79), all P-values &lt;0.004). However, all the estimators turned out to be non-significant in the ITT analyses. A high sensitivity to unobservable confounders was proved (c-dependence 0.135, Γ = 1.5).

CONCLUSIONS
VATS can reduce the risk of 90-day mortality after anatomical lung resection. However, the implications of conversion to thoracotomy, comparing ITT versus treatment analysis, and the potential impact of hidden bias should deserve further attention in the future.
Hospitalization and Mortality Risk for COVID-19 Cases With SARS-CoV-2 AY.4.2 (VUI-21OCT-01) Compared to Non-AY.4.2 Delta Variant Sublineages
Authors: Nyberg Tommy , Harman Katie , Zaidi Asad , Seaman Shaun R , Andrews Nick , Nash Sophie G , Charlett Andre , Lopez Bernal Jamie , Myers Richard , Groves Natalie , Gallagher Eileen , Gharbia Saheer , Chand Meera , Thelwall Simon , De Angelis Daniela , Dabrera Gavin , Presanis Anne M 
Published: February 2022

Abstract
To investigate if the AY.4.2 sublineage of the SARS-CoV-2 delta variant is associated with hospitalization and mortality risks that differ from non-AY.4.2 delta risks, we performed a retrospective cohort study of sequencing-confirmed COVID-19 cases in England based on linkage of routine health care datasets. Using stratified Cox regression, we estimated adjusted hazard ratios (aHR) of hospital admission (aHR = 0.85; 95% confidence interval [CI], .77–.94), hospital admission or emergency care attendance (aHR = 0.87; 95% CI, .81–.94), and COVID-19 mortality (aHR = 0.85; 95% CI, .71–1.03). The results indicate that the risks of hospitalization and mortality are similar or lower for AY.4.2 compared to cases with other delta sublineages.
P11 The ratio and antibiotic resistance profiles of Serratia species among other causative bacteria isolated from blood cultures between 2015 and 2020
Authors: Özcan Nida , Atmaca Selahattin , Özbek Erdal 
Published: February 2022

Abstract

Background
Serratia spp., especially Serratia marcescens, have become one of the main drug-resistant causes of hospital infections in the last five decades.1 There are a limited number of publications on Serratia spp., which cause sporadic infections or outbreaks in ICU patients, especially paediatric patients.2 S. marcescens was reported to have intrinsic resistance to many β-lactam antibiotics, tetracyclines and polymyxins.3–5

Objectives
To investigate the antibiotic resistance profiles of the Serratia spp. and detection rates among blood cultures.

Materials and methods
This retrospective study was approved by Dicle University Medicine Faculty Non-Invasive Clinical Research Committee (no: 361, 1 September 2021). Blood culture samples sent from Dicle University Hospital clinics and ICUs between 2015 and 2020 were included. Blood culture samples were incubated in the BD BACTEC FX (Becton Dickinson, USA) system, and the isolates were identified at genus and/or species level by MS using the MALDI Biotyper 3 (Bruker Daltonics, USA). Antimicrobial susceptibility tests (AST) of the isolates were performed with the BD Phoenix 100 (Becton Dickinson, USA) automated system. AST results were interpreted according to the EUCAST criteria.6

Results
Among 9730 agents isolated from blood cultures over a 6 year period, 69 (0.7%) were identified as Serratia spp., 56 of them being S. marcescens (Table 1). Of patients from whom Serratia spp. were isolated, 37 (54%) were paediatric and 47 (68%) were ICU patients (Table 2). A total of 20 isolates (29%) were resistant to at least one of the carbapenems tested. The most effective antibiotics against Serratia spp. were found to be trimethoprim/sulfamethoxazole, ciprofloxacin and amikacin, with resistance rates of 3%, 4% and 7%, respectively (Table 3).

Conclusions
Serratia species were isolated from blood cultures at a rate of 0.7% in a 6 year period, and increased carbapenem resistance among isolates was noteworthy.
P15 Evaluation of the stability of temocillin in elastomeric infusion devices used for outpatient parenteral antimicrobial therapy in accordance with the requirements of the UK NHS Yellow Cover Document
Authors: Sime Fekade B. , Wallis Steven C. , Jamieson Conor , Hills Tim , Gilchrist Mark , Santillo Mark , Seaton R. Andrew , Drummond Felicity , Roberts Jason A. 
Published: February 2022

Abstract

Background
To assess the feasibility of its use in OPAT via continuous infusion, the stability of temocillin solutions at clinically relevant concentrations in two elastomeric infusion devices (B. Braun Medical Ltd Easypump® II LT 270-27- S and Spirit Ltd Medical Dosi-Fuser® L25915-250D1) was evaluated during 14 days of (2°C–8°C) fridge storage followed by 24 h exposure in-use temperature at 32°C, when reconstituted with 0.3% citrate buffer at pH 7.

Methods
Stability testing was conducted in accordance with the standard protocols for deriving and assessment of stability of small molecule aseptic preparation as per the latest UK National Health Service Pharmaceutical Quality Assurance Committee Yellow Cover Document (YCD) requirements. A stability indicating assay method was developed with an ultra-HPLC (UHPLC) system using photodiode array detector. Temocillin concentrations corresponding to low (500 mg/240 mL), intermediate (4000 mg/240 mL) and high (6000 mg/240 mL) dose in triplicate devices were tested with duplicate samples at 11 timepoints during 14 days of fridge storage followed by 24 h in-use temperature exposure at 32°C.

Results
A total of 396 samples were collected and assayed. The percentage of temocillin remaining after 14 days of fridge storage was greater than 97% in both devices and at all concentrations tested. During in-use temperature, 95% stability limit was achieved for 12 h for all doses and devices tested except for the high concentration in the Dosi-Fuser® device, which met this criterion for only 10 h of in-use temperature exposure.

Conclusions
Temocillin reconstituted with 0.3% citrate buffer at pH 7 in elastomeric infusion devices can be stored in a fridge (2°C–8°C) for 2 weeks, meeting the YCD acceptance criteria of &lt;5% degradation. Within the UK, the current data supports twice daily dosing of temocillin with &lt;5% degradation at in-use temperature of 32°C for 12 h, except at high dose (6000 mg/240 mL) in the Dosi-Fuser® device, which must be limited to 10 h. The limits of accepted degradation do vary in other countries. Temocillin is an important addition to the anti-Gram-negative OPAT armamentarium and may reduce reliance on other broader spectrum, higher consequence agents.
P19 IV antimicrobial duration in practice
Authors: Akintimehin Abisoye O. , Wade Paul , Brown Aisling F. 
Published: February 2022

Abstract

Background
Tackling antimicrobial resistance by reducing unnecessary or inappropriate prescribing is a key priority.

Objectives
To review current clinical practice at Guy's and St Thomas’ Hospital around duration of IV antimicrobial therapy framed with Start Smart Then Focus national guidelines.

Methods
Newly started inpatient prescriptions for IV antimicrobials over three consecutive Mondays were reviewed. Prescriptions not for treatment of acute infections were excluded, as were patients admitted to critical care, obstetrics/gynaecology and paediatric wards. Each patient's record was reviewed at Day 0, 3 and 5. Data were analysed using IBM® SPSS Statistics version 27.

Results
In total, 80 patients with 89 antibiotic prescriptions (71 = β-lactam, 5 = aminoglycoside, 2 = glycopeptide, 1 = ciprofloxacin, 9 = metronidazole, 1 = linezolid) were included. Median age was 66 (IQR 53–75). Documented indications were for suspected or proven infection of urinary tract (15%), respiratory tract (25%), skin/soft tissue (14%), sepsis (1.25%), intra-abdominal (15%), bacteraemia (7.5%), bone and joint infections (2.5%) or other (20%). Median initial NEWS2 on Day 0 was 3 (IQR 1–4), WCC 11.45 (IQR 8.27–14.15) and CRP 121 (IQR 47–208). Median length of stay was 7.5 days. Median duration of IV antimicrobial was 4 (IQR 2–6) days. By D3, 3 patients had died and 16 had been discharged. Of 61 remaining inpatients on D3, 4 had their antimicrobials switched, 14 had been switched to PO antimicrobials, 43 were continued on IV antibiotics. By D5, 17 further patients had been discharged, 44 remained inpatients. Twenty-two had stopped antimicrobials with 22 continuing IV therapy. A number of patients could have been switched from IV to oral therapy by current guidance but were not (D3 x = 11, D5 n = 8). Higher median D0 CRP was seen in those who continued on IV therapy on D3 (139 versus 79 mg/dL) as was higher D3 WCC (13.9 versus 11.9 × 109/L). There was no significant relationship between a NEWS2 score ≥3 and IV to PO switch at D3 or D5. Thirty-two patients had input from the Infection team within 7 days of first prescription. Fifteen patients (21%) received IV antibiotics for more than 7 days, and 14/15 had Infection team input. Three patients were discharged with OPAT.

Conclusions
Median duration of IV therapy for suspected/proven infections in our centre is less than 5 days and only 28% of patients were still receiving IV antibiotics by D5. A number of missed opportunities for earlier switch to oral therapy were identified. The potential for earlier safe discontinuation of IV therapy using patient-specific measures should be explored. A minority of patients received IV therapy for &gt;7 days, and this was almost universally associated with specialist Infection involvement in complex infections with a view to optimizing patient management and antimicrobial stewardship.