bluuebunny/crossref_metadata_2025_split huggingface dataset:
The Antibiotic Efflux Protein TolC Is a Highly Evolvable Target under Colicin E1 or TLS Phage Selection
Authors: Tamer Yusuf Talha , Gaszek Ilona , Rodrigues Marinelle , Coskun Fatma Sevde , Farid Michael , Koh Andrew Y , Russ William , Toprak Erdal 
Published: June 2021

Abstract
Bacteriophages and bacterial toxins are promising antibacterial agents to treat infections caused by multidrug-resistant (MDR) bacteria. In fact, bacteriophages have recently been successfully used to treat life-threatening infections caused by MDR bacteria (Schooley RT, Biswas B, Gill JJ, Hernandez-Morales A, Lancaster J, Lessor L, Barr JJ, Reed SL, Rohwer F, Benler S, et al. 2017. Development and use of personalized bacteriophage-based therapeutic cocktails to treat a patient with a disseminated resistant Acinetobacter baumannii infection. Antimicrob Agents Chemother. 61(10); Chan BK, Turner PE, Kim S, Mojibian HR, Elefteriades JA, Narayan D. 2018. Phage treatment of an aortic graft infected with Pseudomonas aeruginosa. Evol Med Public Health. 2018(1):60–66; Petrovic Fabijan A, Lin RCY, Ho J, Maddocks S, Ben Zakour NL, Iredell JR, Westmead Bacteriophage Therapy Team. 2020. Safety of bacteriophage therapy in severe Staphylococcus aureus infection. Nat Microbiol. 5(3):465–472). One potential problem with using these antibacterial agents is the evolution of resistance against them in the long term. Here, we studied the fitness landscape of the Escherichia coli TolC protein, an outer membrane efflux protein that is exploited by a pore forming toxin called colicin E1 and by TLS phage (Pagie L, Hogeweg P. 1999. Colicin diversity: a result of eco-evolutionary dynamics. J Theor Biol. 196(2):251–261; Andersen C, Hughes C, Koronakis V. 2000. Chunnel vision. Export and efflux through bacterial channel-tunnels. EMBO Rep. 1(4):313–318; Koronakis V, Andersen C, Hughes C. 2001. Channel-tunnels. Curr Opin Struct Biol. 11(4):403–407; Czaran TL, Hoekstra RF, Pagie L. 2002. Chemical warfare between microbes promotes biodiversity. Proc Natl Acad Sci U S A. 99(2):786–790; Cascales E, Buchanan SK, Duché D, Kleanthous C, Lloubès R, Postle K, Riley M, Slatin S, Cavard D. 2007. Colicin biology. Microbiol Mol Biol Rev. 71(1):158–229). By systematically assessing the distribution of fitness effects of ∼9,000 single amino acid replacements in TolC using either positive (antibiotics and bile salts) or negative (colicin E1 and TLS phage) selection pressures, we quantified evolvability of the TolC. We demonstrated that the TolC is highly optimized for the efflux of antibiotics and bile salts. In contrast, under colicin E1 and TLS phage selection, TolC sequence is very sensitive to mutations. Finally, we have identified a large set of mutations in TolC that increase resistance of E. coli against colicin E1 or TLS phage without changing antibiotic susceptibility of bacterial cells. Our findings suggest that TolC is a highly evolvable target under negative selection which may limit the potential clinical use of bacteriophages and bacterial toxins if evolutionary aspects are not taken into account.
Kmerator Suite: design of specific k-mer signatures and automatic metadata discovery in large RNA-seq datasets
Authors: Riquier Sébastien , Bessiere Chloé , Guibert Benoit , Bouge Anne-Laure , Boureux Anthony , Ruffle Florence , Audoux Jérôme , Gilbert Nicolas , Xue Haoliang , Gautheret Daniel , Commes Thérèse 
Published: June 2021

Abstract
The huge body of publicly available RNA-sequencing (RNA-seq) libraries is a treasure of functional information allowing to quantify the expression of known or novel transcripts in tissues. However, transcript quantification commonly relies on alignment methods requiring a lot of computational resources and processing time, which does not scale easily to large datasets. K-mer decomposition constitutes a new way to process RNA-seq data for the identification of transcriptional signatures, as k-mers can be used to quantify accurately gene expression in a less resource-consuming way. We present the Kmerator Suite, a set of three tools designed to extract specific k-mer signatures, quantify these k-mers into RNA-seq datasets and quickly visualize large dataset characteristics. The core tool, Kmerator, produces specific k-mers for 97% of human genes, enabling the measure of gene expression with high accuracy in simulated datasets. KmerExploR, a direct application of Kmerator, uses a set of predictor gene-specific k-mers to infer metadata including library protocol, sample features or contaminations from RNA-seq datasets. KmerExploR results are visualized through a user-friendly interface. Moreover, we demonstrate that the Kmerator Suite can be used for advanced queries targeting known or new biomarkers such as mutations, gene fusions or long non-coding RNAs for human health applications.
Critical Presentation of a Severe Acute Respiratory Syndrome Coronavirus 2 Reinfection: A Case Report
Authors: Massanella Marta , Martin-Urda Anabel , Mateu Lourdes , Marín Toni , Aldas Irene , Riveira-Muñoz Eva , Kipelainen Athina , Jiménez-Moyano Esther , Rodriguez de la Concepción Maria Luisa , Avila-Nieto Carlos , Trinité Benjamin , Pradenas Edwards , Rodon Jordi , Marfil Silvia , Parera Mariona , Carrillo Jorge , Blanco Julià , Prado Julia G , Ballana Ester , Vergara-Alert Júlia , Segalés Joaquim , Noguera-Julian Marc , Masabeu Àngels , Clotet Bonaventura , Toda Maria de la Roca , Paredes Roger 
Published: June 2021

AbstractBackgroundSevere acute respiratory syndrome coronavirus 2 (SARS-CoV-2) reinfections have been reported; however, most cases are milder than the primary infection. We report the first case of a life-threatening critical presentation of a SARS-CoV-2 reinfection.MethodsA 62-year-old man from Palamós (Spain) suffered a first mild coronavirus disease 2019 (COVID-19) episode in March 2020, confirmed by 2 independent SARS-CoV-2 nasopharyngeal polymerase chain reaction (PCR) assays and a normal radiograph. He recovered completely and tested negative on 2 consecutive PCRs. In August 2020, the patient developed a second SARS-CoV-2 infection with life-threatening bilateral pneumonia and Acute respiratory distress syndrome criteria, requiring COVID-19–specific treatment (remdesivir + dexamethasone) plus high-flow oxygen therapy. Nasopharyngeal swabs from the second episode were obtained for virus quantification by real-time PCR, for virus outgrowth and sequencing. In addition, plasma and peripheral blood mononuclear cells during the hospitalization period were used to determine SARS-CoV-2–specific humoral and T-cell responses.ResultsGenomic analysis of SARS-CoV-2 showed that the virus had probably originated shortly before symptom onset. When the reinfection occurred, the subject showed a weak immune response, with marginal humoral and specific T-cell responses against SARS-CoV-2. All antibody isotypes tested as well as SARS-CoV-2 neutralizing antibodies increased sharply after day 8 postsymptoms. A slight increase of T-cell responses was observed at day 19 after symptom onset.ConclusionsThe reinfection was firmly documented and occurred in the absence of robust preexisting humoral and cellular immunity. SARS-CoV-2 immunity in some subjects is unprotective and/or short-lived; therefore, SARS-CoV-2 vaccine schedules inducing long-term immunity will be required to bring the pandemic under control.
Social Determinants of Health and Care Outcomes Among People With HIV in the United States
Authors: Menza Timothy W , Hixson Lindsay K , Lipira Lauren , Drach Linda 
Published: June 2021

Abstract

Background
Fewer than 70% of people with HIV (PWH) in the United States have achieved durable viral suppression. To end the HIV epidemic in the United States, clinicians, researchers, and public health practitioners must devise ways to remove barriers to effective HIV treatment. To identify PWH who experience challenges to accessing health care, we created a simple assessment of social determinants of health (SDOH) among PWH and examined the impact of cumulative social and economic disadvantage on key HIV care outcomes.

Methods
We used data from the 2015–2019 Medical Monitoring Project, a yearly cross-sectional survey of PWH in the United States (n = 15 964). We created a 10-item index of SDOH and assessed differences in HIV care outcomes of missed medical appointments, medication adherence, and durable viral suppression by SDOH using this index using prevalence ratios with predicted marginal means.

Results
Eighty-three percent of PWH reported at least 1 SDOH indicator. Compared with PWH who experienced none of the SDOH indicators, people who experienced 1, 2, 3, and 4 or more SDOH indicators were 1.6, 2.1, 2.6, and 3.6 as likely to miss a medical appointment in the prior year; 11%, 17%, 20%, and 31% less likely to report excellent adherence in the prior 30 days; and 2%, 4%, 10%, and 20% less likely to achieve durable viral suppression in the prior year, respectively.

Conclusions
Among PWH, cumulative exposure to social and economic disadvantage impacts care outcomes in a dose-dependent fashion. A simple index may identify PWH experiencing barriers to HIV care, adherence, and durable viral suppression in need of critical supportive services.
Real-world Effectiveness and Tolerability of Monoclonal Antibody Therapy for Ambulatory Patients With Early COVID-19
Authors: Webb Brandon J , Buckel Whitney , Vento Todd , Butler Allison M , Grisel Nancy , Brown Samuel M , Peltan Ithan D , Spivak Emily S , Shah Mark , Sakata Theadora , Wallin Anthony , Stenehjem Eddie , Poulsen Greg , Bledsoe Joseph 
Published: June 2021

Abstract

Background
Neutralizing monoclonal antibodies (MAbs) are a promising therapy for early coronavirus disease 2019 (COVID-19), but their effectiveness has not been confirmed in a real-world setting.

Methods
In this quasi-experimental pre-/postimplementation study, we estimated the effectiveness of MAb treatment within 7 days of symptom onset in high-risk ambulatory adults with COVID-19. The primary outcome was a composite of emergency department visits or hospitalizations within 14 days of positive test. Secondary outcomes included adverse events and 14-day mortality. The average treatment effect in the treated for MAb therapy was estimated using inverse probability of treatment weighting and the impact of MAb implementation using propensity-weighted interrupted time series analysis.

Results
Pre-implementation (July–November 2020), 7404 qualifying patients were identified. Postimplementation (December 2020–January 2021), 594 patients received MAb treatment and 5536 did not. The primary outcome occurred in 75 (12.6%) MAb recipients, 1018 (18.4%) contemporaneous controls, and 1525 (20.6%) historical controls. MAb treatment was associated with decreased likelihood of emergency care or hospitalization (odds ratio, 0.69; 95% CI, 0.60–0.79). After implementation, the weighted probability that a given patient would require an emergency department visit or hospitalization decreased significantly (0.7% per day; 95% CI, 0.03%–0.10%). Mortality was 0.2% (n = 1) in the MAb group compared with 1.0% (n = 71) and 1.0% (n = 57) in pre- and postimplementation controls, respectively. Adverse events occurred in 7 (1.2%); 2 (0.3%) were considered serious.

Conclusions
MAb treatment of high-risk ambulatory patients with early COVID-19 was well tolerated and likely effective at preventing the need for subsequent emergency department or hospital care.
Pre-Visit Education on Pain Management Options Prior to the First Clinic Visit Improves Chronic Pain Patient Satisfaction with Proposed Treatment Plans
Authors: Unnithan Ajay S , Chidgey Brooke A 
Published: June 2021

Abstract

Objective
This study sought to evaluate if actively informing new chronic pain patients about treatment options and setting realistic expectations for care, through the use of a pre-visit informational handout prior to the first clinic visit, improved patient satisfaction with subsequently proposed treatment plans.

Methods
The study was divided into two 3-month periods. During the first 3 months, with our current pain clinic practices in place, new patients (n = 147) were given surveys to establish a baseline of patient satisfaction with treatment plans proposed on their first visit. During the second 3 months, a different group of new patients (n = 156) was given a detailed informational handout which described our clinic’s multimodal approach to pain management and therapeutic expectations prior to their visit with a provider. Patient satisfaction with subsequently proposed treatment plans was then assessed and compared with the baseline group.

Results
The average patient satisfaction score for the group of patients given the informational handout was 4.21 (on a 5-point Likert scale), compared to an average score of 3.25 for the baseline group (P &lt; .0001, unpaired t-test). 77.6% of patients given the informational handout said their proposed treatment plan met their expectations compared to 46.3% of patients in the baseline group (χ2= 31.61, two-tailed P &lt; .0001).

Conclusions
Patient satisfaction with proposed chronic pain treatment plans was improved when clinic approaches to pain were explicitly outlined and therapeutic expectations were clearly established in the form of an informational handout at the outset of the first visit.
Differential Pain Presentations Observed across Post-Traumatic Stress Disorder Symptom Trajectories after Combat Injury
Authors: Giordano Nicholas A , Richmond Therese S , Farrar John T , ‘Trip’ Buckenmaier III Chester C , Gallagher Rollin M , Polomano Rosemary C 
Published: June 2021

AbstractObjectiveThis study evaluated the association between pain outcomes and post-traumatic stress disorder (PTSD) symptom trajectories after combat-related injury, while adjusting for receipt of regional anesthesia (RA) soon after injury.MethodsThe PTSD symptom trajectories of N = 288 combat-injured service members were examined from within a month of injury up to two-years after. Linear mixed-effects models evaluated the association between PTSD symptom trajectories and average pain and pain interference outcomes while adjusting for receipt of RA during combat casualty care.ResultsFour PTSD trajectories were characterized: resilient, recovering, worsening, and chronic. Differential pain presentations were associated with PTSD symptom trajectories, even after adjusting for receipt of RA. Compared to those with a resilient PTSD symptom trajectory, individuals presenting with chronic PTSD trajectories were estimated to experience average pain scores 2.61 points higher (95% CI: 1.71, 3.14). Participants presenting with worsening (β = 1.42; 95% CI: 0.77, 1.78) and recovering PTSD trajectories (β = 0.65; 95% CI: 0.09, 1.08) were estimated to experience higher average pain scores than participants with resilient PTSD trajectories. Significant differences in pain interference scores were observed across PTSD trajectories. Receiving RA was associated with improved pain up to two years after injury (β = -0.31; 95% CI: -0.90, -0.04), however no statistically significant association was detected between RA and PTSD trajectories.ConclusionsChronic and worsening PTSD trajectories were associated with greater pain intensity and interference following combat injury even when accounting for receipt of early RA for pain management. These findings underscore the need to jointly assess pain and PTSD symptoms across the trauma care continuum.
TIME, AND TIME AGAIN
Authors: Baron Sam , Lin Yi-Cheng 
Published: June 2021

Abstract
A number of philosophers uphold a metaphysical symmetry between time and hypertime, in this sense: in so far as hypertime exists, the nature of hypertime should agree with the nature of time. Others allow that we can mix and match the metaphysics of time and hypertime. Thus, it may be that time really passes, but hypertime does not or vice versa. In this paper, we provide a preliminary defense of the mix and match approach. We outline a number of arguments for the claim that time and hypertime must share a common nature and find them all wanting.
Serological abnormalities that predict progression to systemic autoimmune rheumatic diseases in antinuclear antibody–positive individuals
Authors: Muñoz-Grajales Carolina , Prokopec Stephenie D , Johnson Sindhu R , Touma Zahi , Ahmad Zareen , Bonilla Dennisse , Hiraki Linda , Bookman Arthur , Boutros Paul C , Chruscinski Andrzej , Wither Joan 
Published: June 2021

Abstract

Objective
We investigated the autoantibody (autoAb) profiles in ANA+ individuals lacking systemic autoimmune rheumatic disease (SARD) and early SARD patients to determine the key differences between these groups and identify factors that are associated with an increased risk of symptomatic progression within the next 2 years in ANA+ individuals.

Methods
Using custom antigen (Ag) microarrays, 144 IgM and IgG autoAbs were surveyed in 84 asymptomatic and 123 symptomatic (48 UCTD and 75 SARD patients) ANA+ individuals. AutoAbs were compared in ANA+ individuals lacking a SARD diagnosis with ≥2 years follow-up (n = 52), including all those who demonstrated progression (n = 14) during this period, with changes over time assessed in a representative subset.

Results
We show that ANA+ individuals have autoAb to many self-Ags that are not being captured by current screening techniques and very high levels of these autoAbs are predominantly restricted to early SARD patients, with SLE patients displaying reactivity to many more autoAgs than the other groups. In general, the symptoms that developed in progressors mirrored those seen in SARD patients with similar patterns of autoAbs. Only anti-Ro52 Abs were found to predict progression (positive predictive value 46%, negative predictive value 89%). Surprisingly, over 2 years of follow-up the levels of autoAbs remained remarkably stable regardless of whether individuals progressed or not.

Conclusion
Our findings strongly argue that development of assays with an expanded set of auto-Ags and enhanced dynamic range would improve the diagnostic and prognostic ability of autoAb testing.
Is the Association Between Parents’ Mental Illness and Child Psychopathology Mediated via Home Environment and Caregiver’s Psychosocial Functioning? A Mediation Analysis of the Danish High Risk and Resilience Study—VIA7, a Population-Based Cohort Study
Authors: Uddin Md Jamal , Ekstrøm Claus Thorn , Hemager Nicoline , Christiani Camilla A J , Gregersen Maja , Ellersgaard Ditte Vestbjerg , Spang Katrine Søborg , Greve Aja , Gantriis Ditte Lou , Burton Birgitte Klee , Søndergaard Anne , Nudel Ron , Mortensen Preben Bo , Pedersen Marianne Giørtz , Pedersen Carsten Bøcker , Wang Yunpeng , Werge Thomas , Bybjerg-Grauholm Jonas , von Plessen Kerstin J , Bliksted Vibeke , Mors Ole , Thorup Anne A E , Nordentoft Merete 
Published: June 2021

Abstract
We aimed to investigate to which degree the home environment and/or primary caregivers’ level of functioning mediate the association between parental mental illness (eg, schizophrenia) and child psychopathology. We used data from the nationwide Danish High Risk and Resilience Study—VIA7. The study sample comprised 522 seven-year-old children. The main outcome was the child psychopathology, assessed with the Child Behavior Checklist (CBCL). The exposure variable had 3 categories: children at familial high risk of schizophrenia spectrum psychosis (FHR-SZ), bipolar disorder (FHR-BP), and population-based controls. Mediators were quality of the Home Observation for Measurement of the Environment (HOME) and primary caregiver’s Personal and Social Performance Scale (primary caregiver functioning). Primary caregiver’s IQ and polygenic risk scores (PRS) for the educational attainment of the children were considered as covariates. We found a significant indirect adjusted effect of FHR status vs controls on CBCL total scores (FHR-SZ = 5.34, 95% confidence interval [CI]: 3.50–7.47 and FHR-BP = 4.54, 95% CI: 2.65–6.68), through primary caregiver functioning and HOME. Both mediators combined explained 53% and 64% variation of the total effects of FHR-SZ and FHR-BP, respectively. Adjusting for the PRS in the mediation models only resulted in minor changes in the FHR effects on the CBCL. We conclude that the HOME and the primary caregiver functioning are important mediating factors for child psychopathology, especially in children born with familial risk for severe mental illness. This knowledge may represent a window of opportunity for the development of preventive strategies (eg, intervention to improve primary caregiver functioning and home environment).
A nationwide cross-sectional study of difficulty waking up for school among adolescents
Authors: Kinoshita Yu , Itani Osamu , Otsuka Yuichiro , Matsumoto Yuuki , Nakagome Sachi , Osaki Yoneatsu , Higuchi Susumu , Maki Jike , Kanda Hideyuki , Kaneita Yoshitaka 
Published: June 2021

Abstract

Study Objectives
To determine the prevalence of and risk-factors for difficulty waking up for school among adolescents.

Methods
We used a self-administered questionnaire (140 junior high schools [JHSs]; 124 senior high schools [SHSs]) selected randomly in 2012 from throughout Japan.

Results
Total response rate: 60.7%. Data from 38 494 JHS and 61 556 SHS students were analyzed. The prevalence of at least one instance of school tardiness/absence due to difficulty waking up over a 30-day period was 10.9 (95% confidence-interval:10.5–11.3)%/2.9(2.7–3.1)% for JHS-boys and 7.7(7.3–8.1)%/2.0(1.8–2.2)% for JHS-girls. The prevalence was 15.5(15.1–15.9)%/5.6(5.3–5.9)% for SHS-boys and 14.4(14.0–14.8)%/5.9(5.6–6.2)% for SHS-girls. We used ordinal regression to identify the risk factors associated with the experience of school tardiness/absence. Factors significantly associated with school tardiness in all four groups (JHS boys/girls, SHS boys/girls) were “no-participation-in-club-activities,” “early-morning-awakening,” “feeling bad throughout a morning,” “drinking,” and “smoking.” Among associated factors, the highest odds ratio was found for monthly smoking-days (none vs. at least one-day or more) for JHS-girls at 5.30(3.57–7.85). Factors significantly associated with school absence in all four groups were “no wishing to go to university,” “no participation in club activities,” “disorders of initiating and maintaining sleep,” “long internet use,” “drinking,” “smoking,” “poor-mental-health” and “feeling bad throughout a morning.” Among associated factors, the highest odds ratio was found for monthly smoking-days (none vs. at least one-day or more) for JHS-girls at 4.60(3.45–6.15).

Conclusions
These results suggest that the risk factors for difficulty waking up among adolescents are sleep status, lifestyle, and mental health, which can indicate the presence of an underlying disease.
IX The Seventeenth Century: Part I
Authors: Baker William , Gwynn Lucy , Doelman James , James Anne , Urban David 
Published: June 2021

AbstractThis chapter combines what previously were Chapter IX, focusing on the early seventeenth century, and Chapter X, on Milton and poetry 1603–1660. Some of the content transcends historical dates and covers material from the latter half of the seventeenth century too; in other words, the long seventeenth century. It has seven sections:1. General; 2. Bacon; 3. Browne; 4. Burton; 5. Herbert; 6. Donne; 7. Milton. Sections 1 and 2 are by William Baker; section 3 is by Lucy Gwynn; section 4 is by William Baker; section 5 is by James Doelman; section 6 is by Anne James; section 7 is by David Urban.