bluuebunny/crossref_metadata_2025_split huggingface dataset:
Diet effects on mouse meiotic recombination: a warning for recombination studies
Authors: Belmonte-Tebar Angela , San Martin Perez Estefania , Nam Cha Syonghyun , Soler Valls Ana Josefa , Singh Nadia D , de la Casa-Esperon Elena 
Published: November 2021

AbstractMeiotic recombination is a critical process for sexually reproducing organisms. This exchange of genetic information between homologous chromosomes during meiosis is important not only because it generates genetic diversity, but also because it is often required for proper chromosome segregation. Consequently, the frequency and distribution of crossovers are tightly controlled to ensure fertility and offspring viability. However, in many systems, it has been shown that environmental factors can alter the frequency of crossover events. Two studies in flies and yeast point to nutritional status affecting the frequency of crossing over. However, this question remains unexplored in mammals. Here, we test how crossover frequency varies in response to diet in Mus musculus males. We use immunohistochemistry to estimate crossover frequency in multiple genotypes under two diet treatments. Our results indicate that while crossover frequency was unaffected by diet in some strains, other strains were sensitive even to small composition changes between two common laboratory chows. Therefore, recombination is both resistant and sensitive to certain dietary changes in a strain-dependent manner and, hence, this response is genetically determined. Our study is the first to report a nutrition effect on genome-wide levels of recombination. Moreover, our work highlights the importance of controlling diet in recombination studies and may point to diet as a potential source of variability among studies, which is relevant for reproducibility.
Establishment of local adaptation in partly self-fertilizing populations
Authors: Trickovic Bogi , Glémin Sylvain 
Published: November 2021

Abstract
Populations often inhabit multiple ecological patches and thus experience divergent selection, which can lead to local adaptation if migration is not strong enough to swamp locally adapted alleles. Conditions for the establishment of a locally advantageous allele have been studied in randomly mating populations. However, many species reproduce, at least partially, through self-fertilization, and how selfing affects local adaptation remains unclear and debated. Using a two-patch branching process formalism, we obtained a closed-form approximation under weak selection for the probability of establishment of a locally advantageous allele (P) for arbitrary selfing rate and dominance level, where selection is allowed to act on viability or fecundity, and migration can occur via seed or pollen dispersal. This solution is compared to diffusion approximation and used to investigate the consequences of a shift in a mating system on P, and the establishment of protected polymorphism. We find that selfing can either increase or decrease P, depending on the patterns of dominance in the two patches, and has conflicting effects on local adaptation. Globally, selfing favors local adaptation when locally advantageous alleles are (partially) recessive, when selection between patches is asymmetrical and when migration occurs through pollen rather than seed dispersal. These results establish a rigorous theoretical background to study heterogeneous selection and local adaptation in partially selfing species.
Interpreting ciliopathy-associated missense variants of uncertain significance (VUS) inCaenorhabditis elegans
Authors: Lange Karen I , Best Sunayna , Tsiropoulou Sofia , Berry Ian , Johnson Colin A , Blacque Oliver E 
Published: November 2021

AbstractBetter methods are required to interpret the pathogenicity of disease-associated variants of uncertain significance (VUS), which cannot be actioned clinically. In this study, we explore the use of an animal model (Caenorhabditis elegans) for in vivo interpretation of missense VUS alleles of TMEM67, a cilia gene associated with ciliopathies. CRISPR/Cas9 gene editing was used to generate homozygous knock-in C. elegans worm strains carrying TMEM67 patient variants engineered into the orthologous gene (mks-3). Quantitative phenotypic assays of sensory cilia structure and function (neuronal dye filling, roaming and chemotaxis assays) measured how the variants impacted mks-3 gene function. Effects of the variants on mks-3 function were further investigated by looking at MKS-3::GFP localization and cilia ultrastructure. The quantitative assays in C. elegans accurately distinguished between known benign (Asp359Glu, Thr360Ala) and known pathogenic (Glu361Ter, Gln376Pro) variants. Analysis of eight missense VUS generated evidence that three are benign (Cys173Arg, Thr176Ile and Gly979Arg) and five are pathogenic (Cys170Tyr, His782Arg, Gly786Glu, His790Arg and Ser961Tyr). Results from worms were validated by a genetic complementation assay in a human TMEM67 knock-out hTERT-RPE1 cell line that tests a TMEM67 signalling function. We conclude that efficient genome editing and quantitative functional assays in C. elegans make it a tractable in vivo animal model for rapid, cost-effective interpretation of ciliopathy-associated missense VUS alleles.
PAR-1 Antagonism to Promote Gut Mucosa Healing in Crohn’s Disease Patients: A New Avenue for CVT120165
Authors: Motta Jean-Paul , Deraison Celine , Le Grand Sylvie , Le Grand Bruno , Vergnolle Nathalie 
Published: November 2021

Abstract
A new paradigm has been added for the treatment of inflammatory bowel diseases such as Crohn’s disease and ulcerative colitis. In addition to resolving symptoms and inflammatory cell activation, the objective of tissue repair and mucosal healing is also now considered a primary goal. In the search of mediators that would be responsible for delayed mucosal healing, protease-activated receptor-1 (PAR-1) has emerged as a most interesting target. Indeed, in Crohn’s disease, the endogenous PAR-1 agonist thrombin is drastically activated. Activation of PAR-1 is known to be associated with epithelial dysfunctions that hamper mucosal homeostasis. This review gathers the scientific evidences of a potential role for PAR-1 in mucosal damage and mucosal dysfunctions associated with chronic intestinal inflammation. The potential clinical benefits of PAR-1 antagonism to promote mucosal repair in CD patients are discussed. Targeted local delivery of a PAR-1 antagonist molecule such as CVT120165, a formulated version of the FDA-approved PAR-1 antagonist vorapaxar, at the mucosa of Crohn’s disease patients could be proposed as a new indication for IBD that could be rapidly tested in clinical trials.
Primary Versus Staged Reconstruction and Risk of Surgical Failure in Patients With Ulcerative Colitis: a Nation-wide Cohort Study
Authors: Westberg Karin , Olén Ola , Söderling Jonas , Bengtsson Jonas , Ludvigsson Jonas F , Everhov Åsa H , Myrelid Pär , Nordenvall Caroline 
Published: November 2021

Abstract

Background
Restorative surgery after colectomy due to ulcerative colitis (UC) may be performed simultaneously with colectomy (primary) or as a staged procedure. Risk factors for failure after restorative surgery are not fully explored. This study aimed to compare the risk of failure after primary and staged reconstruction.

Methods
This is a national register-based cohort study of all patients 15 to 69 years old in Sweden treated with colectomy due to UC and who received an ileorectal anastomosis (IRA) or ileal pouch-anal anastomosis (IPAA) between 1997 and 2017. Failure was defined as a reoperation with new ileostomy after restorative surgery or a remaining defunctioning ileostomy after 2 years. Risk of failure was calculated using the Kaplan-Meier method and Cox regression adjusted for sex, age, calendar period, primary sclerosing cholangitis, and duration of UC.

Results
Of 2172 included patients, 843 (38.8%) underwent primary reconstruction, and 1329 (61.2%) staged reconstruction. Staged reconstruction was associated with a decreased risk of failure compared with primary reconstruction (hazard ratio, 0.73; 95% CI, 0.58–0.91). The 10-year cumulative risk of failure was 15% vs 20% after staged and primary reconstruction, respectively. In all, 1141 patients (52.5%) received an IPAA and 1031 (47.5%) an IRA. In stratified multivariable models, staged reconstruction was more successful than primary reconstruction in both IRA (hazard ratio, 0.75; 95% CI, 0.54–1.04) and IPAA (hazard ratio, 0.73; 95% CI, 0.52–1.01), although risk estimates failed to attain statistical significance.

Conclusions
In UC patients undergoing colectomy, postponing restorative surgery may decrease the risk of failure.
RAID Prediction: Pilot Study of Fecal Microbial Signature With Capacity to Predict Response to Anti-TNF Treatment
Authors: Busquets David , Oliver Lia , Amoedo Joan , Ramió-Pujol Sara , Malagón Marta , Serrano Marta , Bahí Anna , Capdevila Montse , Lluansí Aleix , Torrealba Leyanira , Peries Laia , Chavero Rosa , Gilabert Pau , Sàbat Miriam , Guardiola Jordi , Serra-Pagès Mariona , Garcia-Gil Jesús , Aldeguer Xavier 
Published: November 2021

Abstract

Background and Aims
Crohn’s disease and ulcerative colitis evolve with alternate outbreaks and remissions of variable duration in both cases. Despite the advances, about 10-30% of patients do not respond to the treatment after the induction period. Besides, between 20% to 50% further patients need an optimization of the dose to respond the treatment. Recent studies have pointed gut microbiota can play a role in the anti-TNF treatment response. This study aimed to define a bacterial signature that could be used to predict the response of patients to anti-TNF treatment.

Methods
There were obtained 38 stool samples from 38 IBD patients before starting anti-TNF treatments: Adalimumab, Golimumab or Infliximab. Patients were differentiated in 2 groups: responders and non-responders to biological treatment. From each sample, DNA was purified and used in a qPCR for the quantification of the 8 microbial markers.

Results
In this proof of concept, the predictive ability to identify anti-TNF treatment responders was analyzed. An algorithm consisting in the combination of 4 bacterial markers showed a high capacity to discriminate between responders and non- responders. The algorithm proved high sensitivity and specificity reporting values of 93.33% and 100% respectively, with a positive predictive value of 100% and a negative predictive value of 75% for predicting response to biologic treatment.

Conclusions
A specific bacterial signature could beneficiate patients with inflammatory bowel disease predicting the therapeutic effectiveness of an anti-TNF treatment, leading to a personalized therapy, improving the patients’ quality of life, saving costs and gaining time in patient improvement.
A phase 1b open-label dose-finding study of ustekinumab in young adults with type 1 diabetes
Authors: Marwaha Ashish K , Chow Samuel , Pesenacker Anne M , Cook Laura , Sun Annika , Long S Alice , Yang Jennie H M , Ward-Hartstonge Kirsten A , Williams Evangelia , Domingo-Vila Clara , Halani Khalif , Harris Kristina M , Tree Timothy I M , Levings Megan K , Elliott Thomas , Tan Rusung , Dutz Jan P 
Published: November 2021

Summary

Objectives
We assessed the safety of ustekinumab (a monoclonal antibody used in psoriasis to target the IL-12 and IL-23 pathways) in a small cohort of recent-onset (&lt;100 days of diagnosis) adults with type 1 diabetes (T1D) by conducting a pilot open-label dose-finding and mechanistic study (NCT02117765) at the University of British Columbia.

Methods
We sequentially enrolled 20 participants into four subcutaneous dosing cohorts: (i) 45 mg loading weeks 0/4/16, (ii) 45 mg maintenance weeks 0/4/16/28/40, (iii) 90 mg loading weeks 0/4/16, and (iv) 90 mg maintenance weeks 0/4/16/28/40. The primary endpoint was safety as assessed by an independent data and safety monitoring board (DSMB) but we also measured mixed meal tolerance test C-peptide, insulin use/kg, and HbA1c. Immunophenotyping was performed to assess immune cell subsets and islet antigen-specific T cell responses.

Results
Although several adverse events were reported, only two (bacterial vaginosis and hallucinations) were thought to be possibly related to drug administration by the study investigators. At 1 year, the 90 mg maintenance dosing cohort had the smallest mean decline in C-peptide area under the curve (AUC) (0.1 pmol/ml). Immunophenotyping showed that ustekinumab reduced the percentage of circulating Th17, Th1, and Th17.1 cells and proinsulin-specific T cells that secreted IFN-γ and IL-17A.

Conclusion
Ustekinumab was deemed safe to progress to efficacy studies by the DSMB at doses used to treat psoriasis in adults with T1D. A 90 mg maintenance dosing schedule reduced proinsulin-specific IFN-γ and IL-17A-producing T cells. Further studies are warranted to determine if ustekinumab can prevent C-peptide AUC decline and induce a clinical response.
Long-Time Estimates for Heat Flows on Asymptotically Locally Euclidean Manifolds
Authors: Kröncke Klaus , Petersen Oliver L 
Published: November 2021

AbstractWe consider the heat equation associated to Schrödinger operators acting on vector bundles on asymptotically locally Euclidean (ALE) manifolds. Novel $L^p - L^q$ decay estimates are established, allowing the Schrödinger operator to have a non-trivial $L^2$-kernel. We also prove new decay estimates for spatial derivatives of arbitrary order, in a general geometric setting. Our main motivation is the application to stability of non-linear geometric equations, primarily Ricci flow, which will be presented in a companion paper. The arguments in this paper use that many geometric Schrödinger operators can be written as the square of Dirac-type operators. By a remarkable result of Wang, this is even true for the Lichnerowicz Laplacian, under the assumption of a parallel spinor. Our analysis is based on a novel combination of the Fredholm theory for Dirac-type operators on ALE manifolds and recent advances in the study of the heat kernel on non-compact manifolds.
Hierarchy in Regime Complexes: Understanding Authority in Antarctic Governance
Authors: Green Jessica F 
Published: November 2021

Abstract
Many scholars argue that regime complexes are nonhierarchical. However, if that is true, then how does authority function? This article argues that the conceptualization of regime complexes as largely devoid of hierarchy is mistaken. Instead, it offers a new definition of regime complexes: emergent patterns of authority among state and non-state actors, which vary in their degree of hierarchy. Hierarchy in regime complexes looks different from political scientists’ traditional conceptualization. It is systemic, emergent, and positional. I present two dimensions of variation in hierarchy: deference and autonomy. These dimensions provide both a conceptual and an empirical strategy for understanding how authority relations are constituted. Conceptually, they allow us to “see” hierarchy in regime complexes. Empirically, they provide transparent, replicable and variable measures, which have eluded much of the work to date. I use topic modeling coupled with network analysis to detect hierarchy in the regime complex for Antarctica. I demonstrate that the inclusion of non-state actors and their governance activities changes our understanding of the Antarctic regime complex. This approach reveals a hierarchical regime complex, where some non-state actors have considerable authority and are governing issues not regulated by formal rules.
Aminoglycoside- and glycopeptide-induced ototoxicity in children: a systematic review
Authors: Diepstraten F A , Hoetink A E , van Grotel M , Huitema A D R , Stokroos R J , van den Heuvel-Eibrink M M , Meijer A J M 
Published: November 2021

AbstractBackgroundOtotoxicity has been reported after administration of aminoglycosides and glycopeptides.ObjectivesTo identify available evidence for the occurrence and determinants of aminoglycoside- and glycopeptide-related ototoxicity in children.Materials and methodsSystematic electronic literature searches that combined ototoxicity (hearing loss, tinnitus and/or vertigo) with intravenous aminoglycoside and/or glycopeptide administration in children were performed in PubMed, EMBASE and Cochrane Library databases. Studies with sample sizes of ≥50 children were included. The QUIPS tool and Cochrane criteria were used to assess the quality and risk of bias of included studies.ResultsTwenty-nine aminoglycoside-ototoxicity studies met the selection criteria (including 7 randomized controlled trials). Overall study quality was medium/low. The frequency of hearing loss within these studies ranged from 0%–57%, whereas the frequency of tinnitus and vertigo ranged between 0%–53% and 0%–79%, respectively. Two studies met the criteria on glycopeptide-induced ototoxicity and reported hearing loss frequencies of 54% and 55%. Hearing loss frequencies were higher in gentamicin-treated children compared to those treated with other aminoglycosides. In available studies aminoglycosides had most often been administered concomitantly with platinum agents, diuretics and other co-medication.ConclusionsIn children the reported occurrence of aminoglycoside/glycopeptide ototoxicity highly varies and seems to depend on the diagnosis, aminoglycoside subtype and use of co-administered medication. More research is needed to investigate the prevalence and determinants of aminoglycoside/glycopeptide ototoxicity. Our results indicate that age-dependent audiological examination may be considered for children frequently treated with aminoglycosides/glycopeptides especially if combined with other ototoxic medication.
Examining perspectives on the adoption and use of computer-based patient-reported outcomes among clinicians and health professionals: a Q methodology study
Authors: Burton Shirley V , Valenta Annette L , Starren Justin , Abraham Joanna , Nelson Therese , Kochendorfer Karl , Hughes Ashley , Harris Bhrandon , Boyd Andrew 
Published: November 2021

AbstractObjectiveTo determine factors that influence the adoption and use of patient-reported outcomes (PROs) in the electronic health record (EHR) among users.Materials and MethodsQ methodology, supported by focus groups, semistructured interviews, and a review of the literature was used for data collection about opinions on PROs in the EHR. An iterative thematic analysis resulted in 49 statements that study participants sorted, from most unimportant to most important, under the following condition of instruction: “What issues are most important or most unimportant to you when you think about the adoption and use of patient-reported outcomes within the electronic health record in routine clinical care?” Using purposive sampling, 50 participants were recruited to rank and sort the 49 statements online, using HTMLQ software. Principal component analysis and Varimax rotation were used for data analysis using the PQMethod software.ResultsParticipants were mostly physicians (24%) or physician/researchers (20%). Eight factors were identified. Factors included the ability of PROs in the EHR to enable: efficient and reliable use; care process improvement and accountability; effective and better symptom assessment; patient involvement for care quality; actionable and practical clinical decisions; graphical review and interpretation of results; use for holistic care planning to reflect patients’ needs; and seamless use for all users.DiscussionThe success of PROs in the EHR in clinical settings is not dependent on a “one size fits all” strategy, demonstrated by the diversity of viewpoints identified in this study. A sociotechnical approach for implementing PROs in the EHR may help improve its success and sustainability.ConclusionsPROs in the EHR are most important to users when the technology is used to improve patient outcomes. Future research must focus on the impact of embedding this EHR functionality on care processes.
The role of electronic health record developers in hospital patient sharing
Authors: Pylypchuk Yuriy , Meyerhoefer Chad D , Encinosa William , Searcy Talisha 
Published: November 2021

Abstract

Objective
To determine whether hospital adoption of a new electronic health record (EHR) developer increases patient sharing with hospitals using the same developer.

Materials and Methods
We extracted data on patients shared with other hospitals for 3076 US nonfederal acute care hospitals from the 2011 to 2016 Centers for Medicare & Medicaid Services Physician Shared Patient Patterns database. We calculated the ratio of patients shared with hospitals outside of the focal hospital’s network that use the same EHR developer as the focal hospital, and estimated difference-in-differences models to compare same-developer patient sharing among hospitals that switched to a new developer with those that did not switch developer.

Results
Switching to a new EHR developer increased the ratio of patients shared with other hospitals having the same EHR developer by 4.1–19.3%, depending on model specification. The magnitude of this effect varied by EHR developer and was increasing in developer market share.

Discussion
Consolidation in the EHR industry has led to higher patient sharing among hospitals with the same EHR developer. Contributing factors could include the growth of developer-based health information exchanges, customizable referral management systems, and provider preferences for easy and reliable data exchange. However, hospital transfers that are significantly influenced by EHR developer could lead to poor patient-provider matches.

Conclusion
Hospitals’ choice of EHR developer impacts the flow of patients across hospitals, which could have both desirable and undesirable effects on patient care. Future research should investigate whether health outcomes decline with greater same-developer patient sharing.
An analysis of the structure and content of dashboards used to monitor patient safety in the inpatient setting
Authors: Kuznetsova Masha , Frits Michelle L , Dulgarian Sevan , Iannaccone Christine , Mort Elizabeth , Bates David W , Salmasian Hojjat 
Published: November 2021

Abstract
The objective of this study is to review and compare patient safety dashboards used by hospitals and identify similarities and differences in their design, format, and scope. We reviewed design features of electronic copies of patient safety dashboards from a representative sample of 10 hospitals. The results show great heterogeneity in the format, presentation, and scope of patient safety dashboards. Hospitals varied in their use of performance indicators (targets, trends, and benchmarks), style of color coding, and timeframe for the displayed metrics. The average number of metrics per dashboard display was 28, with a wide range from 7 to 84. Given the large variation in dashboard design, there is a need for future work to assess which approaches are associated with the best outcomes, and how specific elements contribute to usability, to help customize dashboards to meet the needs of different clinical, and operational stakeholders.