bluuebunny/crossref_metadata_2025_split huggingface dataset:
Estimating cost-effectiveness thresholds under a managed healthcare system: experiences from Colombia
Authors: Espinosa Oscar , Rodríguez-Lesmes Paul , Orozco Luis , Ávila Diego , Enríquez Hernán , Romano Giancarlo , Ceballos Mateo 
Published: December 2021

Abstract
Like most of the world, low- and middle-income countries have faced a growing demand for new health technologies and higher budget constraints. It is necessary to have technical instruments to make decisions based on real-world evidence that allows maximization of the population’s health with a limited budget. We estimated the supply-based cost-effectiveness elasticity, which was then used to determine the cost-effectiveness threshold for the healthcare system of Colombia, a middle-income country where multiple insurers, paid under capitation rules, manage the compulsory contributions of the citizens and government subsidies. Using administrative data, we explored the variation of health expenditures and outcomes at the insurer, geographical region, diagnosis group and year levels. To deal with endogeneity in a two-way fixed-effects model, we instrumented health expenditures using characteristics of the health system such as drug-price regulation. We estimated the threshold to be US$4487.5 per years of life lost avoided [14.7 million Colombian pesos (COP) at 2019 prices] and US$5180.8 per quality-adjusted life-years gained (17 million COP at 2019 prices), around one times the gross domestic product GDP per capita. To the best of our knowledge, this is the first estimation of the cost-effectiveness threshold elasticity supply-based in a middle-income country with a managed healthcare system.
Impaired cooperation between IFT74/BBS22–IFT81 and IFT25–IFT27/BBS19 causes Bardet-Biedl syndrome
Authors: Zhou Zhuang , Qiu Hantian , Castro-Araya Roiner-Francisco , Takei Ryota , Nakayama Kazuhisa , Katoh Yohei 
Published: December 2021

AbstractThe IFT-B complex mediates ciliary anterograde protein trafficking and membrane protein export together with the BBSome. Bardet-Biedl syndrome (BBS) is caused by mutations in not only all BBSome subunits but also in some IFT-B subunits, including IFT74/BBS22 and IFT27/BBS19, which form heterodimers with IFT81 and IFT25, respectively. We found that the IFT25–IFT27 dimer binds the C-terminal region of the IFT74–IFT81 dimer and that the IFT25–IFT27-binding region encompasses the region deleted in the BBS variants of IFT74. In addition, we found that the missense BBS variants of IFT27 are impaired in IFT74–IFT81 binding and are unable to rescue the BBS-like phenotypes of IFT27-knockout (KO) cells. Furthermore, the BBS variants of IFT74 rescued the ciliogenesis defect of IFT74-KO cells, but the rescued cells demonstrated BBS-like abnormal phenotypes. Taken together, we conclude that the impaired interaction between IFT74–IFT81 and IFT25–IFT27 causes the BBS-associated ciliary defects.
Predicting prey recovery from scats of California sea lions (Zalophus californianus) for novel prey species and sizes
Authors: Curtis K Alexandra , Lowry Mark S , Sweeney Joelle M , Orr Anthony J , Harvey James T 
Published: December 2021

ABSTRACTDiet studies of marine top predators increasingly inform assessments of prey stocks and ecosystems, as well as predator ecology. Prey hard parts provide quantitative information on diet composition. However, species and size variation in digestion of hard parts, and thus in recovery rates, introduces bias in diet reconstruction. Captive feeding studies estimate species- and size-specific recovery rates of prey hard parts in pinnipeds, but such studies can only include a small subset of prey species and sizes consumed by these commonly generalist predators. We developed a generalized linear mixed effects model that estimates recovery rates of otoliths in California sea lion (Zalophus californianus) scats from otolith morphometrics, based on previously published captive feeding studies. The resulting model explains 85% of the variance in recovery rates among common teleost prey species of California sea lions. We also reestimated cephalopod beak recovery rate in California sea lion scats using an intercept-only mixed effects model. The resulting models can estimate recovery rates—and numerical correction factors—for novel teleost and cephalopod prey species and sizes in California sea lion scats, supporting more accurate reconstruction of diet composition in the wild and suggesting a way forward for other pinniped species.
Bayesian logistic regression for online recalibration and revision of risk prediction models with performance guarantees
Authors: Feng Jean , Gossmann Alexej , Sahiner Berkman , Pirracchio Romain 
Published: December 2021

Abstract

Objective
After deploying a clinical prediction model, subsequently collected data can be used to fine-tune its predictions and adapt to temporal shifts. Because model updating carries risks of over-updating/fitting, we study online methods with performance guarantees.

Materials and Methods
We introduce 2 procedures for continual recalibration or revision of an underlying prediction model: Bayesian logistic regression (BLR) and a Markov variant that explicitly models distribution shifts (MarBLR). We perform empirical evaluation via simulations and a real-world study predicting Chronic Obstructive Pulmonary Disease (COPD) risk. We derive “Type I and II” regret bounds, which guarantee the procedures are noninferior to a static model and competitive with an oracle logistic reviser in terms of the average loss.

Results
Both procedures consistently outperformed the static model and other online logistic revision methods. In simulations, the average estimated calibration index (aECI) of the original model was 0.828 (95%CI, 0.818–0.938). Online recalibration using BLR and MarBLR improved the aECI towards the ideal value of zero, attaining 0.265 (95%CI, 0.230–0.300) and 0.241 (95%CI, 0.216–0.266), respectively. When performing more extensive logistic model revisions, BLR and MarBLR increased the average area under the receiver-operating characteristic curve (aAUC) from 0.767 (95%CI, 0.765–0.769) to 0.800 (95%CI, 0.798–0.802) and 0.799 (95%CI, 0.797–0.801), respectively, in stationary settings and protected against substantial model decay. In the COPD study, BLR and MarBLR dynamically combined the original model with a continually refitted gradient boosted tree to achieve aAUCs of 0.924 (95%CI, 0.913–0.935) and 0.925 (95%CI, 0.914–0.935), compared to the static model’s aAUC of 0.904 (95%CI, 0.892–0.916).

Discussion
Despite its simplicity, BLR is highly competitive with MarBLR. MarBLR outperforms BLR when its prior better reflects the data.

Conclusions
BLR and MarBLR can improve the transportability of clinical prediction models and maintain their performance over time.
The protection and recovery strategy development of dynamic resilience analysis and cost consideration in the infrastructure network
Authors: Su Yi-Zhu , Yeh Wei-Chang 
Published: December 2021

Abstract
Modern life is becoming more and more convenient, all because of the perfect operation of the infrastructure network. However, if these infrastructure networks encounter interference, the operation of the network system will be delayed or even shut down, often causing huge losses in livelihood, economy, and society. Therefore, how to evaluate the resilience of the network system and provide protection and recovery strategies to deal with attacks that interfere with the system are important issues. This study considers a situation with protection, attack, and recovery strategies, proposes the time-related Binary-Addition Tree-based Resilience Assessment to consider more decision variables and parameters, and further includes the costs in the formulation of the protection and recovery strategies. Moreover, a new performance measure oriented to the degree of network reliability recovery to quantify the resilience of the network system is developed.
Molecular characterization and secreted production of basidiomycetous cell-bound β-glycosidases applicable to production of galactooligosaccharides
Authors: Ishikawa Eiji , Ikeda Masakazu , Sotoya Hidetsugu , Anbe Minako , Matsumoto Hoshitaka , Kiwaki Mayumi , Hatano Hiroshi 
Published: December 2021

Abstract
Cell-bound β-glycosidases of basidiomycetous yeasts show promise as biocatalysts in galactooligosaccharide (GOS) production. Using degenerated primers designed from Hamamotoa singularis (Hs) bglA gene, we newly identified three genes that encode cell-bound β-glycosidase from Sirobasidium magnum (Sm), Rhodotorula minuta (Rm), and Sterigmatomyces elviae (Se). These three genes, also named bglA, encoded family 1 glycosyl hydrolases with molecular masses of 67‒77 kDa. The BglA enzymes were approximately 44% identical to the Hs-BglA enzyme and possessed a unique domain at the N-terminus comprising 110 or 210 amino acids. The Sm-, Rm-, and Se-BglA enzymes as well as the Hs-BglA enzyme were successfully produced by recombinant Aspergillus oryzae, and all enzymes were entirely secreted to the supernatants. Furthermore, addition of some nonionic detergents (e.g. 0.4% [v/v] Triton-X) increased the production, especially of the Hs- or Se-BglA enzyme. Out of the BglA enzymes, the Se-BglA enzyme showed remarkable thermostability (∼70°C). Additionally, the Sm- and Se-BglA enzymes had better GOS yields, so there was less residual lactose than in others. Accordingly, the basidiomycetous BglA enzymes produced by recombinant A. oryzae would be applicable to GOS production, and the Se-BglA enzyme appeared to be the most promising enzyme for industrial uses.
Double trouble: synchronous extrahepatic cholangiocarcinoma and gallbladder cancer in a Caucasian woman with no pancreaticobiliary maljunction
Authors: Simpson Fraser Hugh , Auld Michael , Kandpal Harsh , Tran Kayla , Chandrasegaram Manju D 
Published: December 2021

Abstract
Synchronous malignancies of the bile duct and the gallbladder are rare. These cases are often associated with pancreaticobiliary maljunction which is characterized by a long common shared pancreatobiliary channel leading to the Sphincter of Oddi. This predisposes the biliary epithelium to pancreatic enzyme reflux and makes the development of neoplasia more likely. We describe the case of a 64-year-old Caucasian female who presented with new jaundice and severe cholecystitis secondary to an impacted gallstone which was seen on ultrasound. Magnetic resonance cholangiopancreatography was organized with suspicion of a possible Mirizzi syndrome. This revealed a mid-distal bile duct cancer in addition to cholecystitis from an impacted gallstone. She was treated with intravenous antibiotics for her cholecystitis and underwent an urgent endoscopic retrograde cholangiopancreatography procedure for biliary decompression and stenting for her obstructive jaundice. The patient proceeded to pancreaticoduodenectomy with final histopathology revealing a synchronous primary gallbladder malignancy in addition to the known bile duct cancer.
Functional Constraints on Insect Immune System Components Govern Their Evolutionary Trajectories
Authors: Ruzzante Livio , Feron Romain , Reijnders Maarten J M F , Thiébaut Antonin , Waterhouse Robert M 
Published: December 2021

Abstract
Roles of constraints in shaping evolutionary outcomes are often considered in the contexts of developmental biology and population genetics, in terms of capacities to generate new variants and how selection limits or promotes consequent phenotypic changes. Comparative genomics also recognizes the role of constraints, in terms of shaping evolution of gene and genome architectures, sequence evolutionary rates, and gene gains or losses, as well as on molecular phenotypes. Characterizing patterns of genomic change where putative functions and interactions of system components are relatively well described offers opportunities to explore whether genes with similar roles exhibit similar evolutionary trajectories. Using insect immunity as our test case system, we hypothesize that characterizing gene evolutionary histories can define distinct dynamics associated with different functional roles. We develop metrics that quantify gene evolutionary histories, employ these to characterize evolutionary features of immune gene repertoires, and explore relationships between gene family evolutionary profiles and their roles in immunity to understand how different constraints may relate to distinct dynamics. We identified three main axes of evolutionary trajectories characterized by gene duplication and synteny, maintenance/stability and sequence conservation, and loss and sequence divergence, highlighting similar and contrasting patterns across these axes amongst subsets of immune genes. Our results suggest that where and how genes participate in immune responses limit the range of possible evolutionary scenarios they exhibit. The test case study system of insect immunity highlights the potential of applying comparative genomics approaches to characterize how functional constraints on different components of biological systems govern their evolutionary trajectories.
Genome-wide chromosomal association of Upf1 is linked to Pol II transcription in Schizosaccharomyces pombe
Authors: De Sandip , Edwards David M , Dwivedi Vibha , Wang Jianming , Varsally Wazeer , Dixon Hannah L , Singh Anand K , Owuamalam Precious O , Wright Matthew T , Summers Reece P , Hossain Md Nazmul , Price Emily M , Wojewodzic Marcin W , Falciani Francesco , Hodges Nikolas J , Saponaro Marco , Tanaka Kayoko , Azzalin Claus M , Baumann Peter , Hebenstreit Daniel , Brogna Saverio 
Published: December 2021

Abstract
Although the RNA helicase Upf1 has hitherto been examined mostly in relation to its cytoplasmic role in nonsense mediated mRNA decay (NMD), here we report high-throughput ChIP data indicating genome-wide association of Upf1 with active genes in Schizosaccharomyces pombe. This association is RNase sensitive, correlates with Pol II transcription and mRNA expression levels. Changes in Pol II occupancy were detected in a Upf1 deficient (upf1Δ) strain, prevalently at genes showing a high Upf1 relative to Pol II association in wild-type. Additionally, an increased Ser2 Pol II signal was detected at all highly transcribed genes examined by ChIP-qPCR. Furthermore, upf1Δ cells are hypersensitive to the transcription elongation inhibitor 6-azauracil. A significant proportion of the genes associated with Upf1 in wild-type conditions are also mis-regulated in upf1Δ. These data envisage that by operating on the nascent transcript, Upf1 might influence Pol II phosphorylation and transcription.
Statewide Longitudinal Trends in Transmitted HIV-1 Drug Resistance in Rhode Island, USA
Authors: Novitsky Vlad , Steingrimsson Jon , Gillani Fizza S , Howison Mark , Aung Su , Solomon Matthew , Won Cindy Y , Brotherton Amy , Shah Rajeev , Dunn Casey , Fulton John , Bertrand Thomas , Civitarese Anna , Howe Katharine , Marak Theodore , Chan Philip , Bandy Utpala , Alexander-Scott Nicole , Hogan Joseph , Kantor Rami 
Published: December 2021

Abstract

Background
HIV-1 transmitted drug resistance (TDR) remains a global challenge that can impact care, yet its comprehensive assessment is limited and heterogenous. We longitudinally characterized statewide TDR in Rhode Island.

Methods
Demographic and clinical data from treatment-naïve individuals were linked to protease, reverse transcriptase, and integrase sequences routinely obtained over 2004–2020. TDR extent, trends, impact on first-line regimens, and association with transmission networks were assessed using the Stanford Database, Mann-Kendall statistic, and phylogenetic tools.

Results
In 1123 individuals, TDR to any antiretroviral increased from 8% (2004) to 26% (2020), driven by non-nucleotide reverse transcriptase inhibitor (NNRTI; 5%–18%) and, to a lesser extent, nucleotide reverse transcriptase inhibitor (NRTI; 2%–8%) TDR. Dual- and triple-class TDR rates were low, and major integrase strand transfer inhibitor resistance was absent. Predicted intermediate to high resistance was in 77% of those with TDR, with differential suppression patterns. Among all individuals, 34% were in molecular clusters, some only with members with TDR who shared mutations. Among clustered individuals, people with TDR were more likely in small clusters.

Conclusions
In a unique (statewide) assessment over 2004–2020, TDR increased; this was primarily, but not solely, driven by NNRTIs, impacting antiretroviral regimens. Limited TDR to multiclass regimens and pre-exposure prophylaxis are encouraging; however, surveillance and its integration with molecular epidemiology should continue in order to potentially improve care and prevention interventions.
Regioselectivity mechanism of the Thunbergia alata Δ6-16:0-acyl carrier protein desaturase
Authors: Guy Jodie E , Cai Yuanheng , Baer Marcel D , Whittle Edward , Chai Jin , Yu Xiao-Hong , Lindqvist Ylva , Raugei Simone , Shanklin John 
Published: December 2021

Abstract
Plant plastidial acyl–acyl carrier protein (ACP) desaturases are a soluble class of diiron-containing enzymes that are distinct from the diiron-containing integral membrane desaturases found in plants and other organisms. The archetype of this class is the stearoyl-ACP desaturase which converts stearoyl-ACP into oleoyl (18:1Δ9cis)-ACP. Several variants expressing distinct regioselectivity have been described including a Δ6-16:0-ACP desaturase from black-eyed Susan vine (Thunbergia alata). We solved a crystal structure of the T. alata desaturase at 2.05 Å resolution. Using molecular dynamics (MD) simulations, we identified a low-energy complex between 16:0-ACP and the desaturase that would position C6 and C7 of the acyl chain adjacent to the diiron active site. The model complex was used to identify mutant variants that could convert the T. alata Δ6 desaturase to Δ9 regioselectivity. Additional modeling between ACP and the mutant variants confirmed the predicted regioselectivity. To validate the in-silico predictions, we synthesized two variants of the T. alata desaturase and analyzed their reaction products using gas chromatography-coupled mass spectrometry. Assay results confirmed that mutants designed to convert T. alata Δ6 to Δ9 selectivity exhibited the predicted changes. In complementary experiments, variants of the castor desaturase designed to convert Δ9 to Δ6 selectivity lost some of their Δ9 desaturation ability and gained the ability to desaturate at the Δ6 position. The computational workflow for revealing the mechanistic understanding of regioselectivity presented herein lays a foundation for designing acyl-ACP desaturases with novel selectivities to increase the diversity of monoenes available for bioproduct applications.
Iontophoresis of treprostinil promotes wound healing in a murine model of scleroderma-related ulcers
Authors: Kotzki Sylvain , Savina Yann , Bouvet Raphael , Gil Hugo , Blaise Sophie , Cracowski Jean-Luc , Roustit Matthieu 
Published: December 2021

Abstract

Objective
Systemic sclerosis (SSc) is a rare, chronic disease characterized by fibrosis, vascular alterations and digital ulcerations. Few drugs have shown efficacy to enhance wound healing of existing SSc-related ulcers. Local delivery of treprostinil, a prostacyclin analogue, may improve wound healing. The present work aimed first at developing a mouse model of SSc-related ulcerations and second at assessing the effect of iontophoresis of treprostinil on wound healing.

Methods
We used two murine models of SSc: chemically induced with HOCl, and urokinase-type plasminogen activator receptor (uPAR)-deficient. Excisional wounding was performed on the dorsal midline with a biopsy punch. Animals were randomized into three groups: treated with electrostimulation alone, with treprostinil iontophoresis or untreated. We assessed wound healing over time, as well as skin microvascular reactivity, inflammation, microvessel density and collagen distribution, before wounding and after re-epithelialization.

Results
uPAR–/– mice, but not HOCl-treated mice, showed impaired wound healing and decreased microvascular reactivity compared with their controls. Treprostinil iontophoresis improved wound healing and microvascular density and decreased inflammation in uPAR–/– mice, while electro-stimulation did not. However, treprostinil had no effect on microvascular reactivity and collagen distribution.

Conclusion
This study suggests that excisional wounds in uPAR–/– mice are a relevant model of SSc-related ulcers. In addition, treprostinil iontophoresis enhances wound healing in this model. Further work in now needed to show whether this effect translates in humans.
A multidimensional examination of psychopathy traits and gray matter volume in adults
Authors: Miglin Rickie , Rodriguez Samantha , Bounoua Nadia , Sadeh Naomi 
Published: December 2021

AbstractUncovering the neurobiological abnormalities that may contribute to the manifestation of psychopathic traits is an important step toward understanding the etiology of this disorder. Although many studies have examined gray matter volume (GMV) in relation to psychopathy, few have examined how dimensions of psychopathic traits interactively relate to GMV, an approach that holds promise for parsing heterogeneity in neurobiological risk factors for this disorder. The aim of this study was to investigate the affective-interpersonal (Factor 1) and impulsive-antisocial (Factor 2) dimensions of psychopathy in relation to cortical surface and subcortical GMV in a mixed-gender, high-risk community sample with significant justice-system involvement (N = 156, 50.0% men). Cortex-wide analysis indicated that (i) the Factor 1 traits correlated negatively with GMV in two cortical clusters, one in the right rostral middle frontal region and one in the occipital lobe, and (ii) the interaction of the affective-interpersonal and impulsive-antisocial traits was negatively associated with GMV bilaterally in the parietal lobe, such that individuals high on both trait dimensions evidenced reduced GMV relative to individuals high on only one psychopathy factor. An interactive effect also emerged for bilateral amygdalar and hippocampal GMV, such that Factor 1 psychopathic traits were significantly negatively associated with GMV only at high (but not low) levels of Factor 2 traits. Results extend prior research by demonstrating the neurobiological correlates of psychopathy differ based on the presentation of Factor 1 and 2 traits.
Anatomy and phylogenetic relationships of Temnodontosaurus zetlandicus (Reptilia: Ichthyosauria)
Authors: Laboury Antoine , Bennion Rebecca F , Thuy Ben , Weis Robert , Fischer Valentin 
Published: December 2021

Abstract
Parvipelvia is a major clade of ichthyosaurians that diversified during the Triassic-Jurassic transition. The interrelationships of early parvipelvians remain unclear and many genera are loosely diagnosed, such as Temnodontosaurus, an ecologically important genus from the Early Jurassic of Western Europe. One taxon concentrates many taxonomic issues: ‘Ichthyosaurus’ acutirostris was previously assigned to Temnodontosaurus and for which ‘Ichthyosaurus’ zetlandicus represents a junior synonym. We redescribe the holotype of ‘Ichthyosaurus’ zetlandicus (CAMSM J35176) and a new specimen probably attributable to this taxon (MNHNL TU885) from the Toarcian of Luxembourg. We find that Temnodontosaurus zetlandicus comb. nov. is a valid species that should be referred to the genus Temnodontosaurus, sharing a number of traits with Temnodontosaurus nuertingensis and Temnodontosaurus trigonodon, despite having a distinct cranial architecture. Our phylogenetic analyses under both implied weighting maximum parsimony and Bayesian inference recover T. zetlandicus as closely related to several species currently assigned to Temnodontosaurus. Species included in Temnodontosaurus form a polyphyletic yet well-clustered group among basal neoichthyosaurians, demonstrating that the monophyly of this genus needs to be thoroughly investigated.