bluuebunny/crossref_metadata_2025 huggingface dataset:
Comparison of the in vitro activities of delafloxacin and comparators against Staphylococcus epidermidis clinical strains involved in osteoarticular infections: a CRIOGO multicentre retrospective study
Authors: Tessier E , Ruffier d’Epenoux L , Lartigue M F , Chaufour L , Plouzeau-Jayle C , Chenouard R , Guérin F , Tandé D , Lamoureux C , Bémer P , Corvec S ,   CRIOGO study group, Abgueguen Pierre , Caubrière Marin , Lemarie Carole , Chenouard Rachel , Pailhories Hélène , Vildy Amandine , Ansart Séverine , Quaesaet Luc , Stindel Eric , Tandé Didier , Lamoureux Claudie , Greves Anaïs , Boutoille David , Lecomte Raphaël , Deschanvres Colin , Nich Christophe , Crenn Vincent , Bémer Pascale , Corvec Stéphane , Ruffier d’Epenoux Louise , Paquin Axelle , Grégoire Matthieu , Bourigault Céline , Plantard Barbara , Cazenave-Roblot France , Le Moal Gwenaël , Pries Pierre , Plouzeau-Jayle Chloé , Thomas Céline , Arvieux Cédric , Baldeyrou Marion , Common Harold , Cattoir Vincent , Reissier Sophie , Méheut Anne , Bernard Louis , Lemaignen Adrien , Lacasse Marion , Rosset Philippe , Le Nail Louis-Romée , Lartigue Marie-Frédérique , Laplaige Isabelle , Chaufour Laura
Published: March 2024

Objectives

Staphylococcus epidermidis bone and joint infections (BJIs) on material are often difficult to treat. The activity of delafloxacin has not yet been studied on S. epidermidis in this context. The aim of this study was to assess its in vitro activity compared with other fluoroquinolones, against a large collection of S. epidermidis clinical strains.

Methods

We selected 538 S. epidermidis strains isolated between January 2015 and February 2023 from six French teaching hospitals. One hundred and fifty-two strains were ofloxacin susceptible and 386 were ofloxacin resistant. Identifications were performed by MS and MICs were determined using gradient concentration strips for ofloxacin, levofloxacin, moxifloxacin and delafloxacin.

Results

Ofloxacin-susceptible strains were susceptible to all fluoroquinolones. Resistant strains had higher MICs of all fluoroquinolones. Strains resistant to ofloxacin (89.1%) still showed susceptibility to delafloxacin when using the Staphylococcus aureus 2021 CA-SFM/EUCAST threshold of 0.25 mg/L. In contrast, only 3.9% of the ofloxacin-resistant strains remained susceptible to delafloxacin with the 0.016 mg/L S. aureus breakpoint according to CA-SFM/EUCAST guidelines in 2022. The MIC50 was 0.094 mg/L and the MIC90 was 0.38 mg/L.

Conclusions

We showed low delafloxacin MICs for ofloxacin-susceptible S. epidermidis strains and a double population for ofloxacin-resistant strains. Despite the absence of breakpoints for S. epidermidis, delafloxacin may be an option for the treatment of complex BJI, including strains with MICs of ≤0.094 mg/L, leading to 64% susceptibility. This study underlines the importance for determining specific S. epidermidis delafloxacin breakpoints for the management of BJI on material.
Towards optimizing cefepime/tazobactam (WCK 4282) exposure to achieve efficacy against piperacillin/tazobactam-resistant ESBL infections: dose recommendations for various renal functions, including intermittent haemodialysis, in healthy individuals
Authors: Muller Anouk E , De Winter Brenda C M , Koch Birgit C P
Published: March 2024

Objectives

WCK 4282 is a novel combination of cefepime 2 g and tazobactam 2 g being developed for the treatment of infections caused by piperacillin/tazobactam-resistant ESBL infections. The dosing regimen for cefepime/tazobactam needs to be optimized to generate adequate exposures to treat infections caused by ESBL-producing pathogens resistant to both cefepime and piperacillin/tazobactam.

Methods

We developed pharmacokinetic population models of cefepime and tazobactam to evaluate the optimal dose adjustments in patients, including those with augmented renal clearance as well as various degrees of renal impairment, and also for those on intermittent haemodialysis. Optimal doses for various degrees of renal function were identified by determining the PTA for a range of MICs. To cover ESBL-producing pathogens with an cefepime/tazobactam MIC of 16 mg/L, a dosing regimen of 2 g q8h infused over 1.5 h resulted in a combined PTA of 99% for the mean murine 1 log10-kill target for the cefepime/tazobactam combination.

Results

We found that to adjust for renal function, doses need to be reduced to 1 g q8h, 500 mg q8h and 500 mg q12h for patients with CLCR of 30–59, 15–29 and 8–14 mL/min (as well as patients with intermittent haemodialysis), respectively. In patients with high to augmented CLR (estimated CLCR 120–180 mL/min), a prolonged 4 h infusion of standard dose is required.

Conclusions

The suggested dosing regimens will result in exposures of cefepime and tazobactam that would be adequate for infections caused by ESBL-producing pathogens with a cefepime/tazobactam MICs up to 16 mg/L.
When False-Positives Arise: Troubleshooting a SARS-Coronavirus-2 (SARS-CoV-2) Detection Assay on a Semi-Automated Platform
Authors: Hampel Kenneth J , Gerrard Diana L , Francis Denise , Armstrong Jordan , Cameron Margaret , Ostafin Alexa , Mahoney Briege , Malik Miles , Sidiropoulos Nikoletta
Published: March 2024

Background

During the COVID-19 pandemic, many molecular diagnostic laboratories performed high-throughput SARS-CoV-2 testing often with implementation of automated workflows. In parallel, vaccination campaigns resulted increasingly in specimens from fully vaccinated patients, with resultant clinical inquiries regarding positive results in this patient population. This prompted a quality improvement initiative to investigate the semi-automated testing workflow for false-positive results. The troubleshooting workflow is described and procedural improvements are outlined that serve as a resource for other molecular diagnostic laboratories that need to overcome testing anomalies in a semi-automated environment.

Methods

This workflow utilized the MagMax-96 Viral RNA kit and the CDC 2019-nCoV RT-qPCR Panel on the Agilent Bravo Liquid-Handler (Bravo). Screening of the environment, personnel, and the mechanical performance of instrumentation using low Ct checkerboard challenges was executed to identify sources of cross-contamination. Evaluation of the assay and reporting design was conducted.

Results

Specimen contamination was observed during the viral extraction process on the Bravo. Changes to the program reduced plate contamination by 50% and importantly revealed consistent hallmarks of contaminated samples. We adjusted the reporting algorithm using these indicators of false positives. False positives that were identified made up 0.11% of the 45 000+ tests conducted over the following 8 months.

Conclusions

These adjustments provided confident and quality results while maintaining turnaround time for patients and pandemic-related public health initiatives. This corrected false-positive rate is concordant with previously published studies from diagnostic laboratories utilizing automated systems and may be considered a laboratory performance standard for this type of testing.
Accountability as a service for robotics: Performance assessment of different accountability strategies for autonomous robots
Authors: Fernández-Becerra Laura , Manuel Guerrero-Higueras Ángel , Rodríguez-Lera Francisco Javier , Matellán Vicente
Published: March 2024

An essential requirement for increasing human confidence in computer systems is knowing an event’s origin. Therefore, it is necessary to have an efficient method to record such information. It is especially challenging in robotics, where unexpected behaviours can have unpredictable consequences, endangering the interests of people or even their safety. Furthermore, to analyse an incident’s cause or anticipate future behaviours, we must identify the events that cause a specific action. Although it is common to use logging systems for such purposes, issues such as partial recording of events, unhelpful data or the impact on robot performance suggest conceiving new accountability solutions that assist when determining the responsible entities or the provenance of specific information. This paper presents a general-purpose approach to developing an accountability system for autonomous robots. It consists of four main components: a system event logger, a message producer, a distributed event streaming platform and a database. Our proposal is completely decoupled from the monitored system and allows real-time analysis, improving flexibility, besides system protection and transparency. Finally, the need to reduce the impact of the audit process and logging tasks on robot performance has promoted the development of different assessment scenarios to determine the best strategy for providing accounting services.
The Syntax of the Jewish Arabic Dialect of Wad-Souf (Saharan Algeria)
Authors: Gębski Wiktor
Published: March 2024

Jewish dialects of Algerian Arabic remain terra incognita within Arabic dialectology. This paper addresses this lacuna and examines specific syntactic aspects within the critically endangered Jewish dialect of Wad-Souf. The study selectively focuses on the topics relevant to the ongoing discussions in the field of Arabic dialectology and the sub-field of Judaeo-Arabic. This research builds on my prior work concerning the phonology and morphology of Jewish Wad-Souf, emphasising linguistic traits that align with Bedouin dialects and showcasing historical connections to sedentary Jewish dialects. The article includes glossed text samples and analytical sections exploring noun, verb and pronoun syntax. While presenting tendencies rather than rigid rules, this research lays the groundwork for future studies on the Jewish dialect of Wad-Souf and on Algerian Judaeo-Arabic in general, forming a basis for a deeper understanding of its syntax and linguistic nuances. The data were obtained during three periods of fieldwork in Israel between March and December 2022.
The Bible, Exile, and Migration
Authors: Hamilton Mark W.
Published: March 2024

The 8th to 6th centuries bce in southwestern Asia and the eastern Mediterranean were a period of imperial expansion and, as a result, the forced movements of peoples. The Assyrian and Babylonian Empires used forced migration as an instrument of rule, forcibly moving several million people over a period of a century and a half. The earlier empire used these forcibly removed populations to settle new agricultural land as part of a centralized economy focused on the benefits of the Assyrian homeland. The Babylonian realm was too short-lived and fragile to develop its own policies distinct from the Assyrians. Most significantly, these events influenced the formation of many parts of the Bible. The reflections on those events profoundly shaped the theological work of Israelite thinkers and through them Judaism and Christianity ever afterward. It would be hard to overstate the impacts of these events on human history. Since the mid-first millennium bce, concern for the refugee and migrant has figured in the ethical reflections of these traditions. Migration also became a rich source of metaphors for human existence writ large, as well as for the work of God. Understanding the events and their consequences is not easy, however. The text evidence comes from Mesopotamian royal inscriptions and, more limitedly, business documents, as well as from literary texts from the colonized populations in Israel and (again in royal inscriptions) further north in Syria and southern Anatolia. All of these documents exhibit their creators’ varying perspectives and aims. And the accident of survival or disappearance complicates study of them. Moreover, archaeological evidence for these empires and their impacts on local population is often hard to pin down. At the same time, scholars have made much progress in understanding the history of this period and its aftermath. Methodologically sophisticated studies have appeared, and the subfield is changing rapidly.
Mary Shepherd
Authors: Fasko Manuel
Published: March 2024

Mary Shepherd (née Primrose, b. 1777–d. 1847) is the author of at least two books and three essays published during her lifetime. One of the key focuses of her work rests on the issue of causation. In 1824, the first book, An Essay upon the Relation of Cause and Effect, Controverting the Doctrine of Mr. Hume, concerning the Nature of the Relation; with Observations upon the Opinions of Dr. Brown and Mr. Lawrence, Connected with the Same Subject (ERCE) is published. In ERCE she argues against a Humean notion of causation as constant conjunction that cause and effect are necessarily connected, and that causation requires the causal interaction (‘mixing’) of at least two partial causes. Shepherd returns to the issue of causation, employing the insights from her first book, in the first part of her second book, Essays on the Perception of an External Universe, and Other Subjects Connected with the Doctrine of Causation (EPEU), from 1827. In EPEU she primarily argues that there is a continually existing, mind-independent, and external world. In the second part of this book, we find fourteen essays that discuss a variety of topics ranging from criticizing Berkeley’s mistakes, to discussing various issues in the philosophy of mind and perception. These topics are also the focus in the essays published in 1828. Her last essay, “Lady Mary Shepherd’s Metaphysics” (LMSM) from 1832, contains a dense summary of her metaphysics, which is defended against the criticism of John Fearn (an autodidact and former naval officer). Shepherd’s work seems to have been well-regarded in her day—or at least other participants of the so-called republic of letters were far from indifferent toward it. Her daughter, Mary Brandreth, even writes that William Whewell, a philosopher of science, used one of her books when he was teaching at Cambridge. From the mid-nineteenth century onward, however, Shepherd’s work comes to share the story of most women philosophers and her works drop from view for over a century. It was only around the twentieth century that scholars such as Margaret Atherton, Martha Bolton, and Jennifer McRobert started the work of recovering Shepherd. In the subsequent decades, some articles and overviews were published. Those are mostly concerned with her notion of causation, her criticism of Berkely and Hume or with establishing that she ought to be taken seriously as a philosopher. It is only more recent years, from 2017 onward, that have seen an exponential growth in the philosophical secondary literature on Shepherd. While her notion of causation attracts a lot of attention, as do her criticisms of Berkeley, Hume, and Reid, her metaphysics and epistemology as well as her philosophy of mind now garner significant scholarly engagement. This article, moreover, provides an overview on the primary sources, modern editions, overview articles, and anthologies that are currently available.
Black Political Participation and Representation
Authors: Scott Jamil
Published: March 2024

Two of the most enduring threads in the study of Black politics are political participation and representation. Over time, scholars have grappled with the meaningfulness of representation by someone who shares the identity of the represented as well as which acts of participation are effective in achieving the political aims of the group. These bodies of work give scholars much to consider on why Black people engage in politics—from the mass public to the elite level—and push scholars to consider the implications of elites’ decision-making on behalf of the Black community. With the development of the literature, there have also been changes to the political landscape. Namely, the number of Black elected and appointed officials has continued to grow across levels of office, and the idea that large-scale protest was a product of the civil rights movement alone was laid to rest in the face of protests in support of Black Lives Matter. Yet, there continue to be instances in which Black people are prevented from engaging in politics. These literatures remain important reminders of what can be learned from the past and the ever-shifting political context raises new questions that direct where the literature should go next. The literature on Black political participation and political representation have certainly developed separately—the former focused on political behavior and the latter couched in the study of institutions—but what remains a throughline in the study of these topics is the relationship between the mass public and elites. That is, citizens engage in political participation to influence some change—whether that be the behavior of government officials, a policy outcome, or even who is in office altogether. When it comes to representation, there is an expectation that representatives are looking for cues from the public to legislate—whether that be a mandate from being elected to office or explicit messages of the political outcomes that the public wants to see. While these interactions between the mass public and elites are not exclusive to Black politics, what is unique is the political and social meaning that is attached to the relationship between the Black mass public and Black elites. In what follows, this work addresses the foundational concepts that undergird the study of representation and political participation, it turns to our understanding of the role of descriptive representation on legislative outcomes, and then to the implications of Black political participation. Next, this work reviews the literature on the psychological impact of descriptive representation on Black political participation, and how Black political engagement, in turn, shapes the behavior of elites.
Francisco de Zurbarán
Authors: Letvin Alexandra
Published: March 2024

Francisco de Zurbarán (b. 1598–d. 1664) was a leading painter in Seville between the 1620s and 1650s. Born in Fuente de Cantos, a small village in Extremadura, he trained in Seville between 1614 and 1617 before establishing himself in Llerena, a town near his birthplace. In 1626, he returned to Seville with a commission to execute twenty-one paintings for the Dominican Monastery of San Pablo el Real. This project led to commissions from many of the city’s monastic institutions, which became a primary source of patronage for him. As demand for Zurbarán’s paintings increased both in Spain and the Spanish Viceroyalties, he established a workshop. While based in Seville, he traveled at least twice to Madrid: once, in 1634, to participate in the pictorial decoration for Philip IV’s Hall of Realms at the Buen Retiro Palace, and again in 1658 when he moved permanently to the city. Zurbarán’s fame had already begun to wane in the decade before his death and it was only in the 18th century that he came to be rediscovered by Spanish artists and critics. A familiarity with the artist’s early reception history is key to understanding the framework and arguments of the 20th- and 21st-century monographs and monographic exhibitions dedicated to him. Scholarship on his work can be divided into categories including: technical studies, monastic commissions, series made for private and ecclesiastical patrons as well as the open market, still lifes, paintings made in Madrid, paintings made for export to the Spanish Viceroyalties, and self-reflexive paintings that demonstrate the artist’s engagement with the condition of his art.
Computational Modeling of Rhythm Perception and the Role of Enculturation
Authors: van der Weij Bastiaan , Pearce Marcus T. , Honing Henkjan
Published: March 2024

This chapter compares a variety of computational models of rhythm perception and discusses them in three sections, each focusing on one of various different theoretical perspectives that exist in cognitive modeling, namely cognitivism, embodied cognition, and predictive processing. The different perspectives suggest different computational modeling techniques, which this chapter uses to differentiate models of rhythm perception. Cognitivism most naturally accommodates rule-based models, coupled oscillation models use mathematical tools associated with embodied cognition, and probabilistic generative models are consistent with predictive processing theories of cognition. Each section provides a short description of a theoretical perspective, followed by a discussion of rhythm perception models consistent with that perspective. Furthermore, the chapter draws attention to the influence that Western music theory may have had on models and theories of rhythm perception. This potential influence is of interest because rhythm perception is thought to be shaped by the history of experiences and activities of listeners, enabling the culture in which a listener is embedded to influence their perception. The chapter briefly reviews what effects this influence may have on rhythm perception, suggesting the need for modeling enculturated rather than “universal” listeners. Throughout, the chapter notes that rule-based models do not take previous experiences and activities of listeners into account, while some coupled oscillation models and probabilistic generative models, computational paradigms that gained popularity more recently, do, albeit to varying degrees. Additionally, probabilistic generative models, consistent with predictive processing, suggest a normative explanation of how previous experiences and activities shape perception.
Research on predicting hematoma expansion in spontaneous intracerebral hemorrhage based on deep features of the VGG-19 network
Authors: Wu Fa , Wang Peng , Yang Huimin , Wu Jie , Liu Yi , Yang Yulin , Zuo Zhiwei , Wu Tingting , Li Jianghao
Published: March 2024

Purpose

To construct a clinical noncontrastive computed tomography (NCCT) deep learning joint model for predicting early hematoma expansion (HE) after cerebral hemorrhage (sICH) and evaluate its predictive performance.

Methods

All 254 patients with primary cerebral hemorrhage from January 2017 to December 2022 in the General Hospital of the Western Theater Command were included. According to the criteria of hematoma enlargement exceeding 33% or the volume exceeding 6 ml, the patients were divided into the HE group and the hematoma non-enlargement (NHE) group. Multiple models and the 10-fold cross-validation method were used to screen the most valuable features and model the probability of predicting HE. The area under the curve (AUC) was used to analyze the prediction efficiency of each model for HE.

Results

They were randomly divided into a training set of 204 cases in an 8:2 ratio and 50 cases of the test set. The clinical imaging deep feature joint model (22 features) predicted the area under the curve of HE as follows: clinical Navie Bayes model AUC 0.779, traditional radiology logistic regression (LR) model AUC 0.818, deep learning LR model AUC 0.873, and clinical NCCT deep learning multilayer perceptron model AUC 0.921.

Conclusion

The combined clinical imaging deep learning model has a high predictive effect for early HE in sICH patients, which is helpful for clinical individualized assessment of the risk of early HE in sICH patients.
Nondilutive CoCo Bonds: A Necessary Evil?
Authors: Gamba Andrea , Gong Joe Yanxiong , Ma Kebin
Published: March 2024

Banks predominantly issue nondilutive CoCos, contrary to the suggestion that CoCos should be dilutive to reduce risk-taking. In an agency model of two moral hazards, we show that, although dilutive CoCos deter ex ante risk-taking and prevent banks from being undercapitalized, penalizing shareholders of a distressed bank with dilution leads to ex post risk-shifting. CoCos’ design and risk implications depend on bank capitalization: equity-constrained banks prefer nondilutive CoCos because they maximize the financing capacity by tackling ex post risk shifting only. Nondilutive CoCos can be used to implement the constrained social optimum for highly leveraged banks, and regulators can induce appropriate CoCo designs with capital regulations. (JEL G21, G28)
Impact of body composition on clinical outcomes in patients with active radiographic axial spondyloarthritis under biological therapy
Authors: Rios Rodriguez Valeria , Torgutalp Murat , Proft Fabian , Rademacher Judith , Protopopov Mikhail , Spiller Laura , Haibel Hildrun , Sieper Joachim , Poddubnyy Denis
Published: March 2024

Objective

To assess the association of body composition (BC), evaluated by bioimpedance analysis (BIA), with disease activity, physical function and mobility in patients with axSpA undergoing bDMARD treatment for one year.

Methods

Patients with AS (radiographic axSpA) were enrolled in an extension of the German Spondyloarthritis Inception Cohort (GESPIC). Patients were required to be candidates for bDMARD therapy at baseline presenting high disease activity despite previous treatment with nonsteroidal anti-inflammatory drugs. Outcomes (disease activity, function and mobility) and BC parameters were assessed at baseline and every 6 months thereafter. The association between BC parameters and outcomes over 1 year was analysed using longitudinal generalized estimating equations.

Results

Seventy-four patients with radiographic axSpA were included in current analysis with a mean age of 36.5 years, disease duration of 6.2 years and Axial Spondyloarthritis Disease Activity Score (ASDAS) of 3.4 at baseline. Fat mass value and fat mass index were positively associated with disease activity (ASDAS: ß = 0.012, 95% CI [−0.003, 0.027] and ß = 0.035, 95% CI [−0.010, 0.081], respectively) and functional disability (BASFI: ß = 0.037, 95% CI [0.004, 0.070] and ß = 0.125, 95% CI [0.031, 0.219], respectively). Visceral adipose tissue (VAT) was associated with reduced spine mobility (BASMI: ß = 0.20, 95% CI [0.07, 0.33]). Additionally, increase in VAT and fat mass parameters was linked to worse disease activity and functional disability in women, while they were strongly associated with reduced spinal mobility in men.

Conclusion

Higher levels of body fat and VAT were positively associated with increased disease activity, functional disability, and reduced spinal mobility in patients with radiographic axSpA treated with bDMARDs.
Evaluation of Epiconus and Conus Medullaris Disorders due to Thoracolumbar Vertebral Fracture using Motor-evoked Potentials
Authors: Kamei Naosuke , Nakamae Toshio , Maruyama Toshiaki , Nakao Kazuto , Farid Fadlyansyah , Fukui Hiroki , Adachi Nobuo
Published: March 2024

Study Design.

A retrospective case-control study.

Objective.

To characterize the motor evoked potential (MEP) when the epiconus or conus medullaris is compressed by a fracture of the T12 or L1 vertebra.

Summary of Background Data.

Although the characteristics of compressive cervical and thoracic myelopathy with transcranial magnetic stimulation MEP have been reported, the MEP parameters in compressive disorders of the epiconus and conus medullaris have not yet been characterized.

Methods.

Twenty patients with T12 or L1 vertebral fractures who had lower extremity symptoms due to compression of the epiconus or conus medullaris were included. These patients were compared with 28 healthy controls and 32 patients with cervical spondylotic radiculopathy (CSR) without spinal cord compression. MEPs of abductor hallucis muscles were recorded using transcranial magnetic stimulation and electrical stimulation of the tibial nerve. MEP latency, central motor conduction time (CMCT), and peripheral conduction time (PCT) were evaluated.

Results.

MEP latency, CMCT, and PCT were significantly longer in patients with fractures than in healthy controls and patients with CSR. MEP latency was most accurate for differentiating patients with fracture from healthy controls (cutoff value, 40.0 ms, sensitivity, 95.0%; specificity, 100%), and CMCT was most accurate for comparing patients with fracture and CSR (cutoff value, 15.5 ms, sensitivity, 80.0%; specificity, 93.8%). In the distinction between patients with fracture and CSR, 16 of the 20 patients with fracture exceeded the cutoff values for any of the parameters, and 12 of them exceeded the cutoff values for all parameters. There was no significant correlation between the linear distance from the most inferior end of the spinal cord to the site of compression and any of the MEP parameters.

Conclusion.

Both CMCT and PCT are often prolonged in compressive lesions of the epiconus and conus medullaris, and MEP latency and CMCT are useful in the diagnosis.
Primary biliary cholangitis drug evaluation and regulatory approval: Where do we go from here?
Authors: Jones David E.J. , Beuers Ulrich , Bonder Alan , Carbone Marco , Culver Emma , Dyson Jessica , Gish Robert G. , Hansen Bettina E. , Hirschfield Gideon , Jones Rebecca , Kowdley Kris , Kremer Andreas E. , Lindor Keith , Mayo Marlyn , Mells George , Neuberger James , Prince Martin , Swain Mark , Tanaka Atsushi , Thorburn Douglas , Trauner Michael , Trivedi Palak , Weltman Martin , Yeoman Andrew , Levy Cynthia
Published: March 2024

Primary biliary cholangitis (PBC) is a chronic cholestatic liver disease. The management landscape was transformed 20 years ago with the advent of ursodeoxycholic acid. Up to 40% of patients do not, however, respond adequately to ursodeoxycholic acid and therefore still remain at risk of disease progression to cirrhosis. The introduction of obeticholic acid as a second-line therapy for patients failing ursodeoxycholic acid has improved outcomes for patients with PBC. There remains, however, a need for better treatment for patients at higher risk. The greatest threat facing our efforts to improve treatment in PBC is, paradoxically, the regulatory approval model providing conditional marketing authorization for new drugs based on biochemical markers on the condition that long-term, randomized placebo-controlled outcome trials are performed to confirm efficacy. As demonstrated by the COBALT confirmatory study with obeticholic acid, it is difficult to retain patients in the required follow-on confirmatory placebo-controlled PBC outcome trials when a licensed drug is commercially available. New PBC therapies in development, such as the peroxisome proliferator–activated receptor agonists, face even greater challenges in demonstrating outcome benefit through randomized placebo-controlled studies once following conditional marketing authorization, as there will be even more treatment options available. A recently published EMA Reflection Paper provides some guidance on the regulatory pathway to full approval but fails to recognize the importance of real-world data in providing evidence of outcome benefit in rare diseases. Here we explore the impact of the EMA reflection paper on PBC therapy and offer pragmatic solutions for generating evidence of long-term outcomes through real-world data collection.
The Effect of Childhood Obesity on Intraocular Pressure, Corneal Biomechanics, Retinal Nerve Fiber Layer, and Central Macular Thickness
Authors: Aydin Eroglu Sayime , Akyuz Unsal Ayse Ipek , Verdi Furkan , Kurt Omurlu Imran , Unuvar Tolga , Anik Ahmet
Published: March 2024

Précis:

Elevated corneal hysteresis (CH) and resistance factor (CRF) in obese and overweight children imply weight’s effect on corneal biomechanics. Increased Goldmann-correlated intraocular pressure (IOPg) in obese children indicates glaucoma risk, emphasizing screening for IOP and retinal changes.

Purpose:

To evaluate the effect of obesity on corneal biomechanics, retinal nerve fiber layer (RNFL), and central macular thickness (CMT) in children.

Patients and Methods:

In this prospective, cross-sectional, comparative study, 146 eyes of normal-weight, over-weight, and obese children aged between 6 to 17 years were evaluated. The IOPg, corneal compensated IOP (IOPcc), CH, CRF, and the average retinal nerve fiber layer (RNFL), average cup-to-disk ratio (c/d), and central macular thickness (CMT) were measured by Ocular Response Analyser and Spectral-Domain Optical Coherence Tomography (SD-OCT), respectively.

Results:

There was no statistically significant difference regarding age, gender, IOPcc, average RNFL thickness, c/d ratio, and CMT among the groups (P≥0.05). The IOPg was significantly higher in obese children compared with normal-weight children, while CH and CRF values were significantly higher in both obese and over-weight children compared with healthy ones (P<0.05). There was a positive correlation between BMI percentile and IOPg, CH, and CRF values.

Conclusion:

In our study, higher IOPg, corneal hysteresis, and corneal resistance factor values suggest that obese children could be potential candidates for glaucoma. Therefore, it would be appropriate to screen them for IOP and retinal alterations. Further investigations with larger sample size and longer follow-up are needed to understand the risk of glaucoma in obese children.
Gonioscopy-Assisted Transluminal Trabeculotomy in Uveitis-Related Ocular Hypertension and Glaucoma
Authors: Bouhout Soumaya , Bachour Kenan , Harasymowycz Paul , Jaworski Laurence , Wang Qianqian , Durr Georges M.
Published: March 2024

Précis:

Gonioscopy-assisted transluminal trabeculotomy (GATT) may be an effective first-line surgery for decreasing intraocular pressure (IOP) and medication burden in patients with uveitis-related ocular hypertension (OHT) or glaucoma.

Objective:

The purpose of the study is to determine the efficacy of GATT in lowering IOP in uveitis-related OHT or glaucoma.

Methods:

Retrospective case series that included patients with uveitis-related OHT or glaucoma who underwent GATT with or without concomitant cataract extraction and intraocular lens implantation at 2 Canadian academic centres from July 2018 to May 2022. Primary outcomes were: complete (no medications) and qualified success (with medication), and failure defined as (1) IOP >21 mm Hg with maximal medical therapy, (2) the need for additional glaucoma procedure, (3) loss of light perception secondary to glaucoma, and (4) IOP <6 mm Hg for 3 months.

Results:

Twenty-one eyes from 18 patients were included with a mean preoperative IOP of 26.2 ± 7.3 mm Hg on 4.3 ± 0.7 classes of glaucoma drops. The average follow-up was 29.2 ± 17.6 months and 76% of eyes (n = 16) had reached at least 12 months of follow-up. At the 12-month follow-up visit, there was a significant decrease in average IOP by 9.9 ± 7.9 mm Hg (38%, P = 0.005) and a decrease of 1.9 in glaucoma medication classes (P = 0.002). Of eyes, 14% achieved complete success, whereas 80% of eyes achieved qualified success. Six eyes failed (29%) and 5 patients (24%) required additional glaucoma surgery. The most common postoperative complication was hyphema (n = 9; 43%).

Conclusion:

This small case series suggests that GATT may be an effective first-line surgery for decreasing IOP and medication burden in patients with uveitis-related OHT or glaucoma. Further studies with longer follow-ups should be conducted to assess its long-term outcomes.
Violaceous Papules
Authors: Leigh Rebekah , Goldenberg Alina
Published: March 2024

Teledermatology is a term to describe the provision of dermatologic medical services through telecommunication technology. This is a teledermatology case of violaceous papules on the genital region.
Suspicious Papule on Lower Vermillion Border
Authors: Patrick Genevieve , Melchor Julian , Pascoe David , Derosier Chris , Stewart David
Published: March 2024

Molluscum contagiosum (MC) is a highly contagious, cutaneous infection caused by a double-stranded DNA poxvirus. Mollusca are characterized by a firm, dome-shaped, flesh-colored, pearly papule with a white, umbilicated center. Generally, lesions occur in clusters and range in size from 1 to 5 millimeters. Although unusual and infrequent, MC occurring in an epidermal inclusion cyst has been reported.

This case involves an 83-year-old woman with a flesh-colored, slightly tender papule on the right lower vermillion border, which had been enlarging over several months. Histopathology showed prominent molluscum bodies present in the adjacent epidermis and focally lining the central epidermal cyst.

The findings observed in this case support the hypothesized pathophysiological co-inoculation theory for the development of molluscum-infected epidermal inclusion cysts. This is clinically significant given the infectivity of cyst contents and the potential for direct inoculation of the cyst. Given its rarity, treatment protocols for epidermal inclusion cysts containing MC have not been established. However, management requires care to avoid viral transmission.
Speech and Language Development, Hearing, and Feeding in Patients With Genetically Confirmed Crouzon Syndrome With Acanthosis Nigricans: A 36-Year Longitudinal Retrospective Review of Patients at the Oxford Craniofacial Unit
Authors: Kilcoyne Sarah , Scully Paula , Overton Sarah , Brockbank Sally , Thomas Gregory P.L. , Ching Rosanna C. , Jayamohan Jayaratnam , Ramsden James D. , Jones Jon , Wilkie Andrew O.M. , Johnson David
Published: March 2024

Objective:

Crouzon syndrome with acanthosis nigricans (CAN) is caused by the specific mutation c.1172C>A (p.Ala391Glu) in the fibroblast growth factor receptor 3 gene, and has an estimated prevalence of 1:1,000,000 births. Most cases occur de novo; however, autosomal dominant inheritance may occur. The clinical presentation typically includes craniosynostosis, midface and maxillary hypoplasia, choanal atresia/stenosis, hydrocephalus, and intracranial hypertension. Patients develop acanthosis nigricans, a hyperkeratotic skin disorder. The authors present the first known study to investigate the speech, language, hearing, and feeding of patients with CAN.

Methods:

A retrospective case-note review of patients with a genetically confirmed diagnosis of CAN attending the Oxford Craniofacial Unit during a 36-year period (1987–2023) was undertaken.

Results:

Participants were 6 patients with genetically-confirmed CAN (5 females, 1 male), all cases arose de novo. All patients had craniosynostosis (n = 5/6 multisuture synostosis, n = 1/6 left unicoronal synostosis). Hydrocephalus was managed through ventriculoperitoneal shunt in 67% (n = 4/6) of patients, and 67% (n = 4/6) had a Chiari 1 malformation. Patients had a complex, multifactorial feeding history complicated by choanal atresia/stenosis (100%; n = 6/6), and significant midface hypoplasia. All patients required airway management through tracheostomy (83%; n = 5/6); and/or continuous positive airway pressure (67%; n = 4/6). All patients underwent adenotonsillectomy (100%; n = 6/6). Initial failure to thrive, low weight, and/or height were seen in 100% (n = 6/6) patients; 80% (n = 4/5) had reflux; 100% (n = 6/6) had nasogastric, or percutaneous endoscopic gastrostomy based feeding during their treatment journey. All patients had hearing loss (100%; n = 6/6). Early communication difficulties were common: receptive language disorder (50%; n = 3/6); expressive language disorder (50%; n = 3/6); and speech sound disorder in 50% (n = 3/6)—necessitating the use of Makaton in 80% of patients (n = 3/5).

Conclusions:

Patients with CAN experience significant respiratory, neurological, and structural obstacles to hearing, speech, language, and feeding. The authors present a recommended pathway for management to support patients in these domains.
Raising laying hens: housing complexity and genetic strain affect startle reflex amplitude and behavioural response to fear-inducing stimuli
Authors: Rentsch Ana K. , Harlander Alexandra , Niel Lee , Siegford Janice M. , Widowski Tina M.
Published: March 2024

Individual variation in fearfulness can be modified during ontogeny, and high levels of fear can affect animal welfare. We asked whether early-life environmental complexity and genetic strain affect fear behaviour in young laying hens (pullets). Four replicates of brown (B) and white (W) genetic strains (breeds) of layers were each raised in four environmental treatments (housing): conventional cages (
Conv
) and different rearing aviaries with increasing space and complexity (
Low
<
Mid
<
High
). We used a startle reflex test (weeks 4 and 14) to measure startle amplitude and autonomic response (i.e. comb temperature). A combination of novel arena (NA) and novel object (NO) tests was used (week 14) to assess NA exploration and alertness, latency to approach the centre and initial NO avoidance and investigation. Housing × strain affected startle amplitude (B-Conv, B-High < B-Low, B-Mid; B > W; no housing effect in W) but not autonomic response. Fear behaviour was affected by housing (NA exploration, investigation: Conv < Low, Mid, High; NO avoidance: Conv, High < Low, Mid), strain (NA alertness: B > W, NO avoidance: W > B) and their interaction (NA centre approach: B-Conv < all other groups). We present evidence for strain-specific fear responses depending on early experience.
SimMiL: Simulating Microbiome Longitudinal Data
Authors: Weaver Nicholas E , Hendricks Audrey
Published: March 2024

0.

Structured Abstract

Motivation

The quantity of statistical tools designed for omics data analysis has grown rapidly with the ability to collect large sets of human health data, particularly longitudinal data sets. Most tools are assessed for performance using simulated datasets constructed to mimic a handful of relevant characteristics from real world data sets. Consequently, the simulated data sets, and their respective simulation frameworks, are too narrow in scope to qualify as a standard for assessment in longitudinal omics analyses.

Results

Here we present the flexible and accessible simulation framework and software package called SimMiL (SimulatingMicrobiomeLongitudinal data) capturing three general components of longitudinal microbiome data: (i) absence/presence of microbes, (ii) individual microbe abundance, and (iii) microbiome community composition over time. The framework is assessed by replicating the Type I error and Power analyses of a broad range of statistical tools (MirKAT, repeated measures permANOVA, and a modified kernel association test).

Software Avaliability

The simulation framework is athttps://github.com/nweaver111/SimMiL
Seaweed Amino Acid and L-Amino Acid Improve Coriander Growth
Authors: Chen Xingqiang , Shang Zheng , Chen Haidong , Wan Shulin
Published: March 2024

This study investigates the impact of Seaweed amino acid (SG) and L-amino acid (LG) treatments on the growth and root development of coriander plants compared to a control group (CG). The results from Figure 1 illustrate a significant increase in biomass and foliage density for the SG and LG groups, suggesting an enhanced nutritional uptake resulting from these amino acid treatments. Both SG and LG treatments produced more vigorous growth and higher plant height compared to the CG, which received only water. Additionally, a closer inspection of coriander root systems in Figure 2 reveals an improvement in root biomass and architecture, indicating that both SG and LG applications contribute positively to root development, potentially enhancing plant resilience and yield. While both treatments showed comparable effects on root morphology, further research is required to determine if one has superior long-term benefits over the other. The findings point towards the efficacy of using amino acid treatments as bio-stimulants in agricultural practices to improve crop yield, especially in challenging growth conditions such as those found in Guangzhou, China.
A Holistic Approach to Cognitive Frailty in Community-dwelling Older Adults in India: Evidence from a Nationally Representative Survey
Authors: Das Sayani , Pooley Emma , Holland Carol
Published: March 2024

Background:Cognitive frailty (CF), a complex intersection of physical frailty (PF) and cognitive impairment (CI), remains inadequately explored in the Indian context. Given its potential link to dementia and reversible characteristics, this study aims to understand the national-level prevalence of CF, its regional variations, and its holistic association with socio-demographic, physical, psychosocial, and lifestyle factors.Methods:The present study employed data from the Longitudinal Ageing Study in India (LASI-Wave-I), a nationally representative survey that included 27,379 individuals (13,293 men and 14,086 women) aged 60+. CF was defined as the presence of both PF and CI without dementia. PF was assessed using the modified Community-Oriented Frailty Index, comprising a 20-item deficits frailty index. CI was evaluated using the composite score, which considered five cognitive domains and seven difficulties with IADL. To investigate the association between the outcome variable (CF) and predictor variables (socio-demographic, physical, psychosocial, and lifestyle factors), the study utilised stepwise binary logistic regression (backward elimination) and presented the results as adjusted odds ratios (AOR) with corresponding 95% confidence intervals.Results:The overall prevalence of CF amongst those aged 60+ was found to be 4.5%, with higher rates evident in the Western (6.2%) and Southern (5.3%) regions. Several factors exhibited significant associations with CF (p < 0.01), including being aged 80 and above (AOR 4.7, 95% CI: 3.9–5.6), being female (AOR 1.6, 95% CI: 1.4–1.9), and having less than primary education (AOR 15.3, 95% CI: 7.2–32.5, p < 0.01). Mobility impairment (AOR 6.7, 95% CI: 4.7–9.8) also exhibited a strong effect on CF. Psychosocial factors, such as low social participation (AOR 2.1, 95% CI: 1.8–2.4), major depression (AOR 1.7, 95% CI: 1.4–2.0), sleep problems (AOR 1.6, 95% CI: 1.4–1.9), and low life satisfaction (AOR 1.4, 95% CI: 1.2–1.6), were also found to have significant associations with CF.Conclusions:This pioneering study outlines the prevalence of CF in India, revealing elevated rates among the community-dwelling population aged over 60 compared to global figures, accompanied by notable regional variations, and underscores the importance of future longitudinal data and targeted investigations for informing policy implications.