bluuebunny/crossref_metadata_2025 huggingface dataset:
Statutory Nuisance: Law and Practice
Authors: Malcolm Rosalind , Pointing John
Published: January 2025

Statutory Nuisance: Law and Practice offers a comprehensive resource for practitioners in the legal and environmental health professions, guiding the reader through the complex practical and legal issues associated with statutory nuisance. It focuses on the problems that local authorities face in enforcing this area, as well as the issues facing those advising defendants. This title examines the role, powers, and duties of the local authorities, and the problems associated with drafting abatement notices and with the prosecution of nuisances. It also covers defences and proceedings brought by private individuals against neighbours and local authority landlords. The book analyses what happens in court, considering in detail the procedure and requirements in appeals against notices and in prosecutions, as well as the grounds for bringing further appeals and judicial review. It covers important recent decisions and key legislation. This new edition provides an update on the various types of statutory nuisance, additional chapters on new forms of statutory nuisance, and expanded material on adjacent areas of enforcement to statutory nuisance, notably those arising from the Anti-Social Behaviour agenda.
The Historical Context of Statutory Nuisance and Public Health Legislation
Authors: Malcolm Rosalind , Pointing John
Published: January 2025

Statutory nuisance is a concept that originated in the huge changes and adverse environmental conditions brought about during the Industrial Revolution in Great Britain. It was fundamental to the sanitary legislation that was first enacted in the 1840s and 1850s, and which continued into the twentieth century in the Public Health Act of 1936. Some of this early sanitary legislation continues in Part III of the Environmental Protection Act 1990 (EPA 1990), either virtually unaltered from its original formulation or in an amended form; some early formulations are to be found in other legislation, such as the Building Act 1984.
Animals
Authors: Malcolm Rosalind , Pointing John
Published: January 2025

At common law, for the keeping of animals to become actionable as a nuisance some ‘extraordinary, non-natural or unreasonable action’ is required. Section 79(1)(f) of the Environmental Protection Act 1990 (EPA 1990) defines as a statutory nuisance: ‘any animal kept in such a place or manner as to be prejudicial to health or a nuisance’.
Miscellaneous Nuisances in Other Legislation
Authors: Malcolm Rosalind , Pointing John
Published: January 2025

Section 79(1)(h) of the Environmental Protection Act 1990 (EPA 1990) provides for ‘any other matter declared by any enactment to be a statutory nuisance’. This provision could apply to prospective forms of statutory nuisance, though in practice it applies to a miscellaneous body of historic nuisances. Those enacted since the EPA 1990 came into effect, such as statutory nuisances from artificial light and insects, have been given their own subsections under section 79 and have not engaged section 79(1)(h).
Tree age affects key fine root morphological traits but does not interfere strongly with (ecto-)mycorrhizal traits
Authors: Qin Yu , Valverde-Barrantes Oscar J , Jin Guangze , Liu Zhili , Freschet Grégoire T
Published: January 2025

Background and Aims

It is assumed that trees should adapt their above and belowground organs as they age. However, most studies to date have quantified these trait adjustments in homogeneous forest stands, confounding the effect of stand aging on soil properties and the intrinsic response of trees to aging.

Methods

Here, we examined 11 morphological, architectural, anatomical and mycorrhizal fine root traits of each of the first five orders for 66 Pinus koraiensis individuals of 16 to 285 years old in northeast China, while accounting for soil characteristics (pH and total C, N and P concentrations).

Key Results

Across all absorptive root orders, Hartig net area and mantle thickness, representative of P. koraiensis reliance on ectomycorrhizal association, displayed an orthogonal pattern to traits describing root economics strategy, specific root length and root tissue density. Hartig net area and mantle thickness were not significantly related to root mycorrhizal colonization intensity and root branching intensity. As tree aged, there was a trade-off between increasing specific root length and decreasing root tissue density in all root orders we measured. Trees facing soil conditions with lower N or P concentrations showed higher dependence on ectomycorrhizal fungi.

Conclusions

This work provides evidence that tree belowground economics strategy can change significantly along the life of trees. In the ectomycorrhizal tree species studied, morphological adjustments are most pronounced, whereas mycorrhizal strategy remains largely consistent. The more conservative root strategy of younger trees than older ones contradicts previous results on the aging of homogeneous tree stands, suggesting that individual tree responses to aging in mixed-aged forests may strongly differ from those in homogeneous forest stands experiencing multiple confounding environmental influences.
Classification-based pathway analysis using GPNet with novel P-value computation
Authors: Lu Hao , Rezapour Mostafa , Baha Haseebullah , Khalid Khan Niazi Muhammad , Narayanan Aarthi , Nafi Gurcan Metin
Published: January 2025

Pathway analysis plays a critical role in bioinformatics, enabling researchers to identify biological pathways associated with various conditions by analyzing gene expression data. However, the rise of large, multi-center datasets has highlighted limitations in traditional methods like Over-Representation Analysis (ORA) and Functional Class Scoring (FCS), which struggle with low signal-to-noise ratios (SNR) and large sample sizes. To tackle these challenges, we use a deep learning-based classification method, Gene PointNet, and a novel $P$-value computation approach leveraging the confusion matrix to address pathway analysis tasks. We validated our method effectiveness through a comparative study using a simulated dataset and RNA-Seq data from The Cancer Genome Atlas breast cancer dataset. Our method was benchmarked against traditional techniques (ORA, FCS), shallow machine learning models (logistic regression, support vector machine), and deep learning approaches (DeepHisCom, PASNet). The results demonstrate that GPNet outperforms these methods in low-SNR, large-sample datasets, where it remains robust and reliable, significantly reducing both Type I error and improving power. This makes our method well suited for pathway analysis in large, multi-center studies. The code can be found at https://github.com/haolu123/GPNet_pathway">https://github.com/haolu123/GPNet_pathway
Prediction of gene expression using histone modification patterns extracted by Particle Swarm Optimization
Authors: Paul Niels Benjamin , Wolber Jonas Chanrithy , Sahrhage Malte Lennart , Beißbarth Tim , Haubrock Martin
Published: January 2025

Motivation

Histone modifications play an important role in transcription regulation. Although the general importance of some histone modifications for transcription regulation has been previously established, the relevance of others and their interaction is subject to ongoing research. By training Machine Learning models to predict a gene’s expression and explaining their decision making process, we can get hints on how histone modifications affect transcription. In previous studies, trained models were either hardly explainable or the models were trained solely on the abundance of histone modifications. Based on other studies, which used histone modification patterns, rather than their abundance, to identify potential regulatory elements, we hypothesize the histone modification pattern in a gene’s promoter to be more predictive for gene expression. We used an optimization algorithm to extract predictive histone modification profiles.

Results

Our algorithm called PatternChrome achieved an average area under curve (AUC) score of 0.9029 over 56 samples for binary classification, outperforming all previous algorithms for the same task. We explained the models decisions to deduce the effect of specific features, certain histone modifications or promoter positions on transcription regulation. Although the predictive histone modification patterns were extracted for each sample separately, they can be used to predict gene expression in other samples, implying that the created patterns are largely generalizable. Interestingly, the impact of histone modifications on gene regulation appears predominantly indifferent to cellular specificity. Through explanation of the classifier’s decisions, we substantiate established literature knowledge while concurrently revealing novel insights into the intricate landscape of transcriptional regulation via histone modification.

Availability and implementation

The code for the PatternChrome algorithm, the scripts for the analyses and the required data can be found at (https://gitlab.gwdg.de/MedBioinf/generegulation/patternchrome).
Enhanced O-glycosylation site prediction using explainable machine learning technique with spatial local environment
Authors: Hong Seokyoung , Chattaraj Krishna Gopal , Guo Jing , Trout Bernhardt L , Braatz Richard D
Published: January 2025

Motivation

The accurate prediction of O-GlcNAcylation sites is crucial for understanding disease mechanisms and developing effective treatments. Previous machine learning (ML) models primarily relied on primary or secondary protein structural and related properties, which have limitations in capturing the spatial interactions of neighboring amino acids. This study introduces local environmental features as a novel approach that incorporates three-dimensional spatial information, significantly improving model performance by considering the spatial context around the target site. Additionally, we utilize sparse recurrent neural networks to effectively capture sequential nature of the proteins and to identify key factors influencing O-GlcNAcylation as an explainable ML model.

Results

Our findings demonstrate the effectiveness of our proposed features with the model achieving an F1 score of 28.3%, as well as feature selection capability with the model using only the top 20% of features achieving the highest F1 score of 32.02%, a 1.4-fold improvement over existing PTM models. Statistical analysis of the top 20 features confirmed their consistency with literature. This method not only boosts prediction accuracy but also paves the way for further research in understanding and targeting O-GlcNAcylation.

Availability and implementation

The entire code, data, features used in this study are available in the GitHub repository: https://github.com/pseokyoung/o-glcnac-prediction
Young people’s perspectives on barriers to accessing supports and services in Drayton Valley, Canada
Authors: Adisaputri Gianisa , Grant Tonya , Ungar Michael
Published: January 2025

As young people transition to adulthood, they are required to exercise more autonomy when accessing informal psychosocial support and formal health and social services. This qualitative study examines the lived experience of forty-nine young people aged thirteen to twenty-four in Drayton Valley, Canada, and their accounts of accessing support and services in response to mental and physical health needs. Drayton Valley is an economically volatile community dependent on the oil and gas industry. Using data from the Resilient Youth in Stressed Environment project, we investigated the experiences of young people when accessing healthcare, social, and community services. We used a general inductive analysis approach to develop a framework for how young people decide whether or not to engage with support and services. In general, youth reported needing positive knowledge about services, trust in both the organization and providers of services, the independence to seek supports and/or services that they valued, and the need to experience a fit with the mandate of their service provider. Our findings suggest that to increase the use of supports and services, policies need to better account for young people’s experiences when seeking help.
Development and validation of a measure to assess patient experience of needling of arteriovenous fistulas or grafts for haemodialysis access: the NPREM
Authors: Moore Currie , Busby Amanda , Flanagan Rebecca , Ellis-Caird Helen , Awan Faizan , Paul Tarsem , Fielding Catherine , McCafferty Kieran , van der Veer Sabine N , Farrington Ken , Wellsted David
Published: January 2025

Background

Needling is a key step in haemodialysis. Research suggests needling experience is sub-optimal; however, no validated measure exists to inform improvements. We addressed this by developing the Needling Patient Reported Experience Measure (NPREM).

Methods

We used mixed methods and co-production. All participants were adults with working fistulas/grafts from eight UK kidney centres.

Phase 1: Developing concepts and items, In interviews (n=41), we explored patients’ needling experience and identified key aspects of needling using thematic analysis. This informed the 98-item NPREM(v0.1).

Phase 2: Piloting the measure Cognitive interviews (n=16) assessed face validity. Items were amended or removed, yielding a 48-item NPREM(v0.2).

A pilot survey (n=183) examined initial psychometric properties. NPREM(v0.2) showed good internal consistency (Cronbach's alpha=0.95). Review of analyses resulted in a 35-item NPREM(v0.3).

Phase 3: Evaluating the measure's dimensionality, validity, and reliability Patients (n=468) completed the NPREM(v0.3), Vascular Access Quality of Life (VASQoL), EuroQol 5-Dimension-5-Level (EQ5D-5L), Patient Activation Measure (PAM), with a sub-set completing a follow-up NPREM (n=99). Items were evaluated with 28 items retained in the NPREM(v1.0). Confirmatory factor analysis confirmed a unidimensional model fit (CFI=0.899). Validity of the NPREM(v1.0) was good [convergent: VASQoL (r=0.60) and overall experience (r=0.79); divergent: EQ-5D (r=-0.31), EQ-5D VAS (r=0.24) and PAM (r=0.17)]. Test-retest scores were strongly correlated (r=0.88), demonstrating high reliability. Known-groups validity was demonstrated between centre scores (range 5.21 (SD 1.20) to 5.94 (SD 0.75)).

Conclusion

The NPREM measures patient experience of needling for haemodialysis. It offers kidney services a means of assessing needling experience, informing patient-focused clinical and service improvements.
Helping authors produce FAIR taxonomic data: evaluation of an author-driven phenotype data production prototype
Authors: Zhang Limin , Starr Julian , Ford Bruce , Reznicek Anton , Zhou Yuxuan , Léveillé-Bourret Étienne , Lacroix-Carignan Étienne , Cayouette Jacques , Smith Tyler W , Sutherland Donald , Catling Paul , Saarela Jeffery M , Cui Hong , Macklin James
Published: January 2025

It is well-known that the use of vocabulary in phenotype treatments is often inconsistent. An earlier survey of biologists who create or use phenotypic characters revealed that this lack of standardization leads to ambiguities, frustrating both the consumers and producers of phenotypic data. Such ambiguities are challenging for biologists, and more so for Artificial Intelligence, to resolve. That survey also indicated a strong interest in a new authoring workflow supported by ontologies to ensure published phenotype data are FAIR (Findable, Accessible, Interoperable, and Reusable) and suitable for large-scale computational analyses.

In this article, we introduce a prototype software system designed for authors to produce computational phenotype data. This platform includes a web-based, ontology-enhanced editor for taxonomic characters (Character Recorder), an Ontology Backend holding standardized vocabulary (the Cared Ontology), and a mobile application for resolving ontological conflicts (Conflict Resolver). We present two formal user evaluations of Character Recorder, the main interface authors would interact with to produce FAIR data. The evaluations were conducted with undergraduate biology students and Carex experts. We evaluated Character Recorder against Microsoft Excel on their effectiveness, efficiency, and the cognitive demands of the users in producing computable taxon-by-character matrices.

The evaluations showed that Character Recorder is quickly learnable for both student and professional participants, with its cognitive demand comparable to Excel’s. Participants agreed that the quality of the data Character Recorder yielded was superior. Students praised Character Recorder’s educational value, while Carex experts were keen to recommend it and help evolve it from a prototype into a comprehensive tool. Feature improvements recommended by expert participants have been implemented after the evaluation.
Prognostic impact of 1-year permanent pacemaker implantation after mitral valve surgery with the Cox-maze procedure
Authors: Lee Jun Ho , Kim Yun Jin , Kim Ji Eon , Song Kyungsub , Shin Yonghoon , Jung Jae Seung , Son Ho Sung , Lee Seung Hyun , Kim Hee Jung
Published: January 2025

OBJECTIVES

This study aimed to evaluate the prognostic impact of permanent pacemaker (PPM) implantation within the first year after mitral valve (MV) surgery combined with the Cox-maze procedure, focusing on long-term outcomes, including overall mortality, infective endocarditis (IE) and ischaemic stroke.

METHODS

We conducted a retrospective cohort study using data from the National Health Insurance Service (NHIS) in South Korea, identifying 10 127 patients who underwent MV surgery with the Cox-maze procedure between 2005 and 2020. Patients were classified into the PPM and non-PPM groups based on PPM implantation within 1 year postoperatively. The primary outcome was overall mortality, and secondary outcomes included risk factors for overall mortality, IE and ischaemic stroke. Multivariable Cox proportional hazards regression and Fine-Gray competing risk models were utilized for statistical analysis.

RESULTS

Of the total cohort, 178 patients (1.76%) underwent PPM implantation. The overall mortality during the follow-up period was 20.5%, with no significant difference between the PPM and non-PPM groups. PPM implantation was not a significant risk factor for overall mortality (hazard ratio [HR], 0.825; 95% confidence interval [CI] 0.598–1.140; P = 0.244) or ischaemic stroke. However, PPM implantation was associated with a significantly increased risk of IE (HR, 2.015; 95% CI 1.179–3.442; P = 0.010).

CONCLUSIONS

PPM implantation within the first year after MV surgery with the Cox-maze procedure does not significantly impact long-term mortality or ischaemic stroke risk but is associated with an increased risk of IE. The Cox-maze procedure remains advisable for patients with atrial fibrillation undergoing MV surgery.
Educational Disparities in Age-Related Hearing Loss and Hearing Aid Use Across Age, Gender, and European Region
Authors: Stonkute Donata , Vierboom Yana
Published: January 2025

Objectives

Affecting 1 in 5 adults in Europe, hearing loss (HL) is linked to adverse health outcomes, including dementia. We aim to investigate educational inequalities in hearing health in Europe and how these inequalities change with age, gender, and region.

Methods

Utilizing 2004–2020 data from the Harmonized Survey of Health, Ageing, and Retirement in Europe (SHARE), a representative sample of Europeans aged 50 and older, we analyze: (1) age-standardized prevalence of HL and hearing aid (HA) use among eligible individuals and (2) educational inequalities therein using the Relative Index of Inequality across age, gender, and European regions.

Results

The prevalence of self-reported HL increases with age, is greater among men, and is consistently higher among those with lower levels of education. At age 50–64, particularly in Southern and Eastern Europe, low-educated women experience more than 3 times the risk of HL compared to highly educated women. These inequalities diminish as women age. Northern Europe is a front-runner in meeting HA needs. Southern and Eastern Europe lag behind, with less than 2 in 10 individuals eligible for HAs utilizing them.

Discussion

Substantial variations in the educational gradient of hearing health across age, gender, and European regions underscore the importance of targeting specific subpopulations in efforts to mitigate health inequalities. Of particular concern is the regional discrepancy between the prevalence of HL and the use of HAs. The example of Northern Europe suggests that there is unused potential to improve healthy aging in Europe through enhanced access to HAs.
State-level variation in access to long-acting injectable antiretroviral therapy for HIV in the United States
Authors: Zalla Lauren C , Horn Tim , Lujintanon Sita , Lesko Catherine R
Published: January 2025

Long-acting injectable antiretroviral therapy (LAI-ART) is expected to improve health outcomes among persons with HIV. Yet, uptake has been slow and data on potential barriers to access are sparse. We used medication formulary data from state Medicaid and AIDS Drug Assistance Programs (ADAPs) to examine state-level variation in access to LAI-ART among uninsured and low-income persons with HIV. We identified substantial coverage gaps: cabotegravir/rilpivirine was not covered without prior authorization by 26 state Medicaid programs and not covered at all by 15 state ADAPs; lenacapavir was not covered without prior authorization by 32 Medicaid programs and not covered at all by 18 ADAPs. As a result of these gaps, many US persons with HIV are currently unable to access LAI-ART. Policies that increase access are needed to ensure the equitable distribution of LAI-ART. As states work to reduce supply and payment chain barriers, the US Department of Health and Human Services, notably its Centers for Medicare & Medicaid Services and the Health Resources and Services Administration, should provide increased federal assistance, guidance, and oversight to improve LAI-ART access among people with HIV.
Publishers face antitrust lawsuit with potential implications for peer review, duplicate submission, and dissemination practices
Authors: Curfman Gregory
Published: January 2025

Scientific, technical, and medical (STM) publishers follow 3 basic tenets: (1) no compensation for peer reviewers; (2) manuscript submission only to one journal; and (3) no dissemination of manuscripts while under review. An antitrust lawsuit was filed in federal district court against STM publishers challenging these tenets. The lawsuit will have important implications for how STM research is published and will also affect authors and editors. Academic researchers (plaintiffs) who have served as authors and reviewers allege that the 6 largest STM publishers (defendants) have conspired to require authors to abide by the 3 basic tenets. The plaintiffs argue that the publishers have substantial market power, pursue anticompetitive policies, and violate Section 1 of the Sherman Antitrust Act. This article focuses principally on the second tenet, that research manuscripts may be submitted to only one journal. This requirement, which the plaintiffs believe is an antitrust violation, is not a feature of law journals, where multiple simultaneous submissions of manuscripts are a central part of the publishing process. This article will explain how the court may approach the legal analysis in this lawsuit and the important implications of the outcome of this litigation for the scholarly publishing ecosystem.
The Framing of Federal Investigations: Exploring How Frames Altered the Impact of the Hur Report on Citizens’ Impressions
Authors: Fridkin Kim , Kenney Patrick J
Published: January 2025

The frames used to describe political events can powerfully influence the public’s understanding, interpretation, and evaluation of events. In this research note, we examine how the framing of a federal investigation of a sitting president can alter views of the investigation as well as evaluations of the president. In February 2024, Special Counsel Robert Hur released his year-long investigation into President Joe Biden’s handling of classified documents. We conduct a survey experiment to compare the impact of alternative framing of the Hur report. We find that alternative frames (i.e., the original Hur frame v. an alternative frame) significantly and consistently influence people’s views of the report’s findings. We also show that differing views of the report’s findings ultimately influence changes in evaluations of Joe Biden. Our results demonstrate how the framing of investigative findings by government officials can dramatically alter citizens’ assessments, producing consequential political evaluations.
Antibiotic duration for common bacterial infections—a systematic review
Authors: Mo Yin , Tan Wei Cong , Cooper Ben S
Published: January 2025

Background

Reducing antibiotic duration is a key stewardship intervention to mitigate antimicrobial resistance (AMR). We examined current evidence informing antibiotic duration for common bacterial infections to identify any gaps in terms of settings, patient populations and infectious conditions. Trial methodologies were assessed to identify areas for improvement.

Methods

MEDLINE and Embase were searched up to July 2024 for randomized trials comparing antibiotic durations in hospital and community settings (PROSPERO 2021, CRD42021276209). A narrative synthesis of the results was performed with a review on the major guidelines published by IDSA, NICE, WHO and other international societies to assess the impact of these trials on practice guidance.

Results

Out of 315 studies, 85% concluded equivalence or non-inferiority of shorter courses. Adult bacterial sinusitis, community-acquired pneumonia, female cystitis/pyelonephritis, uncomplicated cellulitis and intra-abdominal infection with adequate source control and perioperative prophylaxis had robust evidence supporting shorter durations. Few trials studied severe infections, such as bloodstream infections and ventilator-associated pneumonia. Twenty-three (7%) of the trials were conducted in intensive care settings and only 43 trials (14%) enrolled patients from low-to-middle- or low-income countries. Only 15% of studies were at low risk for bias.

Conclusions

Reducing antibiotic duration likely remains an important strategy for antibiotic stewardship, and an area of active research. While shorter antibiotic courses may be suitable for many bacterial infections, more evidence is needed for severe infections and in low- and middle-income settings.
An audit of antibiotic prescriptions: an antimicrobial stewardship pre-implementation study at a tertiary care public hospital
Authors: Cassim Jowhara , Essack Sabiha Y , Chetty Sarentha
Published: January 2025

Objective

To audit the prescribing of antibiotics at a tertiary-level public hospital, in preparation for the implementation of an antimicrobial stewardship programme.

Methods

A retrospective audit of antibiotic prescriptions for the period April 2020 to June 2020 was conducted to ascertain appropriate antibiotic prescribing based on a set of process measures, which included whether cultures were taken before the initiation of empirical antibiotics, the duration of antibiotic therapy, de-escalation to a narrower spectrum antibiotic, the concurrent use of four or more antibiotics, documented indication for antibiotic use, and parenteral to oral conversion. Statistics were calculated using Stata (Version 17).

Results

A total of 380 patient medical charts were reviewed. It was noted that there were no standalone antibiotic charts, and antibiotics were prescribed alongside other medication in one prescription record. There was non-compliance to one or more of the process measures in two-thirds of antibiotic prescriptions audited. Excessive duration of therapy was evident in 3.16% (12) prescriptions. There were 18 (4.74%) instances in which de-escalation to a narrower spectrum antibiotic based on susceptibility results did not occur. Only a small proportion of patients were switched from parenteral to oral antibiotics (n = 12, 3.16%). Some of the additional findings included redundant antibiotic coverage (n = 137, 36.05%) and prescription of an antibiotic that did not align with the susceptibility results (n = 98, 25.79%).

Conclusions

Inappropriate antibiotic prescribing did occur in some cases. The results from this pre-implementation study highlight the importance of introducing antimicrobial stewardship interventions with process and outcome measures.
Enhancing the general public knowledge of antimicrobial resistance (AMR) in Africa: a video-based Brief Educational Resource Review
Authors: Nkaiwuatei Jimmy , Hamza Hafeez , Akbi Samar , Muzondo Ngoni
Published: January 2025

Background

The ability of microorganisms to resist antimicrobial medicines is called antimicrobial resistance (AMR). AMR awareness among the general public may be increased via a variety of approaches including the use of social media campaigns, traditional media, influencer outreach storytelling, community theatre, interactive games and quizzes and art and music. This analysis aims to evaluate YouTube videos to educate the general public about AMR.

Methods

A content analysis was performed on the AMR educational videos that were retrieved from YouTube using the following keyword phrases: ‘what is antimicrobial resistance’, ‘causes of antimicrobial resistance’ and ‘prevention of antimicrobial resistance’.

Results

A total of 74 AMR educational videos were identified and analysed based on predefined selection criteria. Subsequently, three online videos that met the inclusion criteria were selected and analysed.

Conclusions

The analysed AMR educational videos were easily accessible and comprehensible, and serve as valuable resources for promoting AMR awareness and education among the general population.
Biases in the performance of FRAX without BMD in predicting fracture risk in a multiethnic population with diabetes: the Diabetes & Aging Study
Authors: Jain Rajesh K , Liu Jennifer Y , Grant Richard W , Haider Shanzay , Huang Elbert S , Laiteerapong Neda , Lipska Kasia J , Lo Joan C , Moffet Howard H , Parker Melissa M , Karter Andrew J
Published: January 2025

Fracture risk calculators, such as the Fracture Risk Assessment Tool (FRAX), calculate the risk of major osteoporotic (MOF) and hip fracture, but do not account for the excess risk of fracture in people with diabetes. We examined the predictive performance of FRAX without BMD in ethnically diverse, older patients with diabetes. Patients included were between ages 65-89 from the Kaiser Permanente Northern California Diabetes Registry and not already taking osteoporosis medications. Race and ethnicity were self-identified. We calculated FRAX without BMD based on baseline characteristics and assessed how well FRAX predicted MOF and hip fracture over follow-up. Predictive performance was based on measures of discrimination (area under the receiver operator curve, AUC) and calibration (observed-to-predicted ratio, O/P). We identified 96 914 patients (47.0% female), of whom 5383 (5.6%) and 1767 (1.8%) had MOF and hip fracture, respectively, over a mean follow-up of 4.3 years. The AUC for MOF and hip fracture were 0.72 and 0.77, respectively. FRAX mildly underestimated MOF and hip fracture rates (O/P 1.2 for both) overall. Discrimination was similar by race and ethnicity and diabetes duration but was worse in those over age 75 (AUC < 0.7). In some groups, there were substantial calibration errors, such as Hispanic women (O/P: 1.8 and 1.5), Black men (O/P: 1.5 and 1.8), those with duration of diabetes ≥20 years (O/P: 1.6 and 1.5), and those over the age of 80 (O/P: 1.4 and 1.2) for MOF and hip fracture, respectively. While the discriminatory performance of FRAX without BMD was good overall in patients with diabetes, it underestimated risk in Hispanic women, Black men, those with long duration of diabetes, and in the oldest patients with diabetes. These algorithmic biases suggest that diabetes-specific tools may be needed to stratify fracture risk in patients with diabetes.
Phase 2 randomized study of abobotulinumtoxinA in patients with provoked vestibulodynia: dose-finding results
Authors: Goldstein Andrew , Rubin Rachel , Dahir Melissa , Goldstein Irwin , Faught Brooke M , Bohm-Starke Nina , Krapf Jill , Caetano Peter , Volteau Magali , Silva Robert
Published: January 2025

Background

Hypertonicity of the pelvic floor muscles is commonly associated with provoked vestibulodynia (PVD); therefore, patients may benefit from treatments that relax the pelvic floor.

Aim

To define optimal (safe and efficacious) doses of abobotulinumtoxinA (aboBoNT-A) for the treatment of PVD associated with hypertonic pelvic floor muscle dysfunction and to explore use of a novel endpoint for pain assessment for PVD.

Methods

This phase 2, randomized, placebo-controlled study comprised two steps: dose escalation (Stage 1) and dose expansion (Stage 2). Stage 1 included up to four treatment cycles; Cycle 1 was double blind, Cycles 2–4 open label. Patients were assessed for retreatment every 6 weeks. Stage 2 was not conducted because of early study termination by the sponsor, unrelated to observed safety signals. Enrolled patients—premenopausal women with PVD with associated pelvic-floor hypertonia—were randomized (n = 60) 4:1 to receive aboBoNT-A (doses: 100, 300, 400, or 500 units [U]) or placebo.

Outcomes

The primary endpoint was safety. Additionally, a novel composite endpoint, dilator maximum tested size was evaluated. This endpoint combined assessment of vaginal-dilator tolerability with patient-reported pain assessment on an 11-point numeric rating scale, used as a surrogate measure of sexual activity in this study.

Results

All treatment-emergent adverse events (AEs) were mild or moderate in intensity, with no serious AEs or AEs leading to withdrawal reported in the double-blind period. AEs of special interest (urinary incontinence, anal sphincter atonia) were observed at low incidence and predominantly with higher aboBoNT-A doses. The dilator test composite score might be a useful endpoint for pain assessment, with a greater reduction in pain score noted for the 300 U dose group compared with other dose groups and placebo.

Clinical implications

aboBoNT-A was well tolerated in patients with PVD and a novel method for assessing dilator-induced pain was introduced.

Strengths and limitations

The study provided valuable data on use of aboBoNT-A in women with primary or secondary PVD and introduced a novel composite endpoint for assessing dilator-induced pain. Study limitations included the small sample size, limiting formal statistical analysis.

Conclusion

aboBoNT-A was well tolerated in patients with PVD with no safety signals reported. Further studies are warranted to demonstrate clinically meaningful benefits with repeated treatment.

Clinical trial registration number

NCT03598777.
Is the JWST detecting too many AGN candidates?
Authors: Habouzit Melanie
Published: January 2025

In less than two years of operation, the JWST has already accelerated significantly our quest to identify active massive black holes (BHs) in the first billion years of the Universe’s history. At the time of writing, about 50 active galactic nucleus (AGN) detections and candidates have been identified through spectroscopy, photometry, and/or morphology. Broad-line AGN are about a hundred times more numerous than the faint end of the UV-bright quasar population at $z\sim 5{-}6$. In this paper, we compare the observational constraints on the abundance of these AGN at $z\sim 5$ to the populations of AGN produced in large-scale cosmological simulations. Assuming a null fraction of obscured simulated AGN, we find that while some simulations produce more AGN than discovered so far, some others produce a similar abundance or even fewer AGN in the bolometric luminosity range probed by JWST. Keeping in mind the large uncertainty on the constraints, we discuss the implications for the theoretical modelling of BH formation and evolution in case similar constraints continue to accumulate. At the redshift of interest, the simulated AGN populations diverge the most at $L_{\rm bol}\sim 10^{44}\, {\rm erg\, s}^{-1}$ (by more than a dex in the bolometric luminosity function). This regime is most affected by incompleteness in JWST surveys. However, it holds significant potential for constraining the physical processes determining the assembly of BHs (e.g. seeding, feedback from supernova, and AGN) and the current abundance of broad-line AGN with $\geqslant 10^{44.5}\, {\rm erg\, s}^{-1}$.
The Mystery of Alpha and the Isotopes
Authors: Webb John K , Lee Chung-Chi , Milaković Dinko , Flambum Victor V , Dzuba Vladimir A , Magueijo João
Published: January 2025

We report unbiased AI measurements of the fine structure constant α in two proximate absorption regions in the spectrum of the quasar HE0515−4414. The data are high resolution, high signal to noise, and laser frequency comb calibrated, obtained using the ESPRESSO spectrograph on the VLT. The high quality of the data and proximity of the regions motivate a differential comparison, exploring the possibility of spatial variations of fundamental constants, as predicted in some theories. We show that if the magnesium isotopic relative abundances are terrestrial, the fine structure constants in these two systems differ at the 7σ level. A 3σ discrepancy between the two measurements persists even for the extreme non-terrestrial case of 100% 24Mg, if shared by both systems. However, if Mg isotopic abundances take independent values in these two proximate systems, one terrestrial, the other with no heavy isotopes, both can be reconciled with a terrestrial α, and the discrepancy between the two measurements falls to 2σ. We cannot rule out other systematics that are unaccounted for in our study that could masquerade as a varying alpha signal. We discuss varying constant and varying isotope interpretations and resolutions to this conundrum for future high precision measurements.
Molecular and Functional Convergences Associated with Complex Multicellularity in Eukarya
Authors: Pereira Lobo Francisco , Benjamim Dalbert Macedo , da Silva Thieres Tayroni Martins , de Oliveira Maycon Douglas
Published: January 2025

A key trait of Eukarya is the independent evolution of complex multicellularity in animals, land plants, fungi, brown algae, and red algae. This phenotype is characterized by the initial exaptation of cell–cell adhesion genes followed by the emergence of mechanisms for cell–cell communication, together with the expansion of transcription factor gene families responsible for cell and tissue identity. The number of cell types is commonly used as a quantitative proxy for biological complexity in comparative genomics studies. While expansions of individual gene families have been associated with variations in the number of cell types within individual complex multicellular lineages, the molecular and functional roles responsible for the independent evolution of complex multicellular across Eukarya remain poorly understood. We employed a phylogeny-aware strategy to conduct a genomic-scale search for associations between the number of cell types and the abundance of genomic components across a phylogenetically diverse set of 81 eukaryotic species, including species from all complex multicellular lineages. Our annotation schemas represent 2 complimentary aspects of genomic information: homology, represented by conserved sequences, and function, represented by Gene Ontology terms. We found many gene families sharing common biological themes that define complex multicellular to be independently expanded in 2 or more complex multicellular lineages, such as components of the extracellular matrix, cell–cell communication mechanisms, and developmental pathways. Additionally, we describe many previously unknown associations of biological themes and biological complexity, such as expansions of genes playing roles in wound response, immunity, cell migration, regulatory processes, and response to natural rhythms. Together, our findings unveil a set of functional and molecular convergences independently expanded in complex multicellular lineages likely due to the common selective pressures in their lifestyles.
Telomemore enables single-cell analysis of cell cycle and chromatin condensation
Authors: Yakovenko Iryna , Mihai Ionut Sebastian , Selinger Martin , Rosenbaum William , Dernstedt Andy , Gröning Remigius , Trygg Johan , Carroll Laura , Forsell Mattias , Henriksson Johan
Published: January 2025

Single-cell RNA-seq methods can be used to delineate cell types and states at unprecedented resolution but do little to explain why certain genes are expressed. Single-cell ATAC-seq and multiome (ATAC + RNA) have emerged to give a complementary view of the cell state. It is however unclear what additional information can be extracted from ATAC-seq data besides transcription factor binding sites. Here, we show that ATAC-seq telomere-like reads counter-inituively cannot be used to infer telomere length, as they mostly originate from the subtelomere, but can be used as a biomarker for chromatin condensation. Using long-read sequencing, we further show that modern hyperactive Tn5 does not duplicate 9 bp of its target sequence, contrary to common belief. We provide a new tool, Telomemore, which can quantify nonaligning subtelomeric reads. By analyzing several public datasets and generating new multiome fibroblast and B-cell atlases, we show how this new readout can aid single-cell data interpretation. We show how drivers of condensation processes can be inferred, and how it complements common RNA-seq-based cell cycle inference, which fails for monocytes. Telomemore-based analysis of the condensation state is thus a valuable complement to the single-cell analysis toolbox.
An evolved, orthogonal ssDNA generator for targeted hypermutation of multiple genomic loci
Authors: Chu Weiran , Tian Rongzhen , Guo Yaxin , Wu Yaokang , Rehm Fabian B H , Liu Long , Li Jianghua , Du Guocheng , Chen Jian , Liu Yanfeng
Published: January 2025

Achieving targeted hypermutation of specific genomic sequences without affecting other regions remains a key challenge in continuous evolution. To address this, we evolved a T7 RNA polymerase (RNAP) mutant that synthesizes single-stranded DNA (ssDNA) instead of RNA in vivo, while still exclusively recognizing the T7 promoter. By increasing the error rate of the T7 RNAP mutant, it generates mutated ssDNA that recombines with homologous sequences in the genome, leading to targeted genomic hypermutation. This approach, termed T7 RNAP mutant-assisted continuous evolution (T7ACE), functions effectively in both typical prokaryotic and eukaryotic microorganisms (Escherichia coli and Saccharomyces cerevisiae), achieving targeted hypermutations at rates 2800- and 1200-fold higher than the genomic mutation rates, respectively. Using T7ACE, we successfully evolved an eight-fold increase in tigecycline resistance within 7 days and doubled the efficiency of a xylose utilization pathway in 10 days, demonstrating the efficiency and broad applicability of this single-component tool for continuous evolution.
The role of nutritional vitamin D in CKD-MBD in children and adults with CKD, on dialysis and after kidney transplantation – a European consensus statement
Authors: Jørgensen Hanne Skou , Vervloet Marc , Cavalier Etienne , Bacchetta Justine , de Borst Martin H , Bover Jordi , Cozzolino Mario , Ferreira Ana Carina , Hansen Ditte , Herrmann Markus , de Jongh Renate , Mazzaferro Sandro , Wan Mandy , Shroff Rukshana , Evenepoel Pieter
Published: January 2025

Vitamin D deficiency is common in patients with chronic kidney disease (CKD) and associates with poor outcomes. Current clinical practice guidelines recommend supplementation with nutritional vitamin D as for the general population. However, recent large-scale, clinical trials in the general population failed to demonstrate a benefit of vitamin D supplementation on skeletal or non-skeletal outcomes, fueling a debate on the rationale for screening for and correcting vitamin D deficiency, both in non-CKD and CKD populations. In a collaboration between the European Renal Osteodystrophy initiative of the European Renal Association (ERA) and the European Society for Paediatric Nephrology (ESPN), an expert panel performed an extensive literature review and formulated clinical practice points on vitamin D supplementation in children and adults with CKD and after kidney transplantation. These were reviewed by a Delphi panel of members from relevant working groups of the ERA and ESPN. Key clinical practice points include recommendations to monitor for, and correct, vitamin D deficiency in children and adults with CKD and after kidney transplantation, targeting 25-hydroxyvitamin D levels >75 nmol/L (>30 ng/mL). While vitamin D supplementation appears well-tolerated and safe, it is recommended to avoid mega-doses (≥100 000 IU) and very high levels of 25 hydroxyvitamin D (>150-200 nmol/L, or 60-80 ng/mL) to reduce the risk of toxicity. Future clinical trials should investigate the benefit of vitamin D supplementation on patient-relevant outcomes in the setting of vitamin D deficiency across different stages of CKD.
DSCT: A novel deep learning framework for rapid and accurate spatial transcriptomic cell typing
Authors: Xu Yiheng , Yu Bin , Chen Xuan , Peng Aibing , Tao Quyuan , He Youzhe , Wang Yueming , Li Xiao-Ming
Published: January 2025

Unraveling the complex cell-type composition and gene expression patterns at the cellular spatial resolution is crucial for understanding intricate cell functions in the brain. In this study, we developed Deep Neural Network-based Spatial Cell Typing (DSCT), an innovative framework for spatial cell typing within spatial transcriptomic datasets. This approach utilizes a synergistic integration of an enhanced gene selection strategy and a lightweight deep neural network for data training, offering a more rapid and accurate solution for the analysis of spatial transcriptomic data. Based on comprehensive analysis, DSCT achieved exceptional accuracy in cell-type identification across various brain regions, species, and spatial transcriptomic platforms. It also performed well in mapping finer cell types, thereby showcasing its versatility and adaptability across diverse datasets. Strikingly, DSCT exhibited high efficiency and remarkable processing speed, with fewer computational resource demands. As such, this novel approach opens new avenues for exploring the spatial organization of cell types and gene expression patterns, advancing our understanding of biological functions and pathologies within the nervous system.