bluuebunny/crossref_metadata_2025_split huggingface dataset:
A Phase 1 Clinical Trial to Assess the Safety and Pharmacokinetics of a Tenofovir Alafenamide/Elvitegravir Insert Administered Rectally for HIV Prevention
Authors: Riddler Sharon A , Kelly Clifton W , Hoesley Craig J , Ho Ken S , Piper Jeanna M , Edick Stacey , Heard Faye , Doncel Gustavo F , Johnson Sherri , Anderson Peter L , Brand Rhonda M , Kunjara Na Ayudhya Ratiya Pamela , Bauermeister José A , Hillier Sharon L , Hendrix Craig W 
Published: April 2024

AbstractBackgroundOn-demand topical products could be an important tool for human immunodeficiency virus (HIV) prevention. We evaluated the safety, pharmacokinetics, and ex vivo pharmacodynamics of a tenofovir alafenamide/elvitegravir (TAF/EVG, 20 mg/16 mg) insert administered rectally.MethodsMTN-039 was a phase 1, open-label, single-arm, 2-dose study. Blood, rectal fluid, and rectal tissue were collected over 72 hours following rectal administration of 1 and 2 TAF/EVG inserts for each participant.ResultsTAF/EVG inserts were safe and well tolerated. EVG and tenofovir (TFV) were detected in blood plasma at low concentrations: median peak concentrations after 2 inserts were EVG 2.4 ng/mL and TFV 4.4 ng/mL. Rectal tissue EVG peaked at 2 hours (median, 2 inserts = 9 ng/mg) but declined to below limit of quantification in the majority of samples at 24 hours, whereas tenofovir diphosphate (TFV-DP) remained high &gt;2000 fmol/million cells for 72 hours with 2 inserts. Compared to baseline, median cumulative log10 HIV p24 antigen of ex vivo rectal tissue HIV infection was reduced at each time point for both 1 and 2 inserts (P &lt; .065 and P &lt; .039, respectively).DiscussionRectal administration of TAF/EVG inserts achieved high rectal tissue concentrations of EVG and TFV-DP with low systemic drug exposure and demonstrable ex vivo inhibition of HIV infection for 72 hours.Clinical Trials Registration . NCT04047420.
Endocytic recycling in plants: pathways and regulation
Authors: Qi Wencai , Zhang Yu , Li Mengting , Zhang Peipei , Xing Jingjing , Chen Yanmei , Zhang Liang 
Published: April 2024

Abstract
Endocytic recycling is an intracellular trafficking pathway that returns endocytosed molecules to the plasma membrane via the recycling endosome. This pathway plays a crucial role in remodelling plasma membrane composition and is thus essential for cellular homeostasis. In plants, endocytic recycling regulates the localization and abundance of receptors, transporters, and channels at the plasma membrane that are involved in many aspects of plant growth and development. Despite its importance, the recycling endosome and the underlying sorting mechanisms for cargo recycling in plants remain understudied in comparison to the endocytic recycling pathways in animals. In this review, we focus on the cumulative evidence suggesting the existence of endosomes decorated by regulators that contribute to recycling in plant cells. We summarize the chemical inhibitors used for analysing cargo recycling and discuss recent advances in our understanding of how endocytic recycling participates in various plant cellular and physiological events.
World War I and the Thomas Splint: A Historical Review
Authors: Danford Joseph R , Stinner Daniel J 
Published: April 2024

Abstract
The Thomas splint, the first practical traction splint for femoral fractures, revolutionized the capabilities of military medicine. Its usage in WWI lowered the mortality rate from 80% to nearly 15%. Its development not only shaped modern orthopedics but also established the splint as standard equipment in hospitals worldwide.
The effect of thermal torques on AGN disc migration traps and gravitational wave populations
Authors: Grishin Evgeni , Gilbaum Shmuel , Stone Nicholas C 
Published: April 2024

ABSTRACT
Accretion discs in active galactic nuclei (AGNs) foster black hole (BH) formation, growth, and mergers. Stellar mass BHs migrate inwards under the influence of hydrodynamical torques unless they encounter a region where the torque flips sign. At these migration traps, BHs accumulate and merge via dynamical or gas-assisted interactions, producing high-frequency LIGO/Virgo/KAGRA (LVK) gravitational wave (GW) sources and potentially cutting off the supply of extreme mass ratio inspirals that would otherwise make low-frequency, LISA-band GWs. In this paper, we study the interplay between different types of migration torques, focusing especially on the ‘thermal torques’ generated by the thermal response of the AGN to embedded stellar-mass BHs that accrete through their own mini-discs. In contrast to previous work, we find that Type I torques cannot produce migration traps on their own, but thermal torques often do, particularly in low-mass AGN. The migration traps produced by thermal torques exist at much larger distances (∼103−5 gravitational radii) than do previously identified Type I traps, carrying implications for GW populations at multiple frequencies. Finally, we identify a bifurcation of AGN discs into two regimes: migration traps exist below a critical AGN luminosity, and do not at higher luminosities. This critical luminosity is fit as $\log _{10} L_{\rm AGN}^c = 45 {\!-\!} 0.32 \log _{10}{(\alpha /0.01)}$ where α is the Shakura–Sunyaev viscosity parameter, a range compatible with recent claims that LVK GWs are not preferentially associated with high-luminosity AGN.
Whole-Blood PCR Preferred for Timely Diagnosis of Neuroinvasive West Nile Virus Infections: Lessons From the 2021 Arizona Outbreak
Authors: Kasule Sabirah , Fernholz Emily , Grant Leah , Kole Amy , Grys Thomas E , Kaleta Erin , Theel Elitza S , Pritt Bobbi , Graf Erin H 
Published: April 2024

Abstract

Background
In 2021, the state of Arizona experienced the largest focal outbreak of West Nile virus (WNV) in US history. Timely and accurate diagnostic testing remains a challenge for WNV due to transient viremia and limited immunoassay specificity. Recent studies have identified whole blood (WB) and urine as more sensitive specimen types for the detection of WNV RNA.

Methods
We evaluated ordering practices, test performance, and patient characteristics of probable and confirmed cases. In total, we identified 190 probable and proven cases, including 127 patients (66.8%) with neuroinvasive disease.

Results
Among all cases, only 29.5% had WNV polymerase chain reaction (PCR) testing ordered on WB, of which 80.3% resulted as positive, including 7 cases in which WNV serologic testing was negative and 5 cases for which serologic testing was not ordered. In comparison, only 23.7% of cases that had cerebrospinal fluid (CSF) PCR ordered had a positive result, including 3 cases that were negative by PCR on WB. In contrast, WNV PCR on WB detected 12 neuroinvasive cases that were CSF PCR negative. WNV PCR testing in urine was only ordered on 2 patients, both of whom were positive. Crossing cycle threshold (Ct) values were not significantly different between WB and CSF specimen types, nor was there a correlation between Ct value and days from symptom onset at the time of sample collection; all specimen types and time points had Ct values, with 98% above 30. WB was positive by WNV PCR in several patients for &gt;7 days (range, 7–25 days) after symptom onset, as was the CSF PCR.

Conclusions
Taken together, these findings indicate that WNV PCR testing on WB may be the best initial test for timely diagnosis of WNV infection, irrespective of clinical manifestation; however, if negative in patients with suspected neuroinvasive disease, WNV PCR testing on CSF should be ordered.
Sex Differences in the Immunogenicity and Efficacy of Seasonal Influenza Vaccines: A Meta-analysis of Randomized Controlled Trials
Authors: Tadount Fazia , Kiely Marilou , Assi Ali , Rafferty Ellen , Sadarangani Manish , MacDonald Shannon E , Quach Caroline 
Published: April 2024

Abstract

Background
Sex impacts individuals’ response to vaccination. However, most vaccine studies do not report these differences disaggregated by sex. The aim of this study was to assess sex differences in the immunogenicity and efficacy of influenza vaccine.

Methods
We performed a meta-analysis using phase 3 randomized controlled trial data conducted between 2010 and 2018. Using hemagglutination inhibition antibody titers for each strain, differences in geometric mean ratios (GMRs) were calculated by sex. Risk ratios (RRs) comparing seroconversion proportions were pooled for females and males using random-effects models. Vaccine efficacy (VE) was assessed. Data were analyzed by age group (18–64 vs ≥65 years).

Results
A total of 33 092 healthy adults from 19 studies were included for immunogenicity analysis, and 6740 from 1 study for VE. Whereas no sex differences in immunogenicity were found in adults &lt;65 years old, older females had a significantly greater chance to seroconvert compared to older males for all strains: RRH1N1 = 1.17 [95% confidence interval {CI}, 1.12–1.23]; RRH3N2 = 1.09 [95% CI, 1.05–1.14]; RRVictoria = 1.23 [95% CI, 1.14–1.31]; RRYamagata = 1.22 [95% CI, 1.14–1.30]. GMRs were also higher in older females for all strains compared to older males. VE in preventing laboratory-confirmed influenza was higher in older females compared to older males with VEs of 27.32% (95% CI, 1.15%–46.56%) and 6.06% (95% CI, −37.68% to 35.90%), respectively.

Conclusions
Our results suggest a higher immunogenicity and VE in females compared to males in older adults. These differences in immunogenicity and VE support the disaggregation of vaccine data by sex in clinical trials and observational studies.

Clinical Trials Registration
CRD42018112260.
Community-Based Services for Hospitalized Patients With Serious Injection-Related Infections in Alabama: A Brief Report
Authors: Gagnon Kelly W , Bradford William , Bassler John , Nassel Ariann , Kay Emma Sophia , Jeziorski Madison , Prados Myles , McCleskey Brandi , Kobie James , Eaton Ellen 
Published: April 2024

Abstract
Injection-related infections continue to rise, particularly in the South. People who inject drugs are increasingly utilizing hospital services for serious injection-related infections but may be discharged to areas without harm reduction services. We explored the availability and travel time to services for HIV and substance use in Alabama.
Automated Quantitative CD8+ Tumor-Infiltrating Lymphocytes and Tumor Mutation Burden as Independent Biomarkers in Melanoma Patients Receiving Front-Line Anti-PD-1 Immunotherapy
Authors: Fortman Dylan , Karunamurthy Arivarasan , Hartman Douglas , Wang Hong , Seigh Lindsey , Abukhiran Ibrahim , Najjar Yana G , Pantanowitz Liron , Zarour Hassane M , Kirkwood John M , Davar Diwakar 
Published: April 2024

Abstract

Background
CD8+ tumor-infiltrating lymphocyte (TIL) predicts response to anti-PD-(L)1 therapy. However, there remains no standardized method to assess CD8+ TIL in melanoma, and developing a specific, cost-effective, reproducible, and clinically actionable biomarker to anti-PD-(L)1 remains elusive. We report on the development of automatic CD8+ TIL density quantification via whole slide image (WSI) analysis in advanced melanoma patients treated with front-line anti-PD-1 blockade, and correlation immunotherapy response.

Methods
Seventy-eight patients treated with PD-1 inhibitors in the front-line setting between January 2015 and May 2023 at the University of Pittsburgh Cancer Institute were included. CD8+ TIL density was quantified using an image analysis algorithm on digitized WSI. Targeted next-generation sequencing (NGS) was performed to determine tumor mutation burden (TMB) in a subset of 62 patients. ROC curves were used to determine biomarker cutoffs and response to therapy. Correlation between CD8+ TIL density and TMB cutoffs and response to therapy was studied.

Results
Higher CD8+ TIL density was significantly associated with improved response to front-line anti-PD-1 across all time points measured. CD8+ TIL density ≥222.9 cells/mm2 reliably segregated responders and non-responders to front-line anti-PD-1 therapy regardless of when response was measured. In a multivariate analysis, patients with CD8+ TIL density exceeding cutoff had significantly improved PFS with a trend toward improved OS. Similarly, increasing TMB was associated with improved response to anti-PD-1, and a cutoff of 14.70 Mut/Mb was associated with improved odds of response. The correlation between TMB and CD8+ TIL density was low, suggesting that each represented independent predictive biomarkers of response.

Conclusions
An automatic digital analysis algorithm provides a standardized method to quantify CD8+ TIL density, which predicts response to front-line anti-PD-1 therapy. CD8+ TIL density and TMB are independent predictors of response to anti-PD-1 blockade.
Erasing marks: Functions of plant deubiquitylating enzymes in modulating the ubiquitin code
Authors: Vogel Karin , Isono Erika 
Published: April 2024

Abstract
Plant cells need to respond to environmental stimuli and developmental signals accurately and promptly. Ubiquitylation is a reversible posttranslational modification that enables the adaptation of cellular proteostasis to internal or external factors. The different topologies of ubiquitin linkages serve as the structural basis for the ubiquitin code, which can be interpreted by ubiquitin-binding proteins or readers in specific processes. The ubiquitylation status of target proteins is regulated by ubiquitylating enzymes or writers, as well as deubiquitylating enzymes (DUBs) or erasers. DUBs can remove ubiquitin molecules from target proteins. Arabidopsis (A. thaliana) DUBs belong to 7 protein families and exhibit a wide range of functions and play an important role in regulating selective protein degradation processes, including proteasomal, endocytic, and autophagic protein degradation. DUBs also shape the epigenetic landscape and modulate DNA damage repair processes. In this review, we summarize the current knowledge on DUBs in plants, their cellular functions, and the molecular mechanisms involved in the regulation of plant DUBs.
Sexual harassment and psychological distress experienced by women police: The role of embitterment and psychological contract breach
Authors: Drew Jacqueline M , Chevroulet Chantal 
Published: April 2024

Abstract
Despite decades of workplace interventions, often focussed on increasing women police numbers, women continue to be under-represented in policing. Understanding the experiences of women once they have entered policing has been an area of ongoing interest. Examination of the experiences of women police is often undertaken with reference to its masculinized culture. Stemming from these discussions, sexual harassment remains a persistent concern across many police agencies. This study involves 491 women police employed in one large Australian, state police organization. Derived from the study findings, the concepts of psychological contract breach (PCB) and embitterment, two factors that have been rarely studied in policing, are critical to understanding the relationship between sexual harassment and psychological distress. Using mediated regression analysis, the research found PCB and embitterment provide a more nuanced explanation of outcomes of sexual harassment experiences and in turn, provided insight into why sexual harassment is associated with greater psychological distress. This research positions police agencies and their leaders to develop and implement more effective support strategies for women police who have experienced sexual harassment and mitigate negative psychological health impacts that may result.
The normative property dualism argument
Authors: Hambly Jesse 
Published: April 2024

AbstractIn this paper, I develop an argument against a type of Non-Analytic Normative Naturalism. This argument, the Normative Property Dualism Argument, suggests that if Non-Analytic Normative Naturalists posit that normative properties are identical to natural properties and that such identities are a posteriori, they will be forced to posit that these properties that are both normative and natural have higher-order normative properties of their own.
Consensual discrimination
Authors: Bengtson Andreas , Munch Lauritz Aastrup 
Published: April 2024

Abstract
What makes discrimination morally bad? In this paper, we discuss the putative badness of a case of consensual discrimination to show that prominent accounts of the badness of discrimination—appealing, inter alia, to harm, disrespect, and inequality—fail to provide a satisfactory answer to this question. In view of this, we present a more promising account.
Do thematic funding instruments lead researchers in new directions? Strategic funding priorities and topic switching among British grant recipients
Authors: Madsen Emil Bargmann , Nielsen Mathias Wullum 
Published: April 2024

Abstract
Research agencies increasingly use thematic funding schemes to steer scientists toward issues of political interest. Funders set strategic priorities and expect scientists to follow the money. Using statistical-matching methods, we paired 10,475 UK-based recipients of thematic grants (with aims proposed by the funding agency) and responsive-mode grants (with aims proposed by researchers) in Physics, Engineering, and Bioscience to investigate the relation between funding-type and shifts in scientists’ research interests. We applied citation-based community detection to create individual time-series of topic distributions based on the grantees’ publications, and used these to estimate funding-related shifts in research focus. Our analysis, which estimates the similarity of the grantees’ research focus before, during and after a grant, suggests that scientists acquiring thematic funding alter their research interests more than comparable scientists funded through responsive-mode schemes. However, recipients of both types of grants tend to revert toward their original research interests when the funding expires. We find no evidence that thematic funding increases the level of diversity in a recipient’s research portfolio. Our study thus highlights an ambiguous link between thematic funding mechanisms and researchers’ orientations.
OA13 Alkaptonuria: a big mimic
Authors: Shah Meera , Kumar Upadhyaya Sundeep 
Published: April 2024

Abstract

Background/Aims
Alkaptonuria is a rare metabolic disorder, often misdiagnosed as spondyloarthritis or degenerative musculoskeletal disease. The population most affected are young males in their 30s with characteristic arthritis involving the spine and large joints. The patient may notice their urine turning dark on standing and pigmentation over the skin and connective tissues (ochronosis); however, these subtle features may sometimes go unnoticed.

Methods
A 38-year-old-male with long standing back pain presented with right knee swelling. With a diagnosis of spondyloarthritis, he was previously treated with DMARDS but did not have any relief. There was a history of urine turning dark on standing. On examination, there was subtle hyperpigmentation over left ear concha and a spot on the sclera. An x-ray of the thoracic spine showed flattening and calcification of intervertebral disc spaces at multiple levels. Aspiration of synovial fluid showed suspended fragments of articular cartilage. His inflammatory markers were negative. We performed gas chromatography mass spectrometry which showed elevated excretion of homogentisic acid (HGA). A homozygous pathogenic variant in the homogentisate 1,2-dioxygenase gene associated with alkaptonuria was reported on whole genome sequencing.

Results
Ochronotic arthropathy is defined as progressive degenerative joint disease mainly affecting the spine and large joints. Most patients require at least one joint replacement by age 55. Small joints of hands and feet and sacroiliac joints are usually spared. Arthroscopy of the joint may reveal dark brown to black pigmented cartilage defects. The synovium may show fragments of pigmented cartilage suspended in the fluid (ground pepper sign). Plain spine radiographs may show flattening and calcifications of the intervertebral discs with a characteristic vacuum phenomenon (radiolucent gas collection). Periarticular structures like tendons and ligaments are also affected, leading to rupture in around 20-30% of patients. Alkaptonuria is also associated with decreased bone mineral density and subsequent risk for fragility fracture.

Conclusion
Alkaptonuria often mimics ankylosing spondylitis. A triad of ochronosis, dark urine and ochronotic arthropathy is the key to diagnosis. Definitive diagnosis is through biochemical or genetic testing. Nitisinone has proved to be effective but shows significant side effects. Management mainly involves physiotherapy and palliative care.

Disclosure
M. Shah: None. S. Upadhyaya: None.
OA33 Factors associated with systemic lupus erythematosus patient concordance to medication: does nurse initiated therapy make a difference?
Authors: Salerno Rosaria , Ali Sasha Saadia , Dell’Accio Flora , Lapham Heather , Dobson Joanne , Gordon Patrick , Wincup Chris 
Published: April 2024

Abstract

Background/Aims
Medication non-concordance in systemic lupus erythematosus (SLE) is associated with a higher risk of flares, hospitalisations and mortality. Patient non-concordance involves a complex interplay of both patient and physician factors including communication, the nature and severity of disease, treatment and the clinician-patient relationship. We hypothesise that patients starting medication initiated by a specialist nurse would achieve better rates of medication concordance.

Methods
A retrospective analysis of patients attending the tertiary lupus clinic at King’s College Hospital was undertaken. Inclusion criteria included patients with a diagnosis of lupus being initiated on conventional DMARD therapy (mycophenolate, methotrexate or azathioprine) who had their medication prescribed and dispensed by the hospital pharmacy. Those starting biologics or receiving medication via shared care agreements were excluded. Patients were defined as concordant if they renewed all 3-monthly prescriptions over a 12 month period. Demographics, disease activity, employment status and ethnicity were recorded. We sought to assess differences in concordance between those initiated by nurse specialists vs doctors, and between those given written vs online information about the drug. Statistical analyses was performed using t-tests and Chi square.

Results
45 patients were included in the analysis. The median age was 41.52 ± 12.04 years old with 86.9% females. 65% of patients were of black ethnicity, 56.5% of patients were employed and the median SLEDAI-2K score was 6 (6,8). 65% of patients were on mycophenolate, 26% on azathioprine and 6.5% on methotrexate. Concordance is summarised in the attached Table. In total, 64% (29/45) were concordant with medications over 12 months. All patients initiated by a nurse were concordant for the full 12 months, compared to only 6% (1/17) if initiated by a doctor. Interestingly, concordance was significantly higher if patients were given an online link to an information leaflet compared to when a paper leaflet was provided.

Conclusion
These findings suggest that patients with SLE who are initiated on DMARD therapy by a nurse specialist are markedly more likely to be concordant at 12 months when compared with those initiated by doctors, emphasising the vital role of nurse specialists in the care of patients with SLE.

Disclosure
R. Salerno: None. S. Ali: None. F. Dell’Accio: None. H. Lapham: None. J. Dobson: None. P. Gordon: None. C. Wincup: None.