bluuebunny/crossref_metadata_2025_split huggingface dataset:
Genomic-inferred cross-selection methods for multi-trait improvement in a recurrent selection breeding program
Authors: Atanda Sikiru Adeniyi , Bandillo Nonoy 
Published: September 2024

AbstractThe major drawback to the implementation of genomic selection in a breeding program lies in long-term decrease in additive genetic variance, which is a trade-off for rapid genetic improvement in short term. Balancing increase in genetic gain with retention of additive genetic variance necessitates careful optimization of this trade-off. In this study, we proposed an integrated index selection approach within the genomic inferred cross-selection (GCS) framework to maximize genetic gain across multiple traits. With this method, we identified optimal crosses that simultaneously maximize progeny performance and maintain genetic variance for multiple traits. Using a stochastic simulated recurrent breeding program over a 40-years period, we evaluated different GCS methods along with other factors, such as the number of parents, crosses, and progeny per cross, that influence genetic gain in a pulse crop breeding program. Across all breeding scenarios, the posterior mean variance consistently enhances genetic gain when compared to other methods, such as the usefulness criterion, optimal haploid value, mean genomic estimated breeding value, and mean index selection value of the superior parents. In addition, we provide a detailed strategy to optimize the number of parents, crosses, and progeny per cross that can potentially maximize short- and long-term genetic gain in a public breeding program.
Novel engineered IL-2 Nemvaleukin alfa combined with PD1 checkpoint blockade enhances the systemic anti-tumor responses of radiation therapy
Authors: He Kewen , Puebla-Osorio Nahum , Barsoumian Hampartsoum B. , Sezen Duygu , Rafiq Zahid , Riad Thomas S. , Hu Yun , Huang Ailing , Voss Tiffany A. , Leyton Claudia S. Kettlun , Schuda Lily Jae , Hsu Ethan , Heiber Joshua , Cortez Maria-Angelica , Welsh James W. 
Published: September 2024

Abstract
Background
Combining interleukin-2 (IL-2) with radiotherapy (RT) and immune checkpoint blockade (ICB) has emerged as a promising approach to address ICB resistance. However, conventional IL-2 cytokine therapy faces constraints owing to its brief half-life and adverse effects. RDB 1462, the mouse ortholog of Nemvaleukin alfa, is an engineered IL-2 with an intermediate affinity that selectively stimulates antitumor CD8 T and NK cells while limiting regulatory T cell expansion. This study aimed to evaluate the antitumor activity and mechanism of action of the combination of RDB 1462, RT, and anti-PD1 in mouse tumor models.

Methods
Two bilateral lung adenocarcinoma murine models were established using 344SQ-Parental and 344SQ anti-PD1-resistant cell lines. Primary tumors were treated with RT, and secondary tumors were observed for evidence of abscopal effects. We performed immune phenotyping by flow cytometry, analyzed 770 immune-related genes using NanoString, and performed T cell receptor (TCR) repertoire analysis. Serum pro-inflammatory cytokine markers were analyzed by 23-plex kit.

Results
Compared to native IL-2 (RDB 1475), RDB 1462 demonstrated superior systemic antitumoral responses, attributable, at least in part, to augmented levels of CD4 and CD8 T cells with the latter. Our findings reveal substantial reductions in primary and secondary tumor volumes compared to monotherapy controls, with some variability observed among different dosing schedules of RDB 1462 combined with RT. Blood and tumor tissue-based flow cytometric phenotyping reveals an increase in effector memory CD8 and CD4 T cells and a decrease in immunosuppressive cells accompanied by a significant increase in IL-2, IFN-γ, and GM-CSF levels in the combination group. Transcriptomic profiling and TCR sequencing reveal favorable gene expression and T cell repertoire patterns with the dual combination. Furthermore, integrating anti-PD1 therapy with RT and RDB 1462 further reduced primary and secondary tumor volumes, prolonged survival, and decreased lung metastasis. Observations of immune cell profiles indicated that RT with escalating doses of RDB 1462 significantly reduced tumor growth and increased tumor-specific immune cell populations.

Conclusion
The addition of Nemvaleukin therapy may enhance responses to RT alone and in combination with anti-PD1.

Graphical Abstract
Saving lives with statistics
Authors: Røislien Jo 
Published: September 2024

AbstractHealthcare is awash with numbers, and figuring out what knowledge these numbers might hold is worthwhile in order to improve patient care. Numbers allow for objective mathematical analysis of the information at hand, but while mathematics is objective by design, our choice of mathematical approach in a given situation is not. In prehospital and critical care, numbers stem from a wide range of different sources and situations, be it experimental setups, observational data or data registries, and what constitutes a “good” statistical analysis can be unclear. A well-crafted statistical analysis can help us see things our eyes cannot, and find patterns where our brains come short, ultimately contributing to changing clinical practice and improving patient outcome. With increasingly more advanced research questions and research designs, traditional statistical approaches are often inadequate, and being able to properly merge statistical competence with clinical knowhow is essential in order to arrive at not only correct, but also valuable and usable research results. By marrying clinical knowhow with rigorous statistical analysis we can accelerate the field of prehospital and critical care.
SMSs as an alternative to provider-delivered care for unhealthy alcohol use: study protocol for Leseli, an open-label randomised controlled trial of mhGAP-Remote vs mhGAP-Standard in Lesotho
Authors: Belus Jennifer M. , Johnson Natalie E. , Yoon Grace H. , Tschumi Nadine , Lerotholi Malebanye , Falgas-Bague Irene , Lee Tristan T. , Letsoela Pearl , Magidson Jessica F. , Amstutz Alain , Labhardt Niklaus D. 
Published: September 2024

Abstract
Background
The World Health Organization’s (WHO) Mental Health Gap Action Programme (mhGAP) is a validated intervention that can be provided by non-specialised healthcare workers to individuals with unhealthy alcohol use. However, it typically requires several in-person sessions at a health facility, which may limit its feasibility and effectiveness in remote settings. This trial compares mhGAP-Standard, a 4 to 6 in-person session intervention, to mhGAP-Remote, a 1 in-person session intervention followed by 8 week of short message service (SMS) in Lesotho. We hypothesise that mhGAP-Remote is superior to mhGAP-Standard in reducing alcohol use (as detailed by the primary and secondary outcomes below).

Methods
This is a two-arm randomised open-label multicentre superiority trial. Participants allocated to mhGAP-Standard receive 4 in-person sessions using motivational interviewing, identifying triggers, and alternative behaviours, with the option of two additional booster sessions. Participants in the mhGAP-Remote arm receive 1 in-person session covering the same content, followed by standardised SMSs over 8 weeks that reinforce intervention content. Non-specialist providers deliver the intervention and receive weekly supervision. Adults (Nplanned = 248) attending participating health facilities for any reason and who meet criteria for unhealthy alcohol use based on the Alcohol Use Disorders Identification Test ([AUDIT] score ≥ 6 for women, ≥ 8 for men) are individually randomised to the two arms (1:1 allocation, stratified by participant sex and age (≥ 50 vs < 50 years old). Follow-up assessments occur at 8, 20, and 32 weeks post-randomisation. The primary outcome is change in self-reported alcohol use (continuous AUDIT score), from baseline to 8 weeks follow-up. Change in the AUDIT from baseline to 20 and 32 weeks follow-up is a secondary outcome. Change in the biomarker phosphatidylethanol (secondary), liver enzyme values in serum (exploratory), and HIV viral load (for people with HIV only; exploratory) are also evaluated from baseline throughout the entire follow-up period. A linear regression model will be conducted for the primary analysis, adjusted for the stratification factors. Three a priori sensitivity analyses for the primary outcome are planned based on per protocol treatment attendance, recovery from unhealthy alcohol use, and clinically significant and reliable change.

Discussion
This trial will provide insight into feasibility and effectiveness of a shortened and primarily SMS supported version of mhGAP, which is especially relevant for settings where regular clinic attendance is a major barrier.

Trial registration
clinicaltrials.gov NCT05925270. Approved on June 29th, 2023.
Cleavage and polyadenylation factors are potential regulators of adipogenesis
Authors: Mostafa Salwa Mohd , Moore Claire 
Published: September 2024

Abstract
Objective
Alternative polyadenylation (APA) is a co-transcriptional process that leads to isoform diversity in the 3’ ends of mRNAs. APA is known to occur during differentiation, and its dysregulation is observed in diseases like cancer and autoimmune disorders. It has been previously reported that differentiation of 3T3-L1 cells to adipocytes leads to an overall lengthening of mRNAs, but the proteins involved in this regulation have not been identified. The expression levels of subunits of the cleavage and polyadenylation (C/P) complex can regulate the choice of poly(A) site, which in turn can affect different cellular activities. In this paper, we studied the change in levels of C/P proteins during 3T3-L1 differentiation.

Results
We observed that while the RNA expression of these proteins is unchanged during differentiation, the protein levels of some subunits do change, including a decrease in levels of CPSF73, the nuclease that cuts at the poly(A) site. However, overexpression of CPSF73 alone does not affect the efficiency and rate of differentiation.
Prostatic lineage differentiation from human embryonic stem cells through inducible expression of NKX3-1
Authors: Wang Songwei , Yu Yangyang , Li Yinglei , Zhang Tianzhe , Jiang Wei , Wang Xinghuan , Liu Ran 
Published: September 2024

Abstract
Background
Understanding the lineage differentiation of human prostate not only is crucial for basic research on human developmental biology but also significantly contributes to the management of prostate-related disorders. Current knowledge mainly relies on studies on rodent models, lacking human-derived alternatives despite clinical samples may provide a snapshot at certain stage. Human embryonic stem cells can generate all the embryonic lineages including the prostate, and indeed a few studies demonstrate such possibility based on co-culture or co-transplantation with urogenital mesenchyme into mouse renal capsule.

Methods
To establish a stepwise protocol to obtain prostatic organoids in vitro from human embryonic stem cells, we apply chemicals and growth factors by mimicking the regulation network of transcription factors and signal transduction pathways, and construct cell lines carrying an inducible NKX3-1 expressing cassette, together with three-dimensional culture system. Unpaired t test was applied for statistical analyses.

Results
We first successfully generate the definitive endoderm, hindgut, and urogenital sinus cells. The embryonic stem cell-derived urogenital sinus cells express prostatic key transcription factors AR and FOXA1, but fail to express NKX3-1. Therefore, we construct NKX3-1-inducible cell line by homologous recombination, which is eventually able to yield AR, FOXA1, and NKX3-1 triple-positive urogenital prostatic lineage cells through stepwise differentiation. Finally, combined with 3D culture we successfully derive prostate-like organoids with certain structures and prostatic cell populations.

Conclusions
This study reveals the crucial role of NKX3-1 in prostatic differentiation and offers the inducible NKX3-1 cell line, as well as provides a stepwise differentiation protocol to generate human prostate-like organoids, which should facilitate the studies on prostate development and disease pathogenesis.
Sex specific analysis of patients with and without reported statin intolerance referred to a specialized outpatient lipid clinic
Authors: Muck Maximilian A. , Fischer Marcus , Hamerle Michael , Strack Christina , Holzhaeuer Maxime , Pfeffer Dennis , Hubauer Ute , Maier Lars S. , Baessler Andrea 
Published: September 2024

Abstract
Background
Lowering LDL-cholesterol is a fundamental goal for both primary and secondary prevention of atherosclerotic cardiovascular diseases. Our study aims to analyse potential sex disparities regarding the tolerability and effectiveness of lipid-lowering therapy in patients with and without reported statin intolerance who are being treated at a lipid-outpatient clinic.

Methods
From 2017 to 2022, n = 1062 patients (n = 612 men, n = 450 women) at high-risk were referred to our lipid-outpatient clinic because of difficulties in lipid control by primary healthcare providers. The main therapeutic objective was to optimize lipid-lowering therapy according to current treatment guidelines.

Results
Patients presented with high LDL-C baseline levels (4.97 ± 1.81 mmol/l (192 ± 70 mg/dL) in men and 5.46 ± 2.04 mmol/l (211 ± 79 mg/dL) in women). Intolerance towards statins was reported more frequently by women (48.2%) than by men (38.9%, p = 0.004). LDL-C continuously decreased with individual treatment adjustments across follow-up visits. In total, treatment goals (LDL < 1.4 mmol/l (< 55 mg/dl) or < 1.8 mmol/l (< 70 mg/dl)) were accomplished in 75.8% of men and 55.5% of women after the last follow-up visit (p < 0.0001). In men, these data are almost identical in subjects with statin intolerance. In contrast, treatment goals were reached less frequently in women with statin intolerance compared to women tolerant to statin therapy.

Conclusion
Even if treated in a specialized lipid clinic, women are less likely to reach their target LDL-C than men, particularly when statin intolerant. Nevertheless, many patients with statin intolerance can be successfully treated using oral combination and PCSK9 inhibitor therapy. However, ongoing follow-up care to monitor progress and to adjust treatment plans is necessary to reach this goal.
Provider perceptions of young people living with HIV and unhealthy alcohol use in Southwestern Uganda: a qualitative study
Authors: Odokonyero Raymond Felix , Nakasujja Noeline , Turiho Andrew , Sanyu Naomi , Muyindike Winnie R. , Nansera Denis , Semitala Fred , Kamya Moses R. , Katahoire Anne R. , Hahn Judith A. , Camlin Carol C. , Muhwezi Wilson W. 
Published: September 2024

Abstract
Background
Unhealthy alcohol use is a common public health problem in HIV care settings in Africa and it affects the HIV continuum of care. In Uganda and other low-income countries, HIV care providers are a key resource in caring for young people (15–24 years) living with HIV (YPLH) with unhealthy alcohol use. Caring for YPLH largely depends on care providers’ perceptions of the problem. However, data that explores HIV care providers’ perceptions about caring for YPLH with unhealthy drinking are lacking in Uganda. We sought to describe the perceptions of HIV care providers regarding caring for YPLH with unhealthy drinking in the Immune Suppression Syndrome (ISS) Clinic of Mbarara Regional Referral Hospital in southwestern Uganda.

Methods
We used semi-structured in-depth interviews (IDIs) to qualitatively explore HIV care providers’ perceptions regarding caring for YPLH with unhealthy alcohol use. The study was conducted at the adolescent immunosuppression (ISS) clinic of Mbarara Regional Referral Hospital. Interviews were tape-recorded and transcribed verbatim. Using thematic content analysis, data from 10 interviews were analyzed.

Results
HIV care providers were concerned and intended to care for YPLH with unhealthy alcohol use. They understood that unhealthy drinking negatively impacts HIV care outcomes and used counseling, peer support, and referrals to routinely intervene. They however, did not apply other known interventions such as health education, medications and follow-up visits because these required family and institutional support which was largely lacking. Additional barriers that HCPs faced in caring for YPLH included; gaps in knowledge and skills required to address alcohol use in young patients, heavy workloads that hindered the provision of psychosocial interventions, late payment of and low remunerations, lack of improvement in some YPLH, and inadequate support from both their families and hospital management.

Conclusion
HIV care providers are important stakeholders in the identification and care of YPLH with unhealthy alcohol use in Southwestern Uganda. There is a need to train and skill HCPs in unhealthy alcohol use care. Such training ought to target the attitudes, subjective norms, and perceived control of the providers.
“What if the patient has a severe reaction, and it is my fault?” A qualitative study exploring factors for sustainable implementation of penicillin allergy delabelling
Authors: Bjørbak Alnæs Marie , Skodvin Brita , Anker Jahnsen Jan , Kalleklev Velure Grete , Oppegaard Oddvar , Reiakvam Kittang Bård , Storaas Torgeir , Aase Schaufel Margrethe 
Published: September 2024

Abstract
Background
Penicillin allergy delabelling (PAD), the process of evaluating penicillin allergy labels, is a key target in antibiotic stewardship, but uptake of the procedure outside clinical studies is limited. We aimed to explore factors that need to be addressed to sustainably implement a clinical pathway for PAD.

Methods
We conducted a qualitative study based on semi-structured interviews with focus groups consisting of a purposive sample of twenty-five nurses and physicians working in four different hospitals in Western Norway. Systematic text condensation was applied for analysis.

Results
Psychological safety was reported as crucial for clinicians to perform PAD. A narrative of uncertainty and anticipated negative outcomes were negatively associated with PAD performance. Education, guidelines, and colleague- and leadership support could together create psychological safety and empower health personnel to perform PAD. Key factors for sustainable implementation of PAD were facilitating the informant’s profound motivation for providing optimal health care and for reducing antimicrobial resistance. Informants were motivated by the prospect of a simplified PAD procedure. We identified three main needs for implementation of PAD: (1) creating psychological safety; (2) utilising clinicians’ inherent motivation and (3) optimal organisational structures.

Conclusion
A planned implementation of PAD must acknowledge clinicians’ need for psychological safety and aid reassurance through training, leadership, and guidelines. To implement PAD as an everyday practice it must be minimally disruptive and provide a contextually adaptive logistic chain. Also, the clinician’s motivation for providing the best possible healthcare should be utilised to aid implementation. The results of this study will aid sustainable implementation of PAD in Norway.

Ethics
The study was approved by the Western Norway Regional Committee for Medical Research Ethics (Study No:199210).
Characterizing PFAS hazards and risks: a human population-based in vitro cardiotoxicity assessment strategy
Authors: Ford Lucie C. , Lin Hsing-Chieh , Zhou Yi-Hui , Wright Fred A. , Gombar Vijay K. , Sedykh Alexander , Shah Ruchir R. , Chiu Weihsueh A. , Rusyn Ivan 
Published: September 2024

AbstractPer- and poly-fluoroalkyl substances (PFAS) are emerging contaminants of concern because of their wide use, persistence, and potential to be hazardous to both humans and the environment. Several PFAS have been designated as substances of concern; however, most PFAS in commerce lack toxicology and exposure data to evaluate their potential hazards and risks. Cardiotoxicity has been identified as a likely human health concern, and cell-based assays are the most sensible approach for screening and prioritization of PFAS. Human-induced pluripotent stem cell (iPSC)-derived cardiomyocytes are a widely used method to test for cardiotoxicity, and recent studies showed that many PFAS affect these cells. Because iPSC-derived cardiomyocytes are available from different donors, they also can be used to quantify human variability in responses to PFAS. The primary objective of this study was to characterize potential human cardiotoxic hazard, risk, and inter-individual variability in responses to PFAS. A total of 56 PFAS from different subclasses were tested in concentration-response using human iPSC-derived cardiomyocytes from 16 donors without known heart disease. Kinetic calcium flux and high-content imaging were used to evaluate biologically-relevant phenotypes such as beat frequency, repolarization, and cytotoxicity. Of the tested PFAS, 46 showed concentration-response effects in at least one phenotype and donor; however, a wide range of sensitivities were observed across donors. Inter-individual variability in the effects could be quantified for 19 PFAS, and risk characterization could be performed for 20 PFAS based on available exposure information. For most tested PFAS, toxicodynamic variability was within a factor of 10 and the margins of exposure were above 100. This study identified PFAS that may pose cardiotoxicity risk and have high inter-individual variability. It also demonstrated the feasibility of using a population-based human in vitro method to quantify population variability and identify cardiotoxicity risks of emerging contaminants.
Differential changes in the morphology and fuel loads of obligatory and partial migrant passerines over half a century in Britain
Authors: Pickett Holly R. W. , Robinson Robert A. , Nudds Robert L. 
Published: September 2024

AbstractMigratory distances and stopover locations are changing for many passerines in response to climate change. Morphological changes have been linked to rising global temperatures in both migrants and residents, but the implications of these changes on fuel loads, and associated flight ranges are little studied. Wing length and body mass changes between 1964 and 2020 were calculated for 15 migrant and partially migrant passerines in Britain. Changes in fuel load and lean body mass were also estimated and used to predict flight ranges. Twelve of the species have undergone morphological changes and eight species, estimated fuel load changes. Nine species were estimated to have reduced flight ranges, indicating that the morphological changes have not compensated fully for the reduction in flight range experienced since 1964. Partial migrants showed greater decreases in flight ranges than did full migrants, which may indicate greater behavioural plasticity in the former. Those species which do not adapt morphologically or behaviourally may be unable to complete long migrations, resulting in restriction to sub-optimal breeding/wintering habitats, or a need for a sooner first stop and more stops en route. This highlights the importance of conserving migratory stopover sites, particularly in the Mediterranean and North Africa that immediately precede major geographical barriers, as-well-as breeding and wintering grounds.