bluuebunny/crossref_metadata_2025 huggingface dataset:
The nuclear localization signal of CPSF6 governs post-nuclear import steps of HIV-1 infection
Authors: Rohlfes Nicholas , Radhakrishnan Rajalingam , Singh Parmit K. , Bedwell Gregory J. , Engelman Alan N. , Dharan Adarsh , Campbell Edward M.
Published: June 2024

The early stages of HIV-1 infection include the trafficking of the viral core into the nucleus of infected cells. However, much remains to be understood about how HIV-1 accomplishes nuclear import and the consequences of the import pathways utilized on nuclear events. The host factor cleavage and polyadenylation specificity factor 6 (CPSF6) assists HIV-1 nuclear localization and post-entry integration targeting. Here, we used a CPSF6 truncation mutant lacking a functional nuclear localization signal (NLS), CPSF6-358, and appended heterologous NLSs to rescue nuclear localization. We show that some, but not all, NLSs drive CPSF6-358 into the nucleus. Interestingly, we found that some nuclear localized CPSF6-NLS chimeras supported inefficient HIV-1 infection. We found that HIV-1 still enters the nucleus in these cell lines but fails to traffic to speckle-associated domains (SPADs). Additionally, we show that HIV-1 fails to efficiently integrate in these cell lines. Collectively, our results demonstrate that the NLS of CPSF6 facilitates steps of HIV-1 infection subsequent to nuclear import and additionally identify the ability of canonical NLS sequences to influence cargo localization in the nucleus following nuclear import.

Author Summary

During HIV-1 infection, the viral capsid, which encloses the viral genome and accessory proteins required for reverse transcription (RT) and integration, traffics towards the nucleus and enters through the nuclear pore complex (NPC). Following entry into the nucleus, RT is completed and viral capsid disassembles releasing the preintegration complex (PIC) to integrate with the host chromosome. In this study, we investigated the early HIV-1 host factor CPSF6, and specifically focused on the C-terminal short amino acid nuclear localization signal (NLS) in CPSF6, in mediating viral nuclear entry and subsequent gene expression. Altering the NLS in CPSF6 with NLS from other proteins, significantly impacted HIV-1’s ability to infect those cells. We further showed this defect in infection occurred at the level of viral integration. This study highlights the importance of the NLS in CPSF6 in dictating the NPC it associates with and its effect on HIV-1 infection. Moreover, our study emphasizes the function of NLS in targeting host cargos to different nuclear entry pathways.
Phase-Separating Peptide Coacervates with Programmable Material Properties for Universal Intracellular Delivery of Macromolecules
Authors: Sun Yue , Wu Xi , Li Jianguo , Radiom Milad , Mezzenga Raffaele , Verma Chandra Sekhar , Yu Jing , Miserez Ali
Published: June 2024

Phase-separating peptides (PSPs) self-assembling into coacervate microdroplets (CMs) are a promising new class of intracellular delivery vehicles that can release macromolecular modalities deployed in a wide range of therapeutic treatments. However, the molecular grammar governing intracellular uptake and release kinetics of CMs remains elusive. Here, we systematically manipulated the sequence of PSPs to unravel the relationships between their molecular structure, the physical properties of the resulting CMs, and their delivery efficacy. We show that a few amino acid alterations are sufficient to modulate the viscoelastic properties of CMs towards either a gel-like or a liquid-like state as well as their binding interaction with cellular membranes, collectively enabling to tune the kinetics of intracellular cargo release. Our findings provide molecular guidelines to precisely program the material properties of PSP CMs and achieve tunable cellular uptake and release kinetics depending on the cargo modality, with broad implications for therapeutic applications.
Species identity and composition shape productivity of stony corals
Authors: Vetter Jana , Reichert Jessica , Dietzmann André , Hahn Lisa , Lang Anna E. , Puntin Giulia , Ziegler Maren
Published: June 2024

Coral biodiversity has an enhancing but saturating effect on community productivity, however, the direct effects of neighbouring coral colonies on productivity remain poorly understood due to the complex interplay of biotic and abiotic factors. We set up a fully controlled aquarium experiment, in which we quantified the effects of species identity and composition on the productivity of nine stony coral species from three families. Baseline productivity and the response to neighbouring organisms strongly differed between species. Regardless of whether species increased or decreased productivity, the responses were consistently more pronounced and positive towards conspecific than heterospecific neighbours, indicating kin selection effects between closely related species. Species productivity in monoculture and productivity in polyculture were inversely correlated, with inherently less productive species overperforming in polyculture and vice versa. Our results highlight that contact-free interactions in marine animals shape biodiversity-productivity effects otherwise known from plant communities.
The future is fully defined: recombinant fragment E8 of laminin-511 is a viable xenofree alternative to Matrigel for hiPSC culture and differentiation into neurovascular cell types
Authors: Ferreira Laís A. , do Nascimento Denise Fabiano , Tandon Ishita , Cordes Lance , Balachandran Kartik
Published: June 2024

Matrigel remains the gold standard substrate for culture of induced pluripotent stem cells (iPSCs). However, its highly variable composition, animal origin and unpredictable effects on biological activity have been discussed for more than 3 decades. In this study, we explore the use of fragment E8 of recombinant laminin 511, commercially available in form of iMatrix-511, as an alternative to Matrigel for iPSC maintenance and differentiation. Female iMR90-4 human iPSCs were cultured on either iMatrix or Matrigel and assessed for cell growth and viability, pluripotency, genetic stability, and ability to differentiate into isogenic brain microvascular endothelial cells (iBMECs) and brain pericytes. It was observed that iMatrix facilitated iPSC growth and viability comparable to Matrigel while maintaining a higher number of more consistently sized colonies. Additionally, like Matrigel, iMatrix maintained the expression of pluripotency markers SSEA-4 and OCT-3/4 over 15 passages without inducing DNA damage. iMatrix also supported the differentiation of these iPSCs into isogenic iBMECs and pericytes, which were successfully co-culture for generation of a simplified blood-brain barrier model. Overall, we showed that iMatrix, which is a cost effective, fully defined, and xenofree alternative can be used as a substitute for Matrigel for maintenance and differentiation of iPSCs.
Multiscale regulation of nutrient stress responses in Escherichia coli from chromatin structure to small regulatory RNAs
Authors: Ekdahl Alyssa M. , Julien Tatiana , Suraj Sahana , Kribelbauer Judith , Tavazoie Saeed , Freddolino P. Lydia , Contreras Lydia M.
Published: June 2024

Recent research has indicated the presence of heterochromatin-like regions of extended protein occupancy and transcriptional silencing of bacterial genomes. We utilized an integrative approach to track chromatin structure and transcription in E. coli K-12 across a wide range of nutrient conditions. In the process, we identified multiple loci which act similarly to facultative heterochromatin in eukaryotes, normally silenced but permitting expression of genes under specific conditions. We also found a strong enrichment of small regulatory RNAs (sRNAs) among the set of differentially expressed transcripts during nutrient stress. Using a newly developed bioinformatic pipeline, the transcription factors regulating sRNA expression were bioinformatically predicted, with experimental follow-up revealing novel relationships for 36 sRNA-transcription factors candidates. Direct regulation of sRNA expression was confirmed by mutational analysis for five sRNAs of metabolic interest: IsrB, CsrB and CsrC, GcvB, and GadY. Our integrative analysis thus reveals additional layers of complexity in the nutrient stress response in E. coli and provides a framework for revealing similar poorly understood regulatory logic in other organisms.
Hyperspectral Sensing for High-Throughput Chloride Detection in Grapevines
Authors: Sharma Sadikshya , Wong Christopher , Bhattarai Krishna , Lupo Yaniv , Magney Troy , Diaz-Garcia Luis
Published: June 2024

Soil salinity affects major viticultural areas worldwide with chloride ions being the primary source of salt toxicity in grapevines. This toxicity impacts vine health and reduces fruit yield and quality. Current breeding efforts to improve grapevine salinity tolerance are limited by the low throughput of available phenotyping methods, which are time-consuming, labor-intensive, and destructive. This study demonstrated that hyperspectral proximal sensing can be utilized as a high-throughput, non-destructive screening technique to identify salinity-tolerant grapevine germplasm. The predictive abilities of two different hyperspectral devices, which varied in price, resolution, and sensitivity, were compared across 23Vitisaccessions spanning eight species. Prediction models were built using hyperspectral reflectance and leaf chloride content measured with a lab chloridometer. Three distinct approaches were studied: 1) analyzing the correlation between individual wavelengths and chloride content; 2) employing machine learning models, including Partial Least Squares Regression (PLSR), Random Forest (RF), and Support Vector Machine (SVM), utilizing all wavelengths; and 3) classification-based prediction using Partial Least Squares Discriminant Analysis (PLSDA). Multiple regions in the spectrum, including 613-660 nm, 689-696 nm, and 1357-1358 nm, showed a medium correlation (0.30-0.50) with chloride content in the leaves. PLSR was the most effective machine learning approach, demonstrating moderate predictive capability for chloride content (maximumR²= 0.67), though performance varied between the two devices tested. With PLSDA, predictions increased considerably, up to an accuracy of 0.97, depending on the instrument used and the spectral data transformation. Overall, the more expensive and sensitive device with a wider spectral range outperformed the more affordable, shorter-range device. However, when the prediction model was based on classes (chloride excluders vs. non-excluders) rather than chloride content, the differences in prediction abilities were minimal, with both instruments performing very well. This is promising for identifying breeding materials with chloride exclusion capabilities at low cost and high throughput.
ER-associated biogenesis of PINK1 preprotein for neuronal mitophagy
Authors: Hees J. Tabitha , Segura Inmaculada , Schneider Andrea , Schifferer Martina , Misgeld Thomas , Harbauer Angelika B.
Published: June 2024

A central role in mitochondrial quality control is played by the Parkinson-related mitochondrial kinase PINK1, whose mRNA is transported in neurons by mitochondrial hitch- hiking. Using a live-cell imaging assay for the translation of the PINK1 precursor, we show that local translation of PINK1 requires a concerted interplay between mitochondria and the ER in neurons. For efficient translation, thePink1mRNA needs to relocate to ribosomes located near endolysosomes and the ER. The ER membrane-tethered chaperone DNAJB6 then shields the PINK1 precursor on transit to mitochondria following the ER-SURF pathway. Loss of DNAJB6 hence leads to persistence of ER/endolysosome-associated PINK1 precursor stores and failure of mitophagy upon mitochondrial damage.
Tumour-intrinsic features shape T-cell differentiation through myeloma disease evolution
Authors: Foster Kane A. , Rees Elise , Ainley Louise , Boyle Eileen M. , Lee Lydia , Ward Gwennan , Galas-Filipowicz Daria , Mikolajczak Anna , Lyon Emma J. , Jankovic Dylan , Rahman Jasmine , Turakhia Mahima , Uddin Imran , Beattie Gordon , Hoade Yvette , Zhu Catherine , Reading James L. , Walker Ieuan , Chapman Michael , Ramasamy Karthik , Herrero Javier , Chain Benny , Quezada Sergio A. , Yong Kwee L.
Published: June 2024

The haematological malignancy multiple myeloma is associated with skewed T-cell activation and function. T-cell alterations are detectable in asymptomatic myeloma precursor conditions and have the potential to identify precursor patients at imminent risk of progression. However, what myeloma-associated T-cells alterations represent mechanistically, how they relate to tumour burden and gene expression, and what influences high inter-patient variability in immune composition remains unknown. Here, we assembled the largest ever dataset of published and newly-generated single-cell RNA and TCR sequencing of the marrow and blood from patients with myeloma, precursor conditions, and age-matched non-cancer controls. We show myeloma is not associated with T-cell exhaustion and instead defined by a pattern of T-cell differentiation resembling antigen-driven terminal memory differentiation. Myeloma-associated T-cell differentiation was dependent on tumour-intrinsic features including tumour burden and tumour expression of antigen-presentation genes. Expanded TCR clones accumulating in myeloma were not enriched for viral specificity and were detected in effector states in highly infiltrated marrows. Together, these results suggest anti-tumour immunity drives a novel form of cancer-associated T-cell memory differentiation in myeloma.
Risk Factors and Outcomes of Pulmonary Hemorrhage in Preterm Infants born before 32 weeks
Authors: Tran Gieng Thi My , Nguyen Nhat Phan Minh , Long Nguyen Phuoc , Nguyen Duc Ninh , Nguyen Thu-Tinh
Published: June 2024

Background

Pulmonary hemorrhage (PH) is a catastrophic event associated with significant morbidity and mortality among preterm infants. Understanding PH risk factors in preterm newborns, particularly those in low-to-middle-income countries like Vietnam, remains limited. This study aimed to investigate the risk factors and short-term outcomes of PH in very preterm infants.

Methods

We conducted an observational study of newborns aged < 72 hours with gestational age < 32 weeks, admitted to our unit from April 1, 2018 to March 31, 2019.

Results

Of 118 recruited newborns, 28 (23.7%) had PH. The logistic regression analysis showed that intubation within 24 first hours, blood transfusion, and coagulation disorders within the first 3 days were risk factors for PH (aOR = 4.594, 95% CI = 1.200-17.593; aOR = 5.394, 95% CI = 1.243-23.395 and aOR = 7.242 95% CI = 1.838-28.542, respectively). Intra-ventricular hemorrhage (IVH) and mortality rates were higher in patients with PH compared to those without (p<0.001). The length of invasive ventilation was longer in the PH group (p<0.001).

Conclusion

We have identified intubation, blood transfusion, and coagulation disorders shortly after birth as risk factors for PH in very preterm infants, which was associated with increased mortality and occurrence of IVH.

Impact

High incidence and mortality of pulmonary hemorrhage in preterm infants < 32 weeks’ gestational age with respiratory distress in a Neonatal Intensive Care Unit in Vietnam.

Pulmonary hemorrhage should be considered in the clinical deterioration of preterm infants given invasive ventilation in the first 2-4 days of life.

Independent risk factors for pulmonary hemorrhage: intubation in the first 24 hours, coagulation disorders, and transfusion of blood products in the first 3 days of life.

Urgent need to seek diagnostic criteria for intraventricular hemorrhage as soon as pulmonary hemorrhage occurs.
Growth charts for pontocerebellar hypoplasia type 2A
Authors: Kuhn Alice , Hackenberg Maren , Klauser Anna-Lena , Herrmann Antonia , Matilainen Julia , Mayer Simone , Frölich Saskia , Krägeloh-Mann Ingeborg , Groeschel Samuel , Janzarik Wibke G.
Published: June 2024

Introduction

Pontocerebellar hypoplasia type 2A (PCH2A) is a rare, autosomal recessive disease, caused by a homozygous pathogenic variant in the geneTSEN54(c.919G>A, p.A307S). Apart from the characteristic pontocerebellar hypoplasia in MRI, PCH2A is clinically characterized by a dyskinetic movement disorder, severe neurodevelopment delay, progressive microcephaly, and, less well recognized, failure to thrive. Additional symptoms such as seizures, gastrointestinal or respiratory problems are common. The aim of this study was to document growth data of PCH2A patients, calculate growth charts for height, weight, body mass index (BMI) and head circumference (hc), and compare these to German reference charts.

Patients and methods

In total, data of 65 patients with genetically confirmed PCH2A were included in the study. Growth data were collected retrospectively from medical reports and a parent questionnaire. Disease-specific growth charts were prepared using gamlss package in R. Sex-disaggregated growth charts for PCH2A were compared to German reference data from the KiGGs study.

Results

Height and weight of patients with PCH2A were within the normal range at birth. Mean weight was significantly lower from the age of 3 months onwards, and mean height at the age of 6 months in patients with PCH2A, both, females and males. Mean BMI was statistically lower in patients at the age 4 months. Compared to reference values, mean head circumference of patients with PCH2A was significantly below average at birth, and all patients showed severe and progressive microcephaly in the further course.

Conclusion

In line with previous reports, patients with PCH2A typically exhibit progressive microcephaly, and frequently fail to thrive during infancy. Disease-specific growth charts of pediatric patients with PCH2A are provided as a helpful tool to monitor height, weight, BMI and head circumference of affected children.
Age- and sex- differences in efficacy of treatments for type 2 diabetes: Network meta-analysis of aggregate and individual level data
Authors: Hanlon Peter , Butterly Elaine , Wei Lili , Wightman Heather , Almazam Saleh Ali M , Alsallumi Khalid , Crowther Jamie , McChrystal Ryan , Rennison Heidi , Hughes Katherine , Lewsey Jim , Lindsay Robert , McGurnaghan Stuart , Petrie John , Tomlinson Laurie A , Wild Sarah , Adler Amanda , Sattar Naveed , Phillippo David M , Dias Sofia , Welton Nicky J , McAllister David A
Published: June 2024

Importance

Sodium glucose cotransporter 2 inhibitors (SGLT2i), glucagon-like peptide-1 receptor analogues (GLP1ra) and dipeptidyl peptidase-4 inhibitors (DPP4i) improve hyperglycaemia and, in the case of SGLT2i and GLP1ra, reduce the risk of major adverse cardiovascular events (MACE) in type 2 diabetes. It is not clear whether efficacy varies by age or sex.

Objective

Assess whether age or sex are associated with differences in efficacy of SGL2i, GLP1ra and DPP4i.

Data sources

Medline, Embase and clinical trial registries.

Study selection

Two independent reviewers screened for randomised controlled trials of SGLT2i/GLP1ra/DPP4i, compared to placebo/active comparator, in adults with type 2 diabetes.

Data extraction and synthesis

We sought individual participant data (IPD) all eligible studies. Where IPD were available, we modelled age- and sex-treatment interactions for each trial. Otherwise, we assessed age- sex distributions along with results from aggregate trial data. IPD and aggregate findings were combined in a Bayesian network meta-analysis.

Main outcome measures

HbA1c and MACE.

Results

We identified 616 eligible trials (604 reporting HbA1c, 23 reporting MACE) and obtained IPD for 75 trials (6 reporting MACE). Mean age was 59.0 (10.7) years and 64.0 (8.6) in HbA1c and MACE trials, respectively. Proportions of female were 43.1% and 44.0% in HbA1c and MACE trials, respectively. SGLT2i reduced HbA1c by 0.5-1.0% overall compared to placebo. This reduction versus placebo was attenuated in older participants (change in HbA1c 0.25 percentage-points less for 75-year-olds compared to 45-year-olds). SGLT2i showed greater relative efficacy in MACE risk reduction among older than younger people. This finding was sensitive to the exclusion of one of the IPD MACE trials, however, in all sensitivity analyses, SGLT2i were either as efficacious or more efficacious in older participants. There was no consistently significant difference in efficacy by age for GLP1ra or DPP4i for HbA1c or MACE, nor were there consistent significant sex differences for any class.

Conclusion

Newer glucose-lowering drugs are efficacious across age and sex groups. SGLT2i are more cardioprotective in older than younger people despite smaller HbA1c reductions. Age alone should not be a barrier to treatments with proven cardiovascular benefit providing they are well tolerated align with patient priorities.
Association between Insurance Type and Extended Length of Stay in Urban & Rural Vermont Hospitals
Authors: Payne Patrick C. , Klonsky Mia , Moreau Katrina , Oviedo Alyssa , Nowak Sarah
Published: June 2024

Purpose

To evaluate the link between insurance status and patient length of stay (LOS) for inpatient admissions in rural and urban hospitals in Vermont.

Methods

We conducted a cross-sectional study utilizing 2016 to 2020 data from the Vermont Uniform Hospital at Data Discharge System (VUHDDS). Vermont residents 18-64 years of age admitted for heart and circulatory illnesses who spent least one day as inpatient at one of Vermont’s 14 hospitals were included. Frequency statistics were run to determine distribution of sample characteristics and a two-side Z-test was conducted to compare differences between normal and extended lengths of stay. Three multivariate logistic regression models were utilized to control for confounding factors and identify differences in lengths of stay and mortality.

Findings

Private insurance was more common among patients with a normal LOS (46%) and public insurance more common among patients with extended lengths of stay (54%). Rural Medicare patients have 0.77 (CI: 0.66-0.90) times lower odds of extended LOS, which is distinct from the 95% confidence interval for urban patients (CI: 0.94-1.46). Urban Medicaid insured patients had 1.413 (CI: 1.15-1.74) times greater odds of an extended LOS, which is outside of the 95% confidence interval for rural patients (CI: 0.80-1.09).

Conclusions

In conclusion, the rurality of a patient’s residence appears to impact health outcomes for cardiac related discharges for individuals in Vermont related to their insurer. Further studies with more demographic data are needed to better understand the implications of these findings.
Rare variant effect estimation and polygenic risk prediction
Authors: Nam Kisung , Kho Minjung , Zhou Wei , Mukherjee Bhramar , Lee Seunggeun
Published: June 2024

Due to their low frequency, estimating the effect of rare variants is challenging. Here, we propose RareEffect, a method that first estimates gene or region-based heritability and then each variant effect size using an empirical Bayesian approach. Our method uses a variance component model, popular in rare variant tests, and is designed to provide two levels of effect sizes, gene/region-level and variant-level, which can provide better interpretation. To adjust for the case-control imbalance in phenotypes, our approach uses a fast implementation of the Firth bias correction. We demonstrate the accuracy and computational efficiency of our method through extensive simulations and the analysis of UK Biobank whole exome sequencing data for five continuous traits and five binary disease phenotypes. Additionally, we show that the effect sizes obtained from our model can be leveraged to improve the performance of polygenic scores.
Designing Cell-Type-Specific Promoter Sequences Using Conservative Model-Based Optimization
Authors: Reddy Aniketh Janardhan , Geng Xinyang , Herschl Michael H. , Kolli Sathvik , Kumar Aviral , Hsu Patrick D. , Levine Sergey , Ioannidis Nilah M.
Published: June 2024

Gene therapies have the potential to treat disease by delivering therapeutic genetic cargo to disease-associated cells. One limitation to their widespread use is the lack of short regulatory sequences, or promoters, that differentially induce the expression of delivered genetic cargo in target cells, minimizing side effects in other cell types. Such cell-type-specific promoters are difficult to discover using existing methods, requiring either manual curation or access to large datasets of promoter-driven expression from both targeted and untargeted cells. Model-based optimization (MBO) has emerged as an effective method to design biological sequences in an automated manner, and has recently been used in promoter design methods. However, these methods have only been tested using large training datasets that are expensive to collect, and focus on designing promoters for markedly different cell types, overlooking the complexities associated with designing promoters for closely related cell types that share similar regulatory features. Therefore, we introduce a comprehensive framework for utilizing MBO to design promoters in a data-efficient manner, with an emphasis on discovering promoters for similar cell types. We use conservative objective models (COMs) for MBO and highlight practical considerations such as best practices for improving sequence diversity, getting estimates of model uncertainty, and choosing the optimal set of sequences for experimental validation. Using three relatively similar blood cancer cell lines (Jurkat, K562, and THP1), we show that our approach discovers many novel cell-type-specific promoters after experimentally validating the designed sequences. For K562 cells, in particular, we discover a promoter that has 75.85% higher cell-type-specificity than the best promoter from the initial dataset used to train our models.
Customizing GPT-4 for clinical information retrieval from standard operating procedures
Authors: Muti Hannah Sophie , Lavinia Löffler Chiara Maria , Leßmann Marie-Elisabeth , Stüker Esther Helene , Kirchberg Johanna , von Bonin Malte , Kolditz Martin , Ferber Dyke , Egger-Heidrich Katharina , Merboth Felix , Stange Daniel E. , Distler Marius , Kather Jakob Nikolas
Published: June 2024

Background

The increasing complexity of medical knowledge necessitates efficient and reliable information access systems in clinical settings. For quality purposes, most hospitals use standard operating procedures (SOPs) for information management and implementation of local treatment standards. However, in clinical routine, this information is not always easily accessible. Customized Large Language Models (LLMs) may offer a tailored solution, but need thorough evaluation prior to clinical implementation.

Objective

To customize an LLM to retrieve information from hospital-specific SOPs, to evaluate its accuracy for clinical use and to compare different prompting strategies and large language models.

Methods

We customized GPT-4 with a predefined system prompt and 10 SOPs from four departments at the University Hospital Dresden. The model’s performance was evaluated through 30 predefined clinical questions of varying degree of detail, which were assessed by five observers with different levels of medical expertise through simple and interactive question-and-answering (Q&A). We assessed answer completeness, correctness and sufficiency for clinical use and the impact of prompt design on model performance. Finally, we compared the performance of GPT-4 with Claude-3-opus.

Results

Interactive Q&A yielded the highest rate of completeness (80%), correctness (83%) and sufficiency (60%). Acceptance of the LLM’s answer was higher among early-career medical staff. Degree of detail of the question prompt influenced answer accuracy, with intermediate-detail prompts achieving the highest sufficiency rates. Comparing LLMs, Claude-3-opus outperformed GPT-4 in providing sufficient answers (70.0% vs. 36.7%) and required fewer iterations for satisfactory responses. Both models adhered to the system prompt more effectively in the self-coded pipeline than in the browser application. All observers showed discrepancies between correctness and accuracy of the answers, which rooted in the representation of information in the SOPs.

Conclusion

Interactively querying customized LLMs can enhance clinical information retrieval, though expert oversight remains essential to ensure a safe application of this technology. After broader evaluation and with basic knowledge in prompt engineering, customized LLMs can be an efficient, clinically applicable tool.
Application and content of minimum data sets for care homes: A mapping review
Authors: Hanratty Barbara , Akdur Gizdem , Burton Jennifer Kirsty , Davey Vanessa , Goodman Claire , Gordon Adam Lee , Killett Anne , Liddle Jenny , Rand Stacey , Spilsbury Karen , Towers Ann-Marie
Published: June 2024

Background

Care home residents have complex needs, and minimum data sets (MDSs) provide a unique source of information on their health and wellbeing. Although MDSs were first developed to monitor quality and costs of care, they can make an important contribution to research.

Aim

To describe the research applications of data from care home MDSs, and identify key outcome variables and measures used.

Design

Mapping review of published empirical studies using data generated from minimum data sets in long term care facilities for older adults.

Methods

We performed a comprehensive search of electronic databases (Medline OVID, CINAHL, Embase and ASSIA), using bespoke search strategies to identify English language publications 2011 - 2024. Articles were screened by two independent reviewers. They were grouped by study topic and data (on publication date, country, MDS, outcome variables and specific items or measures) were charted without quality assessment. The key features of the data are described in a narrative synthesis.

Findings

Searches identified 18588 articles published 2011-2024, of which 661 met inclusion criteria. 72% were from the USA, 12% from Canada and the remaining 16% from four European countries, South Korea and New Zealand. The studies encompassed individual resident functioning (e.g. mobility, incontinence), health conditions and symptoms (e.g. depression, pain), healthcare in the home (e.g. prescribing, end of life care), hospital attendances and admissions, transitions to and from care homes, quality of care and systemwide issues. Measures used reflected the content of the major MDSs, but there was a mismatch between the importance of some topics to care homes (e.g. incontinence) and the range of published papers, and limited consensus over how to measure quality of life.

Conclusions

Care home MDSs are a unique resource to support study of care home residents and impact of interventions over time. They are a powerful resource when linked to other datasets, and as an adjunct to primary data collection This analysis may serve as an accessible guide to the content and applications of MDS, allowing researchers to consider the sort of questions that can be posed and the different components of resident care or experience that can be evaluated.
High burden of chronic kidney disease of unknown cause among patients receiving renal replacement therapy in Northeast Nigeria: A cross-sectional survey of haemodialysis units
Authors: Goni Baba Waru , Kwairanga Hamidu Suleiman , Abdu Aliyu , Ummate Ibrahim , Abdu Alhaji , Ba’aba Ahmed Ibrahim , Sulaiman Mohammad Maina , Umar Loskurima , Gana M.L , Abdulkadir Aliyu , Musa Sabiu , Adamu Shatuwa , Usman Idris A. , Sabo Hauwa Alhaji , Abubakar Idris Musa , Adam Hamza Bukar , Umar Ismail Alhaji , Papka Ayabaryu , Mustapha Modu , Saad Yauba Mohammed , Oomatia Amin , Maina Mahmoud Bukar , Pearce Neil , Caplin Ben
Published: June 2024

Introduction

Chronic kidney disease (CKD) is emerging as a significant public health concern in northeastern Nigeria, particularly in states such as Yobe and Borno. Despite its increasing impact, there is a lack of data characterizing this public health issue. This study aims to explore the prevalence, spatial distribution, and risk factors for CKD among patients receiving haemodialysis (HD) in the region.

Methodology

A cross-sectional survey of HD centres in Yobe, Borno, and Jigawa States of Nigeria was conducted. Questionnaire responses were obtained on demographic, social, and clinical data. Spatial analyses were conducted to determine the geographic distribution of the cases.

Results

We identified 376 patients receiving HD services across 4 centres. Of these, 207 (55.1%) were male and the mean age was 46.56 ± 16.4. Most patients reside in urban areas (67.6%). The main pre-dialysis occupations included civil service (100 [26.6%]), agriculture (65 [17.3%]), and trading (58 [15.4%]). ‘Hypertension’ (195 [51.9%]) was the most common self-reported primary renal disease, followed by unknown causes (70 [18.6%]) and Diabetic Kidney Disease (30 [8%]). Regional analysis demonstrated a particularly high burden of disease in Bade and Jakusko Local Government Areas.

Discussion and Conclusion

Spatial analysis suggests the existence of a CKD hotspot geographically associated with communities along the River Yobe, raising the possibility of an important environmental cause of disease. This study also highlights the lack of access to adequate diagnosis and geographical clustering of CKD burden in this region. These findings further reinforce the need for population-representative studies to characterize the burden of CKD alongside strategic healthcare interventions and collaboration among stakeholders aimed at improving access to care.
Opportunities for more powerful statistical analyses of ordinal scales: A scoping review of neurological trials
Authors: Long Yongxi , de Ruiter Sophie C. , Luijten Linda W.G. , Wiegers Eveline J.A. , Dippel Diederik W.J. , van Doorn Pieter A. , Jacobs Bart C. , Steyerberg Ewout W.
Published: June 2024

Background and Objectives

Ordinal scales are widely adopted as outcome measures in neurological randomized controlled trials (RCTs). There have been extensive discussions about appropriate statistical analysis strategies of ordinal neurological outcomes. We aimed to evaluate which statistical methods have been used to test and estimate treatment effects from ordinal outcomes in recent RCTs across a range of acute neurological diseases.

Methods

We searched for RCTs in five acute monophasic neurological diseases (stroke, traumatic brain injury (TBI), subarachnoid hemorrhage (SAH), meningitis, and Guillain-Barré Syndrome (GBS)) published in high-impact journals between January 1, 2015 and November 1, 2023. Trials had to report on an ordinal scale as the primary or secondary outcome. Two independent reviewers assessed whether/how investigators (1) delt with the ordinal nature of outcomes, (2) assessed and reported key assumptions,(3)utilized longitudinal measurements, (4) adjusted for prognostic variables.

Results

We included 70 RCTs for treatment evaluations in stroke (n=36), TBI (n=13), SAH (n=10), meningitis (n=7), and GBS (n=4). In 46/70 (66%) trials, investigators retained the full ordering information, commonly analyzed by a proportional odds model (33/46 trials, 72%). The proportional odds assumption was not addressed in 23/33 (62%) of these trials. In 22/70 (31%) trials, the ordinal outcome was dichotomized, with notable disagreement on the cut-point within neurological diseases. In 41/70 (59%) trials, the ordinal outcome was assessed at multiple time points, while some form of longitudinal data analysis was performed in only three (7%) of these 41 studies. The time point chosen for analysis was inconsistent within neurological diseases.

Discussion

The current practice of analyzing ordinal outcomes is often suboptimal in neurological trials according to modern statistical standards. Dichotomization and focus on a single arbitrary time point are still common, while more efficient analysis strategies exist. Further research needs to clarify the balance between maximizing the statistical power and assumptions made in approaches that better leverage ordinal information.
Epigenetic modulators provide a path to understanding disease and therapeutic opportunity
Authors: Honer Madison A. , Ferman Benjamin I. , Gray Zach H. , Bondarenko Elena A. , Whetstine Johnathan R.
Published: June 2024

The discovery of epigenetic modulators (writers, erasers, readers, and remodelers) has shed light on previously underappreciated biological mechanisms that promote diseases. With these insights, novel biomarkers and innovative combination therapies can be used to address challenging and difficult to treat disease states. This review highlights key mechanisms that epigenetic writers, erasers, readers, and remodelers control, as well as their connection with disease states and recent advances in associated epigenetic therapies.
Theory of symmetry-resolved quench-drive spectroscopy: Nonlinear response of phase-fluctuating superconductors
Authors: Puviani Matteo
Published: June 2024

Recent experiments on cuprates have shown the possibility of opening a gap above the superconducting critical temperature, in the so-called phase-fluctuating state, by enhancing the phase coherence of preformed Cooper pairs. Quench-drive spectroscopy, an implementation of 2D coherent spectroscopy, has emerged as a powerful tool for investigating out-of-equilibrium superconductors and their collective modes. In this paper, we enrich the quench-drive scheme by developing a systematic generalization to study the nonlinear response of d-wave incoherent Cooper pairs in a symmetry-resolved manner. In particular, we not only show that it is possible to obtain a third-harmonic signal from fully incoherent pairs with an equilibrium vanishing order parameter, but we also characterize the full flourishing 2D spectrum of the generated nonlinear response. The results provide a deeper theoretical insight on recent experimental results, opening the door to a symmetry-driven design of future experiments on unconventional and enhanced superconductors.

Published by the American Physical Society
2024
Magnetic ground state of
NdB4
: Interplay between anisotropic exchange interactions and hidden order on a Shastry-Sutherland lattice
Authors: Khalyavin D. D. , Brunt D. , Qureshi N. , Wildes A. R. , Ouladdiaf B. , Johnson R. D. , Balakrishnan G. , Petrenko O. A.
Published: June 2024

The neodymium tetraboride NdB4, crystalizing into a tetragonal crystal structure, has the magnetic ions located on a Shastry-Sutherland lattice. The compound undergoes several magnetic phase transitions and exhibits a complex multi-k ground state that has so far been elusive. Here we report the solution and quantitative refinement of the magnetic ground state of NdB4 based on neutron diffraction data. The magnetic structure consists of two separate components; one of them is confined within the ab plane and makes an orthogonal all-in-all-out spin configuration maintaining translation symmetry of the crystal. Another is pointing along the c axis, and this component forms an anharmonic spin density wave consisting of three-up-two-down sequences with fivefold periodicity. The in-plane and out of plane spin structures represent distinct magnetic instabilities which normally would not coexist. Their simultaneous presence in the same phase is an interesting phenomenon associated with anisotropic exchange interactions and coupling to a symmetry breaking nonmagnetic order parameter undetectable by the available diffraction data.

Published by the American Physical Society
2024
Spin-flip-induced quadrupole resonance in odd-
A
exotic atoms
Authors: Gustafsson Fredrik P. , Pęcak Daniel , Sowiński Tomasz
Published: June 2024

We examine the possible existence of quadrupole resonances in exotic atoms containing odd-A nuclei. We find that the spin flip of the deexciting exotic particle can induce a resonance, altering the orbital angular momentum of the nucleus by one quantum. This process results in an excited nucleus with a suppression in x-ray photon emissions during the exotic atom cascade. We provide specific cases of antiprotonic atoms of stable elements where this resonance effect is expected to occur. The study of this phenomena may provide insight into the strong interaction of deeply bound antiprotonic states in the proximity of the unpaired nucleon, and serve as a tool for probing short-lived excited nuclear states.

Published by the American Physical Society
2024
Reappraisal of SU(3)-flavor breaking in
B→DP
Authors: Davies Jonathan , Schacht Stefan , Skidmore Nicola , Soni Amarjit
Published: June 2024

In light of recently found deviations of the experimental data from predictions from QCD factorization for B(s)→D(s)P decays, where P={π,K}, we systematically probe the current status of the SU(3)F expansion from a fit to experimental branching ratio data without any further theory input. We find that the current data are in agreement with the power counting of the

SU

(

3

)

F

expansion. While the SU(3)F limit is excluded at >5σ, amplitude-level SU(3)F-breaking contributions of ∼20% suffice for an excellent description of the data. SU(3)F breaking is needed in tree (>5σ) and color-suppressed tree (2.4σ) diagrams. We are not yet sensitive to SU(3)F breaking in exchange diagrams. From the underlying SU(3)F parametrization we predict the unmeasured branching ratios B(B¯s0→π−D+)=2B(B¯s0→π0D0)=[0.3,7.2]×10−6 of suppressed decays that can be searched for at the LHCb experiment.

Published by the American Physical Society
2024
Single spin asymmetry
AULsin(2ϕh)
in dihadron production in SIDIS
Authors: Yang Ren , Yu Yangyang , Zhou Qihang , Li Gang , Song Mao , Luo Xuan
Published: June 2024

The paper calculates the helicity-dependent dihadron fragmentation function by extending the dihadron spectator model and examine the single longitudinal spin asymmetry AULsin(2ϕh) from dihadron in semi-inclusive inelastic scattering. This function elucidates the relationship between the longitudinal polarization of the fragmented quark and the transverse momentum of the resulting hadron pairs. A study by the COMPASS collaboration detected a minimal signal in their experimental search for this azimuthal asymmetry in semi-inclusive inelastic scattering. Here, we use the spectator model to calculate the unknown T-odd dihadron fragmentation function H1⊥. Adopting collinear factorization to describe the data, avoiding the transverse momentum dependent factorization and the associated resummation effects, helping us understand the asymmetry and explaining why the signal is so weak. We involve the approach of transverse momentum dependence in the model calculations, in order to formulate the differential cross sections and the spin asymmetries in terms of the collinear parton distributions and the collinear dihadron fragmentation functions. A transverse momentum factor analysis method was used, in which the transverse momentum of the final hadron pairs was not integrated. The asymmetry of sin(2ϕh) in COMPASS kinematics was calculated and compared with experimental data. In addition, predictions for the same asymmetry are also presented for HERMES and the Electron Ion Collider.

Published by the American Physical Society
2024
Self-interacting dark matter implied by nano-Hertz gravitational waves
Authors: Han Chengcheng , Xie Ke-Pan , Yang Jin Min , Zhang Mengchao
Published: June 2024

The self-interacting dark matter (SIDM) paradigm offers a potential solution to the small-scale structure problems faced by collisionless cold dark matter. This framework incorporates self-interactions among dark matter particles, typically mediated by a particle with a MeV-scale mass. Recent evidences of nano-Hertz gravitational waves from pulsar timing arrays (PTAs) such as NANOGrav, CPTA, EPTA, and PPTA suggest the occurrence of a first-order phase transition (FOPT) at a MeV-scale temperature. Considering the close proximity between these two scales, we propose that the mediator mass in the SIDM model originates from the spontaneous breaking of a U(1)′ symmetry, which is driven by the FOPT indicated by PTA data. Consequently, the alignment of these two scales is believed to be deeply connected by the same underlying physics. By extensively exploring the parameter space, remarkably, we find that the parameter space favored by SIDM just provides an explanation for the PTA data.

Published by the American Physical Society
2024
Reactor neutrino background in next-generation dark matter detectors
Authors: Sierra D. Aristizabal , De Romeri V. , Ternes C. A.
Published: June 2024

Third-generation dark matter detectors will be fully sensitive to the B8 solar neutrino flux. Because of this, the characterization of such a background has been the subject of extensive analyses over the last few years. In contrast, little is known about the impact of reactor neutrinos. In this paper, we report on the implications of such a flux for dark matter direct-detection searches. We consider five potential detector deployment sites envisioned by the recently established XLZD Consortium: SURF, SNOLAB, Kamioka, LNGS, and Boulby. By using public reactor data, we construct five reactor clusters—involving about 100 currently operating commercial nuclear reactors each—and determine the net neutrino flux at each detector site. Assuming a xenon-based detector and a 50 ton-year exposure, we show that in all cases the neutrino event rate may be sizable, depending on energy recoil thresholds. Of all possible detector sites, SURF and LNGS are those with the smallest reactor neutrino background. On the contrary, SNOLAB and Boulby are subject to the strongest reactor neutrino fluxes, with Kamioka being subject to a more moderate background. Our findings demonstrate that reactor neutrino fluxes should be taken into account in the next round of dark matter searches. We argue that this background may be particularly relevant for directional detectors, provided they meet the requirements we have employed in this analysis.

Published by the American Physical Society
2024
Illuminating all-hadronic final states with a photon: Exotic decays of the Higgs boson to four bottom quarks in vector boson fusion plus gamma at hadron colliders
Authors: Roche Stephen T. , Carlson Benjamin T. , Hayes Christopher R. , Hong Tae Min
Published: June 2024

We investigate the potential to detect Higgs boson decays to four bottom quarks through a pair of pseudoscalars, a final state that is predicted by many theories beyond the Standard Model. For the first time, the signal sensitivity is evaluated for the final state using the vector boson fusion (VBF) production with and without an associated photon, for the Higgs at mH=125  GeV, at hadron colliders. The signal significance is 0.5σ to 6σ, depending on the pseudoscalar mass ma, when setting the Higgs decay branching ratio to unity, using an integrated luminosity of 150  fb−1 at s=13  TeV. This corresponds to an upper limit of 0.3, on the Higgs branching ratio to four bottom quarks, with a nonobservation of the decay. We also consider several variations of selection requirements—input variables for the VBF tagging and the kinematic variables for the photon—that could help guide the design of new triggers for the Run-3 period of the LHC and for the HL-LHC.

Published by the American Physical Society
2024
Fully Bayesian forecasts with evidence networks
Authors: Gessey-Jones T. , Handley W. J.
Published: June 2024

Sensitivity forecasts inform the design of experiments and the direction of theoretical efforts. To arrive at representative results, Bayesian forecasts should marginalize their conclusions over uncertain parameters and noise realizations rather than picking fiducial values. However, this is typically computationally infeasible with current methods for forecasts of an experiment’s ability to distinguish between competing models. We thus propose a novel simulation-based methodology capable of providing expedient and rigorous Bayesian model comparison forecasts without relying on restrictive assumptions.

Published by the American Physical Society
2024