bluuebunny/crossref_metadata_2025_split huggingface dataset:
Clinical Subphenotypes of Staphylococcus aureus Bacteremia
Authors: Swets Maaike C , Bakk Zsuzsa , Westgeest Annette C , Berry Karla , Cooper George , Sim Wynne , Lee Rui Shian , Gan Tze Yi , Donlon William , Besu Antonia , Heppenstall Emily , Tysall Luke , Dewar Simon , de Boer Mark , Fowler Vance G , Dockrell David H , Thwaites Guy E , Pujol Miquel , Pallarès Natàlia , Tebé Cristian , Carratalà Jordi , Szubert Alexander , Groeneveld Geert H , Russell Clark D 
Published: June 2024

Abstract

Background
Staphylococcus aureus bacteremia (SAB) is a clinically heterogeneous disease. The ability to identify subgroups of patients with shared traits (subphenotypes) is an unmet need to allow patient stratification for clinical management and research. We aimed to test the hypothesis that clinically relevant subphenotypes can be reproducibly identified among patients with SAB.

Methods
We studied 3 cohorts of adults with monomicrobial SAB: a UK retrospective observational study (Edinburgh cohort, n = 458), the UK ARREST trial (n = 758), and the Spanish SAFO trial (n = 214). Latent class analysis was used to identify subphenotypes using routinely collected clinical data without considering outcomes. Mortality and microbiologic outcomes were then compared between subphenotypes.

Results
Included patients had predominantly methicillin-susceptible SAB (1366 of 1430, 95.5%). We identified 5 distinct, reproducible clinical subphenotypes: (A) SAB associated with older age and comorbidity, (B) nosocomial intravenous catheter-associated SAB in younger people without comorbidity, (C) community-acquired metastatic SAB, (D) SAB associated with chronic kidney disease, and (E) SAB associated with injection drug use. Survival and microbiologic outcomes differed between the subphenotypes. Mortality was highest in subphenotype A and lowest in subphenotypes B and E. Microbiologic outcomes were worse in subphenotype C. In a secondary analysis of the ARREST trial, adjunctive rifampicin was associated with increased mortality in subphenotype B and improved microbiologic outcomes in subphenotype C.

Conclusions
We have identified reproducible and clinically relevant subphenotypes within SAB and provide proof of principle of differential treatment effects. Through clinical trial enrichment and patient stratification, these subphenotypes could contribute to a personalized medicine approach to SAB.
Disturbance in the potential cardiovascular–bone–skeletal muscle axis and morbidity and mortality in patients undergoing haemodialysis: the Q-Cohort Study
Authors: Arase Hokuto , Yamada Shunsuke , Taniguchi Masatomo , Ooboshi Hiroaki , Tsuruya Kazuhiko , Kitazono Takanari , Nakano Toshiaki 
Published: June 2024

ABSTRACT

Background
Disturbances in the cardiovascular system, bone and skeletal muscle are independent risk factors for death among patients receiving haemodialysis (HD). However, the combined impact of disorders of these three organs on morbidity and mortality is unclear in the HD population.

Methods
A total of 3031 Japanese patients on maintenance HD were prospectively followed. The outcomes were all-cause mortality, major adverse cardiovascular events (MACE) and bone fracture. Patients were divided into four groups (G1–G4) according to the baseline number of diseased organs represented as histories of cardiovascular disease and bone fractures and the presence of low skeletal muscle mass as follows: G1, no organ; G2, one organ; G3, two organs; G4, three organs. Multivariable-adjusted survival models were used to analyse associations between the number of diseased organs and outcomes.

Results
During a 4-year follow-up, 499 deaths, 540 MACE and 140 bone fractures occurred. In the Cox proportional hazards model, the risk for all-cause mortality was significantly higher in G2, G3 and G4 than in G1 as the reference {hazard ratio: G2, 2.16 [95% confidence interval (CI) 1.65–2.84], G3, 3.10 [95% CI 2.27–4.23] and G4, 3.11 [95% CI 1.89–5.14]}. Similarly, the risks for developing MACE and bone fractures were significantly elevated as the number of organ disorders increased.

Conclusions
Multiple disorders of the cardiovascular–bone–skeletal muscle axis are strong predictors of morbidity and mortality in patients undergoing HD.
Forward programming of human induced pluripotent stem cells via the ETS variant transcription factor 2: rapid, reproducible, and cost-effective generation of highly enriched, functional endothelial cells
Authors: Rieck Sarah , Sharma Kritika , Altringer Carlotta , Hesse Michael , Triantafyllou Christos , Zhang Yanhui , Busskamp Volker , Fleischmann Bernd K 
Published: June 2024

Abstract

Aims
Endothelial cell (EC) dysfunction plays a key role in the initiation and progression of cardiovascular disease. However, studying these disorders in ECs from patients is challenging; hence, the use of human induced pluripotent stem cells (hiPSCs) and their in vitro differentiation into ECs represents a very promising approach. Still, the generation of hiPSC-derived ECs (hECs) remains demanding as a cocktail of growth factors and an intermediate purification step are required for hEC enrichment. Therefore, we probed the utility of a forward programming approach using transgenic hiPSC lines.

Methods and results
We have used the transgenic hiPSC line PGP1 ETV2 isoform 2 to explore the in vitro differentiation of hECs via doxycycline-dependent induction of the ETS variant transcription factor 2 (ETV2) and compared these with a standard differentiation protocol for hECs using non-transgenic control hiPSCs. The transgenic hECs were highly enriched without an intermediate purification step and expressed—as non-transgenic hECs and human umbilical vein endothelial cells—characteristic EC markers. The viability and yield of transgenic hECs were strongly improved by applying EC growth medium during differentiation. This protocol was successfully applied in two more transgenic hiPSC lines yielding reproducible results with low line-to-line variability. Transgenic hECs displayed typical functional properties, such as tube formation and LDL uptake, and a more mature phenotype than non-transgenic hECs. Transgenic hiPSCs preferentially differentiated into the arterial lineage; this was further enhanced by adding a high concentration of vascular endothelial growth factor to the medium. We also demonstrate that complexing lentivirus with magnetic nanoparticles and application of a magnetic field enables efficient transduction of transgenic hECs.

Conclusion
We have established a highly efficient, cost-effective, and reproducible differentiation protocol for the generation of functional hECs via forward programming. The transgenic hECs can be genetically modified and are a powerful tool for disease modelling, tissue engineering, and translational purposes.
Cognitive functions and the brain-derived neurotrophic factor in patients with mild autonomous cortisol secretion
Authors: Barlas Tugba , Aksu Muhammed Hakan , Cerit Ethem Turgay , Yalcin Mehmet Muhittin , Akturk Mujde , Balos Toruner Fusun , Karakoc Mehmet Ayhan , Eroglu Altinova Alev 
Published: June 2024

Abstract

Context
The impact of abnormal cortisol secretion on cognitive functions in patients with mild autonomous cortisol secretion (MACS) remains uncertain.

Objective
To assess cognitive functions, determine serum brain-derived neurotrophic factor (BDNF) concentration in patients with MACS, and investigate the association between cognitive subdomains and BDNF.

Methods
We prospectively recruited 84 participants—28 patients with MACS, 28 patients with nonfunctional adrenal adenoma (NFAA), and 28 control subjects matched for age, gender, body mass index (BMI), visceral adiposity, and educational level. The serum BDNF concentration of participants was measured. The Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition–focused interviews and Montreal Cognitive Assessments (MoCA) were carried out by an experienced psychiatrist.

Results
Patients with MACS had a higher serum BDNF concentration than the NFAA (P = .001), while that of patients with NFAA was lower than the controls (P = .044). Linear regression analysis revealed BMI and morning cortisol after overnight 1 mg dexamethasone (DST) were mostly associated with BDNF (P &lt; .05). No significant difference was found in MoCA scores between MACS and NFAA groups (P = .967), whereas those were lower than the control group (P = .004). When the cognitive subdomains were examined separately, MACS group performed higher memory score than NFAA (P = .045), but lower language scores than both the NFAA (P = .024) and control groups (P &lt; .001). In the whole group, BDNF concentration was positively correlated with memory score (r = 0.337, P = .002), whereas DST was negatively correlated with language score (r = −0.355, P = .008).

Conclusion
Low-grade hypercortisolism is associated with elevated BDNF concentrations, which may be a protective factor for memory function in patients with MACS relative to those with NFAA.
Understanding the incidence of atrial fibrillation and stroke in hypertrophic cardiomyopathy patients: insights from Danish nationwide registries
Authors: Zörner Christopher R , Schjerning Anne-Marie , Jensen Morten Kvistholm , Christensen Alex Hørby , Tfelt-Hansen Jacob , Tønnesen Jacob , Riis-Vestergaard Lise Da , Middelfart Charlotte , Rasmussen Peter Vibe , Gislason Gunnar , Hansen Morten Lock 
Published: June 2024

Abstract

Aims
The treatment of atrial fibrillation (AF) in hypertrophic cardiomyopathy (HCM) can be challenging since AF aggravates symptoms and increases the risk of stroke. Which factors contribute to the development of AF and stroke in HCM remains unknown. The aim of this study was to determine the incidence of AF and stroke in HCM patients and identify the risk factors.

Methods and results
Using Danish national registries, all HCM patients from 2005 to 2018 were included. The association between HCM, incident AF, and stroke was investigated using multivariable Cox proportional hazards analysis. Cumulative incidences were calculated using the Aalen–Johansen estimator. Among the 3367 patients without prevalent AF, 24% reached the endpoint of incident AF with death as a competing risk. Median follow-up time was 4 years. Atrial fibrillation incidence was equal between sexes and increased for patients with ischaemic heart disease [IHD; hazard ratio (HR) 1.33, 95% confidence interval (CI) 1.08–1.63], hypertension (HT) (HR 1.36, 95% CI 1.14–1.67), and obstructive HCM (HR 1.27, 95% CI 1.05–1.52). Seven per cent developed stroke, with no difference detected stratifying for the presence of AF. Sub-analysis revealed that when AF was treated with oral anticoagulants (OACs), stroke was less likely (HR 0.4, 95% CI 0.18–0.86, P = 0.02). However, 34% of patients were not receiving adequate anticoagulation following AF diagnosis.

Conclusion
Obstructive HCM, HT, and IHD were associated with increased risk of AF. Prevalent AF alone was not predictive of stroke; however, AF patients treated with OAC were significantly less likely to develop stroke, suggesting that this development is driven by the protective effect of OAC. Despite this, 34% of patients did not receive OAC.
Effectiveness of physical activity interventions on undergraduate students’ mental health: systematic review and meta-analysis
Authors: Huang Kevin , Beckman Emma M , Ng Norman , Dingle Genevieve A , Han Rong , James Kari , Winkler Elisabeth , Stylianou Michalis , Gomersall Sjaan R 
Published: June 2024

AbstractThis systematic review and meta-analysis assessed the effectiveness of physical activity interventions on undergraduate students’ mental health. Seven databases were searched and a total of 59 studies were included. Studies with a comparable control group were meta-analysed, and remaining studies were narratively synthesized. The included studies scored very low GRADE and had a high risk of bias. Meta-analyses indicated physical activity interventions are effective in reducing symptoms of anxiety (n = 20, standardized mean difference (SMD) = −0.88, 95% CI [−1.23, −0.52]), depression (n = 14, SMD = −0.73, 95% CI [−1.00, −0.47]) and stress (n = 10, SMD = −0.61, 95% CI [−0.94, −0.28]); however, there was considerable heterogeneity (anxiety, I2 = 90.29%; depression I2 = 49.66%; stress I2 = 86.97%). The narrative synthesis had mixed findings. Only five studies reported being informed by a behavioural change theory and only 30 reported intervention fidelity. Our review provides evidence supporting the potential of physical activity interventions in enhancing the mental health of undergraduate students. More robust intervention design and implementation are required to better understand the effectiveness of PA interventions on mental health outcomes.
CsPHRs-CsJAZ3 incorporates phosphate signaling and jasmonate pathway to regulate catechin biosynthesis in Camellia sinensis
Authors: Li Linying , Zhang Xueying , Li Da , Su Hui , He Yuqing , Xu Zelong , Zhao Yao , Hong Yiyi , Li Qingsheng , Xu Ping , Hong Gaojie 
Published: June 2024

Abstract
Catechins constitute abundant metabolites in tea and have potential health benefits and high economic value. Intensive study has shown that the biosynthesis of tea catechins is regulated by environmental factors and hormonal signals. However, little is known about the coordination of phosphate (Pi) signaling and the jasmonic acid (JA) pathway on biosynthesis of tea catechins. We found that Pi deficiency caused changes in the content of catechins and modulated the expression levels of genes involved in catechin biosynthesis. Herein, we identified two transcription factors of phosphate signaling in tea, named CsPHR1 and CsPHR2, respectively. Both regulated catechin biosynthesis by activating the transcription of CsANR1 and CsMYB5c. We further demonstrated CsSPX1, a Pi pathway repressor, suppressing the activation by CsPHR1/2 of CsANR1 and CsMYB5c. JA, one of the endogenous plant hormones, has been reported to be involved in the regulation of secondary metabolism. Our work demonstrated that the JA signaling repressor CsJAZ3 negatively regulated catechin biosynthesis via physical interaction with CsPHR1 and CsPHR2. Thus, the CsPHRs–CsJAZ3 module bridges the nutrition and hormone signals, contributing to targeted cultivation of high-quality tea cultivars with high fertilizer efficiency.
Evaluation of phenotypic and genotypic methods for the identification and characterization of bacterial isolates recovered from catheter-associated urinary tract infections
Authors: Varney Adam M , Mannix-Fisher Eden , Thomas Jonathan C , McLean Samantha 
Published: June 2024

Abstract

Aims
Urinary tract infections are the most common hospital-acquired infection, 80% of which are associated with catheterization. Diagnostic methods may influence the reported identities of these pathogens, and phenotypic testing under laboratory conditions may not reflect infection phenotypes. This study aimed to evaluate the efficacy of diagnostic methods and whether medium composition alters phenotypes by characterizing catheter-associated urinary tract infection isolates from a UK hospital.

Methods and results
We compared five bacterial identification methods, including biochemical testing, matrix-assisted laser desorption/ionization biotyping, and genome sequencing, finding differences in genus- or species-level identifications. Antibiotic susceptibility comparisons between phenotypic assays and genomic predictions showed high agreement only in multidrug-resistant strains. To determine whether growth rate and biofilm formation were affected by medium composition, strains were grown in both planktonic and biofilm states. Low planktonic growth and significant biofilm formation were observed in artificial urine compared to rich laboratory media, underscoring the importance of assay design.

Conclusions
This study highlights the risks of relying on a single diagnostic method for species identification, advocating for whole-genome sequencing for accuracy. It emphasizes the continued importance of phenotypic methods in understanding antibiotic resistance in clinical settings and the need for characterization conditions that mirror those encountered by pathogens in the body.
Using patient portals for large-scale recruitment of individuals underrepresented in biomedical research: an evaluation of engagement patterns throughout the patient portal recruitment process at a single site within the All of Us Research Program
Authors: Beaton Maura , Jiang Xinzhuo , Minto Elise , Lau Chun Yee , Turner Lennon , Hripcsak George , Chaudhari Kanchan , Natarajan Karthik 
Published: June 2024

Abstract

Objective
To evaluate the use of patient portal messaging to recruit individuals historically underrepresented in biomedical research (UBR) to the All of Us Research Program (AoURP) at a single recruitment site.

Materials and Methods
Patient portal-based recruitment was implemented at Columbia University Irving Medical Center. Patient engagement was assessed using patient’s electronic health record (EHR) at four recruitment stages: Consenting to be contacted, opening messages, responding to messages, and showing interest in participating. Demographic and socioeconomic data were also collected from patient’s EHR and univariate logistic regression analyses were conducted to assess patient engagement.

Results
Between October 2022 and November 2023, a total of 59 592 patients received patient portal messages inviting them to join the AoURP. Among them, 24 445 (41.0%) opened the message, 8983 (15.1%) responded, and 3765 (6.3%) showed interest in joining the program. Though we were unable to link enrollment data with EHR data, we estimate about 2% of patients contacted ultimately enrolled in the AoURP. Patients from underrepresented race and ethnicity communities had lower odds of consenting to be contacted and opening messages, but higher odds of showing interest after responding.

Discussion
Patient portal messaging provided both patients and recruitment staff with a more efficient approach to outreach, but patterns of engagement varied across UBR groups.

Conclusion
Patient portal-based recruitment enables researchers to contact a substantial number of participants from diverse communities. However, more effort is needed to improve engagement from underrepresented racial and ethnic groups at the early stages of the recruitment process.
Disambiguation of acronyms in clinical narratives with large language models
Authors: Kugic Amila , Schulz Stefan , Kreuzthaler Markus 
Published: June 2024

Abstract

Objective
To assess the performance of large language models (LLMs) for zero-shot disambiguation of acronyms in clinical narratives.

Materials and Methods
Clinical narratives in English, German, and Portuguese were applied for testing the performance of four LLMs: GPT-3.5, GPT-4, Llama-2-7b-chat, and Llama-2-70b-chat. For English, the anonymized Clinical Abbreviation Sense Inventory (CASI, University of Minnesota) was used. For German and Portuguese, at least 500 text spans were processed. The output of LLM models, prompted with contextual information, was analyzed to compare their acronym disambiguation capability, grouped by document-level metadata, the source language, and the LLM.

Results
On CASI, GPT-3.5 achieved 0.91 in accuracy. GPT-4 outperformed GPT-3.5 across all datasets, reaching 0.98 in accuracy for CASI, 0.86 and 0.65 for two German datasets, and 0.88 for Portuguese. Llama models only reached 0.73 for CASI and failed severely for German and Portuguese. Across LLMs, performance decreased from English to German and Portuguese processing languages. There was no evidence that additional document-level metadata had a significant effect.

Conclusion
For English clinical narratives, acronym resolution by GPT-4 can be recommended to improve readability of clinical text by patients and professionals. For German and Portuguese, better models are needed. Llama models, which are particularly interesting for processing sensitive content on premise, cannot yet be recommended for acronym resolution.
All of whom? Limitations encountered using All of Us Researcher Workbench in a Primary Care residents secondary data analysis research training block
Authors: LaPolla Fred Willie Zametkin , Barber Grossi Marco , Chen Sharon , Guo Tai Wei , Havranek Kathryn , Jebb Olivia , Nguyen Minh Thu , Panganamamula Sneha , Smith Noah , Sundaresh Shree , Yu Jonathan , Mayer Gabrielle 
Published: June 2024

Abstract

Objectives
The goal of this case report is to detail experiences and challenges experienced in the training of Primary Care residents in secondary analysis using All of Us Researcher Workbench. At our large, urban safety net hospital, Primary Care/Internal Medicine residents in their third year undergo a research intensive block, the Research Practicum, where they work as a team to conduct secondary data analysis on a dataset with faculty facilitation. In 2023, this research block focused on use of the All of Us Researcher Workbench for secondary data analysis.

Materials and Methods
Two groups of 5 residents underwent training to access the All of Us Researcher Workbench, and each group explored available data with a faculty facilitator and generated original research questions. Two blocks of residents successfully completed their research blocks and created original presentations on “social isolation and A1C” levels and “medical discrimination and diabetes management.”

Results
Departmental faculty were satisfied with the depth of learning and data exploration. In focus groups, some residents noted that for those without interest in performing research, the activity felt extraneous to their career goals, while others were glad for the opportunity to publish. In both blocks, residents highlighted dissatisfaction with the degree to which the All of Us Researcher Workbench was representative of patients they encounter in a large safety net hospital.

Discussion
Using the All of Us Researcher Workbench provided residents with an opportunity to explore novel questions in a massive data source. Many residents however noted that because the population described in the All of Us Researcher Workbench appeared to be more highly educated and less racially diverse than patients they encounter in their practice, research may be hard to generalize in a community health context. Additionally, given that the data required knowledge of 1 of 2 code-based data analysis languages (R or Python) and work within an idiosyncratic coding environment, residents were heavily reliant on a faculty facilitator to assist with analysis.

Conclusion
Using the All of Us Researcher Workbench for research training allowed residents to explore novel questions and gain first-hand exposure to opportunities and challenges in secondary data analysis.
Application of functional genomics for domestication of novel non-model microbes
Authors: Bales Margaret K , Vergara Michael Melesse , Eckert Carrie A 
Published: June 2024

Abstract

With the expansion of domesticated microbes producing biomaterials and chemicals to support a growing circular bioeconomy, the variety of waste and sustainable substrates that can support microbial growth and production will also continue to expand. The diversity of these microbes also requires a range of compatible genetic tools to engineer improved robustness and economic viability. As we still do not fully understand the function of many genes in even highly studied model microbes, engineering improved microbial performance requires introducing genome-scale genetic modifications followed by screening or selecting mutants that enhance growth under prohibitive conditions encountered during production. These approaches include adaptive laboratory evolution, random or directed mutagenesis, transposon-mediated gene disruption, or CRISPR interference (CRISPRi). Although any of these approaches may be applicable for identifying engineering targets, here we focus on using CRISPRi to reduce the time required to engineer more robust microbes for industrial applications.

One-Sentence Summary
The development of genome scale CRISPR-based libraries in new microbes enables discovery of genetic factors linked to desired traits for engineering more robust microbial systems.