bluuebunny/crossref_metadata_2025_split huggingface dataset:
Implementation and evaluation of a nurse-led intervention to augment an existing residential aged care facility outreach service with a visual telehealth consultation: stepped-wedge cluster randomised controlled trial
Authors: Sunner Carla , Giles Michelle , Ball Jean , Barker Roslyn , Hullick Carolyn , Oldmeadow Christopher , Foureur Maralyn 
Published: December 2023

Abstract
Background
Up to 75% of residents from residential aged care facilities (RACF) are transferred to emergency departments (ED) annually to access assessment and care for unplanned or acute health events. Emergency department presentations of RACF residents can be both expensive and risky, and many are unnecessary and preventable. Processes or triage systems to assess residents with a health event, prior to transfer, may reduce unnecessary ED transfer. The Aged Care Emergency (ACE) service is a nurse-led ED outreach service that provides telephone support to RACF nurses regarding residents’ health events. This service is available Monday to Friday, 8am to 4 pm (ED ACE hours). The primary objective of this study was to assess whether the augmentation of the phone-based ED ACE service with the addition of a visual telehealth consultation (VTC) would reduce RACF rate of ED presentations compared to usual care. The secondary objectives were to 1) monitor presentations to ED within 48 h post VTC to detect any adverse events and 2) measure RACF staff perceptions of VTC useability and acceptability.

Methods
This implementation study used a stepped wedge cluster randomised controlled trial design. Study settings were four public hospital EDs and 16 RACFs in two Local Health Districts. Each ED was linked to 4 RACFs with approximately 350 RACF beds, totalling 1435 beds across 16 participating RACFs. Facilities were randomised into eight clusters with each cluster comprising one ED and two RACFs.

Results
A negative binomial regression demonstrated a 29% post-implementation reduction in the rate of ED presentations (per 100 RACF beds), within ED ACE hours (IRR [95% CI]: 0.71 [0.46, 1. 09]; p = 0.122). A 29% reduction, whilst not statistically significant, is still clinically important and impactful for residents and EDs. A post-hoc logistic regression demonstrated a statistically significant 69% reduction in the probability that an episode of care resulted in an ED presentation within ED ACE hours post-implementation compared to pre-implementation (OR [95% CI]: 0.31 [0.11, 0.87]; p = 0.025).

Conclusion
Findings have shown the positive impact of augmenting ACE with a VTC. Any reduction of resident presentations to a busy ED is beneficial to healthcare overall, but more so to the individual older person who can recover safely and comfortably in their own RACF.

Trial registration
Australian New Zealand Clinical Trials Registry (ID ACTR N12619001692123) (02/12/2019) https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=378629andisReview=true
Knowledge and attitudes of German and Swiss community pharmacists towards biologicals and biosimilars – a prospective survey before and after the COVID-19 pandemic
Authors: Messner Kirstin , Eickhoff Christiane , Schulz Martin , Allemann Samuel S. , Arnet Isabelle 
Published: December 2023

Abstract
Background
Knowledge, attitudes and substitution laws of biosimilars are not consistent across countries. Biosimilar acceptance among patients and healthcare professionals may be suffering from gaps in knowledge and understanding about biosimilars and their regulatory approval process. Pharmacists' roles and responsibilities changed considerably during the COVID-19 pandemic. Thus, they might have gained new skills and self-confidence in counseling and substitution of biosimilars.

Aims
To examine and compare the knowledge, perceptions and information needs of German and Swiss pharmacists regarding original biologicals and biosimilars in 2020 and 2022.

Methods
We conducted an online survey among Swiss and German community pharmacies in February 2020 (before) and August 2022 (after the COVID-19 pandemic). Descriptive statistics were calculated and the Chi-Square test was used for comparisons among categorical variables.

Results
A total of 764 pharmacists took part in the survey (390 in 2020 and 374 in 2022) with comparable demographics. The frequency of dispensing biologicals remained similar between German and Swiss pharmacists in 2020 and 2022, but the Swiss dispensation of biosimilars increased significantly in 2022 compared to 2020. Concerning the understanding of the term biosimilars, knowledge remained moderate in both countries in both years. Participants were equally familiar with the term and most felt sufficiently informed. In both countries, substitution with a biosimilar showed the least confidence of all attitudes. A third of the participants indicated correct substitution rules in their country. In both years, around 85% of the participants were highly interested in additional training on this topic.

Discussion/Conclusion
The results indicate that similarities and differences between Germany and Switzerland regarding knowledge and attitudes towards biologicals and biosimilars remained unchanged before and after the COVID-19 pandemic. An influence of the pandemic is unlikely. There is still a clear lack of knowledge among community pharmacists on biosimilars, especially regarding the substitution rules. Due to a rising market with many benefits but also big challenges to overcome, the topic of biosimilars should receive more attention in the future. This requires additional training for pharmacists.
MiR-146b-5p enriched bioinspired exosomes derived from fucoidan-directed induction mesenchymal stem cells protect chondrocytes in osteoarthritis by targeting TRAF6
Authors: Lou Chao , Jiang Hongyi , Lin Zhongnan , Xia Tian , Wang Weidan , Lin Chihao , Zhang Zhiguang , Fu Haonan , Iqbal Shoaib , Liu Haixiao , Lin Jian , Wang Jilong , Pan Xiaoyun , Xue Xinghe 
Published: December 2023

AbstractOsteoarthritis (OA) is a common degenerative joint disease characterized by progressive cartilage degradation and inflammation. In recent years, mesenchymal stem cells (MSCs) derived exosomes (MSCs-Exo) have attracted widespread attention for their potential role in modulating OA pathology. However, the unpredictable therapeutic effects of exosomes have been a significant barrier to their extensive clinical application. In this study, we investigated whether fucoidan-pretreated MSC-derived exosomes (F-MSCs-Exo) could better protect chondrocytes in osteoarthritic joints and elucidate its underlying mechanisms. In order to evaluate the role of F-MSCs-Exo in osteoarthritis, both in vitro and in vivo studies were conducted. MiRNA sequencing was employed to analyze MSCs-Exo and F-MSCs-Exo, enabling the identification of differentially expressed genes and the exploration of the underlying mechanisms behind the protective effects of F-MSCs-Exo in osteoarthritis. Compared to MSCs-Exo, F-MSCs-Exo demonstrated superior effectiveness in inhibiting inflammatory responses and extracellular matrix degradation in rat chondrocytes. Moreover, F-MSCs-Exo exhibited enhanced activation of autophagy in chondrocytes. MiRNA sequencing of both MSCs-Exo and F-MSCs-Exo revealed that miR-146b-5p emerged as a promising candidate mediator for the chondroprotective function of F-MSCs-Exo, with TRAF6 identified as its downstream target. In conclusion, our research results demonstrate that miR-146b-5p encapsulated in F-MSCs-Exo effectively inhibits TRAF6 activation, thereby suppressing inflammatory responses and extracellular matrix degradation, while promoting chondrocyte autophagy for the protection of osteoarthritic cartilage cells. Consequently, the development of a therapeutic approach combining fucoidan with MSC-derived exosomes provides a promising strategy for the clinical treatment of osteoarthritis.
Clinical value of station 4R node dissection in esophageal squamous cell carcinoma
Authors: Wang Xin-ye , Fu Xia-yu , Yang Hong , Wen Jing , Lin Peng , Fu Jian-hua 
Published: December 2023

Abstract
Background
Many controversies still exist concerning the optimal extent of lymphadenectomy during esophagectomy in esophageal squamous cell carcinoma (ESCC). The objective of this study was to explore the characteristics of 4R metastasis and evaluate the clinical value of 4R node dissection in ESCC.

Methods
A total of 736 ESCC patients who underwent radical esophagectomy between 2005 and 2013 were retrospectively collected, among which 393 ones underwent 4R dissection. Propensity score matching (PSM) method was applied to reduce the effects of confounding variables between the 4R dissection and non-dissection groups to analyze overall survival.

Results
Patients showed a low 4R metastasis rate of 5.1% (20/393) (5.2%, 5.8%, and 1.8% for upper, middle, and lower tumors, respectively). Correlation analyses identified that 4R metastasis was significantly associated with station 2R metastasis (p < 0.001) and pathologic tumor-node-metastasis (pTNM) stage (p < 0.001). All 4R metastases were observed in stages IIIB and IVA. Moreover, patients with station 4R dissection failed to achieve significantly improved overall survival compared with those without 4R dissection, regardless of tumor stage (overall: p = 0.696; stage 0-IIIA: p = 0.317; stage IIIB-IVA: p = 0.619).

Conclusion
4R metastasis is likely to be associated with more aggressive disease, and routine 4R node dissection might not be necessary for ESCC patients.
Targeting Src homology phosphatase 2 ameliorates mouse diabetic nephropathy by attenuating ERK/NF-κB pathway-mediated renal inflammation
Authors: Yu Che , Li Zhuo , Nie Cuili , Chang Lei , Jiang Tao 
Published: December 2023

AbstractRenal inflammation is a pivotal mechanism underlying the pathophysiology of diabetic nephropathy (DN). The Src homology phosphatase 2 (SHP2) has been demonstrated to be linked to diabetes-induced inflammation, yet its roles and explicit molecular mechanisms in DN remain unexplored. Here, we report that SHP2 activity is upregulated in both DN patients and db/db mice. In addition, pharmacological inhibition of SHP2 with its specific inhibitor PHPS1 alleviates DN in db/db mice and attenuates renal inflammation. In vitro, PHPS1 administration prevents inflammatory responses in HK-2 cells stimulated by high glucose (HG). Mechanistically, PHPS1 represses HG-induced activation of the proinflammatory ERK/NF-κB signaling pathway, and these inhibitory effects are blocked in the presence of an ERK specific inhibitor, hence demonstrating that PHPS1 suppresses ERK/NF-κB pathway-mediated inflammation. Moreover, PHPS1 retards ERK/NF-κB pathway activation in db/db mice, and histologically, SHP2 activity is positively correlated with ERK/NF-κB activation in DN patients. Taken together, these findings identify SHP2 as a potential therapeutic target and show that its pharmacological inhibition might be a promising strategy to mitigate DN.
scNAT: a deep learning method for integrating paired single-cell RNA and T cell receptor sequencing profiles
Authors: Zhu Biqing , Wang Yuge , Ku Li-Ting , van Dijk David , Zhang Le , Hafler David A. , Zhao Hongyu 
Published: December 2023

AbstractMany deep learning-based methods have been proposed to handle complex single-cell data. Deep learning approaches may also prove useful to jointly analyze single-cell RNA sequencing (scRNA-seq) and single-cell T cell receptor sequencing (scTCR-seq) data for novel discoveries. We developed scNAT, a deep learning method that integrates paired scRNA-seq and scTCR-seq data to represent data in a unified latent space for downstream analysis. We demonstrate that scNAT is capable of removing batch effects, and identifying cell clusters and a T cell migration trajectory from blood to cerebrospinal fluid in multiple sclerosis.
Performance evaluation of protocols for Taenia saginata and Ascaris suum egg recovery from the house fly’s gastrointestinal tract and exoskeleton
Authors: De Bock Sophie , Duchateau Luc , Levecke Bruno , Gabriël Sarah 
Published: December 2023

Abstract
Background
The synanthropic house fly (Musca domestica) can potentially contribute to the mechanical spread of eggs of Taenia and Ascaris spp. in the environment and between hosts. However, the absence of validated protocols to recover eggs hampers an in-depth analysis of the house fly's role in parasite egg transmission.

Methods
The gastrointestinal tract and exoskeleton of euthanized house flies were spiked with Taenia saginata eggs. The performance of several recovery protocols, in terms of both the recovery rate and ease-of-use, was (microscopically) evaluated and compared. These protocols employed steps such as washing, maceration, filtration, flotation and both passive and centrifugal sedimentation. The final validated protocols were subsequently evaluated for the recovery of Ascaris suum eggs.

Results
The final protocol validated for the recovery of T. saginata eggs from the house fly’s gastrointestinal tract involved homogenization in phosphate-buffered saline and centrifugation at 2000 g for 2 min, yielding a recovery rate of 79.7%. This protocol required 6.5 min to perform (which included 1.5 min of hands-on time) and removed large debris particles that could hinder the differentiation of eggs from debris. Similarly, the final protocol validated for the recovery of T. saginata eggs from the fly’s exoskeleton involved washing by vortexing for 2 min in Tween 80 (0.05%), 15 min of passive sedimentation and centrifugation at 2000 g for 2 min, yielding a recovery rate of 77.4%. This protocol required 20.5 min to perform (which included 3.5 min of hands-on time) and successfully removed debris. The same protocols yielded recovery rates of 74.2% and 91.5% for the recovery of A. suum eggs from the fly’s gastrointestinal tract and exoskeleton, respectively.

Conclusions
Effective, simple and easy-to-use protocols were developed and validated for the recovery of T. saginata and A. suum eggs from the house fly’s gastrointestinal tract and exoskeleton. These protocols can be applied to investigate the importance of flies as parasite egg transmitters in laboratory and field settings.

Graphical Abstract
Quantitative thresholds for variant enrichment in 13,845 cases: improving pathogenicity classification in genetic hearing loss
Authors: Liu Sihan , Zhong Mingjun , Huang Yu , Zhang Qian , Chen Ting , Xu Xiaofei , Peng Wan , Wang Xiaolu , Feng Xiaoshu , Kang Lu , Lu Yu , Cheng Jing , Bu Fengxiao , Yuan Huijun 
Published: December 2023

Abstract
Background
The American College of Medical Genetics and Genomics (ACMG)/Association for Molecular Pathology (AMP) guidelines recommend using variant enrichment among cases as "strong" evidence for pathogenicity per the PS4 criterion. However, quantitative support for PS4 thresholds from real-world Mendelian case–control cohorts is lacking.

Methods
To address this gap, we evaluated and established PS4 thresholds using data from the Chinese Deafness Genetics Consortium. A total of 9,050 variants from 13,845 patients with hearing loss (HL) and 6,570 ancestry-matched controls were analyzed. Positive likelihood ratio and local positive likelihood ratio values were calculated to determine the thresholds corresponding to each strength of evidence across three variant subsets.

Results
In subset 1, consisting of variants present in both cases and controls with an allele frequency (AF) in cases ≥ 0.0005, an odds ratio (OR) ≥ 6 achieved strong evidence, while OR ≥ 3 represented moderate evidence. For subset 2, which encompassed variants present in both cases and controls with a case AF < 0.0005, and subset 3, comprising variants found only in cases and absent from controls, we defined the PS4_Supporting threshold (OR > 2.27 or allele count ≥ 3) and the PS4_Moderate threshold (allele count ≥ 6), respectively. Reanalysis applying the adjusted PS4 criteria changed the classification of 15 variants and enabled diagnosis of an additional four patients.

Conclusions
Our study quantified evidence strength thresholds for variant enrichment in genetic HL cases, highlighting the importance of defining disease/gene-specific thresholds to improve the precision and accuracy of clinical genetic testing.
Multimodal lifestyle engagement patterns support cognitive stability beyond neuropathological burden
Authors: Paolillo Emily W. , Saloner Rowan , VandeBunte Anna , Lee Shannon , Bennett David A. , Casaletto Kaitlin B. 
Published: December 2023

Abstract
Background
Modifiable lifestyle behaviors account for a large proportion of dementia risk. However, the combined contributions of multidomain lifestyle patterns to cognitive aging are poorly understood, as most studies have examined individual lifestyle behaviors in isolation and without neuropathological characterization. This study examined data-driven patterns of lifestyle behaviors across multiple domains among older adults and tested their associations with disease-specific neuropathological burden and cognitive decline.

Methods
Participants included 2059 older adults enrolled in the longitudinal Memory and Aging Project (MAP) at the Rush Alzheimer’s Disease Center; none of whom had dementia at baseline (73% no cognitive impairment (NCI), 27% mild cognitive impairment [MCI]). All participants completed cognitive testing annually. Lifestyle factors were measured during at least one visit and included (1) actigraphy-measured physical activity, as well as self-reported (2) sleep quality, (3) life space, (4) cognitive activities, (5) social activities, and (6) social network. A subset of participants (n = 791) had autopsy data for which burden of Alzheimer’s disease (AD), cerebrovascular disease (CVD), Lewy body disease, and hippocampal sclerosis/TDP-43 was measured. Latent profile analysis across all 2059 participants identified distinct subgroups (i.e., classes) of lifestyle patterns. Linear mixed-effects models examined relationships between lifestyle classes and global cognitive trajectories, with and without covarying for all neuropathologies. Classes were also compared on rates of incident MCI/dementia.

Results
Five classes were identified: Class 1Low Life Space (lowest lifestyle engagement), Class 2PA (high physical activity), Class 3Low Avg (low to average lifestyle engagement), Class 4Balanced (high average lifestyle engagement), and Class 5Social (large social network). Classes 4Balanced and 5Social had the lowest AD burden, and Class 2PA had the lowest CVD burden. Classes 2–5 had significantly less steep global cognitive decline compared to Class 1Low Life Space, with comparable effect sizes before and after covarying for neuropathological burden. Classes 4Balanced and 5Social exhibited the lowest rates of incident MCI/dementia.

Conclusions
Lifestyle behavior patterns among older adults account for differential rates of cognitive decline and clinical progression. Those with at least average engagement across all lifestyle domains exhibit greater cognitive stability after adjustment for neuropathology, highlighting the importance of engagement in multiple healthy lifestyle behaviors for later life cognitive health.
Uncertain of uncertainties? A comparison of uncertainty quantification metrics for chemical data sets
Authors: Rasmussen Maria H. , Duan Chenru , Kulik Heather J. , Jensen Jan H. 
Published: December 2023

AbstractWith the increasingly more important role of machine learning (ML) models in chemical research, the need for putting a level of confidence to the model predictions naturally arises. Several methods for obtaining uncertainty estimates have been proposed in recent years but consensus on the evaluation of these have yet to be established and different studies on uncertainties generally uses different metrics to evaluate them. We compare three of the most popular validation metrics (Spearman’s rank correlation coefficient, the negative log likelihood (NLL) and the miscalibration area) to the error-based calibration introduced by Levi et al. (Sensors2022, 22, 5540). Importantly, metrics such as the negative log likelihood (NLL) and Spearman’s rank correlation coefficient bear little information in themselves. We therefore introduce reference values obtained through errors simulated directly from the uncertainty distribution. The different metrics target different properties and we show how to interpret them, but we generally find the best overall validation to be done based on the error-based calibration plot introduced by Levi et al. Finally, we illustrate the sensitivity of ranking-based methods (e.g. Spearman’s rank correlation coefficient) towards test set design by using the same toy model ferent test sets and obtaining vastly different metrics (0.05 vs. 0.65).
Higher levels of circulating desphospho-uncarboxylated matrix Gla protein over time are associated with worse survival: the prospective Maastricht Intensive Care COVID cohort
Authors: Mulder Mark M. G. , Schellens Joep , Sels Jan-Willem E. M. , van Rosmalen Frank , Hulshof Anne-Marije , de Vries Femke , Segers Ruud , Mihl Casper , van Mook Walther N. K. A. , Bast Aalt , Spronk Henri M. H. , Henskens Yvonne M. C. , van der Horst Iwan C. C. , Cate Hugo ten , Schurgers Leon J. , Drent Marjolein , van Bussel Bas C. T. 
Published: December 2023

Abstract
Background
Extra-hepatic vitamin K-status, measured by dephosphorylated uncarboxylated matrix Gla protein (dp-ucMGP), maintains vascular health, with high levels reflecting poor vitamin K status. The occurrence of extra-hepatic vitamin K deficiency throughout the disease of COVID-19 and possible associations with pulmonary embolism (PE), and mortality in intensive care unit (ICU) patients has not been studied. The aim of this study was to investigated the association between dp-ucMGP, at endotracheal intubation (ETI) and both ICU and six months mortality. Furthermore, we studied the associations between serially measured dp-ucMGP and both PE and mortality.

Methods
We included 112 ICU patients with confirmed COVID-19. Over the course of 4 weeks after ETI, dp-ucMGP was measured serially. All patients underwent computed tomography pulmonary angiography (CTPA) to rule out PE. Results were adjusted for patient characteristics, disease severity scores, inflammation, renal function, history of coumarin use, and coronary artery calcification (CAC) scores.

Results
Per 100 pmol/L dp-ucMGP, at ETI, the odds ratio (OR) was 1.056 (95% CI: 0.977 to 1.141, p = 0.172) for ICU mortality and 1.059 (95% CI: 0.976 to 1.059, p = 0.170) for six months mortality. After adjustments for age, gender, and APACHE II score, the mean difference in plasma dp-ucMGP over time of ICU admission was 167 pmol/L (95% CI: 4 to 332, p = 0.047). After additional adjustments for c-reactive protein, creatinine, and history of coumarin use, the difference was 199 pmol/L (95% CI: 50 to 346, p = 0.010). After additional adjustment for CAC score the difference was 213 pmol/L (95% CI: 3 to 422, p = 0.051) higher in ICU non-survivors compared to the ICU survivors. The regression slope, indicating changes over time, did not differ. Moreover, dp-ucMGP was not associated with PE.

Conclusion
ICU mortality in COVID-19 patients was associated with higher dp-ucMGP levels over 4 weeks, independent of age, gender, and APACHE II score, and not explained by inflammation, renal function, history of coumarin use, and CAC score. No association with PE was observed. At ETI, higher levels of dp-ucMGP were associated with higher OR for both ICU and six month mortality in crude and adjusted modes, although not statistically significantly.