bluuebunny/crossref_metadata_2025_split huggingface dataset:
Pembrolizumab combined with low-dose cyclophosphamide and intra-tumoral injection of the toll-like receptor 4 agonist G100 in patients with advanced pretreated soft tissue sarcoma: results from the PEMBROSARC basket study
Authors: Spalato-Ceruso Mariella , Bouteiller Fanny , Guegan Jean-Philippe , Toulmonde Maud , Bessede Alban , Kind Michèle , Cousin Sophie , Buy Xavier , Palussiere Jean , Le Loarer François , Dadone-Montaudie Berengere , Pulido Marina , Italiano Antoine 
Published: October 2022

AbstractSoft tissue sarcomas (STS) are heterogeneous mesenchymal tumors with limited therapeutic options in the advanced setting. Immune checkpoint inhibitors have been shown to have significant clinical activity in inflamed STS which are characterized by the presence of tertiary lymphoid structures (TLS). New strategies are needed to sensitize TLS-negative STS to immunotherapy. Engagement of the toll-Like Receptor 4 (TLR4) signal pathway contributes to the development of a favorable tumor microenvironment in solid tumors. G100 is a highly potent toll-like receptor 4 (TLR4) agonist. We hypothesized that intra-tumoral G100 would induce a robust local and potentially systemic anti-tumor immune response in the microenvironment of TLS-negative sarcoma, leading to improved response to PD1 inhibition. Twenty metastatic STS patients who had a superficial injectable lesion were treated with 50 mg of cyclophosphamide (CP) orally twice daily (1 week on and 1 week off), 200 mg of pembrolizumab intravenously on day 8 of a planned 21-day cycle and G100 20 µg one weekly intra-tumoral injection for at least 6 weeks and for a maximum of 12 weeks (1st injection one week before CP administration, ie. Day -7). Biopsies and blood were collected pre and post treatment. Of the 17 patients assessable for efficacy analysis, 2 were progression-free at 6 months, and the 6-month non-progression rate was 11.8% (95% CI: 1.5–36.4), indicating that the first endpoint of the study was not reached. In 8 patients, there was an increase in T-cell infiltration into tumor after treatment. The ratio CD8/Fox-P3 + CD4 on treatment decreased in 11 cases out of 14 suggesting a predominant induction of Treg. Soluble PDL1 levels at baseline were also with adverse outcome. G100 appears to modulate the tumor microenvironment with significant infiltration of T cells. However, clinical activity in combination with PD1 inhibition was limited and no clear correlation was observed between tumor shrinkage and increased inflammation. TLR4 stimulation might have both antitumor and pro-tumor consequences.Trial registration: This study was registered with ClinicalTrial.gov, number NCT02406781.
Native-valve endocarditis detected by point-of-care echocardiography
Authors: Blanco Pablo , Figueroa Liliana , Menéndez María Fernanda 
Published: October 2022

Abstract
Background
Infective endocarditis carries a high morbidity and mortality; therefore, a rapid diagnosis and timely treatment is crucial to improve outcomes. Diagnosis of infective endocarditis is supported on echocardiogram findings.

Case presentation
An adult male with history of long-term hemodialysis, presented with embolic manifestations (cerebral, skin) and fever. A large vegetation in the mitral valve and other in the tricuspid valve were detected by point-of-care transthoracic echocardiogram, while blood cultures subsequently resulted positive for methicillin-resistant Staphylococcus aureus. Despite therapeutic efforts, the patient developed into an irreversible shock and died.

Conclusions
Point-of-care echocardiogram has a pivotal role in diagnosis and decision-making of infective endocarditis.
Association of H3K9me3 with breast cancer prognosis by estrogen receptor status
Authors: Zhou Meng , Yan Jin-qi , Chen Qian-xin , Yang Yuan-zhong , Li Yue-lin , Ren Yue-xiang , Weng Zi-jin , Zhang Xiao-fang , Guan Jie-xia , Tang Lu-ying , Ren Ze-fang 
Published: October 2022

Abstract
Background
Cellular experiments revealed that a decreased histone H3 lysine 9 trimethylation (H3K9me3) level was associated with the upregulation of oncogenes in breast cancer cells. Moreover, the role of H3K9me3 in breast cancer was closely associated with estrogen receptor (ER) status. Therefore, we aimed to examine the prognostic value of H3K9me3 on breast cancer by ER status. The level of H3K9me3 in tumors were evaluated with tissue microarrays by immunohistochemistry for 917 women diagnosed with primary invasive breast cancer. Hazard ratios (HRs) and their 95% confidence intervals (CIs) for overall survival (OS) and progression-free survival (PFS) were estimated using Cox regression models. Interaction between H3K9me3 and ER on the prognosis was assessed on multiplicative scale.

Results
The level of H3K9me3 in tumor tissues was lower than that in adjacent tissues. The high level of H3K9me3 was associated with a better OS (HR = 0.43, 95% CI: 0.21–0.86) and PFS (HR = 0.49, 95% CI: 0.29–0.81) among only ER-positive but not ER-negative tumors. Moreover, the interaction between the level of H3K9me3 and ER status (negative and positive) on the prognosis was significant (Pinteraction = 0.011 for OS; Pinteraction = 0.022 for PFS). Furthermore, the ER-positive tumors were stratified by ER-low and ER-high positive tumors, and the prognostic role of H3K9me3 was significant among only ER-high positive patients (HR = 0.34, 95% CI: 0.13–0.85 for OS; HR = 0.47, 95% CI: 0.26–0.86 for PFS).

Conclusions
Our study showed that the prognostic value of H3K9me3 on breast cancer was related to ER status and expression level, and the high level of H3K9me3 was associated with a better prognosis among ER-positive tumors, particularly ER-high positive tumors.
Reproducibility of artificial intelligence models in computed tomography of the head: a quantitative analysis
Authors: Gunzer Felix , Jantscher Michael , Hassler Eva M. , Kau Thomas , Reishofer Gernot 
Published: October 2022

AbstractWhen developing artificial intelligence (AI) software for applications in radiology, the underlying research must be transferable to other real-world problems. To verify to what degree this is true, we reviewed research on AI algorithms for computed tomography of the head. A systematic review was conducted according to the preferred reporting items for systematic reviews and meta-analyses. We identified 83 articles and analyzed them in terms of transparency of data and code, pre-processing, type of algorithm, architecture, hyperparameter, performance measure, and balancing of dataset in relation to epidemiology. We also classified all articles by their main functionality (classification, detection, segmentation, prediction, triage, image reconstruction, image registration, fusion of imaging modalities). We found that only a minority of authors provided open source code (10.15%, n 0 7), making the replication of results difficult. Convolutional neural networks were predominantly used (32.61%, n = 15), whereas hyperparameters were less frequently reported (32.61%, n = 15). Data sets were mostly from single center sources (84.05%, n = 58), increasing the susceptibility of the models to bias, which increases the error rate of the models. The prevalence of brain lesions in the training (0.49 ± 0.30) and testing (0.45 ± 0.29) datasets differed from real-world epidemiology (0.21 ± 0.28), which may overestimate performances. This review highlights the need for open source code, external validation, and consideration of disease prevalence.
Tocilizumab for relapsing and remitting giant cell arteritis: a case series
Authors: Saha Pratyasha , Srikantharajah Denesh , Kaul Arvind , Sofat Nidhi 
Published: October 2022

Abstract
Background
Giant cell arteritis is a large vessel vasculitis of the arteries in the head and neck. The mainstay of management is with high-dose corticosteroids, and patients often face difficulties stopping or reducing steroids without recurrence of symptoms. Corticosteroids are well established to have numerous associated side effects, including osteoporosis, weight gain, and diabetes. Therefore, when tocilizumab was approved for up to 1 year for cases of relapsing or refractory giant cell arteritis by the National Institute of Health and Care Excellence (NICE) in April 2018, this offered an opportunity to benefit from new funding and to reduce steroid burden.

Case presentation
This case series describes the impact of the establishment of a new hub and spoke referral pathway for the use of tocilizumab in refractory or relapsing giant cell arteritis, with case examples from consecutive patients who accessed the funding between August 2018 and April 2021. A total of 16 patients were identified: 11 female and 5 male, with an average age of 72.4 (range 61–82) years, with a majority of 11 ethnically white. The central assessing hub is St George’s University Hospitals NHS Foundation Trust Hospital, serving a population of 1.3 million in the south of England. This is the first large case series looking into the impact of the establishment of a regional clinical pathway for the new tocilizumab funding.

Conclusions
The case series demonstrates that the use of tocilizumab has reduced both the duration and the dose of corticosteroids in these 16 cases (mean prednisolone reduction 20.4 mg: 95% CI 13.0–27.8 mg), with 50% of patients continuing on tocilizumab after the initial 12 month funding period. The disease course, patterns of response, and maintenance of remission are discussed, and we describe the benefits of replicating this hub and spoke tocilizumab pathway in other centers.
A physics-informed neural network to model COVID-19 infection and hospitalization scenarios
Authors: Berkhahn Sarah , Ehrhardt Matthias 
Published: October 2022

AbstractIn this paper, we replace the standard numerical approach of estimating parameters in a mathematical model using numerical solvers for differential equations with a physics-informed neural network (PINN). This neural network requires a sequence of time instances as direct input of the network and the numbers of susceptibles, vaccinated, infected, hospitalized, and recovered individuals per time instance to learn certain parameters of the underlying model, which are used for the loss calculations.The established model is an extended susceptible-infected-recovered (SIR) model in which the transitions between disease-related population groups, called compartments, and the physical laws of epidemic transmission dynamics are expressed by a system of ordinary differential equations (ODEs). The system of ODEs and its time derivative are included in the residual loss function of the PINN in addition to the data error between the current network output and the time series data of the compartment sizes. Further, we illustrate how this PINN approach can also be used for differential equation-based models such as the proposed extended SIR model, called SVIHR model.In a validation process, we compare the performance of the PINN with results obtained with the numerical technique of non-standard finite differences (NSFD) in generating future COVID-19 scenarios based on the parameters identified by the PINN. The used training data set covers the time between the outbreak of the pandemic in Germany and the last week of the year 2021.We obtain a two-step or hybrid approach, as the PINN is then used to generate a future COVID-19 outbreak scenario describing a possibly next pandemic wave. The week at which the prediction starts is chosen in mid-April 2022.
The underlying molecular mechanisms and biomarkers of plaque vulnerability based on bioinformatics analysis
Authors: Cheng Rui , Xu Xiaojiang , Yang Shurong , mi Zhongqian , Zhao Yong , gao Jinhua , Yu Feiyan , Ren Xiuyun 
Published: October 2022

Abstract
Aim
The study aimed to identify the underlying differentially expressed genes (DEGs) and mechanism of unstable atherosclerotic plaque using bioinformatics methods.

Methods
GSE120521, which includes four unstable samples and four stable atherosclerotic samples, was downloaded from the GEO database. DEGs were identified using LIMMA. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses of DEGs were performed using the Database for metascape Visualization online tool. Based on the STRING database, protein–protein interactions (PPIs) network among DEGs were constructed. Regulatory networks were visualized using Cytoscape. We use the xCell to analyze the different immune cell subtypes.

Results
A total of 1626 DEGs (1034 up-regulated and 592 down-regulated DEGs) were identified between unstable and stable samples. I pulled 62 transcription factors (34 up-regulated TFs and 28 down-regulated TFs) from the Trust database. The up-regulated TFs were mainly enrichment in positive regulation of myeloid leukocyte differentiation, and the down-regulated TFs were mainly enrichment in connective tissue development. In the PPI network, RB1, CEBPA, PPARG, BATF was the most significantly up-regulated gene in ruptured atherosclerotic samples. The immune cell composition enriched in CD cells and macrophages in the unstable carotid plaque.

Conclusions
Upregulated RB1, CEBPA, PPARG, BATF and down-regulated SRF, MYOCD, HEY2, GATA6 might perform critical promotional roles in atherosclerotic plaque rupture, furthermore, number and polarization of macrophages may play an important role in vulnerable plaques.
Biodynamic compost effects on soil parameters in a 27-year long-term field experiment
Authors: Rodas-Gaitan Heberto , Fritz Jürgen , Dahn Christian , Köpke Ulrich , Joergensen Rainer Georg 
Published: October 2022

Abstract
Background
Soil samples were taken after 27 years from a long-term field experiment to study the effects of composted pure cattle farmyard manure (FYM) and two FYM treatments with biodynamic preparations on soil chemical and microbiological properties.

Methods
Soil organic carbon (SOC), total nitrogen, basal respiration, fungal ergosterol, microbial biomass C (MBC) and nitrogen (MBN) were analyzed in a 6-field crop rotation system, conducted as a randomized block design with six replicates. The multi-substrate-induced respiration (multi-SIR) approach was used to assess microbial functional diversity by the respiratory response of 17 low molecular weight organic substances.

Results
All composted FYM treatments revealed generally positive effects on SOC, total N, basal respiration, MBC, and MBN in contrast to control without FYM. Only fungal ergosterol was not increased by FYM application. After 27 experimental years, discriminant function analysis of multi-SIR data not only revealed significant general effects of biodynamic preparations, but was also able to differentiate between the sole application of the Achillea millefolium preparation and the standard application of all 6 biodynamic compost preparations.

Conclusions
The Achillea preparation was specifically able to improve the N status of the microbial community as indicated by the higher catabolic use of D-glucosamine as well as the amino acids γ-aminobutyric acid, L-cysteine, and L-leucine. The reason for different effects of the sole Achillea preparation and all 6 preparations cannot be explained by the current study.

Graphical Abstract
The procurement and supply chain strengthening project: improving public health supply chains for better access to HIV medicines, Uganda 2011–2016
Authors: Muyingo Sowedi , Etoori David , Lotay Paul , Malamba Samuel , Olweny James , Keesler King , Wiersma Steven , Jjemba Pito , Settaala Rashid 
Published: October 2022

Abstract
Background
With countries moving towards reaching the UNAIDS 90-90-90 goal to achieve HIV epidemic control, there are going to be an unprecedented number of persons who will need to be tested, treated, and regularly monitored for viral suppression. However, most of the countries with the greatest burden of HIV/AIDS experience regular stock outages which could be detrimental to reaching these targets. ART and other commodities such as HIV test kits and laboratory supplies need to be readily and consistently available to achieve these targets. The main objective was to improve access to HIV/AIDS related commodities and strengthening institutional capacity for the management of HIV/AIDS logistics services through the MAUL procurement and supply chain strengthening project (PSSP) that rolled out four interventions on mentorship and support supervision, stock level monitoring, spatial visualization of stock indicators using GIS, and using WhatsApp to submit order reports as photo images.

Methods
Medical Access Uganda Limited, a private-not-for-profit supply chain management company in Uganda, implemented these interventions as part of a procurement and supply chain strengthening project (PSSP). These interventions were evaluated using performance monitoring indicators from 2011–2016. We tested for the significance in the change in scores of performance monitoring indicators using the test for difference in proportions. Health facilities were scored on 6 categories and accredited as bronze, silver or gold based on their total scores. Kaplan–Meier estimates were computed for time to silver, and gold ranking and univariate and multivariate Cox proportional hazards models were computed for time to gold ranking.

Results
We observed a significant reduction in reported stock-outs from 46 to 4% (p < 0.001) in the analysis period. Accurate stock card inventory rose from 79 to 91% (p < 0.001); adequate stock levels rose from 54 to 71% (p = 0.002) and stock reporting rates from 91 to 100% (p < 0.001). The stock order fill rate improved from a high of 93% to 97% (p = 0.375). Patient load (medium vs low adjusted hazard ratio (aHR): 2.19, p = 0.026; high vs low aHR: 2.97, p = 0.034) and number of support supervision visits (6–10 aHR: 3.33, p = 0.024; > 10 aHR: 5.78, p = 0.003) were associated with better stock management ranking scores.

Conclusions
Improvements in supply chain management in countries committed to achieving the 90-90-90 goals are crucial to achieving HIV epidemic control. Health system strengthening and mentorship investments in Uganda were feasible and are essential for sustainable disease control efforts.
Team debriefing in the COVID-19 pandemic: a qualitative study of a hospital-wide clinical event debriefing program and a novel qualitative model to analyze debriefing content
Authors: Welch-Horan Thomas B. , Mullan Paul C. , Momin Zobiya , Eggers Jeannie , Lawrence Julia B. , Lichliter Royanne L. , Doughty Cara B. 
Published: October 2022

Abstract
Background
Healthcare workers faced unique challenges during the early months of the COVID-19 pandemic which necessitated rapid adaptation. Clinical event debriefings (CEDs) are one tool that teams can use to reflect after events and identify opportunities for improving their performance and their processes. There are few reports of how teams have used CEDs in the COVID-19 pandemic. Our aim is to explore the issues discussed during COVID-19 CEDs and propose a framework model for qualitatively analyzing CEDs.

Methods
This was a descriptive, qualitative study of a hospital-wide CED program at a quaternary children’s hospital between March and July 2020. CEDs were in-person, team-led, voluntary, scripted sessions using the Debriefing in Suspected COVID-19 to Encourage Reflection and Team Learning (DISCOVER-TooL). Debriefing content was qualitatively analyzed using constant comparative coding with an integrated deductive and inductive approach. A novel conceptual framework was proposed for understanding how debriefing content can be employed at various levels in a health system for learning and improvement.

Results
Thirty-one debriefings were performed and analyzed. Debriefings had a median of 7 debriefing participants, lasted a median of 10 min, and were associated with multiple systems-based process improvements. Fourteen themes and 25 subthemes were identified and categorized into a novel Input-Mediator-Output-Input Debriefing (IMOID) model. The most common themes included communication, coordination, situational awareness, team member roles, and clinical standards.

Conclusions
Teams identified diverse issues in their debriefing discussions related to areas of high performance and opportunities for improvement in their care of COVID-19 patients. This model may help healthcare systems to understand how CED tools can be used to accelerate organizational learning to promote safety and improve outcomes in changing clinical environments.
Wearing hats and blending boundaries: harmonising professional identities for clinician simulation educators
Authors: Dace William , Purdy Eve , Brazil Victoria 
Published: October 2022

AbstractMany clinicians working in healthcare simulation struggle with competing dual identities of clinician and educator, whilst those who harmonise these identities are observed to be highly effective teachers and clinicians. Professional identity formation (PIF) theories offer a conceptual framework for considering this dilemma. However, many clinician simulation educators lack practical guidance for translating these theories and are unable to develop or align their dual identities.An unusual experience involving the first author’s suspension of disbelief as a simulation facilitator sparked a novel reflection on his dual identity as a clinician and as a simulation educator. He re-framed his clinician and simulation ‘hats’ as cooperative and fluid rather than competing and compartmentalised. He recognised that these dual identities could flow between clinical and simulation environments through leaky ‘blended boundaries’ rather than being restricted by environmental demarcations.This personal story is shared and reflected upon to offer a practical ‘hats and boundaries’ model. Experimenting with the model in both clinical and simulation workplaces presents opportunities for PIF and alignment of dual identities. The model may help other clinician simulation educators navigate the complexities of merging their dual identities.
The effect of post-reperfusion levosimendan in an experimental intestinal ischemia–reperfusion model
Authors: Aygun Hakan , Olguner Cimen , Koca Ugur , Ergur Bekir Ugur , Sisman Ali Rıza , Isguven Duyguhan , Girgin Pelin , Akkus Muhammed , Tulgar Serkan 
Published: October 2022

Abstract
Background
Levosimendan has been reported to have a positive effect on ischemia–reperfusion injury. Herein, we aimed to evaluate the effects of levosimendan applied after reperfusion in an experimental intestinal injury-reperfusion (IR) model.

Methods
Twenty-one Wistar-albino male rats were separated into three groups: Sham group (n = 7): solely superior mesenteric artery (SMA) was dissected after laparotomy; intestinal ischemia–reperfusion group (IIR, n = 7): SMA was clamped for 60 min and unclamped for 120 min to cause ischemia–reperfusion; IIR + levosimendan group (IIR + L, n = 7): levosimendan was administered in ischemia–reperfusion model. The mean arterial pressures (MAP) were measured in all groups. MAP measurements were performed at the end of stabilization, at the 15th, 30th, and 60th minute of ischemia; at the 15th, 30th, 60th, and 120th minute of reperfusion; and at the end of levosimendan bolus application and when levosimendan infusion concluded. Reperfusion injury was evaluated with tissue malondialdehyde (MDA) and by Chiu score.

Results
MAP at 15 min, 30 min, and 60 min of reperfusion was lower in IIR and IIR + L groups compared with basal inter-group measurements. Decline in MAP at 30 min after reperfusion was statistically significant in IIR and IIR + L groups when compared with the sham group. There was no significant difference between MDA levels in the groups. Chiu score was significantly lower in the sham group when compared to IIR and IIR + L groups and higher in IIR when compared to the IIR + L group.

Conclusion
Levosimendan leads to a decrease in intestinal damage although it did not affect lipid peroxidation and MAP when administered after reperfusion in an experimental intestinal IR model.