bluuebunny/crossref_metadata_2025_split huggingface dataset:
Exploring relationships between in-hospital mortality and hospital case volume using random forest: results of a cohort study based on a nationwide sample of German hospitals, 2016–2018
Authors: Roessler Martin , Walther Felix , Eberlein-Gonska Maria , Scriba Peter C. , Kuhlen Ralf , Schmitt Jochen , Schoffer Olaf 
Published: January 2022

Abstract
Background
Relationships between in-hospital mortality and case volume were investigated for various patient groups in many empirical studies with mixed results. Typically, those studies relied on (semi-)parametric statistical models like logistic regression. Those models impose strong assumptions on the functional form of the relationship between outcome and case volume. The aim of this study was to determine associations between in-hospital mortality and hospital case volume using random forest as a flexible, nonparametric machine learning method.

Methods
We analyzed a sample of 753,895 hospital cases with stroke, myocardial infarction, ventilation > 24 h, COPD, pneumonia, and colorectal cancer undergoing colorectal resection treated in 233 German hospitals over the period 2016–2018. We derived partial dependence functions from random forest estimates capturing the relationship between the patient-specific probability of in-hospital death and hospital case volume for each of the six considered patient groups.

Results
Across all patient groups, the smallest hospital volumes were consistently related to the highest predicted probabilities of in-hospital death. We found strong relationships between in-hospital mortality and hospital case volume for hospitals treating a (very) small number of cases. Slightly higher case volumes were associated with substantially lower mortality. The estimated relationships between in-hospital mortality and case volume were nonlinear and nonmonotonic.

Conclusion
Our analysis revealed strong relationships between in-hospital mortality and hospital case volume in hospitals treating a small number of cases. The nonlinearity and nonmonotonicity of the estimated relationships indicate that studies applying conventional statistical approaches like logistic regression should consider these relationships adequately.
Avian haemosporidian parasites of accipitriform raptors
Authors: Harl Josef , Himmel Tanja , Valkiūnas Gediminas , Ilgūnas Mikas , Nedorost Nora , Matt Julia , Kübber-Heiss Anna , Alic Amer , Konicek Cornelia , Weissenböck Herbert 
Published: January 2022

Abstract
Background
The order Accipitriformes comprises the largest group of birds of prey with 260 species in four families. So far, 21 haemosporidian parasite species have been described from or reported to occur in accipitriform birds. Only five of these parasite species have been characterized molecular genetically. The first part of this study involved molecular genetic screening of accipitriform raptors from Austria and Bosnia-Herzegovina and the first chromogenic in situ hybridization approach targeting parasites in this host group. The aim of the second part of this study was to summarize the CytB sequence data of haemosporidian parasites from accipitriform raptors and to visualize the geographic and host distribution of the lineages.

Methods
Blood and tissue samples of 183 accipitriform raptors from Austria and Bosnia-Herzegovina were screened for Plasmodium, Haemoproteus and Leucocytozoon parasites by nested PCR, and tissue samples of 23 PCR-positive birds were subjected to chromogenic in situ hybridization using genus-specific probes targeting the parasites’ 18S rRNAs. All published CytB sequence data from accipitriform raptors were analysed, phylogenetic trees were calculated, and DNA haplotype network analyses were performed with sequences from clades featuring multiple lineages detected in this host group.

Results
Of the 183 raptors from Austria and Bosnia-Herzegovina screened by PCR and sequencing, 80 individuals (44%) were infected with haemosporidian parasites. Among the 39 CytB lineages detected, 18 were found for the first time in the present study. The chromogenic in situ hybridization revealed exo-erythrocytic tissue stages of Leucocytozoon parasites belonging to the Leucocytozoon toddi species group in the kidneys of 14 infected birds. The total number of CytB lineages recorded in accipitriform birds worldwide was 57 for Leucocytozoon, 25 for Plasmodium, and 21 for Haemoproteus.

Conclusion
The analysis of the DNA haplotype networks allowed identifying numerous distinct groups of lineages, which have not yet been linked to morphospecies, and many of them likely belong to yet undescribed parasite species. Tissue stages of Leucocytozoon parasites developing in accipitriform raptors were discovered and described. The majority of Leucocytozoon and Haemoproteus lineages are specific to this host group, but most Plasmodium lineages were found in birds of other orders. This might indicate local transmission from birds kept at the same facilities (raptor rescue centres and zoos), likely resulting in abortive infections. To clarify the taxonomic and systematic problems, combined morphological and molecular genetic analyses on a wider range of accipitriform host species are needed.
Vector composition, abundance, biting patterns and malaria transmission intensity in Madang, Papua New Guinea: assessment after 7 years of an LLIN-based malaria control programme
Authors: Keven John B. , Katusele Michelle , Vinit Rebecca , Rodríguez-Rodríguez Daniela , Hetzel Manuel W. , Robinson Leanne J. , Laman Moses , Karl Stephan , Walker Edward D. 
Published: January 2022

Abstract
Background
A malaria control programme based on distribution of long-lasting insecticidal bed nets (LLINs) and artemisinin combination therapy began in Papua New Guinea in 2009. After implementation of the programme, substantial reductions in vector abundance and malaria transmission intensity occurred. The research reported here investigated whether these reductions remained after seven years of sustained effort.

Methods
All-night (18:00 to 06:00) mosquito collections were conducted using human landing catches and barrier screen methods in four villages of Madang Province between September 2016 and March 2017. Anopheles species identification and sporozoite infection with Plasmodium vivax and Plasmodium falciparum were determined with molecular methods. Vector composition was expressed as the relative proportion of different species in villages, and vector abundance was quantified as the number of mosquitoes per barrier screen-night and per person-night. Transmission intensity was quantified as the number of sporozoite-infective vector bites per person-night.

Results
Five Anopheles species were present, but vector composition varied greatly among villages. Anopheles koliensis, a strongly anthropophilic species was the most prevalent in Bulal, Matukar and Wasab villages, constituting 63.7–73.8% of all Anopheles, but in Megiar Anopheles farauti was the most prevalent species (97.6%). Vector abundance varied among villages (ranging from 2.8 to 72.3 Anopheles per screen-night and 2.2–31.1 Anopheles per person-night), and spatially within villages. Malaria transmission intensity varied among the villages, with values ranging from 0.03 to 0.5 infective Anopheles bites per person-night. Most (54.1–75.1%) of the Anopheles bites occurred outdoors, with a substantial proportion (25.5–50.8%) occurring before 22:00.

Conclusion
The estimates of vector abundance and transmission intensity in the current study were comparable to or higher than estimates in the same villages in 2010–2012, indicating impeded programme effectiveness. Outdoor and early biting behaviours of vectors are some of the likely explanatory factors. Heterogeneity in vector composition, abundance and distribution among and within villages challenge malaria control programmes and must be considered when planning them.
Association between dietary choline and betaine intake and 10.6-year cardiovascular disease in adults
Authors: Golzarand Mahdieh , Mirmiran Parvin , Azizi Fereidoun 
Published: January 2022

Abstract
Background
Several studies have assessed the association between dietary choline and betaine and cardiovascular disease (CVD), but their results are inconsistent. The present study aimed to determine the association between dietary intake of choline and betaine and the risk of CVD in the general population over a 10.6-year period of follow-up.

Methods
The present cohort study was conducted on participants in the third wave of the Tehran Lipid and Glucose Study (2006–2008) and was followed-up until March 2018. Dietary intake of choline and betaine was calculated using the United States Department of Agriculture (USDA) database. Patients’ medical records were used to collect data on CVD.

Results
In this study, 2606 subjects with no previous CVD participated and were followed-up for a median of 10.6 years. During the follow-up periods, 187 incidences of CVD were detected. Results of the Cox proportional hazards regression indicated that neither energy-adjusted total choline nor betaine was associated with the incidence of CVD. Among individual choline forms, only higher intake of free choline (FC) was associated with a lower risk of CVD (HR: 0.64, 95% CI: 0.42–0.98). There was no significant association between each 10 mg/d increase in choline and betaine content of each food category and CVD.

Conclusion
Our investigation indicates no association between energy-adjusted total choline and betaine and a 10.6-year risk of CVD among adults. Besides, we found no relationship between individual choline forms (except FC) and CVD. We also found energy-adjusted choline and betaine obtained from food categories were not associated with the risk of CVD.
Combination of extramural venous invasion and lateral lymph node size detected with magnetic resonance imaging is a reliable biomarker for lateral lymph node metastasis in patients with rectal cancer
Authors: Abe Tomoki , Yasui Masayoshi , Imamura Hiroki , Matsuda Chu , Nishimura Junichi , Haraguchi Naotsugu , Nakai Nozomu , Wada Hiroshi , Takahashi Hidenori , Omori Takeshi , Miyata Hiroshi , Ohue Masayuki 
Published: January 2022

Abstract
Purpose
Pathological extramural venous invasion (EMVI) is defined as the active invasion of malignant cells into veins beyond the muscularis propria in colorectal cancer. It is associated with poor prognosis and increases the risk of disease recurrence. Specific findings on MRI (termed MRI-EMVI) are reportedly associated with pathological EMVI. In this study, we aimed to identify risk factors for lateral lymph node (LLN) metastasis related to rectal cancer and to evaluate whether MRI-EMVI could be a new and useful imaging biomarker to help LLN metastasis diagnosis besides LLN size.

Methods
We investigated 67 patients who underwent rectal resection and LLN dissection for rectal cancer. We evaluated MRI-EMVI grading score and examined the relationship between MRI-EMVI and LLN metastasis.

Results
Pathological LLN metastasis was detected in 18 cases (26.9%), and MRI-EMVI was observed in 32 cases (47.8%). Patients were divided into two cohorts, according to LLN metastasis. Multivariate analyses demonstrated that higher risk of LLN metastasis was significantly associated with MRI-EMVI (P = 0.0112) and a short lateral lymph node axis (≥ 5 mm) (P = 0.0002). The positive likelihood ratios of MRI-EMVI alone, LLN size alone, and the combination of both factors were 2.12, 4.84, and 16.33, respectively. Patients negative for both showed better 2-year relapse-free survival compared to other patients (84.4% vs. 62.1%, P = 0.0374).

Conclusions
MRI-EMVI was a useful imaging biomarker for identifying LLN metastasis in patients with rectal cancer. The combination of MRI-EMVI and LLN size can improve diagnostic accuracy.
Skin damage induced by zinc oxide nanoparticles combined with UVB is mediated by activating cell pyroptosis via the NLRP3 inflammasome–autophagy–exosomal pathway
Authors: Chen Yu-Ying , Lee Yu-Hsuan , Wang Bour-Jr , Chen Rong-Jane , Wang Ying-Jan 
Published: January 2022

AbstractBackgroundZinc oxide nanoparticles (ZnONPs) are widely used nanomaterial in personal cosmetics, such as skin creams and sunscreens, due to their whitening properties and strong UV light absorption. However, the safety issues and the hazards of ZnONPs, which can be taken up by the skin and cause skin toxicity, are still unclear. From a chemoprevention point of view, pterostilbene (PT) has been reported to prevent skin damage effectively by its anti-inflammatory and autophagy inducer effect. This study aims to determine the skin toxicity and the potential mechanisms of UVB and ZnONPs exposure and the preventive effect of PT.ResultsThe co-exposure of UVB and ZnONPs elicit NLRP3 inflammasome activation and pyroptosis in keratinocytes. Furthermore, exposure to both UVB and ZnONPs also disrupts cellular autophagy, which increases cell exosome release. In vivo UVB and ZnONPs exposure triggers skin toxicity, as indicated by increased histological injury, skin thickness and transepidermal water loss. Notably, the NLRP3 inflammasome-mediated pyroptosis are also activated during exposure. Topical application of pterostilbene attenuates NLRP3 inflammasome activation and pyroptosis by decreasing ROS generation and mitochondrial ROS (mtROS) levels. In addition to its antioxidant effect, PT also reversed autophagy abnormalities by restoring normal autophagic flux and decreasing NLRP3 inflammasome-loaded exosome release.ConclusionsOur findings reveal that ZnONPs induce skin damage in conjunction with UVB exposure. This process involves an interplay of inflammasomes, pyroptosis, autophagy dysfunction, and exosomes in skin toxicity. PT alleviates skin inflammation by regulating the inflammasome–autophagy–exosome pathway, a finding which could prove valuable when further evaluating ZnONPs effects for cosmetic applications.
Echinacoside exhibits antidepressant-like effects through AMPAR–Akt/ERK–mTOR pathway stimulation and BDNF expression in mice
Authors: Chuang Han-Wen , Wang Tse-Yen , Huang Chih-Chia , Wei I-Hua 
Published: January 2022

Abstract
Background
Several natural products have been demonstrated to be effective in the treatment of depressive disorders. Echinacoside, a naturally occurring phenol extracted from Cistanche tubulosa, Echinacea angustifolia, and Cistanche spp, has a wide range of physiological effects, such as antioxidation, neuroprotection, anti-inflammatory, and immunoregulation, which are closely related to depression. In addition, echinacoside can activate protein kinase B (Akt), extracellular signal–regulated kinase (ERK), and brain-derived neurotrophic factor (BDNF) in the brain. A key downstream event of the Akt, ERK, and BDNF signaling pathways, namely mechanistic target of rapamycin (mTOR) signaling, plays a crucial role in generating an rapid antidepressant effect. Thus, echinacoside is a promising therapeutic agent for depression. However, research regarding the role of echinacoside in antidepressant effect and brain mTOR activation remains lacking.

Materials and methods
The forced swimming test and Western blot analysis in C57BL/6 mice was used to investigate the antidepressant-like activities of echinacoside and the underlying mechanism involved inα-amino3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR)–Akt/ERK–mTOR pathway.

Results
We confirmed the suggestions by previous reports that echinacoside activates Akt/ERK signaling and further demonstrated that echinacoside could provide antidepressant-like effects in mice via the activation of AMPAR–Akt/ERK–mTOR pathway in the hippocampus.

Conclusions
To the best of our knowledge, our study is the first to reveal that echinacoside is a potential treatment for depressive disorders. Moreover, the present study suggests a mechanism for the neuroprotective effect of echinacoside.
Traditional Chinese medicine Lingguizhugan decoction ameliorate HFD-induced hepatic-lipid deposition in mice by inhibiting STING-mediated inflammation in macrophages
Authors: Cao Lin , Xu Erjin , Zheng Rendong , Zhangchen Zhili , Zhong Rongling , Huang Fei , Ye Juan , Sun Hongping , Fan Yaofu , Xie Shaofeng , Chen Yu , Xu Yijiao , Cao Jing , Cao Wen , Liu Chao 
Published: January 2022

Abstract
Background
Stimulator of IFN genes (STING) is highly expressed in the livers of non-alcoholic fatty liver disease (NAFLD) patients and high fat diet (HFD) induced NAFLD mice model. The STING signaling-mediated inflammation has been shown to play a critical role in metabolic disorders. Lingguizhugan decoction (LGZG), a Traditional Chinese herbal decoction, has been applied to treat metabolic disorders for many years. However, whether LGZG can alleviate the progression of NAFLD through inhibiting inflammation remains unclear. This study was to determine the role of STING-mediated inflammation in the HFD-induced hepatic-lipid deposition treated with LGZG.

Methods
The anti-inflammatory and anti-steatotic effects of LGZG in vivo were detected by H&E staining, immunofluorescence and immuno-chemistry. Mice bone-marrow-derived macrophages (BMDMs) and primary liver macrophages were treated with STING-specific agonist (DMXAA), LGZG and its critical components respectively. The treated culture supernatant of BMDMs and primary liver macrophages from each group was co-cultured with palmitic acid-treated mouse primary hepatocytes or mouse liver cell line AML-12 respectively to detect whether the activation of STING-mediated pathway is involved in the anti-steatotic effect of LGZG. The hepatocyte lipid deposition in vivo and in vitro were detected by oil red staining. Mitochondrial DNA release of mouse liver extracts were detected by real time PCR. The expression of proteins and inflammatory cytokines related to STING-TBK1-NF-κB pathway was detected by western blotting and ELISA.

Results
LGZG significantly ameliorated HFD induced hepatic steatosis, oxidative stress, hepatic mitochondrial damage and mitochondrial DNA release, which was correlated with reduction of the expression level of STING as well as the infiltration of STING-positive macrophages in the livers of HFD fed mice. The critical components of LGZG directly inhibited the activation of STING-TBK1-NF-κB pathway in liver macrophages induced by DMXAA, LPS, thereby reducing the release of IFNβ and TNFα. Co-incubating the culture supernatant of LGZG treated liver macrophages and PA-stimulated hepatocytes significantly inhibited the PA-induced lipid deposition.

Conclusion
This study demonstrates that LGZG can ameliorate HFD-induced hepatic-lipid deposition through inhibiting STING-TBK1-NF-κB pathway in liver macrophages, which provides novel insight for elucidating the molecular mechanism of LGZG alleviating HFD induced hepatic steatosis.
Marimo actuated rover systems
Authors: Phillips Neil , Draper Thomas C. , Mayne Richard , Reynolds Darren M. , Adamatzky Andrew 
Published: January 2022

Abstract
Background
The potential to directly harness photosynthesis to make actuators, biosensors and bioprocessors has been previously demonstrated in the literature. Herein, this capability has been expanded to more advanced systems — Marimo Actuated Rover Systems (MARS) — which are capable of autonomous, solar powered, movement.

Results
We demonstrate this ability is both a practical and viable alternative to conventional mobile platforms for exploration and dynamic environmental monitoring. Prototypes have been successfully tested to measure their speed of travel and ability to automatically bypass obstacles. Further, MARS is electromagnetically silent, thus avoiding the background noise generated by conventional electro/mechanical platforms which reduces instrument sensitivity. The cost of MARS is significantly lower than platforms based on conventional technology.

Conclusions
An autonomous, low-cost, lightweight, compact size, photosynthetically powered rover is reported. The potential for further system enhancements are identified and under development.
Statistical analysis plan for the Dual mTorc Inhibition in advanCed/recurrent Epithelial ovarian, fallopian tube or primary peritoneal cancer (of clear cell, endometrioid and high-grade serous type, and carcinosarcoma) trial (DICE)
Authors: de la Rosa Consuelo Nóhpal , Krell Jonathan , Day Emily , Clarke Aaron , Reddi Meena , Webber Lee , Fiorentino Francesca 
Published: January 2022

Abstract
Background
Treatment for ovarian cancer includes platinum-based chemotherapy, but many women become resistant to chemotherapy, becoming platinum-resistant. Standard of care for these women is weekly paclitaxel chemotherapy, but cancers can often become paclitaxel resistant. TAK228, an investigational dual TORC1/2 inhibitor, is an oral therapy that can be added to standard treatment. The DICE trial is a phase II international multicentre, parallel-group, superiority clinical trial with 1:1, open label randomisation which has the aim of investigating the effectiveness of TAK228 plus weekly paclitaxel. The planned sample size is 124 women (62 per treatment arm) with platinum-resistant ovarian cancer.

Objective
To outline the planned analyses for DICE in a statistical analysis plan (SAP) before database hard lock and the start of analysis. This ensures that bias is minimised during the analysis phase.

Results
This SAP provides detailed descriptions of the analysis principles and statistical procedures for analysing primary and secondary outcomes of the trial. The primary outcome is overall progression-free survival (PFS). Secondary outcomes include progression-free survival (PFS) at 24 weeks, overall response rate (ORR), duration of response (DoR), time to progression (TTP), clinical benefit rate (CBR) at 4 months, Cancer Antigen 125 (CA125) response according to Gynaecological Cancer Intergroup (GCIG) criteria, overall survival (OS), safety and tolerability as assessed by adverse events and the quality-of-life questionnaires (EORTC QLQ-C30 and EORTC QLQ-OV28). This detailed description includes significance levels, sensitivity analyses and compliance analysis.

Discussion
The DICE trial will determine whether the addition of TAK228 to weekly paclitaxel chemotherapy shows a statistically significant improvement to participant’s progression free and overall survival and that the adverse events (AEs) and quality of life (QoL) are not significantly worse than the standard treatment.
The study commenced recruitment in September 2018. An interim analysis was performed in early 2021, the results of which advised continuation of the trial. The study recruitment is ongoing and is due to complete by the end of 2021.

Trial registration
ClinicalTrials.govNCT03648489. Registered on 27 August 2018