bluuebunny/crossref_metadata_2025_split huggingface dataset:
Outcome selection for tissue-agnostic drug trials for immune-mediated inflammatory diseases: a systematic review of core outcome sets and regulatory guidance
Authors: Aiyegbusi Olalekan Lee , di Ruffano Lavinia Ferrante , Retzer Ameeta , Newsome Philip N. , Buckley Christopher D. , Calvert Melanie J. 
Published: January 2022

Abstract
Background
Tissue-agnostic drug development provides a paradigm shift in precision medicine and requires innovative trial designs. However, outcome selection for such trials can prove challenging. The objectives of this review were to:

Identify and map core outcome sets (COS), across 11 immune-mediated inflammatory diseases (IMIDs) in order to facilitate the selection of relevant outcomes across the conditions for innovative trials of tissue-agnostic drug therapies.

Compare outcomes or endpoints recommended by the US Food and Drug Administration (FDA) and European Medicines Agency (EMA) to identify and highlight similarities and differences.

Methods
The Core Outcome Measures in Effectiveness Trials (COMET), International Consortium for Health Outcomes Measurement (ICHOM), FDA and EMA databases were searched from inception to 28th December 2019. Two reviewers independently screened titles and abstracts of retrieved entries and conducted the subsequent full text screening. Hand searching of the reference lists and citation searching of the selected publications was conducted. The methodological quality of the included peer-reviewed articles was independently assessed by the reviewers based on the items of the COS–Standards for Development recommendations (COS–STAD) checklist. Core outcomes from the included publications were extracted and mapped across studies and conditions. Regulatory guidance from FDA and EMA, where available for clinical trials for the IMIDs, were obtained from their databases and recommendations on outcomes to measure directly compared.

Results
Forty-four COS publications were included in the final analysis. Outcomes such as disease activity, pain, fatigue, quality of life, physical function, work limitation/productivity, steroid use and biomarkers were recommended across majority of the conditions. There were significant similarities and differences in FDA and EMA recommendations. The only instance where either regulatory body directly referenced a COS was for jSLE—both referenced the Paediatric Rheumatology International Trials Organization (PRINTO) COS.

Conclusions
The findings from this systematic review provide valuable information to inform outcome selection in tissue-agnostic trials for IMIDs. There is a need for increased collaboration between regulators and COS developers and inclusion of regulators as key stakeholders in COS development to enhance the quality of COS.

Trial registration
Not registered.
Association between blood glucose levels and Glasgow Outcome Score in patients with traumatic brain injury: secondary analysis of a randomized trial
Authors: Yuan Tao , He Hongyu , Liu Yuepeng , Wang Jianwei , Kang Xin , Fu Guanghui , Xie Fangfang , Li Aimin , Chen Jun , Wang Wenxue 
Published: January 2022

Abstract
Background
Blood glucose levels that are too high or too low after traumatic brain injury (TBI) negatively affect patient prognosis. This study aimed to demonstrate the relationship between blood glucose levels and the Glasgow Outcome Score (GOS) in TBI patients.

Methods
This study was based on a randomized, dual-center, open-label clinical trial. A total of 208 patients who participated in the randomized controlled trial were followed up for 5 years. Information on the disease, laboratory examination, insulin therapy, and surgery for patients with TBI was collected as candidate variables according to clinical importance. Additionally, data on 5-year and 6-month GOS were collected as primary and secondary outcomes, respectively. For multivariate analysis, a generalized additive model (GAM) was used to investigate relationships between blood glucose levels and GOS. The results are presented as odds ratios (ORs) with 95% confidence intervals (95% CIs). We further applied a two- piecewise linear regression model to examine the threshold effect of blood glucose level and GOS.

Results
A total of 182 patients were included in the final analysis. Multivariate GAM analysis revealed that a bell-shaped relationship existed between average blood glucose level and 5-year GOS score or 6-month GOS score. The inflection points of the average blood glucose level were 8.81 (95% CI: 7.43–9.48) mmol/L considering 5-year GOS as the outcome and were 8.88 (95% CI 7.43−9.74) mmol/L considering 6-month GOS score as the outcome. The same analysis revealed that there was also a bell relationship between average blood glucose levels and the favorable outcome group (GOS score ≥ 4) at 5 years or 6 months.

Conclusion
In a population of patients with traumatic brain injury, blood glucose levels were associated with the GOS. There was also a threshold effect between blood glucose levels and the GOS. A blood glucose level that is either too high or too low conveys a poor prognosis.

Trial registration
ClinicalTrials.gov NCT02161055. Registered on 11 June 2014.
Metabarcoding reveals low prevalence of microsporidian infections in castor bean tick (Ixodes ricinus)
Authors: Trzebny Artur , Liberska Justyna , Slodkowicz-Kowalska Anna , Dabert Miroslawa 
Published: January 2022

AbstractBackgroundMicrosporidia is a large group of eukaryotic obligate intracellular spore-forming parasites, of which 17 species can cause microsporidiosis in humans. Most human-infecting microsporidians belong to the generaEnterocytozoonandEncephalitozoon. To date, only five microsporidian species, includingEncephalitozoon-like, have been found in hard ticks (Ixodidae) using microscopic methods, but no sequence data are available for them. Furthermore, no widespread screening for microsporidian-infected ticks based on DNA analysis has been carried out to date. Thus, in this study, we applied a recently developed DNA metabarcoding method for efficient microsporidian DNA identification to assess the role of ticks as potential vectors of microsporidian species causing diseases in humans.MethodsIn total, 1070 (493 juvenile and 577 adult) unfed host-seekingIxodes ricinusticks collected at urban parks in the city of Poznan, Poland, and 94 engorged tick females fed on dogs and cats were screened for microsporidian DNA. Microsporidians were detected by PCR amplification and sequencing of the hypervariable V5 region of 18S rRNA gene (18S profiling) using the microsporidian-specific primer set. Tick species were identified morphologically and confirmed by amplification and sequencing of the shortened fragment of cytochromecoxidase subunit I gene (mini-COI).ResultsAll collected ticks were unambiguously assigned toI. ricinus. Potentially zoonoticEncephalitozoon intestinaliswas identified in three fed ticks (3.2%) collected from three different dogs. In eight unfed host-seeking ticks (0.8%), including three males (1.1%), two females (0.7%) and three nymphs (0.7%), the new microsporidian sequence representing a species belonging to the genusEndoreticulatuswas identified.ConclusionsThe lack of zoonotic microsporidians in host-seeking ticks suggests thatI.ricinusis not involved in transmission of human-infecting microsporidians. Moreover, a very low occurrence of the other microsporidian species in both fed and host-seeking ticks implies that mechanisms exist to defend ticks against infection with these parasites.Graphical abstract
Creatinine-to-body weight ratio is a predictor of incident diabetes: a population-based retrospective cohort study
Authors: He Jiacheng 
Published: January 2022

Abstract
Purpose
Creatinine to body weight (Cre/BW) ratio is considered the independent risk factor for incident type 2 diabetes mellitus (T2DM), but research on this relationship is limited. The relationship between the Cre/BW ratio and T2DM among Chinse individuals is still ambiguous. This study aimed to evaluate the correlation between the Cre/BW ratio and the risk of T2DM in the Chinese population.

Methods
This is a retrospective cohort study from a prospectively collected database. We included a total of 200,658 adults free of T2DM at baseline. The risk of incident T2DM according to Cre/BW ratio was estimated using multivariable Cox proportional hazards models, and a two-piece wise linear regression model was developed to find out the threshold effect.

Results
With a median follow-up of 3.13 ± 0.94 years, a total of 4001 (1.99%) participants developed T2DM. Overall, there was an L-shaped relation of Cre/BW ratio with the risk of incident T2DM (P for non-linearity < 0.001). When the Cre/BW ratio (× 100) was less than 0.86, the risk of T2DM decreased significantly as the Cre/BW ratio increased [0.01 (0.00, 0.10), P < 0.001]. When the Cre/BW ratio (× 100) was between 0.86 and 1.36, the reduction in the risk of developing T2DM was not as significant as before [0.22 (0.12, 0.38), P < 0.001]. In contrast, when the Cre/BW ratio (× 100) was greater than 1.36, the reduction in T2DM incidence became significantly flatter than before [0.73 (0.29,1.8), P = 0.49].

Conclusion
There was an L-shaped relation of Cre/BW ratio with incidence of T2DM in general Chinese adults. A negative curvilinear association between Cre/BW ratio and incident T2DM was present, with a saturation effect predicted at 0.86 and 1.36 of Cre/BW ratio (× 100).
Association of metabolic syndrome traits with urinary biomarkers in Japanese adults
Authors: Kabasawa Keiko , Hosojima Michihiro , Ito Yumi , Matsushima Kazuo , Tanaka Junta , Hara Masanori , Nakamura Kazutoshi , Narita Ichiei , Saito Akihiko 
Published: January 2022

Abstract
Background
Although metabolic syndrome traits are risk factors for chronic kidney disease, few studies have examined their association with urinary biomarkers.

Methods
Urinary biomarkers, including A-megalin, C-megalin, podocalyxin, albumin, α1-microglobulin, β2-microglobulin, and N-acetyl-β-D-glucosaminidase, were cross-sectionally assessed in 347 individuals (52.7% men) with a urine albumin-to-creatinine ratio (ACR)  < 300 mg/g in a health checkup. Metabolic syndrome traits were adopted from the National Cholesterol Education Program (third revision) of the Adult Treatment Panel criteria modified for Asians.

Results
Participants had a mean body mass index, estimated glomerular filtration rate (eGFR), and median ACR of 23.0 kg/m2, 74.8 mL/min/1.73 m2, and 7.5 mg/g, respectively. In age- and sex-adjusted logistic regression analysis, A-megalin and albumin were significantly associated with the clustering number of metabolic syndrome traits (3 or more). After further adjustment with eGFR, higher quartiles of A-megalin and albumin were each independently associated with the clustering number of metabolic syndrome traits (adjusted odds ratio for A-megalin: 1.30 per quartile, 95% CI 1.03–1.64; albumin: 1.42 per quartile, 95% CI 1.12–1.79).

Conclusions
Both urinary A-megalin and albumin are associated with the clustering number of metabolic syndrome traits. Further research on urinary A-megalin is warranted to examine its role as a potential marker of kidney damage from metabolic risk factors.
AK098656: a new biomarker of coronary stenosis severity in hypertensive and coronary heart disease patients
Authors: Wang Xin , Wu Ya-li , Zhang Yuan-yuan , Ke Jing , Wang Zong-wei , Zhang Bao-yu , Ma Yan , Yang Long-yan , Zhao Dong 
Published: January 2022

Abstract
Background
AK098656 may be an adverse factor for coronary heart disease (CHD), especially in patients with hypertension. This study aimed to analyze the effect of AK098656 on CHD and CHD with various complications.

Methods
A total of 117 CHD patients and 27 healthy control subjects were enrolled in the study. Plasma AK098656 expression was determined using the quantitative real-time polymerase chain reaction. Student’s t-test was used to compare AK098656 expression levels in different groups. Receiver operating characteristic (ROC) curve and area under the curve (AUC) were used to quantify the discrimination ability between CHD patients and health controls and between CHD and CHD + complications patients. The relationship between AK098656 and coronary stenosis was analyzed using Spearman’s correlation.

Results
AK098656 expression was remarkably higher in CHD patients than in healthy controls (P = 0.03). The ROC curve revealed an effective predictive AK098656 expression value for CHD risk, with an AUC of 0.656 (95% CI 0.501–0.809). Moreover, AK098656 expression was increased in CHD + complications patients compared to CHD patients alone (P = 0.005), especially in patients with hypertension (CHD + hHTN, P = 0.030). The ROC curve revealed a predictive AK098656 prognostic value for discriminating between CHD and CHD + hHTN patients, with an AUC of 0.666 (95% CI 0.528–0.805). There was no significant difference in AK098656 expression in CHD patients with diabetes mellitus compared to CHD patients alone. In addition, AK098656 expression in CHD patients was positively correlated with stenosis severity (R = 0.261, P = 0.006).

Conclusion
AK098656 expression was significantly increased in patients with CHD, especially those with hypertension, and its expression level was positively correlated with the degree of coronary stenosis. This implied that AK098656 may be a risk factor for CHD and can potentially be applied in clinical diagnosis or provide a novel target for treatment.
Effect of six-week traditional resistance and functional training on functional performance in female netball players
Authors: Kovac Dimitrije , Krkeljas Zarko , Venter Ranel 
Published: January 2022

Abstract
Background
Improving the quality of functional movements in athletes generally requires additional training targeting specific functional deficiencies. However, well-rounded, traditional strength and conditioning program should also improve player’s movement quality. Therefore, the primary aim of this study was to compare the effect of two different six-week interventions on the functional score of female netball players.

Methods
In a randomized controlled study, players were divided into control and intervention group. Both groups completed identical six-week strength and conditioning program, with the intervention group also completing additional corrective exercises three sessions per week during the same period.

Results
The FMS® score was significantly higher in the intervention group after 6-week program (f = 9.85, p = 0.004). However, the differences in total score may be attributed mainly to differences between groups in active straight leg raise (p = 0.004) and trunk stability push-up test (p = 0.02), as other individual tests demonstrated similar time and group effect.

Conclusion
These results indicate that although FMS® based intervention may improve overall functional movement score, the athletes in both groups have demonstrated similar improvements in most of the individual tests. Hence, a well-rounded strength and conditioning program incorporating athlete-specific exercises based on limitations identified in the functional movement screen, may result in a balanced training strategy and reduce the need for supplementary functional training sessions.
CT angiography for the assessment of EVAR complications: a pictorial review
Authors: Gozzo Cecilia , Caruana Giovanni , Cannella Roberto , Farina Arduino , Giambelluca Dario , Dinoto Ettore , Vernuccio Federica , Basile Antonio , Midiri Massimo 
Published: January 2022

AbstractEndovascular aneurysm repair (EVAR) is a minimally invasive treatment proposed as an alternative to open repair in patients with abdominal aortic aneurysms. EVAR consists in a stent-graft placement within the aorta in order to exclude the aneurysm from arterial circulation and reduce the risk of rupture. Knowledge of the various types of devices is mandatory because some stents/grafts are more frequently associated with complications. CT angiography is the gold standard diagnostic technique for preprocedural planning and postprocedural surveillance. EVAR needs long-term follow-up due to the high rate of complications. Complications can be divided in endograft device-related and systemic complications. The purpose of this article is to review the CT imaging findings of EVAR complications and the key features for the diagnosis.
Postmortem brain 7T MRI with minimally invasive pathological correlation in deceased COVID-19 subjects
Authors: Martin Maria da Graça Morais , Paes Vitor Ribeiro , Cardoso Ellison Fernando , Neto Carlos Eduardo Borges Passos , Kanamura Cristina Takami , Leite Claudia da Costa , Otaduy Maria Concepcion Garcia , Monteiro Renata Aparecida de Almeida , Mauad Thais , da Silva Luiz Fernando Ferraz , Castro Luiz Henrique Martins , Saldiva Paulo Hilario Nascimento , Dolhnikoff Marisa , Duarte-Neto Amaro Nunes 
Published: January 2022

Abstract
Background
Brain abnormalities are a concern in COVID-19, so we used minimally invasive autopsy (MIA) to investigate it, consisting of brain 7T MR and CT images and tissue sampling via transethmoidal route with at least three fragments: the first one for reverse transcription polymerase chain reaction (RT-PCR) analysis and the remaining fixed and stained with hematoxylin and eosin. Two mouse monoclonal anti-coronavirus (SARS-CoV-2) antibodies were employed in immunohistochemical (IHC) reactions.

Results
Seven deceased COVID-19 patients underwent MIA with brain MR and CT images, six of them with tissue sampling. Imaging findings included infarcts, punctate brain hemorrhagic foci, subarachnoid hemorrhage and signal abnormalities in the splenium, basal ganglia, white matter, hippocampi and posterior cortico-subcortical. Punctate brain hemorrhage was the most common finding (three out of seven cases). Brain histological analysis revealed reactive gliosis, congestion, cortical neuron eosinophilic degeneration and axonal disruption in all six cases. Other findings included edema (5 cases), discrete perivascular hemorrhages (5), cerebral small vessel disease (3), perivascular hemosiderin deposits (3), Alzheimer type II glia (3), abundant corpora amylacea (3), ischemic foci (1), periventricular encephalitis foci (1), periventricular vascular ectasia (1) and fibrin thrombi (1). SARS-CoV-2 RNA was detected with RT-PCR in 5 out of 5 and IHC in 6 out 6 patients (100%).

Conclusions
Despite limited sampling, MIA was an effective tool to evaluate underlying pathological brain changes in deceased COVID-19 patients. Imaging findings were varied, and pathological features corroborated signs of hypoxia, alterations related to systemic critically ill and SARS-CoV-2 brain invasion.
Transitory ischemic attack associated with a rare fenestration of the cervical segment of the internal carotid artery: a case report
Authors: Nasel Christian , Poetsch Angelina , Brunner Cornelia , Moser Ewald 
Published: January 2022

Abstract
Background
Fenestration of the cervical segment of the internal carotid artery is a very rare finding, and its origin is still not fully understood. Explanations of its genesis range from dissections leading to the fenestration to the more common interpretation as a developmental vascular variant. However, most reported cases were symptomatic and presented with dissections, where even endovascular treatment of the fenestration of the cervical segment of the internal carotid artery became necessary. Here we report a case of a fenestration of the cervical segment of the internal carotid artery suffering a transitory ischemic attack and local pain in absence of any sign of dissection.

Case presentation
A 62-year-old Caucasian male patient was admitted to our institution because of an episode of amaurosis fugax, initially accompanied with headache. Magnetic resonance imaging revealed an intact fenestration of the cervical segment of the internal carotid artery on the symptomatic side. With antiplatelet therapy, all symptoms vanished within 2 months of the initial event.

Conclusions
Our findings support the interpretation of a fenestration of the cervical segment of the internal carotid artery as a developmental vascular variant, but also suggest a substantial risk for dissection and ischemic stroke. Even in case of an accidental finding, clinicians should be aware of this. At least in this case, antiplatelet therapy seemed beneficial.
Engineered adipose-derived stem cells with IGF-1-modified mRNA ameliorates osteoarthritis development
Authors: Wu Haoyu , Peng Zhi , Xu Ying , Sheng Zixuan , Liu Yanshan , Liao Youguo , Wang Yin , Wen Ya , Yi Junzhi , Xie Chang , Chen Xuri , Hu Jiajie , Yan Bingqian , Wang Huijing , Yao Xudong , Fu Wei , Ouyang Hongwei 
Published: January 2022

Abstract
Background
Osteoarthritis (OA), a prevalent degenerative disease characterized by degradation of extracellular matrix (ECM), still lacks effective disease-modifying therapy. Mesenchymal stem cells (MSCs) transplantation has been regarded as the most promising approach for OA treatment while engrafting cells alone might not be adequate for effective regeneration. Genetic modification has been used to optimize MSC-based therapy; however, there are still significant limitations that prevent the clinical translation of this therapy including low efficacy and safety concerns. Recently, chemically modified mRNA (modRNA) represents a promising alternative for the gene-enhanced MSC therapy. In this regard, we hypothesized that adipose derived stem cells (ADSCs) engineered with modRNA encoding insulin-like growth factor 1 (IGF-1) were superior to native ADSCs on ameliorating OA development.

Methods
Mouse ADSCs were acquired from adipose tissue and transfected with modRNAs. First, the kinetics and efficacy of modRNA-mediated gene transfer in mouse ADSCs were analyzed in vitro. Next, we applied an indirect co-culture system to analyze the pro-anabolic potential of IGF-1 modRNA engineered ADSCs (named as IGF-1-ADSCs) on chondrocytes. Finally, we evaluated the cell retention and chondroprotective effect of IGF-1-ADSCs in vivo using fluorescent labeling, histology and immunohistochemistry.

Results
modRNA transfected mouse ADSCs with high efficiency (85 ± 5%) and the IGF-1 modRNA-transfected ADSCs facilitated burst-like production of bio-functional IGF-1 protein. In vitro, IGF-1-ADSCs induced increased anabolic markers expression of chondrocytes in inflammation environment compared to untreated ADSCs. In a murine OA model, histological and immunohistochemical analysis of knee joints harvested at 4 weeks and 8 weeks after OA induction suggested IGF-1-ADSCs had superior therapeutic effect over native ADSCs demonstrated by lower histological OARSI score and decreased loss of cartilage ECM.

Conclusions
These findings collectively supported the therapeutic potential of IGF-1-ADSCs for clinical OA management and cartilage repair.