bluuebunny/crossref_metadata_2025_split huggingface dataset:
Design and protocol of the multimorbidity and mental health cohort study in frailty and aging (MiMiCS-FRAIL): unraveling the clinical and molecular associations between frailty, somatic disease burden and late life depression
Authors: Aprahamian Ivan , Mamoni Ronei Luciano , Cervigne Nilva Karla , Augusto Taize Machado , Romanini Carla Vasconcelos , Petrella Marina , da Costa Daniele Lima , Lima Natalia Almeida , Borges Marcus K. , Oude Voshaar Richard C. 
Published: December 2020

Abstract
Background
To explore the mutual relationship between multimorbidity, mental illness and frailty, we have set-up the Multimorbidity and Mental health Cohort Study in FRAILty and Aging (MiMiCS-FRAIL) cohort. At the population level, multimorbidity, frailty and late-life depression are associated with similar adverse outcomes (i.e. falls, disability, hospitalization, death), share the same risk factors, and partly overlap in their clinical presentation. Moreover, these three variables may share a common underlying pathophysiological mechanism like immune-metabolic dysregulation. The overall objectives of MiMiCS-FRAIL are 1) to explore (determinants of) the cross-sectional and longitudinal relationship between multimorbidity, depression, and frailty among non-demented geriatric outpatients; 2) to evaluate molecular levels of senoinflammation as a broad pathophysiological process underlying these conditions; and 3) to examine adverse outcomes of multimorbidity, frailty and depression and their interconnectedness.

Methods
MiMiCS-FRAIL is an ongoing observational cohort study of geriatric outpatients in Brazil, with an extensive baseline assessment and yearly follow-up assessments. Each assessment includes a comprehensive geriatric assessment to identify multimorbidity and geriatric syndromes, a structured psychiatric diagnostic interview and administration of the PHQ-9 to measure depression, and several frailty measures (FRAIL, Physical Phenotype criteria, 36-item Frailty Index). Fasten blood samples are collected at baseline to assess circulating inflammatory and anti-inflammatory cytokines, leukocytes' subpopulations, and to perform immune-metabolic-paired miRome analyses. The primary outcome is death and secondary outcomes are the number of falls, hospital admissions, functional ability, well-being, and dementia. Assuming a 5-year mortality rate between 25 and 40% and a hazard rate varying between 1.6 and 2.3 for the primary determinants require a sample size between 136 and 711 patients to detect a statistically significant effect with a power of 80% (beta = 0.2), an alpha of 5% (0.05), and an R2 between the predictor (death) and all covariates of 0.20. Local ethical board approved this study.

Discussion
Frailty might be hypothesized as a final common pathway by which many clinical conditions like depression and chronic diseases (multimorbidity) culminate in many adverse effects. The MiMiCS-FRAIL cohort will help us to understand the interrelationship between these variables, from a clinical perspective as well as their underlying molecular signature.
The impact of COL1A1 and COL6A1 expression on hypospadias and penile curvature severity
Authors: Yuri Prahara , Gunadi  , Lestari Rahmadani Puji , Fardilla Firly Putri , Setyaningsih Wiwit Ananda Wahyu , Arfian Nur , Dachlan Ishandono 
Published: December 2020

Abstract
Background
Hypospadias, the most frequent congenital male external genitalia abnormality, is usually associated with curvature of the ventral penis, i.e. chordee. Abnormality of darto tissue has been suggested as the pathophysiology of chordees. Collagen is one of the most abundant fibrous proteins within the extracellular matrix. In this study, we determined the expression of collagen 1 (COL1A1) and COL6A1 in patients with hypospadias and associated them with the severity of penile curvature.

Methods
We included 60 children < 18 years old, consisting of 20 distal hypospadias, 20 proximal hypospadias patients, and 20 controls in our institution from 2017 – 2020. The expression of COL1A1 and COL6A1 in darto tissue was determined by reverse-transcriptase polymerase chain reaction (qPCR). The penile curvature severity was classified as mild (< 30 degrees), moderate (30–60 degrees), and severe (> 60 degrees).

Results
qPCR showed that COL1A1 and COL6A1 expression was significantly downregulated in the distal (0.88 (0.38–2.53) and 0.54 (0.16–4.35), respectively) and proximal 0.76 (0.33–2.57) and 0.57 (0.18–1.38), respectively) hypospadias groups compared to controls (1.85 (0.24–4.61) and 0.93 (0.17–4.06), respectively) with p-values of 0.024 and 0.018, respectively. Furthermore, there was a moderate correlation between COL1A1 and COL6A1 expression (r = 0.458, p < 0.0001). Interestingly, COL1A1 and COL6A1 were also significantly downregulated in the moderate and severe chordee groups compared to the mild chordee groups, with p-values of 0.003 and 0.037, respectively.

Conclusions
Aberrant COL1A1 and COL6A1 expression might affect abnormalities in darto tissue and penile curvature severity in hypospadias patients.
Google analytics of a pilot study to characterize the visitor website statistics and implicate for enrollment strategies in Medical University
Authors: Chen Szu-Chieh , Tsao Thomas Chang-Yao , Lue Ko-Huang , Tsai Yafang 
Published: December 2020

Abstract
Background
Taiwan’s colleges and universities are struggling to maintain their student enrollment rates owing to the declining fertility rate. Focusing on students in higher education programs, this study aims to analyze online behavioral patterns for university departmental websites and accordingly, suggests response strategies to increase the rate of enrollment.

Methods
We use Google Analytics to examine the websites of two departments in a medical university between February 1 and July 30, 2018. We study website patterns during the study periods for three college admission routes: STARS program, personal applications, and admission through examination and placement.

Results
Most website visitors during the three visiting date ranges for the two departments are 18–24 years. The visitor groups are mainly freshmen at the university and their parents. The homepage and Subject Credits, Course Planning, Teacher Lineup, and Certificate of Subjects were the most visited webpages. The overall number of daily page views varied by academic event.

Conclusions
University departments should enhance the presentation of featured courses on their webpage or distinguish course characteristics from those of competing departments in the curriculum to ensure clear market segmentation. In addition, departments should consider examining online data to identify suitable high schools that can be visited to attract potential students and to improve students’ willingness to choose their university.
The extended lipid panel assay: a clinically-deployed high-throughput nuclear magnetic resonance method for the simultaneous measurement of lipids and Apolipoprotein B
Authors: Garcia Erwin , Bennett Dennis W. , Connelly Margery A. , Jeyarajah Elias J. , Warf Franklin C. , Shalaurova Irina , Matyus Steven P. , Wolak-Dinsmore Justyna , Oskardmay David N. , Young Randolph M. , Sampson Maureen , Remaley Alan T. , Otvos James D. 
Published: December 2020

Abstract
Background
Standard lipid panel assays employing chemical/enzymatic methods measure total cholesterol (TC), triglycerides (TG), and high-density lipoprotein cholesterol (HDL-C), from which are calculated estimates of low-density lipoprotein cholesterol (LDL-C). These lipid measures are used universally to guide management of atherosclerotic cardiovascular disease risk. Apolipoprotein B (apoB) is generally acknowledged to be superior to LDL-C for lipid-lowering therapeutic decision-making, but apoB immunoassays are performed relatively infrequently due to the added analytic cost. The aim of this study was to develop and validate the performance of a rapid, high-throughput, reagent-less assay producing an “Extended Lipid Panel” (ELP) that includes apoB, using the Vantera® nuclear magnetic resonance (NMR) analyzer platform already deployed clinically for lipoprotein particle and other testing.

Methods
Partial least squares regression models, using as input a defined region of proton NMR spectra of plasma or serum, were created to simultaneously quantify TC, TG, HDL-C, and apoB. Large training sets (n > ~ 1000) of patient sera analyzed independently for lipids and apoB by chemical methods were employed to ensure prediction models reflect the wide lipid compositional diversity of the population. The analytical performance of the NMR ELP assay was comprehensively evaluated.

Results
Excellent agreement was demonstrated between chemically-measured and ELP assay values of TC, TG, HDL-C and apoB with correlation coefficients ranging from 0.980 to 0.997. Within-run precision studies measured using low, medium, and high level serum pools gave coefficients of variation for the 4 analytes ranging from 1.0 to 3.8% for the low, 1.0 to 1.7% for the medium, and 0.9 to 1.3% for the high pools. Corresponding values for within-lab precision over 20 days were 1.4 to 3.6%, 1.2 to 2.3%, and 1.0 to 1.9%, respectively. Independent testing at three sites over 5 days produced highly consistent assay results. No major interference was observed from 38 endogenous or exogenous substances tested.

Conclusions
Extensive assay performance evaluations validate that the NMR ELP assay is efficient, robust, and substantially equivalent to standard chemistry assays for the clinical measurement of lipids and apoB. Routine reporting of apoB alongside standard lipid measures could facilitate more widespread utilization of apoB for clinical decision-making.
NOD1/RIP2 signalling enhances the microglia-driven inflammatory response and undergoes crosstalk with inflammatory cytokines to exacerbate brain damage following intracerebral haemorrhage in mice
Authors: Wang Miao , Ye Xinchun , Hu Jinxia , Zhao Qiuchen , Lv Bingchen , Ma Weijing , Wang Weiwei , Yin Hanhan , Hao Qi , Zhou Chao , Zhang Tao , Wu Weifeng , Wang Yan , Zhou Mingyue , Zhang Cong-hui , Cui Guiyun 
Published: December 2020

Abstract
Background
Secondary brain damage caused by the innate immune response and subsequent proinflammatory factor production is a major factor contributing to the high mortality of intracerebral haemorrhage (ICH). Nucleotide-binding oligomerization domain 1 (NOD1)/receptor-interacting protein 2 (RIP2) signalling has been reported to participate in the innate immune response and inflammatory response. Therefore, we investigated the role of NOD1/RIP2 signalling in mice with collagenase-induced ICH and in cultured primary microglia challenged with hemin.

Methods
Adult male C57BL/6 mice were subjected to collagenase for induction of ICH model in vivo. Cultured primary microglia and BV2 microglial cells (microglial cell line) challenged with hemin aimed to simulate the ICH model in vitro. We first defined the expression of NOD1 and RIP2 in vivo and in vitro using an ICH model by western blotting. The effect of NOD1/RIP2 signalling on ICH-induced brain injury volume, neurological deficits, brain oedema, and microglial activation were assessed following intraventricular injection of either ML130 (a NOD1 inhibitor) or GSK583 (a RIP2 inhibitor). In addition, levels of JNK/P38 MAPK, IκBα, and inflammatory factors, including tumour necrosis factor-α (TNF-α), interleukin (IL)-1β, and inducible nitric oxide synthase (iNOS) expression, were analysed in ICH-challenged brain and hemin-exposed cultured primary microglia by western blotting. Finally, we investigated whether the inflammatory factors could undergo crosstalk with NOD1 and RIP2.

Results
The levels of NOD1 and its adaptor RIP2 were significantly elevated in the brains of mice in response to ICH and in cultured primary microglia, BV2 cells challenged with hemin. Administration of either a NOD1 or RIP2 inhibitor in mice with ICH prevented microglial activation and neuroinflammation, followed by alleviation of ICH-induced brain damage. Interestingly, the inflammatory factors interleukin (IL)-1β and tumour necrosis factor-α (TNF-α), which were enhanced by NOD1/RIP2 signalling, were found to contribute to the NOD1 and RIP2 upregulation in our study.

Conclusion
NOD1/RIP2 signalling played an important role in the regulation of the inflammatory response during ICH. In addition, a vicious feedback cycle was observed between NOD1/RIP2 and IL-1β/TNF-α, which could to some extent result in sustained brain damage during ICH. Hence, our study highlights NOD1/RIP2 signalling as a potential therapeutic target to protect the brain against secondary brain damage during ICH.
Prophylactic inhibition of NF-κB expression in microglia leads to attenuation of hypoxic ischemic injury of the immature brain
Authors: Zaghloul Nahla , Kurepa Dalibor , Bader Mohammad Y. , Nagy Nadia , Ahmed Mohamed N. 
Published: December 2020

AbstractBackgroundPeriventricular leukomalacia (PVL), a devastating brain injury affecting premature infants, is the most common cause of cerebral palsy. PVL is caused by hypoxia ischemia (HI) and is characterized by white matter necrotic lesions, microglial activation, upregulation of NF-κB, and neuronal death. The microglia is the main cell involved in PVL pathogenesis. The goal of this study was to investigate the role of microglial NF-κB activity and its prophylactic inhibition in a neonate mouse model of HI.MethodsTransgenic mice with specific knockout NF-κB in microglia and colony stimulating factor 1 receptor Cre with floxed IKKβ (CSF-1R Cre + IKKβflox/wt) were used. Postnatal day 5 (P5) mice underwent sham or bilateral temporary carotid artery ligation followed by hypoxia. After HI insult, inflammatory cytokines, volumetric MRI, histopathology, and immunohistochemistry for oligodendroglia and microglial activation markers were analyzed. Long-term neurobehavioral assessment, including grip strength, rotarod, and open field testing, was performed at P60.ResultsWe demonstrate that selective inhibition of NF-κB in microglia decreases HI-induced brain injury by decreasing microglial activation, proinflammatory cytokines, and nitrative stress. Rescue of oligodendroglia is evidenced by immunohistochemistry, decreased ventriculomegaly on MRI, and histopathology. This selective inhibition leads to attenuation of paresis, incoordination, and improved grip strength, gait, and locomotion.ConclusionWe conclude that NF-κb activation in microglia plays a major role in the pathogenesis of hypoxic ischemic injury of the immature brain, and its prophylactic inhibition offers significant neuroprotection. Using a specific inhibitor of microglial NF-κB may offer a new prophylactic or therapeutic alternative in preterm infants affected by HI and possibly other neurological diseases in which microglial activation plays a role.
Deficiency of Nrf2 exacerbates white matter damage and microglia/macrophage levels in a mouse model of vascular cognitive impairment
Authors: Sigfridsson Emma , Marangoni Martina , Hardingham Giles E. , Horsburgh Karen , Fowler Jill H. 
Published: December 2020

Abstract
Background
Chronic cerebral hypoperfusion causes damage to the brain’s white matter underpinning vascular cognitive impairment. Inflammation and oxidative stress have been proposed as key pathophysiological mechanisms of which the transcription factor Nrf2 is a master regulator. We hypothesised that white matter pathology, microgliosis, blood-brain barrier breakdown and behavioural deficits induced by chronic hypoperfusion would be exacerbated in mice deficient in the transcription factor Nrf2.

Methods
Mice deficient in Nrf2 (male heterozygote or homozygous for Nrf2 knockout) or wild-type littermates on a C57Bl6/J background underwent bilateral carotid artery stenosis (BCAS) to induce chronic cerebral hypoperfusion or sham surgery and survived for a further 6 weeks. White matter pathology was assessed with MAG immunohistochemistry as a marker of altered axon-glial integrity; alterations to astrocytes and microglia/macrophages were assessed with GFAP and Iba1 immunohistochemistry, and blood-brain barrier breakdown was assessed with IgG immunohistochemistry. Behavioural alterations were assessed using 8-arm radial arm maze, and alterations to Nrf2-related and inflammatory-related genes were assessed with qRT-PCR.

Results
Chronic cerebral hypoperfusion induced white matter pathology, elevated microglial/macrophage levels and blood-brain barrier breakdown in white matter tracts that were increased in Nrf2+/− mice and further exacerbated by the complete absence of Nrf2. Chronic hypoperfusion induced white matter astrogliosis and induced an impairment in behaviour assessed with radial arm maze; however, these measures were not affected by Nrf2 deficiency. Although Nrf2-related antioxidant gene expression was not altered by chronic cerebral hypoperfusion, there was evidence for elevated pro-inflammatory related gene expression following chronic hypoperfusion that was not affected by Nrf2 deficiency.

Conclusions
The results demonstrate that the absence of Nrf2 exacerbates white matter pathology and microgliosis following cerebral hypoperfusion but does not affect behavioural impairment.
Laboratory versus daily life gait characteristics in patients with multiple sclerosis, Parkinson’s disease, and matched controls
Authors: Shah Vrutangkumar V. , McNames James , Mancini Martina , Carlson-Kuhta Patricia , Spain Rebecca I. , Nutt John G. , El-Gohary Mahmoud , Curtze Carolin , Horak Fay B. 
Published: December 2020

Abstract
Background and purpose
Recent findings suggest that a gait assessment at a discrete moment in a clinic or laboratory setting may not reflect functional, everyday mobility. As a step towards better understanding gait during daily life in neurological populations, we compared gait measures that best discriminated people with multiple sclerosis (MS) and people with Parkinson’s Disease (PD) from their respective, age-matched, healthy control subjects (MS-Ctl, PD-Ctl) in laboratory tests versus a week of daily life monitoring.

Methods
We recruited 15 people with MS (age mean ± SD: 49 ± 10 years), 16 MS-Ctl (45 ± 11 years), 16 people with idiopathic PD (71 ± 5 years), and 15 PD-Ctl (69 ± 7 years). Subjects wore 3 inertial sensors (one each foot and lower back) in the laboratory followed by 7 days during daily life. Mann–Whitney U test and area under the curve (AUC) compared differences between PD and PD-Ctl, and between MS and MS-Ctl in the laboratory and in daily life.

Results
Participants wore sensors for 60–68 h in daily life. Measures that best discriminated gait characteristics in people with MS and PD from their respective control groups were different between the laboratory gait test and a week of daily life. Specifically, the toe-off angle best discriminated MS versus MS-Ctl in the laboratory (AUC [95% CI] = 0.80 [0.63–0.96]) whereas gait speed in daily life (AUC = 0.84 [0.69–1.00]). In contrast, the lumbar coronal range of motion best discriminated PD versus PD-Ctl in the laboratory (AUC = 0.78 [0.59–0.96]) whereas foot-strike angle in daily life (AUC = 0.84 [0.70–0.98]). AUCs were larger in daily life compared to the laboratory.

Conclusions
Larger AUC for daily life gait measures compared to the laboratory gait measures suggest that daily life monitoring may be more sensitive to impairments from neurological disease, but each neurological disease may require different gait outcome measures.
Advancing clinical leadership to improve the implementation of evidence-based practice in surgery: a longitudinal mixed-method study protocol
Authors: Grove Amy , Clarke Aileen , Currie Graeme , Metcalfe Andy , Pope Catherine , Seers Kate 
Published: December 2020

Abstract
Background
Clinical leadership is fundamental in facilitating service improvements in healthcare. Few studies have attempted to understand or model the different approaches to leadership which are used when promoting the uptake and implementation of evidence-based interventions. This research aims to uncover and explain how distributed clinical leadership can be developed and improved to enhance the use of evidence in practice. In doing so, this study examines implementation leadership in orthopaedic surgery to explain leadership as a collective endeavour which cannot be separated from the organisational context.

Methods
A mixed-method study consisting of longitudinal and cross-sectional interviews and an embedded social network analysis will be performed in six NHS hospitals. A social network analysis will be undertaken in each hospital to uncover the organisational networks, the focal leadership actors and information flows in each organisation. This will be followed by a series of repeated semi-structured interviews, conducted over 4 years, with orthopaedic surgeons and their professional networks. These longitudinal interviews will be supplemented by cross-sectional interviews with the national established surgical leaders. All qualitative data will be analysed using a constructivist grounded theory approach and integrated with the quantitative data. The participant narratives will enrich the social network to uncover the leadership configurations which exist, and how different configurations of leadership are functioning in practice to influence implementation processes and outcomes.

Discussion
The study findings will facilitate understanding about how and why different configurations of leadership develop and under what organisational conditions and circumstances they are able to flourish. The study will guide the development of leadership interventions that are grounded in the data and aimed at advancing leadership for service improvement in orthopaedics. The strength of the study lies in the combination of multi-component, multi-site, multi-agent methods to examine leadership processes in surgery. The findings may be limited by the practical challenges of longitudinal qualitative data collection, such as ensuring participant retention, which need to be balanced against the theoretical and empirical insights generated through this comprehensive exploration of leadership across and within a range of healthcare organisations.