bluuebunny/crossref_metadata_2025_split huggingface dataset:
Optimising the dose of clonidine to achieve sedation in intensive care unit patients with population pharmacokinetics
Authors: Cloesmeijer Michael E. , van den Oever Huub L.A. , Mathôt Ron A.A. , Zeeman Marieke , Kruisdijk‐Gerritsen Arriette , Bles Carmen M.A. , Nassikovker Polina , de Meijer Arthur R. , van Steveninck Fred L. , Arbouw Maurits E.L. 
Published: March 2020

AimsThe aim of this study was to investigate the population pharmacokinetics (PK) of clonidine in intensive care unit (ICU) patients in order to develop a dosing regimen for sedation.MethodsWe included 24 adult mechanically ventilated, sedated patients from a mixed medical and surgical ICU. Intravenous clonidine was added to standard sedation in doses of 600, 1200 or 1800 μg/d. Within each treatment group, 4 patients received a loading dose of half the daily dose administered in 4 hours. Patients gave an average of 12 samples per individual. In total, 286 samples were available for analysis. Model development was conducted with NONMEM and various covariates were tested. After modelling, doses to achieve a target steady‐state plasma concentration of >1.5 μg/L were explored using stochastic Monte Carlo simulations for 1000 virtual patients.ResultsA 2‐compartment model was the best fit for the concentration‐time data. Clearance (CL) increased linearly with 0.213%/h; using allometric scaling, body weight was a significant covariate on the central volume of distribution (V1). Population PK parameters were: CL 17.1 (L/h), V1 124 (L/70 kg), intercompartmental CL 83.7 (L/h), and peripheral volume of distribution 178 (L), with 33.3% CV interindividual variability on CL and 66.8% CV interindividual variability on V1. Simulations revealed that a maintenance dose of 1200 μg/d provides target sedation concentrations of >1.5 μg/L in 95% of the patients.ConclusionA population PK model for clonidine was developed in an adult ICU. A dosing regimen of 1200 μg/d provided a target sedation concentration of >1.5 μg/L.
Ensemble clustering for step data via binning
Authors: Jang Ja‐Yoon , Oh Hee‐Seok , Lim Yaeji , Cheung Ying Kuen 
Published: March 2020

AbstractThis paper considers the clustering problem of physical step count data recorded on wearable devices. Clustering step data give an insight into an individual's activity status and further provide the groundwork for health‐related policies. However, classical methods, such as K‐means clustering and hierarchical clustering, are not suitable for step count data that are typically high‐dimensional and zero‐inflated. This paper presents a new clustering method for step data based on a novel combination of ensemble clustering and binning. We first construct multiple sets of binned data by changing the size and starting position of the bin, and then merge the clustering results from the binned data using a voting method. The advantage of binning, as a critical component, is that it substantially reduces the dimension of the original data while preserving the essential characteristics of the data. As a result, combining clustering results from multiple binned data can provide an improved clustering result that reflects both local and global structures of the data. Simulation studies and real data analysis were carried out to evaluate the empirical performance of the proposed method and demonstrate its general utility.
The UK NCRI study of chlorambucil, mitoxantrone and dexamethasone (CMD) versus fludarabine, mitoxantrone and dexamethasone (FMD) for untreated advanced stage follicular lymphoma: molecular response strongly predicts prolonged overall survival
Authors: Bishton Mark J. , Rule Simon , Wilson William , Turner Deborah , Patmore Russell , Clifton‐Hadley Laura , McMillan Andrew , Lush Richard , Haynes Andrew 
Published: March 2020

SummaryWe present a long‐term follow‐up of the UK chlorambucil, mitoxantrone and dexamethasone (CMD) versus fludarabine, mitoxantrone and dexamethasone (FMD) for untreated advanced, symptomatic follicular lymphoma (FL). This trial was the first to prospectively assess molecular response and the impact on outcomes for 400 patients. The median progression‐free survival (PFS) and overall survival (OS) for CMD were 3·6 and 14·6 years vs. 3·0 and 15·7 years for FMD, respectively. Estimates for Restricted Mean Survival Time (RMST) suggested no difference in PFS or OS. For the whole cohort there was a highly significant difference in survival by POD24, with a median OS from a risk‐defining event of 3·9 years compared to 13·7 years for all others (RMST P < 0·001). Molecular remission was achieved in 25/46 patients (54·3%) in the CMD arm and 20/41 (48·8%) in the FMD arm (P = 0·6). Molecular negativity resulted in median PFS of 5·6 years vs. 2·3 years for molecularly positive (log‐rank P < 0·001) and median OS not reached versus 12·5 years (log‐rank P < 0·01). No cases of progression occurred in minimal residual disease (MRD) negative patients after six years of follow‐up. Although there was no difference in outcomes between arms, this is the first prospective study to report MRD negativity resulting in significantly improved OS.
Bortezomib maintenance after R‐CHOP, cytarabine and autologous stem cell transplantation in newly diagnosed patients with mantle cell lymphoma, results of a randomised phase II HOVON trial
Authors: Doorduijn Jeanette K. , Zijlstra Josee M. , Lugtenburg Pieternella J. , Kersten Marie Josee , Böhmer Lara H. , Minnema Monique C. , MacKenzie Marius A. , van Marwijk Kooij Rien , de Jongh Eva , Snijders Tjeerd J.F. , de Weerdt Okke , van Gelder Michel , Hoogendoorn Mels , Leys Rineke B.L. , Kibbelaar Robby E. , de Jong Daphne , Chitu Dana A. , Van’t Veer Mars B. , Kluin‐Nelemans Hanneke C. 
Published: March 2020

AbstractRituximab‐containing induction followed by autologous stem cell transplantation (ASCT) is the standard first‐line treatment for young mantle cell lymphoma patients. However, most patients relapse after ASCT. We investigated in a randomised phase II study the outcome of a chemo‐immuno regimen and ASCT with or without maintenance therapy with bortezomib. Induction consisted of three cycles R‐CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone), two cycles high‐dose cytarabine, BEAM (carmustine, etoposide, cytarabine, melphalan) and ASCT. Patients responding were randomised between bortezomib maintenance (1·3 mg/m2 intravenously once every 2 weeks, for 2 years) and observation. Of 135 eligible patients, 115 (85%) proceeded to ASCT, 60 (44%) were randomised. With a median follow‐up of 77·5 months for patients still alive, 5‐year event‐free survival (EFS) was 51% (95% CI 42–59%); 5‐year overall survival (OS) was 73% (95% CI 65–80%). The median follow‐up of randomised patients still alive was 71·5 months. Patients with bortezomib maintenance had a 5‐year EFS of 63% (95% CI 44–78%) and 5‐year OS of 90% (95% CI 72–97%). The patients randomised to observation had 5‐year PFS of 60% (95% CI, 40–75%) and OS of 90% (95% CI 72–97%). In conclusion, in this phase II study we found no indication of a positive effect of bortezomib maintenance after ASCT.
SafeSpot: an innovative app and mental health support package for Scottish schools – a qualitative analysis as part of a mixed methods study
Authors: Punukollu Mallika , Leighton Emma L. , Brooks Anna F. , Heron Saoirse , Mitchell Fiona , Regener Paula , Karagiorgou Olga , Bell Caitlin , Gilmour Mhairi , Moya Nasreen , Sharpe Helen , Minnis Helen 
Published: March 2020

AimsThe aim of the study was to investigate teachers’ and pupils’ perceptions about the effect of the SafeSpot mental health curriculum on the well‐being of young people and on their knowledge of mental health conditions. This trial intends to determine the acceptability and benefits of web and mobile technology in delivering emotional well‐being in schools, through use of the SafeSpot programme.BackgroundWith 10% of young people aged 5 to 16 diagnosed with a mental disorder, there is pressure for schools to address their pupils’ emotional well‐being. However, many educators report that their schools have insufficient provisions and feel inadequately equipped to support pupils’ mental health.MethodsThis qualitative analysis was embedded within a randomly allocated stepped‐wedge design, conducted in six West of Scotland secondary schools. A total of 2320 pupils (aged 11 to 14 years) and 90 teachers were included. Young people’s understanding of health‐seeking, and teacher’s confidence in delivering and accessing well‐being information was assessed qualitatively.ResultsQualitative analysis revealed themes highlighting the beneficial nature of SafeSpot, including pupil engagement, content of tutorials, perceived impact of SafeSpot and level of training provided for teachers.ConclusionsWeb technology could potentially offer a more structured way for staff to support their pupils’ mental health, whilst reducing stigma. SafeSpot was perceived, by pupils and teachers, to be engaging.
Design and synthesis of a novel peptide for selective detection of cancer cells
Authors: Rajavenkatesh Krishnamoorthy , Padmaja Murali , Janani Indrakumar , Aishwarya Satish , Purna Sai Korrapati , Thennarasu Sathiah 
Published: March 2020

AbstractUsing a minimalist approach, an 11‐residue peptide (Peptide 1) tagged with rhodamine fluorophore was designed and synthesized for selective detection of cancer cells. Peptide 1 contains RGD and NGR motifs to bind, respectively, integrins and aminopeptidase CD13, which are over expressed in cancer cells. Surface tension measurements revealed that peptide 1 possess surface‐active property owing to the overall hydrophobicity and cationic nature of the peptide. Peptide 1 displays cancer cell‐selective binding at ≤5.0 µM concentrations, while peptide 2 (randomized sequence of 1) shows non‐selective binding to normal and cancer cells. Fluorescence microscopy and FACS analysis demonstrated the intracellular localization of peptide 1 in three different cancer cell lines, confirming the role of RGD and NGR motifs. Cytotoxicity assay exhibited the viability of normal and cancer cells up to 100 µM concentrations of peptide 1. Steady‐state fluorescence measurements disclosed the preferential interactions of the peptide 1 with anionic POPC/POPG bilayers rather than with zwitterionic POPC lipid bilayers. Circular dichroism studies showed minimal changes in the secondary structure of peptide 1 upon binding with the anionic lipid bilayers. Peptide 1 is largely unordered, non‐toxic, and useful for identification of cancer cells. Peptide 1 provides a template for designing drug‐loaded peptides for targeted delivery into cancer cells.
A systematic review of the incidence of thyroid carcinoma in patients undergoing thyroidectomy for thyrotoxicosis
Authors: Varadharajan Kiran , Choudhury Natasha 
Published: March 2020

AbstractIntroductionHyperthyroidism (HT) has been associated with no insignificant rates of thyroid malignancy. There are no current specific guidelines that suggest routine preoperative imaging for thyroid nodules in patients with Grave's disease. We therefore performed a systematic review assessing rates of thyroid malignancy in patients undergoing surgery for different causes of HT: Grave's disease (GD), toxic adenoma (TA) and toxic multinodular goitre (TMNG).MethodsMajor databases (MEDLINE, PubMed and the Cochrane library) were searched to identify eligible studies.ResultsAfter searching and appraising, 33 papers were found to be eligible for analysis. The mean overall rate of malignancy was 8.5% (range 0.8%‐32.4%). The mean rates based on histological subtype were as follows: papillary thyroid cancer (PTC), 3.1% (range 0%‐13.2%); micropapillary carcinoma (mPTC), 5.1% (range 0%‐16.9%); and follicular thyroid cancer (FTC), 0.8% (range 0%‐4.4%). In those patients who had preoperative imaging, mean malignancy rates were higher in patients with pre‐identified nodules (19.8%) compared to those without any nodules (8.7%). Mean rates were lower in patients with GD/diffuse goitre (5.9%) compared to patients with TA (6.5%) and TMNG (12%).ConclusionHyperthyroidism is associated with notable rates of thyroid cancer, although the mechanisms for this are not clear. The presence of nodules increases this risk. This review raises the question for considering preoperative assessment of nodules in all patients undergoing surgery for HT, in order to correctly assess and evaluate any patients with suspected concurrent thyroid malignancy, before proceeding with surgery.
Impact of middle hepatic artery reconstruction after living donor liver transplantation using the left lobe
Authors: Harada Noboru , Yoshizumi Tomoharu , Uchiyama Hideaki , Ikegami Toru , Itoh Shinji , Takeishi Kazuki , Toshima Takeo , Nagao Yoshihiro , Yoshiya Shohei , Mori Masaki 
Published: March 2020

AbstractIntroductionThe aim of this study was to clarify the impact of middle hepatic artery reconstruction on the outcomes of duct‐to‐duct biliary anastomosis after living donor liver transplantation (LDLT) using the left lobe.Materials and MethodsAmong 258 patients who underwent LDLT using the left lobe, 216 patients who underwent hepatic artery reconstruction and one hepatic duct reconstruction with duct‐to‐duct interrupted anastomosis were divided into three groups: Group A (n = 123), one arterial stump with left hepatic artery reconstruction; Group B (n = 32), two arterial stumps with only left hepatic artery reconstruction; and Group C (n = 61), two arterial stumps with reconstruction of the left and middle hepatic arteries. The outcomes after LDLT were compared among the three groups.ResultsNo hepatic artery complications occurred. Group B had a significantly greater incidence of anastomotic biliary stricture than Group C. A multivariate analysis with Cox regression revealed that being in Group B was the only significant independent risk factor for postoperative anastomotic biliary stricture after LDLT.ConclusionsMiddle and left hepatic artery reconstruction is safe in LDLT and may prevent biliary stricture caused by dual hepatic artery reconstruction when the graft has left and middle hepatic artery stumps.
Developmental outcomes after early surgery for complex congenital heart disease: a systematic review and meta‐analysis
Authors: Huisenga Darlene , La Bastide‐Van Gemert Sacha , Van Bergen Andrew , Sweeney Jane , Hadders‐Algra Mijna 
Published: March 2020

Aim(1) To systematically review the literature on developmental outcomes from infancy to adolescence of children with complex congenital heart disease (CHD) who underwent early surgery; (2) to run a meta‐regression analysis on the Bayley Scales of Infant Development, Second Edition Mental Developmental Index and Psychomotor Developmental Index (PDI) of infants up to 24 months and IQs of preschool‐aged children to adolescents; (3) to assess associations between perioperative risk factors and outcomes.MethodWe searched pertinent literature (January 1990 to January 2019) in PubMed, Embase, CINAHL, and PsycINFO. Selection criteria included infants with complex CHD who had primary surgery within the first 9 weeks of life. Methodological quality, including risk of bias and internal validity, were assessed.ResultsIn total, 185 papers met the inclusion criteria; the 100 with high to moderate methodological quality were analysed in detail. Substantial heterogeneity in the group with CHD and in methodology existed. The outcome of infants with single‐ventricle CHD was inferior to those with two‐ventricle CHD (respectively: average scores for PDI 77 and 88; intelligence scores 92 and 98). Perioperative risk factors were inconsistently associated with developmental outcomes.InterpretationThe literature on children undergoing surgery in early infancy suggests that infants with a single ventricle are at highest risk of adverse developmental outcomes.What this paper adds

Children with complex congenital heart disease (CHD) are at increased risk of impaired developmental outcome.

Children with single‐ventricle CHD have worse outcomes than children with two‐ventricle CHD.

Children with two‐ventricle CHD gradually grow out of their initial developmental impairment.

Perioperative factors are inconsistently associated with outcome.
Modulation of respiratory network activity by forelimb and hindlimb locomotor generators
Authors: Le Gal Jean‐Patrick , Colnot Eloïse , Cardoit Laura , Bacqué-Cazenave Julien , Thoby‐Brisson Muriel , Juvin Laurent , Morin Didier 
Published: March 2020

AbstractEarly at the onset of exercise, breathing rate accelerates in order to anticipate the increasing metabolic demand resulting from the extra effort produced. Accordingly, the respiratory neural networks are the target of various input signals originating either centrally or peripherally. For example, during locomotion, the activation of muscle sensory afferents is able to entrain and thereby increase the frequency of spontaneous respiratory rhythmogenesis. Moreover, the lumbar spinal networks engaged in generating hindlimb locomotor rhythms are also capable of activating the medullary respiratory generators through an ascending excitatory command. However, in the context of quadrupedal locomotion, the influence of other spinal cord regions, such as cervical and thoracic segments, remains unknown. Using isolated brainstem‐spinal cord preparations from neonatal rats and mice, we show that cervicothoracic circuitry may also contribute to locomotion‐induced acceleration of respiratory cycle frequency. As previously observed for the hindlimb CPGs, the pharmacological activation of forelimb locomotor networks produces episodes of fictive locomotion that in turn increase the ongoing respiratory rhythm. Thoracic neuronal circuitry may also participate indirectly in this modulation via the activation of both cervical and lumbar CPG neurons. Furthermore, using light stimulation of CHR2‐expressing glutamatergic neurons, we found that the modulation of the respiratory rate during locomotion involves lumbar glutamatergic circuitry. Our results demonstrate that during locomotion, the respiratory rhythm‐generating networks receive excitatory ascending inputs from the spinal circuits responsible for generating and coordinating fore‐ and hindlimb movements. This constitutes a distributed central mechanism that contributes to matching breathing rate to the speed of locomotion.
Uric acid level and risk of symptomatic intracranial haemorrhage in ischaemic stroke treated with endovascular treatment
Authors: Yuan K. , Zhang X. , Chen J. , Li S. , Yang D. , Xie Y. , Xia Y. , Wu M. , Wang H. , Xu G. , Liu X. 
Published: March 2020

Background and purposeThere are limited data on the association between uric acid (UA) and symptomatic intracranial haemorrhage (SICH) in patients who have undergone mechanical thrombectomy [endovascular treatment (EVT)]. In the present study, we aimed to investigate the role of serum UA level in SICH after EVT in a real‐world practice.MethodsPatients were selected from the Endovascular Treatment for Acute Anterior Circulation Ischemic Stroke (ACTUAL) registry. SICH was identified using the Heidelberg Bleeding Classification. Multivariable logistic regression analysis was performed to explore the relationship between serum UA and SICH.ResultsAmong 611 enrolled patients, 90 (14.7%) were diagnosed with SICH within 72 h after EVT. Patients with SICH had a significantly higher level of serum UA (median, 341.0 vs. 302.0 μmol/L; P = 0.003) than those without SICH. Univariate logistic regression analysis indicated that patients with UA levels in the fourth quartile, compared with the first quartile, were more likely to have SICH (odds ratio, 2.846; 95% confidence intervals, 1.429–6.003; P = 0.003). The association remained significant after multivariable adjustment for potential confounders. Furthermore, the multiple‐adjusted spline regression model showed an inverted U‐shaped association between UA and SICH (P = 0.047 for non‐linearity).ConclusionOur study indicated that increased serum UA level was independently associated with SICH after EVT in acute ischaemic stroke.
A longitudinal study on α‐synuclein in plasma neuronal exosomes as a biomarker for Parkinson’s disease development and progression
Authors: Niu M. , Li Y. , Li G. , Zhou L. , Luo N. , Yao M. , Kang W. , Liu J. 
Published: March 2020

Background and purposeThe identification of reliable diagnostic and prognostic biomarkers for Parkinson's disease (PD) is urgently needed. Here, we explored the potential use of α‐synuclein (α‐syn) in plasma neuronal exosomes as a biomarker for early PD diagnosis and disease progression.MethodsThis study included both cross‐sectional and longitudinal designs. The subjects included 36 patients with early‐stage PD, 17 patients with advanced PD, 20 patients with idiopathic rapid eye movement sleep behavior disorder and 21 healthy controls (HCs). α‐syn levels were measured by electrochemiluminescence immunoassay. A subgroup of patients with early‐stage PD (n = 18) participated in a follow‐up examination with repeated blood collection and clinical assessments after an average of 22 months.ResultsThe α‐syn levels in plasma neuronal exosomes were significantly higher in patients with early‐stage PD compared with HCs (P = 0.007). Differences in α‐syn levels between patients with idiopathic rapid eye movement sleep behavior disorder and HCs did not reach statistical significance (P = 0.08). In addition, Spearman correlation analysis revealed that neuronal exosomal α‐syn concentrations were correlated with Movement Disorders Society Unified Parkinson's Disease Rating Scale III/(I + II + III) scores, Non‐Motor Symptom Questionnaire scores and Sniffin' Sticks 16‐item test scores of patients with PD (P < 0.05). After a mean follow‐up of 22 months in patients with early‐stage PD, a Cox regression analysis adjusted for age and gender showed that longitudinally increased α‐syn rather than baseline α‐syn levels were associated with higher risk for motor symptom progression in PD (P = 0.039).ConclusionsOur results suggested that α‐syn in plasma neuronal exosomes may serve as a biomarker to aid early diagnosis of PD and also as a prognostic marker for PD progression.
The development of oral ability in L2 Spanish by English‐home language learners in a TWI program
Authors: Ruiz‐Funes Marcela T. 
Published: March 2020

AbstractThis study reports on a small‐scale, longitudinal investigation on L2 Spanish oral development by English‐home language (EHL) learners in an English/Spanish Two‐Way Immersion (TWI) program in rural, eastern United States. It examined EHL learners' oral ability in L2 Spanish based on longitudinal assessment data from Kindergarten, Grade 2, and Grade 5 in two ways: (a) ratings of students' speech samples and (b) linguistic analysis of the speech samples. Ratings of the students' speech samples were elicited with the SOPA/COPE rating scale and the FLOSEM. In addition, linguistic analyses of the speech samples were performed quantitatively and qualitatively. Findings indicate steady progress from one grade level to the next, along with a marked use of codemixing in Grades 2 and 5. This article provides empirical evidence to inform curriculum design, identify areas in need of future research, and reexamine L2 oral assessment tools.