bluuebunny/crossref_metadata_2025 huggingface dataset:
Effect of early versus standard central line removal on growth of very low birthweight premature infants: a protocol for a non-inferiority randomised controlled trial
Authors: Romańska Justyna , Margas Wojciech , Bokiniec Renata , Krajewski Paweł , Seliga-Siwecka Joanna
Published: September 2019

Introduction

Uncertainty exists regarding the optimal time for removal of central lines used to provide parenteral nutrition in preterm infants. The aim of this study is to determine whether earlier central line removal is non-inferior to its removal after reaching full enteral intake, in respect to growth outcome of preterm infants.

Methods and analysis

Very low birthweight premature infants will be recruited. Eligible infants will be randomised in equal proportions between two groups. In the intervention group central lines will be removed when infants reach 100 mL/kg/day of enteral intake. In the control group central lines will be removed when infants reach 140 mL/kg/day of enteral intake (full enteral intake). The primary outcome measure will be the difference between the two groups in weight at 36 weeks’ postmenstrual age. Non-inferiority will be declared if the mean weight of children in the intervention group will be no worse than the mean weight of children from the control group, by a margin of −210 g.

Ethics and dissemination

The Bioethics Committee of the Medical University of Warsaw approved the study protocol prior to recruitment. The findings of this trial will be submitted to a peer-reviewed journal (neonatology, paediatrics or nutrition). Abstracts will be submitted to relevant national and international conferences.

Trial registration number

NCT03730883.

Protocol version

Version 3. 14.08.2019.
Health economic assessment of a scenario to promote bicycling as active transport in Stockholm, Sweden
Authors: Kriit Hedi Katre , Williams Jennifer Stewart , Lindholm Lars , Forsberg Bertil , Nilsson Sommar Johan
Published: September 2019

Objectives

To conduct a health economic evaluation of a proposed investment in urban bicycle infrastructure in Stockholm County, Sweden.

Design

A cost-effectiveness analysis is undertaken from a healthcare perspective. Investment costs over a 50-year life cycle are offset by averted healthcare costs and compared with estimated long-term impacts on morbidity, quantified in disability-adjusted life years (DALYs). The results are re-calculated under different assumptions to model the effects of uncertainty.

Setting

The Municipality of Stockholm (population 2.27 million) committed funds for bicycle path infrastructure with the aim of achieving a 15% increase in the number of bicycle commuters by 2030. This work is based on a previously constructed scenario, in which individual registry data on home and work address and a transport model allocation to different modes of transport identified 111 487 individuals with the physical capacity to bicycle to work within 30 min but that currently drive a car to work.

Results

Morbidity impacts and healthcare costs attributed to increased physical activity, change in air pollution exposure and accident risk are quantified under the scenario. The largest reduction in healthcare costs is attributed to increased physical activity and the second largest to reduced air pollution exposure among the population of Greater Stockholm. The expected net benefit from the investment is 8.7% of the 2017 Stockholm County healthcare budget, and 3.7% after discounting. The economic evaluation estimates that the intervention is cost-effective and each DALY averted gives a surplus of €9933. The results remained robust under varied assumptions pertaining to reduced numbers of additional bicycle commuters.

Conclusion

Investing in urban infrastructure to increase bicycling as active transport is cost-effective from a healthcare sector perspective.
Comparing docosahexaenoic acid (DHA) concomitant with neoadjuvant chemotherapy versus neoadjuvant chemotherapy alone in the treatment of breast cancer (DHA WIN): protocol of a double-blind, phase II, randomised controlled trial
Authors: Newell Marnie , Mackey John R , Bigras Gilbert , Alvarez-Camacho Mirey , Goruk Susan , Ghosh Sunita , Schmidt Alison , Miede Deborah , Chisotti Ann , Postovit Lynne , Baker Kristi , Mazurak Vera , Courneya Kerry , Berendt Richard , Dong Wei-Feng , Wood George , Basi Sanraj K , Joy Anil Abraham , King Karen , Meza-Junco Judith , Zhu Xiaofu , Field Catherine
Published: September 2019

Introduction

Neoadjuvant chemotherapy for breast cancer treatment is prescribed to facilitate surgery and provide confirmation of drug-sensitive disease, and the achievement of pathological complete response (pCR) predicts improved long-term outcomes. Docosahexaenoic acid (DHA) has been shown to reduce tumour growth in preclinical models when combined with chemotherapy and is known to beneficially modulate systemic immune function. The purpose of this trial is to investigate the benefit of DHA supplementation in combination with neoadjuvant chemotherapy in patients with breast cancer.

Methods and analysis

This is a double-blind, phase II, randomised controlled trial of 52 women prescribed neoadjuvant chemotherapy to test if DHA supplementation enhances chemotherapy efficacy. The DHA supplementation group will take 4.4 g/day DHA orally, and the placebo group will take an equal fat supplement of vegetable oil. The primary outcome will be change in Ki67 labelling index from prechemotherapy core needle biopsy to definitive surgical specimen. The secondary endpoints include assessment of (1) DHA plasma phospholipid content; (2) systemic immune cell types, plasma cytokines and inflammatory markers; (3) tumour markers for apoptosis and tumour infiltrating lymphocytes; (4) rate of pCR in breast and in axillary nodes; (5) frequency of grade 3 and 4 chemotherapy-associated toxicities; and (6) patient-perceived quality of life. The trial has 81% power to detect a significant between-group difference in Ki67 index with a two-sided t-test of less than 0.0497, and accounts for 10% dropout rate.

Ethics and dissemination

This study has full approval from the Health Research Ethics Board of Alberta - Cancer Committee (Protocol #: HREBA.CC-18-0381). We expect to present the findings of this study to the scientific community in peer-reviewed journals and at conferences. The results of this study will provide evidence for supplementing with DHA during neoadjuvant chemotherapy treatment for breast cancer.

Trial registration number

NCT03831178
Identifying patients at risk of futile resuscitation: palliative care indicators in out-of-hospital cardiac arrest
Authors: Cokljat Mia , Lloyd Adam , Clarke Scott , Crawford Anna , Clegg Gareth
Published: September 2019

Objectives

Patients with indicators for palliative care, such as those with advanced life-limiting conditions, are at risk of futile cardiopulmonary resuscitation (CPR) if they suffer out-of-hospital cardiac arrest (OHCA). Patients at risk of futile CPR could benefit from anticipatory care planning (ACP); however, the proportion of OHCA patients with indicators for palliative care is unknown. This study quantifies the extent of palliative care indicators and risk of CPR futility in OHCA patients.

Methods

A retrospective medical record review was performed on all OHCA patients presenting to an emergency department (ED) in Edinburgh, Scotland in 2015. The risk of CPR futility was stratified using the Supportive and Palliative Care Indicators Tool. Patients with 0–2 indicators had a ‘low risk’ of futile CPR; 3–4 indicators had an ‘intermediate risk’; 5+ indicators had a ‘high risk’.

Results

Of the 283 OHCA patients, 12.4% (35) had a high risk of futile CPR, while 16.3% (46) had an intermediate risk and 71.4% (202) had a low risk. 84.0% (68) of intermediate-to-high risk patients were pronounced dead in the ED or ED step-down ward; only 2.5% (2) of these patients survived to discharge.

Conclusions

Up to 30% of OHCA patients are being subjected to advanced resuscitation despite having at least three indicators for palliative care. More than 80% of patients with an intermediate-to-high risk of CPR futility are dying soon after conveyance to hospital, suggesting that ACP can benefit some OHCA patients. This study recommends optimising emergency treatment planning to help reduce inappropriate CPR attempts.
Point-of-care ultrasound compared with conventional radiographic evaluation in children with suspected distal forearm fractures in the Netherlands: a diagnostic accuracy study
Authors: Epema Anniek C , Spanjer Mariëlle J B , Ras Lieselotte , Kelder Johannes C , Sanders Marieke
Published: September 2019

Background

Distal forearm fractures are common in children. The reference standard to diagnose these fractures is by conventional radiography, which exposes these patients to harmful radiation. Ultrasound (US) seems to be a good alternative. However, emergency physicians (EPs) in the Netherlands have limited experience in using US for diagnosing fractures in children.

Objective

The primary objective was to determine the accuracy of US, performed by a Dutch EP, compared with conventional radiography, in diagnosing distal forearm fractures in children. As a secondary objective, differences in pain scores during the performance of both US and plain radiography were determined.

Methods

Children, aged between 0 and 14 years old, suspected of having a distal forearm fracture were enrolled at the Emergency Department. US and radiographic findings were compared. Statistics for accuracy were calculated. Pain scores were recorded during US and radiography and compared as well. All participating operators received an hour-long pretrial training.

Results

100 patients were enrolled. The mean age was 9.5 years (SD, 3.6), and 50% were women. Overall diagnostic accuracy was 92% (95% CI 85%-96%). The sensitivity, specificity, positive and negative predictive values, positive and negative likelihood ratios for US were 95% (95% CI 87% to 99%), 86% (95% CI 71% to 95%), 92% (95% CI 83% to 97%), 91% (95% CI 76% to 98%), 6.86 (95% CI 3.04 to 15.51) and 0.05 (95% CI 0.02 to 0.17), respectively. The pain scores during US and radiographic imaging were 3.3 and 4.6, respectively (p<0.01).

Conclusions

In this study, we showed that US is an accurate method for diagnosing distal forearm fractures in children. The main advantages are that it is radiation-free and rapidly practicable, and that patients experience it as less painful than radiography. Moreover, this study has proven that with minimal experience in US, good diagnostic accuracy can be achieved after brief training.
User-driven design of child restraint information to reduce errors in use: a pilot randomised controlled trial
Authors: Hall Alexandra B , Ho Catherine , Albanese Bianca , Keay Lisa , Hunter Kate , Charlton Judith , Hayen Andrew , Bilston Lynne E , Brown Julie
Published: September 2019

Background

Incorrect use of child restraints is a long-standing problem that increases the risk of injury in crashes. We used user-centred design to develop prototype child restraint instructional materials. The objective of this study was to evaluate these materials in terms of comprehension and errors in the use of child restraints. The relationship between comprehension and errors in use was also explored.

Methods

We used a parallel-group randomised controlled trial in a laboratory setting. The intervention group (n=22) were provided with prototype materials and the control group (n=22) with existing instructional materials for the same restraint. Participants installed the restraint in a vehicle buck, secured an appropriately sized mannequin in the restraint and underwent a comprehension test. Our primary outcome was overall correct use, and our secondary outcomes were (1) comprehension score and (2) percent errors in the installation trial.

Results

There was 27% more overall correct use (p=0.042) and a higher mean comprehension score in the intervention group (mean 17, 95% CI 16 to 18) compared with the control group (mean 12, 95% CI 10 to 14, p<0.001). The mean error percentage in the control group was 23% (95% CI 16% to 31%) compared with 14% in the intervention group (95% CI 8% to 20%, p=0.056). For every one point increase in comprehension, there was an almost 2% (95% CI −2.7% to −1.0%) reduction in errors (y=45.5–1.87x, p value for slope <0.001).

Conclusions

Consumer-driven design of informational materials can increase the correct use of child restraints. Targeting improved comprehension of informational materials may be an effective mechanism for reducing child restraint misuse.
Microsatellite instability detection using a large next-generation sequencing cancer panel across diverse tumour types
Authors: Pang Jiuhong , Gindin Tatyana , Mansukhani Mahesh , Fernandes Helen , Hsiao Susan
Published: September 2019

Aim

Microsatellite instability (MSI), a hallmark of DNA mismatch repair deficiency, is a key molecular biomarker with multiple clinical implications including the selection of patients for immunotherapy, identifying patients who may have Lynch syndrome and predicting prognosis in patients with colorectal tumours. Next-generation sequencing (NGS) provides the opportunity to interrogate large numbers of microsatellite loci concurrently with genomic variants. We sought to develop a method to detect MSI that would not require paired normal tissue and would leverage the sequence data obtained from a broad range of tumours tested using our 467-gene NGS Columbia Combined Cancer Panel (CCCP).

Methods

Altered mononucleotide and dinucleotide microsatellite loci across the CCCP region of interest were evaluated in clinical samples encompassing a diverse range of tumour types. The number of altered loci was used to develop a decision tree classifier model trained on the retrospectively collected cohort of 107 clinical cases sequenced by the CCCP assay.

Results

The classifier was able to correctly classify all cases and was then used to analyse a test set of clinical cases (n=112) and was able to correctly predict their MSI status with 100% sensitivity and specificity. Analysis of recurrently altered loci identified alterations in genes involved in DNA repair, signalling and transcriptional regulation pathways, many of which have been implicated in MSI tumours.

Conclusion

This study highlights the utility of this approach, which should be applicable to laboratories performing similar testing.
Physical and psychosocial work exposures as risk factors for disability retirement due to a shoulder lesion
Authors: Sirén Maria , Viikari-Juntura Eira , Arokoski Jari , Solovieva Svetlana
Published: September 2019

Objective

To assess the longitudinal associations of physical and psychosocial exposures with disability retirement due to a shoulder lesion.

Methods

In a nationwide register-based study, we followed 1 135 654 wage earners aged 30–59 years for the occurrence of disability retirement due to a shoulder lesion. The occupational exposures were assessed with job exposure matrices. We used a competing risk regression model to estimate HRs and their 95% CIs and to test for the association between the exposures and the outcome. We also calculated the attributable fraction of disability retirement due to occupational exposures.

Results

A total of 2472 persons had full disability retirement due to a shoulder lesion during the follow-up. Physically heavy work showed the strongest association with the outcome in both genders, in men with an HR of 2.90 (95% CI 2.37 to 3.55) and in women with an HR of 3.21 (95% CI 2.80 to 3.90). Of the specific physical exposures, working with hands above shoulder level was statistically significantly associated with disability retirement in men. When all physical exposures were taken into consideration, 46% and 41% of disability retirement due to a shoulder lesion were attributed to physical work load factors in men and women, respectively. In addition, 49% (men) and 35% (women) of disability retirement were attributed to psychosocial work-related factors.

Conclusions

Our findings suggest that a considerable proportion of disability retirement due to a shoulder lesion could be prevented by reducing physical and psychosocial exposures at work to a low level.
Establishing a tobacco control fund in Vietnam: some learnings for other countries
Authors: Ngan Tran T , Huyen Doan T T , Minh Hoang Van , Wood Lisa
Published: September 2019

In response to the need for stable and adequate funding for tobacco control and the shortage of personnel working in the field, the Vietnam Tobacco Control Fund (VNTCF) was established through the Law on Prevention and Control of Tobacco Harms in 2012. In September 2014, VNTCF awarded its first set of grants. Built on the local evidence-based context and needs as well as lessons learnt from other countries, VNTCF adapted best practices with adjustments that fit the country’s political, economic and social environment. The key strengths of the VNTCF are the evidence-based model; multisectoral management; clearly dedicated funding mechanism, defined vision, objectives and function; outcomes based mechanism and a multisectoral approach to releasing grants. Although several challenges remain such as insufficient human resources to undertake the workload, complex and cumbersome administrative processes, and limited capacity for tobacco control in the country, VNTCF has achieved several successes. The establishment of VNTCF in Vietnam is a critical milestone within the country’s fight against the tobacco epidemic. It showed not only the commitment of the local authorities to the fight but also their determination to ensure sustainable funding for tobacco control activities in Vietnam. Analysing VNTCF’s critical success elements, key strengths and challenges is helpful for other countries which want to establish or modify a tobacco control fund.
Lifetime reproductive success of northern elephant seals (Mirounga angustirostris)
Authors: Le Boeuf Burney , Condit Richard , Reiter Joanne
Published: September 2019

Lifetime reproductive success of individuals in a natural population provides an estimate of Darwinian fitness. We calculated lifetime reproductive success in a colony of female northern elephant seals (Mirounga angustirostris (Gill, 1866)) by monitoring annual breeding throughout life of 7735 female weanlings marked individually at Año Nuevo, California, USA, from 1963 to 2005. Great variation in lifetime reproductive success was evident in three aspects of life history: (1) 75% of the females died before reaching breeding age and produced no pups; (2) nearly half of the survivors bred for only a few years before dying, and young females had low weaning success; (3) less than 1% of the females in the sample were exceptionally successful producing up to 20 pups in life. Many females that bred early, while still growing, had decreased lifespan, low weaning success, and lower lifetime reproductive success than females that postponed first breeding. Exceptional reproductive success was associated with giving birth annually, living long (up to age 23), and weaning large pups that were more likely to survive and breed. We conclude that there is strong selection for increased lifespan and multiparous supermoms that contribute significantly to pup production in the next generation.
How does an incomplete sky coverage affect the Hubble Constant variance?
Authors: Bengaly Carlos A. P. , Andrade Uendert , Alcaniz Jailson S.
Published: September 2019

We address the $$\simeq 4.4\sigma $$≃4.4σ tension between local and the CMB measurements of the Hubble Constant using simulated Type Ia Supernova (SN) data-sets. We probe its directional dependence by means of a hemispherical comparison through the entire celestial sphere as an estimator of the $$H_0$$H0 cosmic variance. We perform Monte Carlo simulations assuming isotropic and non-uniform distributions of data points, the latter coinciding with the real data. This allows us to incorporate observational features, such as the sample incompleteness, in our estimation. We obtain that this tension can be alleviated to $$3.4\sigma $$3.4σ for isotropic realizations, and $$2.7\sigma $$2.7σ for non-uniform ones. We also find that the $$H_0$$H0 variance is largely reduced if the data-sets are augmented to 4 and 10 times the current size. Future surveys will be able to tell whether the Hubble Constant tension happens due to unaccounted cosmic variance, or whether it is an actual indication of physics beyond the standard cosmological model.
Passive attack to the controlled secure direct communication with seven-qubit entangled states protocol
Authors: Liu Zhihao , Chen Hanwu , Liu Wenjie
Published: September 2019

It is found that the controlled quantum secure direct communication (CQSDC) based on a seven-qubit entangled state protocol [S. K. Wang, X. W. Zha and H. Wu, Int. J. Theor. Phys. 57, 48 (2018)] can be passively attacked. That is to say, this protocol has the security loophole of information leakage. To be specific, the first bit of the sender’s two-bit message can be deduced by an attacker Eve according to the first and the third bits of Alice’s announcement and the first bit of the controller Charlie’s announcement. Then, a way to fix this loophole is discussed.
A large
Taenidium
burrow from the Upper Carboniferous of Corrie, Isle of Arran, and remarks on the association of
Taenidium
burrows and
Diplichnites
trails
Authors: Pearson Paul N. , Gooday Robert J.
Published: September 2019

Large un-walled backfilled burrows of the
Taenidium
type are known from Paleozoic deltaic marine environments worldwide where they are often associated with
Diplichnites
trackways. The latter are generally attributed to arthropleurid myriapods and it may be that the burrows were also made by these animals. Here we describe a
Taenidium
burrow from the Limestone Coal Formation of the Isle of Arran, a formation that also hosts a well-known example of
Diplichnites
, supporting the association of the two types of trace fossil and extending their known co-occurrence upward into the Upper Carboniferous.
Impact of Electrostatic Coupling on Monolithic 3D-enabled Network on Chip
Authors: Lee Dongjin , Das Sourav , Doppa Janardhan Rao , Pande Partha Pratim , Chakrabarty Krishnendu
Published: September 2019

Monolithic-3D-integration (M3D) improves the performance and energy efficiency of 3D ICs over conventional through-silicon-vias-based counterparts. The smaller dimensions of monolithic inter-tier vias offer high-density integration, the flexibility of partitioning logic blocks across multiple tiers, and significantly reduced total wire-length enable high-performance and energy-efficiency. However, the performance of M3D ICs degrades due to the presence of electrostatic coupling when the inter-layer-dielectric thickness between two adjacent tiers is less than 50nm. In this work, we evaluate the performance of an M3D-enabled Network-on-chip (NoC) architecture in the presence of electrostatic coupling. Electrostatic coupling induces significant delay and energy overheads for the multi-tier NoC routers. This in turn results in considerable performance degradation if the NoC design methodology does not incorporate the effects of electrostatic coupling. We demonstrate that electrostatic coupling degrades the energy-delay-product of an M3D NoC by 18.1% averaged over eight different applications from SPLASH-2 and PARSEC benchmark suites. As a countermeasure, we advocate the adoption of electrostatic coupling-aware M3D NoC design methodology. Experimental results show that the coupling-aware M3D NoC reduces performance penalty by lowering the number of multi-tier routers significantly.
Lrrc55 is a novel prosurvival factor in pancreatic islets
Authors: Makkar Guneet , Shrivastava Vipul , Hlavay Brittyne , Pretorius Marle , Kyle Barry D. , Braun Andrew P. , Lynn Francis C. , Huang Carol
Published: September 2019

Pancreatic islets adapt to the increase in insulin demand during pregnancy by upregulating β-cell number, insulin synthesis, and secretion. These changes require prolactin receptor (PrlR) signaling, as mice with PrlR deletion are glucose intolerant with a lower β-cell mass. Prolactin also prevents β-cell apoptosis. Many genes participate in these adaptive changes in the islet, and Lrrc55 is one of the most upregulated genes with unknown function in islets. Because Lrrc55 expression increases in parallel to the increase in β-cell number and insulin production during pregnancy, we hypothesize that Lrrc55 might regulate β-cell proliferation/apoptosis (thus β-cell number) and insulin synthesis. Here, we found that Lrrc55 expression was upregulated by >60-fold during pregnancy in a PrlR-dependent manner, and this increase was restricted only to the islets. Overexpression of Lrrc55 in β-cells had minimal effect on β-cell proliferation and glucose-stimulated insulin secretion but protected β-cells from glucolipotoxicity-induced reduction in insulin gene expression. Moreover, Lrrc55 protects β-cells from glucolipotoxicity-induced apoptosis, with upregulation of prosurvival signals and downregulation of proapoptotic signals of the endoplasmic reticulum (ER) stress pathway. Furthermore, Lrrc55 attenuated calcium depletion induced by glucolipotoxicity, which may contribute to its antiapoptotic effect. Hence our findings suggest that Lrrc55 is a novel prosurvival factor that is upregulated specifically in islets during pregnancy, and it prevents conversion of adaptive unfolded protein response to unresolved ER stress and apoptosis in β-cells. Lrrc55 could be a potential therapeutic target in diabetes by reducing ER stress and promoting β-cell survival.
Exercise plasma metabolomics and xenometabolomics in obese, sedentary, insulin-resistant women: impact of a fitness and weight loss intervention
Authors: Grapov Dmitry , Fiehn Oliver , Campbell Caitlin , Chandler Carol J. , Burnett Dustin J. , Souza Elaine C. , Casazza Gretchen A. , Keim Nancy L. , Newman John W. , Hunter Gary R. , Fernandez Jose R. , Garvey W. Timothy , Hoppel Charles L. , Harper Mary-Ellen , Adams Sean H.
Published: September 2019

Insulin resistance has wide-ranging effects on metabolism, but there are knowledge gaps regarding the tissue origins of systemic metabolite patterns and how patterns are altered by fitness and metabolic health. To address these questions, plasma metabolite patterns were determined every 5 min during exercise (30 min, ∼45% of V̇o2peak, ∼63 W) and recovery in overnight-fasted sedentary, obese, insulin-resistant women under controlled conditions of diet and physical activity. We hypothesized that improved fitness and insulin sensitivity following a ∼14-wk training and weight loss intervention would lead to fixed workload plasma metabolomics signatures reflective of metabolic health and muscle metabolism. Pattern analysis over the first 15 min of exercise, regardless of pre- versus postintervention status, highlighted anticipated increases in fatty acid tissue uptake and oxidation (e.g., reduced long-chain fatty acids), diminution of nonoxidative fates of glucose [e.g., lowered sorbitol-pathway metabolites and glycerol-3-galactoside (possible glycerolipid synthesis metabolite)], and enhanced tissue amino acid use (e.g., drops in amino acids; modest increase in urea). A novel observation was that exercise significantly increased several xenometabolites (“non-self” molecules, from microbes or foods), including benzoic acid-salicylic acid-salicylaldehyde, hexadecanol-octadecanol-dodecanol, and chlorogenic acid. In addition, many nonannotated metabolites changed with exercise. Although exercise itself strongly impacted the global metabolome, there were surprisingly few intervention-associated differences despite marked improvements in insulin sensitivity, fitness, and adiposity. These results and previously reported plasma acylcarnitine profiles support the principle that most metabolic changes during submaximal aerobic exercise are closely tethered to absolute ATP turnover rate (workload), regardless of fitness or metabolic health status.
EpCAMlow Circulating Tumor Cells: Gold in the Waste
Authors: Nicolazzo Chiara , Gradilone Angela , Loreni Flavia , Raimondi Cristina , Gazzaniga Paola
Published: September 2019

The CellSearch® system which is still considered the gold standard for the enumeration of circulating tumor cells (CTC) utilizes antibodies against the epithelial cell adhesion molecule (EpCAM) for CTC enrichment. Recently, CTC discarded by the CellSearch® system due to their low EpCAM expression have been isolated and analyzed. We here sought to discuss technical and biological issues concerning the isolation and characterization of EpCAMlow CTC, highlighting the enormous potential of this subpopulation discarded by CellSearch®, which might instead reveal an unexpected clinical significance in tumor types where CTC enumeration has never been validated for prognostic and predictive purpose.
Parathyroid Hormone Measurement in Chronic Kidney Disease: From Basics to Clinical Implications
Authors: Kritmetapak Kittrawee , Pongchaiyakul Chatlert
Published: September 2019

Accurate measurement of parathyroid hormone (PTH) is crucial for therapeutic decision-making in patients with chronic kidney disease-mineral and bone disorder (CKD-MBD). The second-generation PTH assays, often referred to as “intact PTH” assays, are the current standard and most available assays in clinical practice. However, intact PTH assays measure both full-length biologically active PTH and heterogeneous PTH fragments in the circulation, providing the equivocal value of PTH measurement in patients with CKD-MBD. Due to the variability of PTH assays, preanalytical sample errors, and the phenomenon of end-organ PTH hyporesponsiveness, current CKD-MBD guidelines recommend a wide range for serum PTH targets (2–9 the upper normal limit of the intact PTH assay) in dialysis patients to diminish the risk of developing adynamic bone disease. Nevertheless, a sizeable proportion of CKD patients still experience renal osteodystrophy despite having serum PTH levels within the recommended range. The primary cause of this inconsistency is the analytical interference of various PTH fragments and oxidized PTH forms that considerably accumulate in CKD patients. Therefore, a new mass spectrometry-based assay, which is capable of specifically measuring the whole spectra of PTH fragments, can potentially improve diagnostic accuracy for renal osteodystrophy. However, the effects of different PTH fragments on bone metabolism, vascular calcification, and mortality in CKD patients warrant further research.
Synergistic Improvement in Children with Cerebral Palsy Who Underwent Double-Course Human Wharton’s Jelly Stem Cell Transplantation
Authors: Fu Xiaojun , Hua Rongrong , Wang Xiaodong , Wang Peishen , Yi Long , Yu Aixue , Yang Jing , Li Yan , An Yihua
Published: September 2019

Background. Our previous studies confirmed that human Wharton’s Jelly stem cell (hWJSC) transplantation improved motor function in children with spastic cerebral palsy (CP). This study investigated the dose-effect relationship between the transplanted cell dosage and efficacy in CP children.Methods. CP children who received one- or two-course (four or eight times lumbar puncture, 4 or8×107 hWJSCs) cell therapy were recruited into this study. Assessments of motor function were performed according to scales for gross motor function measurement (GMFM) and fine motor function measurement (FMFM). The measurement data obtained in the two different groups were analyzed byt-test. Univariate repeated measures analysis of variance was used to compare the data obtained at baseline and 6 or 12 months posttransplantation and met the conditions for Mauchly’s sphericity test.Results. The results for fifty-seven pediatric CP patients (including 35 male and 22 female patients) who completed follow-up showed that gross and fine motor functions improved after cell therapy. Interestingly, the GMFM and FMFM scores in patients who received one course of transplantation were significantly increased at 6 months after treatment. Moreover, another course of transplantation further improved gross and fine motor function in children. The scores for GMFM and FMFM were significantly higher at 6 months posttransplantation than at baseline and showed a linear upward trend. There was no gender difference in GMFM. Interestingly, there was a significant difference between male and female patients in the B and C dimensions of FMFM. These results reveal a gender-related susceptibility to stem cell therapy, especially for movement capability of the upper extremity joint and grasping ability. Similarly, in the group aged ≤3 years old, the improvement observed in dimension A (lying and rolling) of GMFM was nearly exponential and showed a quadratic trend. The results for FMFM were similar to those for GMFM. Moreover, the improvement in motor function was not age dependent.Conclusions. In this study, our data collectively reveal that CP children display sex- or age-dependent responses to hWJSC therapy; these results shed light on the clinical utility of this approach in specific populations.
Cooperative Runtime Offloading Decision Algorithm for Mobile Cloud Computing
Authors: Jin Xiaomin , Wang Zhongmin , Hua Wenqiang
Published: September 2019

Mobile cloud computing (MCC) provides a platform for resource-constrained mobile devices to offload their tasks. MCC has the characteristics of cloud computing and its own features such as mobility and wireless data transmission, which bring new challenges to offloading decision for MCC. However, most existing works on offloading decision assume that mobile cloud environments are stable and only focus on optimizing the consumption of offloaded applications but ignore the consumption caused by offloading decision algorithms themselves. This paper focuses on runtime offloading decision in dynamic mobile cloud environments with the consideration of reducing the offloading decision algorithm’s consumption. A cooperative runtime offloading decision algorithm, which takes advantage of the cooperation of online machine learning and genetic algorithm to make offloading decisions, is proposed to address this problem. Simulations show that the proposed algorithm helps offloaded applications save more energy and time while consuming fewer computing resources.
Retrospective Analysis of Microbial Colonization Patterns in Central Venous Catheters, 2013–2017
Authors: He Yu , Zhao Huihan , Wei Yan , Gan Xiao , Ling Ying , Ying Yanping
Published: September 2019

Objectives. This study was performed to provide epidemiological information on microbial colonization in central venous catheters (CVCs). Methods. CVCs submitted to Medical Microbiology Laboratory from January 1, 2013, through October 1, 2017, which met our criteria would be included for analysis. Quantitative culture was used for CVCs. The results of culture and related information on CVCs were collected and recorded in detail. The prevalence was calculated, and related factors were analyzed statistically. Results. A total of 2020 CVCs were submitted for culture and eligible for analysis. Positive microbial culture occurred in 379 catheters with 18.7% (379 of 2020) prevalence of colonization. There were 23 microbial genera and 45 organisms detected. Among the isolated organisms, there were 39 kinds of isolated bacteria and 6 kinds of isolated fungi. Acinetobacter (19.8%) predominated in total isolated microorganisms, followed by Staphylococcus epidermidis (11.3%) and Candida albicans (10.3%). There were no significant differences in isolated organisms and fungal species between different sexes (X2 = 2.365, P=0.50). Conversely, there were significant differences in isolated bacterial and fungal species between different wards and years (X2 = 124.046, P=0.000; X2 = 77.064, P=0.000). A total of 107 (5.3%, 107/2020) CVCs were associated with a diagnosis of central line-associated bloodstream infection (CLABSI). The most common organisms in causing CLABSI were Acinetobacter (23.4%), S. aureus (13.1%), and Candida albicans (12.1%). Conclusion. The prevalence of microbial colonization in CVCs is still significant and even has gradually changed over time. The study provides a new view of microbial colonization pattern in CVCs and a prevalence of CLABSI, which will facilitate catheter-related infection prevention and control in clinic.
Therapeutic Opportunities in Colorectal Cancer: Focus on Melatonin Antioncogenic Action
Authors: Wu Hucong , Liu Jiaqi , Yin Yi , Zhang Dong , Xia Pengpeng , Zhu Guoqiang
Published: September 2019

Colorectal cancer (CRC) influences individual health worldwide with high morbidity and mortality. Melatonin, which shows multiple physiological functions (e.g., circadian rhythm, immune modulation, and antioncogenic action), can be present in almost all organisms and found in various tissues including gastrointestinal tract. Notably, melatonin disruption is closely associated with the elevation of CRC incidence, indicating that melatonin is effective in suppressing CRC development and progression. Mechanistically, melatonin favors in activating apoptosis and colon cancer immunity, while reducing proliferation, autophagy, metastasis, and angiogenesis, thereby exerting its anticarcinogenic effects. This review highlights that melatonin can be an adjuvant therapy and be beneficial in treating patients suffering from CRC.
A Low‐Carbon Design Method Integrating Structure Design and Injection Process Design for Injection Molding Machines
Authors: Wang Zili , Zhang Shuyou , Qiu Lemiao , Liu Xiaojian , Li Heng
Published: September 2019

In the past decades, environmental problems are widely concerned and solved. However, as most solutions, they are methods of “end‐of‐pipe” treatment which are inefficient and of high cost. Low‐carbon design (LCD) is a novel way to solve the problem of pollution emissions at source. Injection molding machine (IMM) as important manufacturing equipment has been widely used in many industries. In the pursuit of high‐quality plastic products, the environmental qualities of IMM are often neglected. To achieve low carbon of IMM at source, a LCD method is proposed combining the structure design and injection process design for IMM. At first, LCD decision variables are determined based on interval number theory. Subsequently, the IMM structural carbon emissions and injection molding process carbon emissions are calculated, respectively. Based on this architecture, the carbon emission mathematical model is constructed. To solve the multiobjective optimization problem, the improved strength Pareto evolutionary algorithm based on epsilon dominance (E‐SPEA‐II) is used, and the design result schemes are sorted using the multiattribute decision‐making method for intervals. Finally, the validity of this method is demonstrated by an IMM injection component‐integrated low carbon design (ILCD) example.
N6-Methyladenosine Modulates Nonsense-Mediated mRNA Decay in Human Glioblastoma
Authors: Li Fuxi , Yi Yang , Miao Yanyan , Long Wenyong , Long Teng , Chen Siyun , Cheng Weisheng , Zou Changye , Zheng Yueyuan , Wu Xingui , Ding Junjun , Zhu Kaiyu , Chen Delin , Xu Qiongcong , Wang Jinkai , Liu Qing , Zhi Feng , Ren Jian , Cao Qi , Zhao Wei
Published: September 2019

The N6-methyladenosine (m6A) modification influences various mRNA metabolic events and tumorigenesis, however, its functions in nonsense-mediated mRNA decay (NMD) and whether NMD detects induced carcinogenesis pathways remain undefined. Here, we showed that the m6A methyltransferase METTL3 sustained its oncogenic role by modulating NMD of splicing factors and alternative splicing isoform switches in glioblastoma (GBM). Methylated RNA immunoprecipitation-seq (MeRIP-seq) analyses showed that m6A modification peaks were enriched at metabolic pathway–related transcripts in glioma stem cells (GSC) compared with neural progenitor cells. In addition, the clinical aggressiveness of malignant gliomas was associated with elevated expression of METTL3. Furthermore, silencing METTL3 or overexpressing dominant-negative mutant METTL3 suppressed the growth and self-renewal of GSCs. Integrated transcriptome and MeRIP-seq analyses revealed that downregulating the expression of METTL3 decreased m6A modification levels of serine- and arginine-rich splicing factors (SRSF), which led to YTHDC1-dependent NMD of SRSF transcripts and decreased SRSF protein expression. Reduced expression of SRSFs led to larger changes in alternative splicing isoform switches. Importantly, the phenotypes mediated by METTL3 deficiency could be rescued by downregulating BCL-X or NCOR2 isoforms. Overall, these results establish a novel function of m6A in modulating NMD and uncover the mechanism by which METTL3 promotes GBM tumor growth and progression.

Significance:

These findings establish the oncogenic role of m6A writer METTL3 in glioblastoma stem cells.
Infiltrating Myeloid Cells Drive Osteosarcoma Progression via GRM4 Regulation of IL23
Authors: Kansara Maya , Thomson Kristian , Pang Puiyi , Dutour Aurelie , Mirabello Lisa , Acher Francine , Pin Jean-Philippe , Demicco Elizabeth G. , Yan Juming , Teng Michele W.L. , Smyth Mark J. , Thomas David M.
Published: September 2019

The glutamate metabotropic receptor 4 (GRM4) locus is linked to susceptibility to human osteosarcoma, through unknown mechanisms. We show that Grm4−/− gene–targeted mice demonstrate accelerated radiation-induced tumor development to an extent comparable with Rb1+/− mice. GRM4 is expressed in myeloid cells, selectively regulating expression of IL23 and the related cytokine IL12. Osteosarcoma-conditioned media induce myeloid cell Il23 expression in a GRM4-dependent fashion, while suppressing the related cytokine Il12. Both human and mouse osteosarcomas express an increased IL23:IL12 ratio, whereas higher IL23 expression is associated with worse survival in humans. Consistent with an oncogenic role, Il23−/− mice are strikingly resistant to osteosarcoma development. Agonists of GRM4 or a neutralizing antibody to IL23 suppressed osteosarcoma growth in mice. These findings identify a novel, druggable myeloid suppressor pathway linking GRM4 to the proinflammatory IL23/IL12 axis.

Significance:

Few novel systemic therapies targeting osteosarcoma have emerged in the last four decades. Using insights gained from a genome-wide association study and mouse modeling, we show that GRM4 plays a role in driving osteosarcoma via a non–cell-autonomous mechanism regulating IL23, opening new avenues for therapeutic intervention.

See related commentary by Jones, p. 1484.

This article is highlighted in the In This Issue feature, p. 1469
Prognostic Impact of Atrial Fibrillation in Electrical Storm
Authors: Müller Julian , Behnes Michael , Ellguth Dominik , Schupp Tobias , Taton Gabriel , Reiser Linda , Engelke Niko , Reichelt Thomas , Bollow Armin , Kim Seung-Hyun , Barth Christian , Rusnak Jonas , Weidner Kathrin , Mashayekhi Kambis , Akin Muharrem , Bertsch Thomas , Weiß Christel , Borggrefe Martin , Akin Ibrahim
Published: September 2019

Background: Data regarding the prognostic impact of atrial fibrillation (AF) in patients with electrical storm (ES) is rare. Objectives: This study sought to assess the prognostic impact of AF in patients with ES on mortality, rehospitalization, major adverse cardiovascular events (MACE) and recurrence of ES (ES-R). Methods: All consecutive implantable cardioverter defibrillator (ICD) patients presenting with ES were included retrospectively from 2002 to 2016. Patients with AF were compared to non-AF patients. The primary prognostic endpoint was all-cause mortality. Secondary endpoints were in-hospital mortality, rehospitalization rates, MACE and ES-R. Results: A total of 87 ES patients with ICD were included and followed up to 2.5 years; 43% suffered from AF. The presence of AF was associated with increased all-cause mortality (47 vs. 29%, log-rank p = 0.052; hazard ratio [HR] 1.969, 95% confidence interval [CI] 0.981–3.952, p = 0.057), which was no longer present after multivariable adjustment for age, diabetes and dilated cardiomyopathy. Furthermore, AF was associated with increased rates of overall rehospitalization (61 vs. 31%, log-rank p = 0.013; HR 2.381, 95% CI 1.247–4.547, p = 0.009), especially due to AF (14 vs. 0%, p = 0.001) and acute heart failure (AHF) (28 vs. 10%, p = 0.018; HR 3.754, 95% CI 1.277–11.038, p = 0.016). Notably, AF was not associated with differences in MACE (55 vs. 37%, log rank p = 0.339) and ES-R (28 vs. 25%, log rank p = 0.704). Conclusion: In ES patients, presence of AF was univariably associated with increased rates of all-cause mortality at 2.5 years. Furthermore, AF was multivariably associated with overall rehospitalization, especially due to AF and AHF.
The Association between Stroke, Integrated Stroke Systems, and the Employability and Productivity of Canadian Stroke Survivors
Authors: Vyas Manav V. , de Oliveira Claire , Laporte Audrey , Kapral Moira K.
Published: September 2019

Background: Integrated stroke systems have been associated with reduced disability in stroke survivors, but their impact on employability and productivity (hours worked/week and hourly wages) of stroke survivors is unclear. Methods: We used Canadian Community Health Surveys (2000–2014) to conduct a quasi-experimental study with the aim of determining the impact of stroke on employability and productivity, and whether the implementation of integrated stroke systems was associated with improvements in the employability and productivity of adult Canadian stroke survivors. Multivariable generalized Poisson regression models were used to determine the effect of stroke on employability; multivariable Heckman models were used to estimate the effect of stroke on productivity. A difference in differences analysis was used to determine the impact of stroke systems on the primary outcomes. Results: The study sample included 400,797 respondents, of whom 5,786 (1.4%) were stroke survivors. Compared to the general population, stroke survivors were less likely to be employed (adjusted incidence rate ratio 0.62, 95% CI 0.59–0.66) and earned an hourly wage that was 5.3% lower (95% CI 1.1–9.3) and worked an average of 1.9 fewer hours per week (95% CI 0.9–2.9). Over the study period, the employability of stroke survivors improved but not productivity. After accounting for temporal changes in overall employment, there was no association between the implementation of integrated stroke systems and either employability or productivity. Conclusion: Employability of stroke survivors improved over the study period but remained lower than the general population, with no differences in provinces with and without integrated stroke systems.