bluuebunny/crossref_metadata_2025 huggingface dataset:
A tailored approach towards informing relatives at risk of inherited cardiac conditions: study protocol for a randomised controlled trial
Authors: van den Heuvel Lieke M , Hoedemaekers Yvonne M , Baas Annette F , van Tintelen J Peter , Smets Ellen M A , Christiaans Imke
Published: July 2019

Introduction

In current practice, probands are asked to inform relatives about the possibility of predictive DNA testing when a pathogenic variant causing an inherited cardiac condition (ICC) is identified. Previous research on the uptake of genetic counselling and predictive DNA testing in relatives suggests that not all relatives are sufficiently informed. We developed a randomised controlled trial to evaluate the effectiveness of a tailored approach in which probands decide together with the genetic counsellor which relatives they inform themselves and which relatives they prefer to have informed by the genetic counsellor. Here, we present the study protocol of this randomised controlled trial.

Methods

A multicentre randomised controlled trial with parallel-group design will be conducted in which an intervention group receiving the tailored approach will be compared with a control group receiving usual care. Adult probands diagnosed with an ICC in whom a likely pathogenic or pathogenic variant is identified will be randomly assigned to the intervention or control group (total sample: n=85 probands). Primary outcomes are uptake of genetic counselling and predictive DNA testing by relatives (total sample: n=340 relatives). Secondary outcomes are appreciation of the approach used and impact on familial and psychological functioning, which will be assessed using questionnaires. Relatives who attend genetic counselling will be asked to fill out a questionnaire as well.

Ethics and dissemination

Ethical approval was obtained from the Medical Ethical Committee of the Amsterdam University Medical Centres (MEC 2017-145), the Netherlands. All participants will provide informed consent prior to participation in the study. Results of the study on primary and secondary outcome measures will be published in peer-reviewed journals.

Trial registration number

NTR6657; Pre-results.
Is maternal weight gain between pregnancies associated with risk of large-for-gestational age birth? Analysis of a UK population-based cohort
Authors: Ziauddeen Nida , Wilding Sam , Roderick Paul J , Macklon Nicholas S , Alwan Nisreen A
Published: July 2019

Objective

Maternal overweight and obesity during pregnancy increases the risk of large-for-gestational age (LGA) birth and childhood obesity. We aimed to investigate the association between maternal weight change between subsequent pregnancies and risk of having a LGA birth.

Design

Population-based cohort.

Setting

Routinely collected antenatal healthcare data between January 2003 and September 2017 at University Hospital Southampton, England.

Participants

Health records of women with their first two consecutive singleton live-birth pregnancies were analysed (n=15 940).

Primary outcome measure

Risk of LGA, recurrent LGA and new LGA births in the second pregnancy.

Results

Of the 15 940 women, 16.0% lost and 47.7% gained weight (≥1 kg/m2) between pregnancies. A lower proportion of babies born to women who lost ≥1 kg/m2(12.4%) and remained weight stable between −1 and 1 kg/m2(11.9%) between pregnancies were LGA compared with 13.5% and 15.9% in women who gained 1–3 and ≥3 kg/m2, respectively. The highest proportion was in obese women who gained ≥3 kg/m2(21.2%). Overweight women had a reduced risk of recurrent LGA in the second pregnancy if they lost ≥1 kg/m2(adjusted relative risk (aRR) 0.69, 95% CI 0.48 to 0.97) whereas overweight women who gained ≥3 kg/m2were at increased risk of new LGA after having a non-LGA birth in their first pregnancy (aRR 1.35, 95% CI 1.05 to 1.75). Normal-weight women who gained weight were also at increased risk of new LGA in the second pregnancy (aRR 1.26, 95% CI 1.06 to 1.50 with gain of 1–3 kg/m2and aRR 1.34, 95% CI 1.09 to 1.65 with gain of ≥3 kg/m2).

Conclusions

Losing weight after an LGA birth was associated with a reduced LGA risk in the next pregnancy in overweight women, while interpregnancy weight gain was associated with an increased new LGA risk. Preventing weight gain between pregnancies is an important measure to achieve better maternal and offspring outcomes.
Safety and efficacy of amnion-derived mesenchymal stem cells (AM01) in patients with steroid-refractory acute graft-versus-host disease after allogeneic haematopoietic stem cell transplantation: a study protocol for a phase I/II Japanese trial
Authors: Yamahara Kenichi , Hamada Akiko , Soma Toshihiro , Okamoto Rika , Okada Masaya , Yoshihara Satoshi , Yoshihara Kyoko , Ikegame Kazuhiro , Tamaki Hiroya , Kaida Katsuji , Inoue Takayuki , Ohsugi Yuko , Nishikawa Hiroki , Hayashi Hiroshi , Ito Yoichi M , Iijima Hiroaki , Ohnishi Shunsuke , Hashimoto Daigo , Isoe Toshiyuki , Teshima Takanori , Ogawa Hiroyasu , Sato Norihiro , Fujimori Yoshihiro
Published: July 2019

Introduction

Regenerative medicine and cell therapies have been gaining much attention among clinicians. Therapeutic infusion of mesenchymal stromal cells (MSCs) is now a leading investigational strategy for the treatment of acute graft-versus-host disease (aGVHD). Bone marrow MSCs are approved for manufacture and marketing as a cell therapy for aGVHD. Our non-clinical studies confirmed that human amnion-derived MSCs had immunomodulatory activity equal to or higher than that of human bone marrow MSCs. This study will aim to evaluate the safety and efficacy of amnion-derived MSCs (AM01) in patients with steroid-refractory aGVHD.

Methods and analysis

This study will be a multicentre, single-arm, open-label trial (an interventional study). This clinical trial will begin with a low-dose group, and when safety has been confirmed in at least three cases in the low-dose group, treatment will begin for the high-dose group, for which the safety will also be verified. The primary endpoint is to assess the safety of intravenous infusion therapy of AM01 within 24 hours after intravenous infusion of AM01. The secondary endpoint is to explore the efficacy of intravenous infusion therapy with AM01.

Ethics and dissemination

The institutional review boards of all participating hospitals approved this study protocol (latest V3.3.0, 3 August 2018). Final data will be publicly announced. A report releasing the study results will be submitted for publication to an appropriate peer-reviewed journal.

Trial registration number

UMIN000029945.
Where there is no nurse: an observational study of large-scale mentoring of auxiliary nurses to improve quality of care during childbirth at primary health centres in India
Authors: Rao Krishna D , Srivastava Swati , Warren Nicole , Mayra Kaveri , Gore Aboli , Das Aritra , Ahmed Saifuddin
Published: July 2019

Objective

Clinician scarcity in Low and Middle-Income Countries (LMIC) often results in de facto task shifting; this raises concerns about the quality of care. This study examines if a long-term mentoring programme improved the ability of auxiliary nurse-midwives (ANMs), who function as paramedical community health workers, to provide quality care during childbirth, and how they compared with staff nurses.

Design

Quasi-experimental post-test with matched comparison group.

Setting

Primary health centres (PHC) in the state of Bihar, India; a total of 239 PHCs surveyed and matched analysis based on 190 (134 intervention and 56 comparison) facilities.

Participants

Analysis based on 335 ANMs (237 mentored and 98 comparison) and 42 staff nurses (28 mentored and 14 comparison).

Intervention

Mentoring for a duration of 6–9 months focused on nurses at PHCs to improve the quality of basic emergency obstetric and newborn care.

Primary outcome measures

Nurse ability to provide correct actions in managing cases of normal delivery, postpartum haemorrhage and neonatal resuscitation assessed using a combination of clinical vignettes and Objective Structured Clinical Examinations.

Results

Mentoring increased correct actions taken by ANMs to manage normal deliveries by 17.5 (95% CI 14.8 to 20.2), postpartum haemorrhage by 25.9 (95% CI 22.4 to 29.4) and neonatal resuscitation 28.4 (95% CI 23.2 to 33.7) percentage points. There was no significant difference between the average ability of mentored ANMs and staff nurses. However, they provided only half the required correct actions. There was substantial variation in ability; 41% of nurses for normal delivery, 60% for postpartum haemorrhage and 45% for neonatal resuscitation provided less than half the correct actions. Ability declined with time after mentoring was completed.

Discussion

Mentoring improved the ability of ANMs to levels comparable with trained nurses. However, only some mentored nurses have the ability to conduct quality deliveries. Continuing education programmes are critical to sustain quality gains.
Prehospital triage of patients with suspected stroke symptoms (PRESTO): protocol of a prospective observational study
Authors: Venema Esmee , Duvekot Martijne H C , Lingsma Hester F , Rozeman Anouk D , Moudrous Walid , Vermeij Frederique H , Biekart Marileen , van der Lugt Aad , Kerkhoff Henk , Dippel Diederik W J , Roozenbeek Bob
Published: July 2019

Introduction

The efficacy of both intravenous treatment (IVT) and endovascular treatment (EVT) for patients with acute ischaemic stroke strongly declines over time. Only a subset of patients with ischaemic stroke caused by an intracranial large vessel occlusion (LVO) in the anterior circulation can benefit from EVT. Several prehospital stroke scales were developed to identify patients that are likely to have an LVO, which could allow for direct transportation of EVT eligible patients to an endovascular-capable centre without delaying IVT for the other patients. We aim to prospectively validate these prehospital stroke scales simultaneously to assess their accuracy in predicting LVO in the prehospital setting.

Methods and analysis

Prehospital triage of patients with suspected stroke symptoms (PRESTO) is a prospective multicentre observational cohort study in the southwest of the Netherlands including adult patients with suspected stroke in the ambulance. The paramedic will assess a combination of items from five prehospital stroke scales, without changing the normal workflow. Primary outcome is the clinical diagnosis of an acute ischaemic stroke with an intracranial LVO in the anterior circulation. Additional hospital data concerning the diagnosis and provided treatment will be collected by chart review. Logistic regression analysis will be performed, and performance of the prehospital stroke scales will be expressed as sensitivity, specificity and area under the receiver operator curve.

Ethics and dissemination

The Institutional Review Board of the Erasmus MC University Medical Centre has reviewed the study protocol and confirmed that the Dutch Medical Research Involving Human Subjects Act (WMO) is not applicable. The findings of this study will be disseminated widely through peer-reviewed publications and conference presentations. The best performing scale, or the simplest scale in case of clinical equipoise, will be integrated in a decision model with other clinical characteristics and real-life driving times to improve prehospital triage of suspected stroke patients.

Trial registration number

NTR7595.
Study protocol for the validation of a new patient-reported outcome measure (PROM) of listening effort in cochlear implantation: the Listening Effort Questionnaire-Cochlear Implant (LEQ-CI)
Authors: Hughes Sarah E , Rapport Frances , Watkins Alan , Boisvert Isabelle , McMahon Catherine M , Hutchings Hayley A
Published: July 2019

Introduction

Listening effort may be defined as the cognitive resources needed to understand an auditory message. A sustained requirement for listening effort is known to have a negative impact on individuals’ sense of social connectedness, well-being and quality of life. A number of hearing-specific patient-reported outcome measures (PROMs) exist currently; however, none adequately assess listening effort as it is experienced in the listening situations of everyday life. The Listening Effort Questionnaire-Cochlear Implant (LEQ-CI) is a new, hearing-specific PROM designed to assess perceived listening effort as experienced by adult CI patients. It is the aim of this study to conduct the first psychometric evaluation of the LEQ-CI’s measurement properties.

Methods and analysis

This study is a phased, prospective, multi-site validation study in a UK population of adults with severe-profound sensorineural hearing loss who meet local candidacy criteria for CI. In phase 1, 250 CI patients from four National Health Service CI centres will self-complete a paper version of the LEQ-CI. Factor analysis will establish unidimensionality and Rasch analysis will evaluate item fit, differential item functioning, response scale ordering, targeting of persons and items, and reliability. Classical test theory methods will assess acceptability/data completeness, scaling assumptions, targeting and internal consistency reliability. Phase 1 results will inform refinements to the LEQ-CI. In phase 2, a new sample of adult CI patients (n=100) will self-complete the refined LEQ-CI, the Speech, Spatial and Qualities of Hearing Scale, the Nijmegen Cochlear Implant Questionnaire and the Fatigue Assessment Scale to assess construct validity.

Ethics and dissemination

This study was approved by the Abertawe Bro Morgannwg University Health Board/Swansea University Joint Study Review Committee and the Newcastle and North Tyneside 2 Research Ethics Committee, Ref: 18/NE/0320. Dissemination will be in high-quality journals, conference presentations and SEH’s doctoral dissertation.
Role ofFAM19A4/miR124-2methylation analysis in predicting regression or non-regression of CIN2/3 lesions: a protocol of an observational longitudinal cohort study
Authors: Kremer Wieke W , Berkhof Johannes , Bleeker Maaike CG , Heideman Daniëlle AM , van Trommel Nienke E , van Baal Marchien W , Verhoeve Harold R , Meijer Chris JLM , Kenter Gemma G
Published: July 2019

Introduction

The clinical course of high-grade cervical intraepithelial neoplasia (CIN2/3) is characterised by a high spontaneous regression rate. Histological assessment is unable to differentiate between CIN2/3 lesions likely to regress and those likely to persist or progress. Most CIN2/3 lesions are treated by surgical excision, leading to overtreatment of a substantial proportion. In this prospective study, we evaluate the value of DNA methylation of host cell genes, which has shown to be particularly sensitive for the detection of advanced CIN2/3 and cervical cancer, in the prediction of regression or non-regression of CIN2/3 lesions.

Methods and analysis

This is a multicentre observational longitudinal study with 24-month follow-up. Women referred for colposcopy with an abnormal cervical scrape, who have been diagnosed with CIN2/3 and a small cervical lesion (≤50% of cervix) will be asked to participate. Participants will be monitored by 6-monthly cytological and colposcopic examination. In case of clinical progression, participants will receive treatment and exit the study protocol. At baseline and during follow-up, self-sampled cervicovaginal brushes and cervical scrapes will be collected for high-risk human papillomavirus (HPV) testing andFAM19A4/miR124-2methylation analysis. A colposcopy-directed biopsy will be taken from all participants at the last follow-up visit. The primary study endpoint is regression or non-regression at the end of the study based on the histological diagnosis. Regression is defined as CIN1 or less. Non-regression is defined as CIN2 or worse. The secondary study endpoint is defined as HPV clearance (double-negative HPV test at two consecutive time-points). The association between methylation status and regression probability will be evaluated by means of χ2testing.

Ethics and dissemination

Ethics approval was obtained in all participating clinics. Results of the main study will be submitted for publication in a peer-reviewed journal.

Trial registration number

NTR6069; Pre-results
Outcomes following early parenteral nutrition use in preterm neonates: protocol for an observational study
Authors: Webbe James , Longford Nicholas , Uthaya Sabita , Modi Neena , Gale Chris
Published: July 2019

Introduction

Preterm babies are among the highest users of parenteral nutrition (PN) of any patient group, but there is wide variation in commencement, duration, and composition of PN and uncertainty around which groups will benefit from early introduction. Recent studies in critically unwell adults and children suggest that harms, specifically increased rates of nosocomial infection, outweigh the benefits of early administration of PN. In this study, we will describe early PN use in neonatal units in England, Wales and Scotland. We will also evaluate if this is associated with differences in important neonatal outcomes in neonates born between 30+0and 32+6weeks+daysgestation.

Methods and analysis

We will use routinely collected data from all neonatal units in England, Wales and Scotland, available in the National Neonatal Research Database (NNRD). We will describe clinical practice in relation to any use of PN during the first 7 postnatal days among neonates admitted to neonatal care between 1 January 2012 and 31 December 2017. We will compare outcomes in neonates born between 30+0and 32+6weeks+daysgestation who did or did not receive PN in the first week after birth using a propensity score-matched approach. The primary outcome will be survival to discharge home. Secondary outcomes will include components of the neonatal core outcome set: outcomes identified as important by former patients, parents, clinicians and researchers.

Ethics and dissemination

We have obtained UK National Research Ethics Committee approval for this study (Ref: 18/NI/0214). The results of this study will be presented at academic conferences; the UK charity Bliss will aid dissemination to former patients and parents.

Trial registration number

NCT03767634
Paediatric parenteral nutrition: current issues
Authors: Cernat Elena , Puntis John
Published: July 2019

Parenteral nutrition transformed the prognosis for infants and children with intestinal failure. Soon after its introduction into clinical care 50 years ago, parenteral nutrition was also rapidly adopted for use in the preterm infant, where immaturity of gastrointestinal motor function precluded enteral feeding. Preterm infants subsequently became the single largest group of patients to be fed in this way. Although the development of scientific knowledge and the lessons of clinical experience have reduced the risk of complications, some of the problems and difficulties associated with this form of nutritional support remain challenging. These include central venous catheter-related sepsis, thrombosis, liver disease, bone disease and metabolic disturbance. In an initiative to promote best practice, guidelines on parenteral nutrition were first published by the European Society for Paediatric Gastroenterology, Hepatology and Nutrition and collaborating organisations in 2005. These were constructed following a thorough review of the scientific literature, allowing a series of evidence-based recommendations to be made. The exercise was repeated just over 10 years later and updated guidelines published in 2018. This review summarises key elements from the new guideline, with a focus on what has changed since 2005.
Quantitative analysis of the distal, lateral, and posterior articular branches of the axillary nerve to the shoulder: implications for intervention
Authors: Bickelhaupt Brittany , Eckmann Maxim S , Brennick Caroline , Rahimi Omid B
Published: July 2019

Introduction

The terminal sensory branches innervating the shoulder joint are potential therapeutic targets for the treatment of shoulder pain. This cadaveric study investigated in detail the anatomic pathway of the posterior terminal sensory branch of the axillary nerve (AN) and its relationship to nearby anatomic structures for applications, such as nerve block or ablation of the shoulder joint.

Methods

For this study, nine shoulders were dissected. Following dissection, methylene blue was used to stain the pathway of the terminal sensory branches of the AN to provide a visual relationship to the nearby bony structures. A transparent grid was overlaid on the humeral head to provide further detailed information regarding the innervation to the shoulder joint.

Results

Eight of the nine shoulders displayed terminal sensory branches of the AN. The terminal sensory branches of the AN innervated the posterolateral head of the humerus and shoulder capsule and were deep and distal to the motor branches innervating the deltoid muscle and teres minor muscle. All terminal branches dissected innervated the shoulder capsule at the posteroinferior-lateral aspect of the greater tuberosity of the humerus. All specimens displayed innervation to the shoulder joint in the lateral most 25% and inferior most 37.5% before methylene blue staining.

Conclusion

The terminal sensory branches of the AN consistently innervate the inferior and lateral aspects of the posterior humeral head and shoulder capsule. These nerves are easily accessible and would provide a practical target for nerve block or ablation to relieve shoulder pain without compromising motor integrity.
A semantic-based framework for automated rule checking in healthcare construction projects
Authors: Soliman-Junior Joao , Formoso Carlos T. , Tzortzopoulos Patricia
Published: July 2019

Healthcare projects are known for having a high degree of complexity. Furthermore, the design of healthcare facilities is highly constrained by regulations containing a wide range of requirements. Using BIM for automated rule checking has been pointed out as an opportunity to improve requirements management in these projects. However, most existing research is focused on hard-coded approaches or on limited sets of requirements. The aim of this investigation is to propose a semantic-based framework for automated rule checking in the context of healthcare design. An empirical study was conducted in the redevelopment of a university hospital, using Design Science Research as a methodological approach. Results indicate that the nature of regulations and the subjectivity of requirements have a major impact on the possibility of their translation into logical rules, which is needed to enable automated checking. The main theoretical contribution is a taxonomy for automated rule checking and information transformation.
Reverse Modeling and Topological Optimization for Lightweight Design of Automobile Wheel Hubs with Hollow Ribs
Authors: Xu P. F. , Duan S. Y. , Wang F.
Published: July 2019

Lightweight of wheel hubs is the linchpin for reducing the unsprung mass and improving the vehicle dynamic and braking performance of vehicles, thus, sustaining stability and comfortability. Current experience-based lightweight designs of wheel hubs have been argued to render uneven distribution of materials. This work develops a novel method to combine the reverse modeling technique with the topological optimization method to derive lightweight wheel hubs based on the principles of mechanics. A reverse modeling technique is first adopted to scan and reproduce the prototype 3D geometry of the wheel hub with solid ribs. The finite element method (FEM) is then applied to perform stress analysis to identify the maximum stress and its location of wheel hub under variable potential physical conditions. The finite element model is then divided into optimization region and nonoptimized region: the former is the interior portion of spoke and the latter is the outer surface of the spoke. A topology optimization is then conducted to remove the optimization region which is interior material of the spokes. The hollow wheel hub is then reconstructed with constant wall thickness about 5[Formula: see text]mm via a reverse modeling technique. The results show that the reconstructed model can reduce the mass of 12.7% compared to the pre-optimized model. The present method of this paper can guarantee the optimal distribution of wheel hub material based on mechanics principle. It can be implemented automatically to shorten the time interval for optimal lightweight designs. It is especially preferable for many existing structures and components as it maintains the structural appearance of optimization object.
On the Mechanics of Periodic Motion and Control of Tethered Satellite System in Elliptical Orbit
Authors: Pang Z. J. , Zhao Z. , Wang Q. T. , Du Z. H.
Published: July 2019

This study investigates the periodic motions of an in-plane tethered satellite system in elliptical orbits. The equations of motion of the system are derived, and periodic solutions are obtained by perturbation method. Then, the stability properties of the periodic solutions are studied. Analysis results show that the periodic solutions become unstable when orbital eccentricity is larger than a critical value. Two classical control schemes are used to convert the unstable periodic motions to stable ones. Stability analyses of periodic solutions of the two controlled systems show that the two control methods can improve the critical value of orbital eccentricity. Numerical simulations of the controlled system are carried out to demonstrate the validity of the stable region.
Refining fine fraction soil extraction methods and analysis for mineral exploration
Authors: Noble R. R. P. , Lau I. C. , Anand R. R. , Pinchand G. T.
Published: July 2019

Soils are widely used as geochemical sample media. In transported cover, the soils that host the mobile element signature are the smallest size fractions, so we should consider concentrating the clay size fraction (<2 µm) as an improved sample medium. Twenty-seven bulk reference soils were collected in the vicinity of known mineral deposits (including background areas) that reflect common soil types of Western Australia. A selection of these soils was used in replicate testing to assess differences in particle size, sample weight, dispersants, and how this relates to the Au and Cu geochemistry. Using multiple analysis of variance tests, the submicron fractions showed that, although the <0.2 µm fraction was slightly different to the <2 µm and <0.75 µm fractions, there was no additional value in the extra effort required to extract these submicron fractions, and the <2 µm fraction was favoured. Ultrasonics and rinsing were not required for Au analysis, and during wet separation no Au is lost in solution and only a small fraction of the overall Cu (0.5%) is lost. Using a dispersant was critical for solid recovery and Na-hexametaphosphate (technical or laboratory grade) was found to be the most effective reagent. The <2 µm size fraction showed no significant differences for assays of Au using 0.1, 0.2, 0.5, 1 and 4 g (
P
 < 0.05) with a microwave-assisted aqua regia digestion being the best analytical method for Au recovery. In addition to the geochemistry, the spectral reflectance variation was investigated with respect to particle size and weight, and showed more variation in the smaller weight fraction of material and a loss of quartz in the fine materials as expected. The integration of results from this study generated a new workflow called UltraFine+™. This workflow provides 40 elements, spectral mineralogy, particle-size distribution, pH, electrical conductivity (EC) and specific surface area, offering more quality data to improve mineral exploration using soil and regolith samples.

Supplementary material:
Spreadsheets of soils and regolith data from orientation sites and regional map sites analysed with the UltraFine+ method is available at
https://doi.org/10.25919/5d1058f8b05fc
Groundwater recharge susceptibility mapping using logistic regression model and bivariate statistical analysis
Authors: Chenini Ismail , Msaddek Mohamed Haythem
Published: July 2019

A logistic regression model and a bivariate statistical analysis were used in this paper to evaluate the groundwater recharge susceptibility. The approach is based on the assessment of the relationship involving groundwater recharge and parameters that influence this hydrological process. Surface parameters and aquifer-related parameters were evaluated as thematic map layers using ArcGIS. Then, a weighted-rating method was adopted to categorize each parameter's map. To assess the role of each parameter in the aquifer recharge, a logistic regression model and a bivariate statistical analysis were applied to the Guenniche phreatic aquifer (Tunisia). Models are explored to establish a map showing the aquifer recharge susceptibility. The code Modflow was used to simulate the consequence of the recharge. The recharge amount was introduced in the model and was tested to verify the recharge effect on the hydraulic head for the two models. The obtained results reveal that the recharge as mapped in the bivariate statistical model has a minor impact on the hydraulic head. Results of the logistic regression model are more significant as the hydraulic head is widely affected. This model provides good results in mapping the spatial distribution of the aquifer recharge susceptibility.
Correct-by-Construction Parallelization of Hard Real-Time Avionics Applications on Off-the-Shelf Predictable Hardware
Authors: Didier Keryan , Potop-Butucaru Dumitru , Iooss Guillaume , Cohen Albert , Souyris Jean , Baufreton Philippe , Graillat Amaury
Published: July 2019

We present the first end-to-end modeling and compilation flow to parallelize hard real-time control applications while fully guaranteeing the respect of real-time requirements on off-the-shelf hardware. It scales to thousands of dataflow nodes and has been validated on two production avionics applications. Unlike classical optimizing compilation, it takes as input non-functional requirements (real time, resource limits). To enforce these requirements, the compiler follows a static resource allocation strategy, from coarse-grain tasks communicating over an interconnection network all the way to individual variables and memory accesses. It controls timing interferences resulting from mapping decisions in a precise, safe, and scalable way.
Bifurcation Analysis of a Delayed Infection Model with General Incidence Function
Authors: Zhang Suxia , Dong Hongsen , Xu Jinhu
Published: July 2019

In this paper, an infection model with delay and general incidence function is formulated and analyzed. Theoretical results reveal that positive equilibrium may lose its stability, and Hopf bifurcation occurs when choosing delay as the bifurcation parameter. The direction of Hopf bifurcation and the stability of the periodic solutions are also discussed. Furthermore, to illustrate the numerous changes in the local stability and instability of the positive equilibrium, we conduct numerical simulations by using four different types of functional incidence, i.e., bilinear incidence, saturation incidence, Beddington–DeAngelis response, and Hattaf–Yousfi response. Rich dynamics of the model, such as Hopf bifurcations and chaotic solutions, are presented numerically.
Shape Prior Embedded Level Set Model for Image Segmentation
Authors: Liu Wansuo , Wang Dengwei , Shi Wenjun
Published: July 2019

This paper presents an optimized level set evolution (LSE) without reinitialization (LSEWR) model and a shape prior embedded level set model (LSM) for robust image segmentation. Firstly, by performing probability weighting and coefficient adaptive processing on the original LSEWR model, the optimized image energy term required by the proposed model is constructed. The purpose of the probability weighting is to introduce region information into the edge stop function to enhance the model’s ability to capture weak edges. The introduction of the adaptive coefficient enables the evolution process to automatically adjust its amplitude and direction according to the current image coordinate and local region information, thus completely solving the initialization sensitivity problem of the original LSEWR model. Secondly, a shape prior term driven by kernel density estimation (KDE) is additionally introduced into the optimized LSEWR model. The role of the KDE-driven shape prior term is to overcome the problem of image segmentation in the presence of geometric transformation and pattern interference. Even if there is obvious affine transformation in the shape prior and the target to be segmented, the target contour can still be reconstructed correctly. The extensive experiments on a large variety of synthetic and real images show that the proposed algorithm achieves excellent performance. In addition, several key factors affecting the performance of the proposed algorithm are analyzed in detail.
Deterioration in Clinical Status Is Not Enough to Suspend Eculizumab: A Genetic Complement-Mediated Atypical Hemolytic Uremic Syndrome Case Report
Authors: Calvaruso Luca , Naticchia Alessandro , Ferraro Pietro Manuel , Vischini Gisella , Costanzi Stefano
Published: July 2019

Background. Atypical hemolytic uremic syndrome (aHUS) is characterized by microangiopathic hemolytic anemia, thrombocytopenia, and renal failure. Mutations in CFI gene coding for complement regulation factors and in THBD gene coding for endothelial cell receptor thrombomodulin could predispose to the disease and hypertension can trigger the onset. Case Presentation. A 51-year-old female patient who had received kidney transplant eighteen years ago presented with hypertensive peak and hemolysis pattern. Normal ADAMTS13 levels as well as negative culture and serology for Shiga-toxin excluded, respectively, thrombotic thrombocytopenic purpura (TTP) and typical HUS caused by Shiga toxin-producing Escherichia coli (STEC-HUS). In suspicion of aHUS, we administered eculizumab and hemodialysis sessions were started as the patient showed severe renal failure. After an initial response, the patient developed cerebral hemorrhage. After last eculizumab administration, according to hematological parameters, an unsatisfactory response was observed: given the worsening clinical scenario, we withdrew eculizumab. Pathogenic mutations in CFI and THBD genes were found. After eculizumab reinitiation, looking at hemolysis indexes, we observed a suboptimal response as well as an otherwise adequate renal one: renal graft function was recovered despite persistence of hemolysis signs, after 6 months on regular dialysis. Conclusion. For the first time, we report an aHUS case in which a peculiar combination of mutations in CFI and THBD is found. We describe the importance of continuing eculizumab despite deterioration of patient’s clinical conditions.
SCFFBXW7/GSK3β-Mediated GFI1 Degradation Suppresses Proliferation of Gastric Cancer Cells
Authors: Kuai Xiaoling , Li Long , Chen Ran , Wang Kangjunjie , Chen Min , Cui Binghai , Zhang Yuxue , Li Junqiang , Zhu Hongwen , Zhou Hu , Huang Jianfei , Qin Jun , Wang Zhiwei , Wei Wenyi , Gao Daming
Published: July 2019

Gastric cancer is the third leading cause of cancer-related death worldwide. The regulatory mechanisms underlying gastric cancer cell proliferation are largely unclear. Here, we show that the transcription factor GFI1 is associated with advanced clinical gastric cancer progression and promoted gastric cancer cell proliferation partially through inhibition of gastrokine-2 (GKN2) transcription. GFI1 was a degrading substrate of FBXW7, whose loss was observed in gastric cancer. Mechanistically, GSK3β-mediated GFI1 S94/S98 phosphorylation triggered its interaction with FBXW7, resulting in SCFFBXW7-mediated ubiquitination and degradation. A nondegradable GFI1 S94A/S98A mutant was more potent in driving gastric cancer cell proliferation and tumorigenesis than wild-type GFI1. Overall, this study reveals the oncogenic role of GFI1 in gastric cancer and provides mechanistic insights into the tumor suppressor function of FBXW7.

Significance:

These findings demonstrate the oncogenic role of the transcription factor GFI1 and the tumor suppressive function of FBXW7 in gastric cancer.
Single-Cell Analysis Reveals a Preexisting Drug-Resistant Subpopulation in the Luminal Breast Cancer Subtype
Authors: Prieto-Vila Marta , Usuba Wataru , Takahashi Ryou-u , Shimomura Iwao , Sasaki Hideo , Ochiya Takahiro , Yamamoto Yusuke
Published: July 2019

Drug resistance is a major obstacle in the treatment of breast cancer. Surviving cells lead to tumor recurrence and metastasis, which remains the main cause of cancer-related mortality. Breast cancer is also highly heterogeneous, which hinders the identification of individual cells with the capacity to survive anticancer treatment. To address this, we performed extensive single-cell gene-expression profiling of the luminal-type breast cancer cell line MCF7 and its derivatives, including docetaxel-resistant cells. Upregulation of epithelial-to-mesenchymal transition and stemness-related genes and downregulation of cell-cycle–related genes, which were mainly regulated by LEF1, were observed in the drug-resistant cells. Interestingly, a small number of cells in the parental population exhibited a gene-expression profile similar to that of the drug-resistant cells, indicating that the untreated parental cells already contained a rare subpopulation of stem-like cells with an inherent predisposition toward docetaxel resistance. Our data suggest that during chemotherapy, this population may be positively selected, leading to treatment failure.

Significance:

This study highlights the role of breast cancer intratumor heterogeneity in drug resistance at a single-cell level.
Novel Pyrrolo[3,2-d]pyrimidine Compounds Target Mitochondrial and Cytosolic One-carbon Metabolism with Broad-spectrum Antitumor Efficacy
Authors: Dekhne Aamod S. , Shah Khushbu , Ducker Gregory S. , Katinas Jade M. , Wong-Roushar Jennifer , Nayeen Md. Junayed , Doshi Arpit , Ning Changwen , Bao Xun , Frühauf Josephine , Liu Jenney , Wallace-Povirk Adrianne , O'Connor Carrie , Dzinic Sijana H. , White Kathryn , Kushner Juiwanna , Kim Seongho , Hüttemann Maik , Polin Lisa , Rabinowitz Joshua D. , Li Jing , Hou Zhanjun , Dann Charles E. , Gangjee Aleem , Matherly Larry H.
Published: July 2019

Folate-dependent one-carbon (C1) metabolism is compartmentalized into the mitochondria and cytosol and supports cell growth through nucleotide and amino acid biosynthesis. Mitochondrial C1 metabolism, including serine hydroxymethyltransferase (SHMT) 2, provides glycine, NAD(P)H, ATP, and C1 units for cytosolic biosynthetic reactions, and is implicated in the oncogenic phenotype across a wide range of cancers. Whereas multitargeted inhibitors of cytosolic C1 metabolism, such as pemetrexed, are used clinically, there are currently no anticancer drugs that specifically target mitochondrial C1 metabolism. We used molecular modeling to design novel small-molecule pyrrolo[3,2-d]pyrimidine inhibitors targeting mitochondrial C1 metabolism at SHMT2. In vitro antitumor efficacy was established with the lead compounds (AGF291, AGF320, AGF347) toward lung, colon, and pancreatic cancer cells. Intracellular targets were identified by metabolic rescue with glycine and nucleosides, and by targeted metabolomics using a stable isotope tracer, with confirmation by in vitro assays with purified enzymes. In addition to targeting SHMT2, inhibition of the cytosolic purine biosynthetic enzymes, β-glycinamide ribonucleotide formyltransferase and/or 5-aminoimidazole-4-carboxamide ribonucleotide formyltransferase, and SHMT1 was also established. AGF347 generated significant in vivo antitumor efficacy with potential for complete responses against both early-stage and upstage MIA PaCa-2 pancreatic tumor xenografts, providing compelling proof-of-concept for therapeutic targeting of SHMT2 and cytosolic C1 enzymes by this series. Our results establish structure–activity relationships and identify exciting new drug prototypes for further development as multitargeted antitumor agents.
Will Nanotechnology Bring New Hope for Stem Cell Therapy?
Authors: Farzamfar Saeed , Nazeri Niloofar , Salehi Majid , Valizadeh Alireza , Marashi Sayed Mahdi , Savari Kouzehkonan Gholamreza , Ghanbari Hossein
Published: July 2019

The potential of stem cell therapy has been shown in preclinical trials for the treatment of damage and replacement of organs and degenerative diseases. After many years of research, its clinical application is limited. Currently there is not a single stem cell therapy product or procedure. Nanotechnology is an emerging field in medicine and has huge potential due to its unique characteristics such as its size, surface effects, tunnel effects, and quantum size effect. The importance of application of nanotechnology in stem cell technology and cell-based therapies has been recognized. In particular, the effects of nanotopography on stem cell differentiation, proliferation, and adhesion have become an area of intense research in tissue engineering and regenerative medicine. Despite the many opportunities that nanotechnology can create to change the fate of stem cell technology and cell therapies, it poses several risks since some nanomaterials are cytotoxic and can affect the differentiation program of stem cells and their viability. Here we review some of the advances and the prospects of nanotechnology in stem cell research and cell-based therapies and discuss the issues, obstacles, applications, and approaches with the aim of opening new avenues for further research.
СТАН СТОМАТОЛОГІЧНОЇ ЗАХВОРЮВАНОСТІ В ДІТЕЙ ІЗ РОЗЛАДОМ АУТИСТИЧНОГО СПЕКТРА
Authors: Hevkaliuk N. O. , Pynda M. Ya. , Pudiak V. Ye. , Posolenyk L. Ya. , Kuchyrka L. I.
Published: July 2019

Мета дослідження – вивчити поширеність та інтенсивність карієсу тимчасових і постійних зубів, захворювань тканин пародонта у дітей із розладом аутистичного спектра.

Матеріали та методи. Дослідження проводили на базі Благодійної організації «Дім милосердя» (м. Чортків), що опікується дітьми з особливими потребами, зокрема з розладом аутистичного спектра. Було обстежено 81 дитину з розладом аутистичного спектра віком від 2 до 18 років. В опитувальному листі для батьків зазначали обсяг санітарно-просвітницької роботи. Стан гігієни порожнини рота визначали за індексом Федорова – Володкіної, стан твердих тканин зубів у дітей – на підставі показників інтенсивності карієсу кп, кпп, КПВ+кп, КПпВ+кпп за методикою ВООЗ. Рівень стоматологічної допомоги оцінювали за П. А. Леусом.

Результати дослідження та їх обговорення. Аналіз опитувальних листів показав недостатній обсяг санітарно-просвітницької роботи серед цього контингенту дітей, тому проведено санітарно-гігієнічне навчання – інформаційно-просвітницьку театралізовану виставу. За результатами опитування батьків дітей із розладом аутистичного спектра щодо особливостей харчування, в 41,97 % дітей була нормальна харчова поведінка, 16,05 % обстежених тривалий час тримали їжу за щокою, а 53,08 % дітей віддавали перевагу м’яким продуктам та кулінарно обробленій їжі. Середнє значення індексу Федорова – Володкіної становило 2,97 бала, що свідчило про поганий рівень гігієни порожнини рота. Рівень стоматологічної допомоги виявився недостатнім (16,7 %). Розповсюдженість карієсу тимчасових та постійних зубів становила 84,81 % при інтенсивності ураження 9,74+0,17. У структурі захворювань тканин пародонта переважав хронічний катаральний гінгівіт (87,65 %), поширеність локалізованого та генералізованого пародонтиту – 17,28 %. Зубощелепні аномалії визначались у 86,04 % дітей. Самотравмування було виявлено в 48,01 % дітей.

Висновок. Висока поширеність та інтенсивність карієсу зубів, захворювань тканин пародонта в дітей із розладом аутис­тичного спектра є підставою для обґрунтування і запровадження ефективних методів первинної профілактики.
ЛІКУВАННЯ ПЕРЕДМЕНСТРУАЛЬНОГО СИНДРОМУ ІЗ ЗАСТОСУВАННЯМ АДАПТОЛУ І СЕДАТИВНИХ ПРЕПАРАТІВ РОСЛИННОГО ПОХОДЖЕННЯ
Authors: Franchuk O. S. , Franchuk M. O.
Published: July 2019

Мета дослідження – досягнути високої ефективності і доброї переносимості препарату при лікуванні пацієнток із передменструальним синдромом із перевагою вегетосудинної і психопатологічної симптоматики.

Матеріали та методи. Ми провели клінічні спостереження при застосуванні адаптолу для лікування ПМС у 20 жінок і седативних рослинних препаратів (настойки валеріани, півонії, персену) – у 12 жінок. Адаптол є похідним двох метильованих фрагментів сечовини і, будучи похідним природних метаболітів організму, має високий ступінь біологічної доступності, велику широту терапевтичної дії, не викликає кумулятивних властивостей. Йому притаманний увесь спектр психотропних впливів, характерних для «традиційних» транквілізаторів, водночас позбавлений основних побічних реакцій, властивих похідним бензодіазепіну. Широта терапевтичного ефекту адаптолу зумовлена вегетостабілізувальною, антиоксидантною, м’якою ноотропною, антигіпоксичною, помірною транквілізувальною дією. Широта поєднання дії цього препарату дозволяє нормалізувати багато функцій організму, а також відновлювати розумову і фізичну працездатність пацієнтів.

Результати дослідження та їх обговорення. Нами проведено спостереження за 32 жінками, у яких діагностовано ПМС. Тривалість ПМС коливалася від одного до п’яти років. Нервово-психічні розлади у всіх обстежених характеризувалися великим поліморфізмом скарг. У клінічній картині домінували вегетосудинні розлади: припливи жару, головний біль, підвищена втомлюваність, розлади сну, депресія; симптоми неврологічного характеру – дратівливість, плаксивість, емоційна лабільність, тривога, озлоблення. Всі ці клінічні прояви ПМС відмічалися в лютеїнову фазу ПМС.

Висновки. 1. Препарат «Адаптол» має високу ефективність і добру переносимість при лікуванні пацієнток із передменструальним синдромом із перевагою вегетосудинної і психопатологічної симптоматики. Його ефективність становить 91,89 %. 2. У пацієнтів із довготривалим передменструальним синдромом і відсутністю ефекту від використання різних методів його лікування необхідно провести 2-3 курси терапії з підвищенням дози адаптолу до 1,2 г на добу.
Comparative Effectiveness of β-Blocker Use Beyond 3 Years After Myocardial Infarction and Long-Term Outcomes Among Elderly Patients
Authors: Shavadia Jay S. , Holmes DaJuanicia N. , Thomas Laine , Peterson Eric D. , Granger Christopher B. , Roe Matthew T. , Wang Tracy Y.
Published: July 2019

Background:

The benefit of β-blocker use beyond 3 years after a myocardial infarction (MI) has not been clearly determined.

Methods and Results:

Using data from the CRUSADE Registry (Can Rapid Risk Stratification of Unstable Angina Patients Suppress Adverse Outcomes With Early Implementation of the American College of Cardiology/American Heart Association Guidelines) linked with Medicare claims, we studied patients ≥65 years of age with MI, discharged on β-blocker therapy and alive 3 years later without a recurrent MI to evaluate β-blocker use and dose (none, <50%, and ≥50% of the recommended target) at 3 years. Using inverse probability of treatment weighting, we then examined the adjusted association between β-blocker use (and dose) at 3 years and the cardiovascular composite of all-cause mortality, hospitalization for recurrent MI, ischemic stroke, or heart failure over the subsequent 5 years. Of the 6893 patients ≥65 years age, β-blocker use at 3 years was 72.2% (n=4980); 43% (n=2162) of these were treated with ≥50% of the target β-blocker dose. β-blocker use was not associated with a significant difference on the composite outcome (52.4% versus 55.4%, adjusted hazard ratio, 0.95; 95% CI, 0.88–1.03;
P
=0.23). Neither low dose (<50% target dose) nor high dose (≥50% target dose) β-blocker use was associated with a significant difference in risk when compared with no β-blocker use. Results were also consistent in patients with and without heart failure or systolic dysfunction (
P
interaction =0.30).

Conclusions:

In this observational analysis, β-blocker use beyond 3 years post-MI, regardless of the dose achieved, was not associated with improved outcomes. The role of prolonged β-blocker use, particularly in older adults, needs further investigation.