bluuebunny/crossref_metadata_2025 huggingface dataset:
Suppression of Cross-Well Oscillations for Bistable Composites Through Potential Well Elimination
Authors: Lee Andrew J. , Xie Antai , Inman Daniel J.
Published: January 2020

Although there have been numerous efforts into harnessing the snap through dynamics of bistable structures with piezoelectric transducers to achieve large energy conversion, these same dynamics are undesirable under morphing applications where stationary control of the structure’s configuration is paramount. To suppress cross-well vibrations that primarily result from periodic excitation at low frequencies, a novel control strategy is proposed and implemented on the piezoelectrically generated bistable laminate, which consists of only macro fiber composites (MFCs) in a [0MFC/90MFC]T layup. While under cross-well regimes such as subharmonic, chaotic, or limit cycle oscillations, a single MFC is actuated to the laminate’s limit voltage to eliminate one of its potential wells and force it into the remaining stable state. Simultaneously, a positive position feedback (PPF) controller suppresses the resulting single-well oscillations through the other MFC. This dual control strategy is numerically and experimentally demonstrated through the suppression of various cross-well regimes and results in significant reduction of amplitude. The active control capability of the laminate prevents snap through instability when under large enough external vibrations.
Stability of Rotating Machinery Supported on Active Magnetic Bearings Subjected to Base Excitation
Authors: Jarroux Clément , Mahfoud Jarir , Defoy Benjamin , Alban Thomas
Published: January 2020

The stability of rotating machinery is a major challenge for the floating production storage and offloading (FPSO) units such as steam turbines or centrifugal compressors. The use of active magnetic bearings (AMBs) in turbomachines enables high operating speeds, active mechatronic system for the diagnostics, and the control and enables downsizing of the whole installation footprint. In case of strong base motions, the rotor can contact its touchdown bearings (TDBs) which are used as emergency and landing bearings. The aim of this study is to assess the stability of a rotating machine supported on AMBs during severe foundation excitation. The combined effect of unbalance forces, base motion excitation, and contact non-linearity on a rotor–AMB system response is analyzed focusing on the capacity of an augmented proportional-integral-derivative controller to maintain the system stable. An academic scale test rig was used for the experimental investigations. The controller was efficient and able to maintain the system stable during and after the application of the excitation, but the dynamic capacity of the AMBs was largely oversized with respect to the studied system. In order to check the capacity of the AMBs, when they are designed as a function of the rotor weight and expected excitation, numerical simulations were carried out (downsized). A finite element (FE) model was developed to model the on-board rotor–AMB system. Predicted and measured responses due to impulse excitation applied on the foundations were compared. The capacity of the controller to maintain the system stability is then discussed.
Non-Linear Coupled Dynamics of a Flexible Propeller-Shaft System Supported by Water Film Bearings
Authors: Lin Chang-Gang , Zou Ming-Song , Sima Can , Qi Li-Bo , Yu Yue
Published: January 2020

A slice method to determine the boundary conditions between the stern bearing and shaft by dividing the journal in the stern bearing into several slice elements along the axial direction is proposed for the first time. A comprehensive finite element model considering the nonlinear force of the water film and the flexibility of the propeller blade is established for a propeller-shaft system. The long bearing approximation is adopted to calculate the pressure distribution around each journal element in the stern bearing. The mode superposition method is employed. The nonlinear equation of motion is solved iteratively using the Newmark method. A parametric study is implemented to analyze the nonlinear vibration characteristics of the system. It is shown that the real motion state of the journal in the stern bearing can be simulated more precisely by the slice method proposed. The responses of the system alternate among period-one, quasi-periodic, multi-periodic, and chaotic motions as the rotating speed increases. The damping ratio has a significant effect on the dynamic characteristics of the propeller-shaft system. The motion of the system is unstable when the damping ratio is very small. At this time, the modes of the flexible propeller blades can be excited readily. The slice method, which can also be extensively used in similar rotor-bearing systems in the engineering field, is very simple and efficient to analyze the nonlinear vibration characteristics of a flexible propeller-shaft system supported by water film bearings.
Identification of Physical and Excitation Parameters of Under-Chassis Equipment for Railway Vehicles
Authors: Chen Jiangxue , Gong Dao , Zhou Jinsong , Sun Wenjing , Sun Yu , You Taiwen
Published: January 2020

The accuracy of the physical parameters and excitation parameters of the under-chassis equipment has a significant impact on investigations of the coupled vibration of the vehicle body and the under-chassis equipment. In this study, an equipment vibration isolator test bench is used to develop a physical parameter identification method based on the free vibration acceleration response of the equipment and an excitation parameter identification method based on the forced vibration acceleration response. The equipment mass parameter and the center of the gravity position parameter can be obtained first through a static load test, and then, the inertia parameters can be obtained through a dynamic test. Identification of the excitation parameters of the equipment is based on the physical parameters and the acceleration response. The accuracy of the physical parameters directly affects the excitation parameter identification results. The larger the frequency ratio, the smaller the identification error will be, and the larger the damping ratio, the larger the identification error will be. The identification test results of single-frequency excitation and multifrequency excitation show that the proposed excitation parameter identification method has high accuracy.
A Re-Examination of Various Resonances in Parametrically Excited Systems1
Authors: Sharma Ashu
Published: January 2020

The dynamics of parametrically excited systems are characterized by distinct types of resonances including parametric, combination, and internal. Existing resonance conditions for these instability phenomena involve natural frequencies and thus are valid when the amplitude of the parametric excitation term is zero or close to zero. In this paper, various types of resonances in parametrically excited systems are revisited and new resonance conditions are developed such that the new conditions are valid in the entire parametric space, unlike existing conditions. This is achieved by expressing resonance conditions in terms of “true characteristic exponents” which are defined using characteristic exponents and their non-uniqueness property. Since different types of resonances may arise depending upon the class of parametrically excited systems, the present study has categorized such systems into four classes: linear systems with parametric excitation, linear systems with combined parametric and external excitations, nonlinear systems with parametric excitation, and nonlinear systems with combined parametric and external excitations. Each class is investigated separately for different types of resonances, and examples are provided to establish the proof of concept. Resonances in linear systems with parametric excitation are examined using the Lyapunov–Poincaré theorem, whereas Lyapunov–Floquet transformation is utilized to generate a resonance condition for linear systems with combined excitations. In the case of nonlinear parametrically excited systems, nonlinear techniques such as “time-dependent normal forms” and “order reduction using invariant manifolds” are employed to express various resonance conditions. It is found that the forms of new resonance conditions obtained in terms of ‘true characteristic exponents’ are similar to the forms of existing resonance conditions that involve natural frequencies.
Application value of real-time shear wave elastography in differential diagnosis of testicular torsion
Authors: Xue Ensheng , Yu Yue , Lin Lulin , LI Zhiyong , Su Huanzhong
Published: January 2020

Aim: To evaluate the clinical value of real-time shear wave elastography (SWE) in differential diagnosis of testicular torsion and acute orchiditis.Material and methods: During a 3-year period, 14 cases of testicular torsion and 16 cases of acute orchiditis met the inclusion criteria. Young’s modulus maximum hardness (Emax) of testicular capsule region, middle testicular parenchyma, warped spermatic segment or inferior spermatic segment was measured in each group. SWE “stiff ring sign” of testis refers to the appearance of a red ring in the testicular capsule area and “stiff knot sign” of spermatic cord refers to the appearance of a red knot in the lower segment of the spermatic cord.Results: Emax value of the testicular capsule in the torsion group was higher than in the acute inflammation group (138.76±58.27 vs 16.40±4.71 kPa, p=0.0001). Emax value in the middle parenchyma of the testis showed no statistically significant difference between groups (p=0.053). Emax value in the twisted spermatic segment was higher than that in the lower spermatic segment with acute inflammation (166.61±60.07 vs 14.14±4.93, p=0.0001). In the torsion group, 12 testicular capsule areas showed “stiff ring sign” and all twisted segments of spermatic cord showed “stiff knot sign” but no signs were found in the inflammatory group.Conclusions: “Stiff ring sign” of testis, “stiff knot sign” of spermatic cord, high stiffness of the testicular capsule and in the twisted spermatic segment are the typical SWE findings of testicular torsion, with important clinical value in the differential diagnosis of testicular torsion and acute orchiditis.
Imaging ellipsometry biosensor: Basic theory, principles of operation, and applications
Authors: Liu Haoyu , Shen Jia , Liu Wei , Niu Yu , Jin Gang
Published: January 2020

The imaging ellipsometry biosensor (IEB), first proposed in 1995, has advanced from a simple concept to a powerful biosensor with high throughput, high sensitivity, high specificity, and low sample consumption. By combining the technique with surface plasmon resonance, IEBs operating under total internal reflection conditions can perform real-time multisample detection of biomolecule interactions. In this paper, the authors discuss the basic theory, principles of operation, design requirements, sensing chip modifications, methodologies and performance, and applications of IEBs.
Influence of unintentionally incorporated Ar atoms on the crystalline polarity of magnetron-sputtered Al-doped ZnO polycrystalline films on glass and sapphire substrates
Authors: Nomoto Junichi , Nakajima Tomohiko , Yamaguchi Iwao , Tsuchiya Tetsuo
Published: January 2020

The authors investigated the relationship between the content of incorporated Ar atoms and the crystalline polarity of polycrystalline Al-doped ZnO (AZO) films and examined the influence of this relationship on the resulting growth rate, crystallographic texture, and electrical properties. They deposited AZO films on glass and c-plane sapphire substrates via radio-frequency magnetron sputtering at substrate temperatures (Ts) of 100 or 200 °C using sintered AZO targets with an Al2O3 content of 2.0 wt. %. The incorporation of a large amount of Ar atoms induced a change in the crystalline polarity from Zn-polar to O-polar, the latter of which is associated with numerous obstacles, such as a lower deposition rate, large residual compressive stress, and increased electrical resistivity. The authors demonstrated that increasing the Ts led to a reduction in the amount of unintentionally retained Ar atoms, thereby affording Zn-polar AZO films with their associated advantages.
Electron emission from particles strongly affects the electron energy distribution in dusty plasmas
Authors: Woodard Austin , Shojaei Kamran , Berrospe-Rodriguez Carla , Nava Giorgio , Mangolini Lorenzo
Published: January 2020

The electron energy distribution of a low-temperature dusty plasma has been measured via a Langmuir probe. An unexpected broad peak at energy in the 2–4 V range has been observed. This can be theoretically reproduced for a sufficiently large electron emission rate from the nanoparticles dispersed in the plasma. A careful analysis of the nanoparticle energy balance, using measured values of nanoparticle concentration and plasma density, confirms that particles are sufficiently hot under the conditions of this study to rapidly inject electrons into the plasma via field-assisted thermionic emission. This work suggests that the presence of dust affects the plasma ionization balance more deeply than previously thought.
Thermophilic Degradation of Hemicellulose, a Critical Feedstock in the Production of Bioenergy and Other Value-Added Products
Authors: Cann Isaac , Pereira Gabriel V. , Abdel-Hamid Ahmed M. , Kim Heejin , Wefers Daniel , Kayang Boniface B. , Kanai Tamotsu , Sato Takaaki , Bernardi Rafael C. , Atomi Haruyuki , Mackie Roderick I.
Published: January 2020

Renewable fuels have gained importance as the world moves toward diversifying its energy portfolio. A critical step in the biomass-to-bioenergy initiative is deconstruction of plant cell wall polysaccharides to their unit sugars for subsequent fermentation to fuels. To acquire carbon and energy for their metabolic processes, diverse microorganisms have evolved genes encoding enzymes that depolymerize polysaccharides to their carbon/energy-rich building blocks. The microbial enzymes mostly target the energy present in cellulose, hemicellulose, and pectin, three major forms of energy storage in plants.
A CRISPR-Assisted Nonhomologous End-Joining Strategy for Efficient Genome Editing in Mycobacterium tuberculosis
Authors: Yan Mei-Yi , Li Si-Shang , Ding Xin-Yuan , Guo Xiao-Peng , Jin Qi , Sun Yi-Cheng
Published: January 2020

The global health impact of
M. tuberculosis
necessitates the development of new genetic tools for its manipulation, to facilitate the identification and characterization of novel drug targets and vaccine candidates. Clustered regularly interspaced short palindromic repeat (CRISPR)–CRISPR-associated protein (Cas) genome editing has proven to be a powerful genetic tool in various organisms; to date, however, attempts to use this approach in
M. tuberculosis
have failed. Here, we describe a genome-editing tool based on CRISPR cleavage and the nonhomologous end-joining (NHEJ) repair pathway that can efficiently generate deletion mutants in
M. tuberculosis
. More importantly, this system can generate simultaneous double mutations and large-scale genetic mutations in this species. We anticipate that this CRISPR-NHEJ-assisted genome-editing system will be broadly useful for research on mycobacteria, vaccine development, and drug target profiling.
Phage Resistance in Multidrug-Resistant Klebsiella pneumoniae ST258 Evolves via Diverse Mutations That Culminate in Impaired Adsorption
Authors: Hesse Shayla , Rajaure Manoj , Wall Erin , Johnson Joy , Bliskovsky Valery , Gottesman Susan , Adhya Sankar
Published: January 2020

The therapeutic use of bacteriophage (phage) is garnering renewed interest in the setting of difficult-to-treat infections. Phage resistance is one major limitation of phage therapy; therefore, developing effective strategies to avert or lessen its impact is critical. Characterization of
in vitro
phage resistance may be an important first step in evaluating the relative likelihood with which phage-resistant populations emerge, the most likely phenotypes of resistant mutants, and the effect of certain phage cocktail combinations in increasing or decreasing the genetic barrier to resistance. If this information confers predictive power
in vivo
, then routine studies of phage-resistant mutants and their
in vitro
evolution should be a valuable means for improving the safety and efficacy of phage therapy in humans.
A Novel Resistance Pathway for Calcineurin Inhibitors in the Human-Pathogenic Mucorales Mucor circinelloides
Authors: Vellanki Sandeep , Billmyre R. Blake , Lorenzen Alejandra , Campbell Micaela , Turner Broderick , Huh Eun Young , Heitman Joseph , Lee Soo Chan
Published: January 2020

Mucor
is intrinsically resistant to most known antifungals, which makes mucormycosis treatment challenging. Calcineurin is a serine/threonine phosphatase that is widely conserved across eukaryotes. When calcineurin function is inhibited in
Mucor
, growth shifts to a less virulent yeast growth form, which makes calcineurin an attractive target for development of new antifungal drugs. Previously, we identified two distinct mechanisms through which
Mucor
can become resistant to calcineurin inhibitors involving Mendelian mutations in the gene for FKBP12, including mechanisms corresponding to calcineurin A or B subunits and epimutations silencing the FKBP12 gene. Here, we identified a third novel mechanism where loss-of-function mutations in the amino acid permease corresponding to the
bycA
gene contribute to resistance against calcineurin inhibitors. When calcineurin activity is absent, BycA can activate protein kinase A (PKA) to promote yeast growth via a cAMP-independent pathway. Our data also show that calcineurin activity contributes to host-pathogen interactions primarily in the pathogenesis of
Mucor.
MicroRNA-889 Inhibits Autophagy To Maintain Mycobacterial Survival in Patients with Latent Tuberculosis Infection by Targeting TWEAK
Authors: Chen Der-Yuan , Chen Yi-Ming , Lin Chin-Fu , Lo Che-Min , Liu Hung-Jen , Liao Tsai-Ling
Published: January 2020

TB remains a leading cause of morbidity and mortality worldwide. Approximately one-quarter of the world’s population has latent TB infection. TWEAK is a multiple-function cytokine and may be used as a target for the treatment of rheumatic diseases, cardiovascular diseases, and renal diseases. Here, we demonstrated a novel relationship between TWEAK and activation of the autophagic machinery which promotes antimycobacterial immunity. Additionally, TB infection is highly dynamic and determined by the interaction between the host and mycobacterium. We demonstrated a mechanism of fine-tuned balance between the mycobacterium and host for granuloma formation and/or maintenance in LTBI status. Once patients entered LTBI status, the upregulation of miR-889 was associated with TNF-α levels and granuloma formation to maintain mycobacterial survival. Adalimumab (a TNF-α inhibitor) reduced both TNF-α and miR-889 levels and caused LTBI reactivation and, thus, TWEAK enhancement. MiR-889 and TWEAK may become potential diagnostic biomarkers or therapeutic targets for LTBI and LTBI reactivation, respectively.
A Novel
Legionella
Genomic Island Encodes a Copper-Responsive Regulatory System and a Single Icm/Dot Effector Protein Transcriptionally Activated by Copper
Authors: Linsky Marika , Vitkin Yevgeniya , Segal Gil
Published: January 2020

Legionella pneumophila
is an intracellular human pathogen that utilizes amoebae as its environmental host. The adaptation of
L. pneumophila
to the intracellular environment requires coordination of expression of its multicomponent pathogenesis system, which is composed of a secretion system and effector proteins. However, the regulatory factors controlling the expression of this pathogenesis system are only partially uncovered. Here, we discovered a novel regulatory system that is activated by copper and controls the expression of a single effector protein. The genes encoding both the regulatory system and the effector protein are located on a genomic island that undergoes horizontal gene transfer within the
Legionella
genus. This regulator-effector genomic island represents the first reported case of local regulation of effectors in
Legionella
. The discovery of this regulatory mechanism is an important step forward in the understanding of how the regulatory network of effectors functions and evolves in the
Legionella
genus.
Adaptation of Lactobacillus plantarum to Ampicillin Involves Mechanisms That Maintain Protein Homeostasis
Authors: Cao Chenxia , Wang Jicheng , Liu Yangshuo , Kwok Lai-Yu , Zhang Heping , Zhang Wenyi
Published: January 2020

Antibiotic resistance acquired by adaptation to certain antibiotics has led to growing public concerns. Here, a long-term evolution experiment was used together with proteomic analysis to identify genes/proteins responsible for the adaptive phenotype. This work has provided novel insights into the biosafety of new probiotics with high tolerance to antibiotics.
Bilateral hypoglossal nerve damage due to the use of the harmonic focus scalpel
Authors: Radcliffe Katherine , Akhtar Shakeel , Wilson Ajay
Published: January 2020

We describe the case of a 68-year-old man who presented with an anterior floor of mouth squamous cell carcinoma and underwent bilateral neck dissection. Subsequently, the patient developed permanent bilateral hypoglossal palsies, causing significant dysphagia, dysarthria and breathing difficulties. Hypoglossal nerve damage from surgical causes is uncommon, occurring in only 0.42% of functional neck dissections. However, it is the bilateral and permanent features of this case which make it unique. This injury may have been caused by incorrect use of the Harmonic Focus scalpel. Therefore, we discuss the literature demonstrating that the Harmonic Focus scalpel causes more lateral thermal damage than alternative tools, and the widely accepted 3 mm safety limit is not enough to protect important surrounding structures. This case report aims to highlight the need for proper training and specific identification of the hypoglossal nerve to prevent this rare and debilitating complication occurring in future patients.
Assessment of assumptions of statistical analysis methods in randomised clinical trials: the what and how
Authors: Nørskov Anders Kehlet , Lange Theis , Nielsen Emil Eik , Gluud Christian , Winkel Per , Beyersmann Jan , de Uña-Álvarez Jacobo , Torri Valter , Billot Laurent , Putter Hein , Wetterslev Jørn , Thabane Lehana , Jakobsen Janus Christian
Published: January 2020

When analysing and presenting results of randomised clinical trials, trialists rarely report if or how underlying statistical assumptions were validated. To avoid data-driven biased trial results, it should be common practice to prospectively describe the assessments of underlying assumptions. In existing literature, there is no consensus on how trialists should assess and report underlying assumptions for the analyses of randomised clinical trials. With this study, we developed suggestions on how to test and validate underlying assumptions behind logistic regression, linear regression, and Cox regression when analysing results of randomised clinical trials.

Two investigators compiled an initial draftbased on a review of the literature. Experienced statisticians and trialists from eight different research centres and trial units then participated in a anonymised consensus process, where we reached agreement on the suggestions presented in this paper.

This paper provides detailed suggestions on 1) which underlying statistical assumptions behind logistic regression, multiple linear regression and Cox regression each should be assessed; 2) how these underlying assumptions may be assessed; and 3) what to do if these assumptions are violated.

We believe that the validity of randomised clinical trial results will increase if our recommendations for assessing and dealing with violations of the underlying statistical assumptions are followed.
Intimate partner violence in 46 low-income and middle-income countries: an appraisal of the most vulnerable groups of women using national health surveys
Authors: Coll Carolina V N , Ewerling Fernanda , García-Moreno Claudia , Hellwig Franciele , Barros Aluisio J D
Published: January 2020

Introduction

Intimate partner violence (IPV) against women is a critical public health issue that transcends social and economic boundaries and considered to be a major obstacle to the progress towards the 2030 women, children and adolescents’ health goals in low-income and middle-income countries (LMICs). Standardised IPV measures have been increasingly incorporated into Demographic and Health Surveys carried out in LMICs. Routine reporting and disaggregated analyses at country level are essential to identify populational subgroups that are particularly vulnerable to IPV exposure.

Methods

We examined data from 46 countries with surveys carried out between 2010 and 2017 to assess the prevalence and inequalities in recent psychological, physical and sexual IPV among ever-partnered women aged 15–49 years. Inequalities were assessed by disaggregating the data according to household wealth, women’s age, women’s empowerment level, polygyny status of the relationship and area of residence.

Results

National levels of reported IPV varied widely across countries—from less than 5% in Armenia and Comoros to more than 40% in Afghanistan. Huge inequalities within countries were also observed. Generally, richer and more empowered women reported less IPV, as well as those whose partners had no cowives. Different patterns across countries were observed according to women’s age and area of residence but in most cases younger women and those living in rural areas tend to be more exposed to IPV.

Conclusion

The present study advances the current knowledge by providing a global panorama of the prevalence of different forms of IPV across LMICs, helping the identification of the most vulnerable groups of women and for future monitoring of leaving no one behind towards achieving the elimination of all forms of violence among women and girls.
Women, children and adolescents in conflict countries: an assessment of inequalities in intervention coverage and survival
Authors: Akseer Nadia , Wright James , Tasic Hana , Everett Karl , Scudder Elaine , Amsalu Ribka , Boerma Ties , Bendavid Eran , Kamali Mahdis , Barros Aluisio J D , da Silva Inácio Crochemore Mohnsam , Bhutta Zulfiqar Ahmed
Published: January 2020

Introduction

Conflict adversely impacts health and health systems, yet its effect on health inequalities, particularly for women and children, has not been systematically studied. We examined wealth, education and urban/rural residence inequalities for child mortality and essential reproductive, maternal, newborn and child health interventions between conflict and non-conflict low-income and middle-income countries (LMICs).

Methods

We carried out a time-series multicountry ecological study using data for 137 LMICs between 1990 and 2017, as defined by the 2019 World Bank classification. The data set covers approximately 3.8 million surveyed mothers (15–49 years) and 1.1 million children under 5 years including newborns (<1 month), young children (1–59 months) and school-aged children and adolescents (5–14 years). Outcomes include annual maternal and child mortality rates and coverage (%) of family planning services, 1+antenatal care visit, skilled attendant at birth (SBA), exclusive breast feeding (0–5 months), early initiation of breast feeding (within 1 hour), neonatal protection against tetanus, newborn postnatal care within 2 days, 3 doses of diphtheria, pertussis and tetanus vaccine, measles vaccination, and careseeking for pneumonia and diarrhoea.

Results

Conflict countries had consistently higher maternal and child mortality rates than non-conflict countries since 1990 and these gaps persist despite rates continually declining for both groups. Access to essential reproductive and maternal health services for poorer, less educated and rural-based families was several folds worse in conflict versus non-conflict countries.

Conclusions

Inequalities in coverage of reproductive/maternal health and child vaccine interventions are significantly worse in conflict-affected countries. Efforts to protect maternal and child health interventions in conflict settings should target the most disadvantaged families including the poorest, least educated and those living in rural areas.
Large and persistent subnational inequalities in reproductive, maternal, newborn and child health intervention coverage in sub-Saharan Africa
Authors: Faye Cheikh Mbacké , Wehrmeister Fernando C , Melesse Dessalegn Y , Mutua Martin Kavao Kavao , Maïga Abdoulaye , Taylor Chelsea Maria , Amouzou Agbessi , Jiwani Safia S , da Silva Inácio Crochemore Mohnsam , Sidze Estelle Monique , Porth Tyler Andrew , Ca Tome , Ferreira Leonardo Zanini , Strong Kathleen L , Kumapley Richard , Carvajal-Aguirre Liliana , Hosseinpoor Ahmad Reza , Barros Aluisio J D , Boerma Ties
Published: January 2020

Subnational inequalities have received limited attention in the monitoring of progress towards national and global health targets during the past two decades. Yet, such data are often a critical basis for health planning and monitoring in countries, in support of efforts to reach all with essential interventions. Household surveys provide a rich basis for interventions coverage indicators on reproductive, maternal, newborn and child health (RMNCH) at the country first administrative level (regions or provinces). In this paper, we show the large subnational inequalities that exist in RMNCH coverage within 39 countries in sub-Saharan Africa, using a composite coverage index which has been used extensively by Countdown to 2030 for Women’s, Children’s and Adolescent’s Health. The analyses show the wide range of subnational inequality patterns such as low overall national coverage with very large top inequality involving the capital city, intermediate national coverage with bottom inequality in disadvantaged regions, and high coverage in all regions with little inequality. Even though nearly half of the 34 countries with surveys around 2004 and again around 2015 appear to have been successful in reducing subnational inequalities in RMNCH coverage, the general picture shows persistence of large inequalities between subnational units within many countries. Poor governance and conflict settings were identified as potential contributing factors. Major efforts to reduce within-country inequalities are required to reach all women and children with essential interventions.
A multidisciplinary approach to mental illness: do inflammation, telomere length and microbiota form a loop? A protocol for a cross-sectional study on the complex relationship between inflammation, telomere length, gut microbiota and psychiatric disorders
Authors: Manchia Mirko , Paribello Pasquale , Arzedi Carlo , Bocchetta Alberto , Caria Paola , Cocco Cristina , Congiu Donatella , Cossu Eleonora , Dettori Tinuccia , Frau Daniela V , Garzilli Mario , Manca Elias , Meloni Anna , Montis Maria A , Mura Andrea , Nieddu Mariella , Noli Barbara , Pinna Federica , Pisanu Claudia , Robledo Renato , Severino Giovanni , Sogos Valeria , Chillotti Caterina , Carpiniello Bernardo , Del Zompo Maria , Ferri Gian Luca , Vanni Roberta , Squassina Alessio
Published: January 2020

Introduction

Severe psychiatric disorders are typically associated with a significant reduction in life expectancy compared with the general population. Among the different hypotheses formulated to explain this observation, accelerated ageing has been increasingly recognised as the main culprit. At the same time, telomere shortening is becoming widely accepted as a proxy molecular marker of ageing. The present study aims to fill a gap in the literature by better defining the complex interaction/s between inflammation, age-related comorbidities, telomere shortening and gut microbiota in psychiatric disorders.

Methods and analysis

A cross-sectional study is proposed, recruiting 40 patients for each of three different diagnostic categories (bipolar disorder, schizophrenia and major depressive disorder) treated at the Section of Psychiatry and at the Unit of Clinical Pharmacology of the University Hospital Agency of Cagliari (Italy), compared with 40 age-matched and sex-matched non-psychiatric controls. Each group includes individuals suffering, or not, from age-related comorbidities, to account for the impact of these medical conditions on the biological make-up of recruited patients. The inflammatory state, microbiota composition and telomere length (TL) are assessed.

Ethics and dissemination

The study protocol was approved by the Ethics Committee of the University Hospital Agency of Cagliari (PG/2018/11693, 5 September 2018). The study is conducted in accordance with the principles of good clinical practice and the Declaration of Helsinki, and in compliance with the relevant Italian national legislation. Written, informed consent is obtained from all participants. Participation in the study is on a voluntary basis only. Patients will be part of the dissemination phase of the study results, during which a local conference will be organised and families of patients will also be involved. Moreover, findings will be published in one or more research papers and presented at national and international conferences, in posters or oral communications.
Pharmacodynamics effects of CDK4/6 inhibitor LEE011 (ribociclib) in high-risk, localised prostate cancer: a study protocol for a randomised controlled phase II trial (LEEP study: LEE011 in high-risk, localised Prostate cancer)
Authors: Scheinberg Tahlia , Kench James , Stockler Martin , Mahon Kate L , Sebastian Lucille , Stricker Phillip , Joshua Anthony M , Woo H , Thanigasalam Ruban , Ahmadi Nariman , Centenera Margaret M , Butler Lisa M , Horvath Lisa G
Published: January 2020

Introduction

Despite the development of new therapies for advanced prostate cancer, it remains the most common cause of cancer and the second leading cause of cancer death in men. It is critical to develop novel agents for the treatment of prostate cancer, particularly those that target aspects of androgen receptor (AR) signalling or prostate biology other than inhibition of androgen synthesis or AR binding. Neoadjuvant pharmacodynamic studies allow for a rational approach to the decisions regarding which targeted therapies should progress to phase II/III trials. CDK4/6 inhibitors have evidence of efficacy in breast cancer, and have been shown to have activity in preclinical models of hormone sensitive and castrate resistant prostate cancer. The LEEP trial aims to assess the pharmacodynamic effects of LEE011 (ribociclib), an orally bioavailable and highly selective CDK4/6 inhibitor, in men undergoing radical prostatectomy for high-risk, localised prostate cancer.

Methods and analysis

The multicentre randomised, controlled 4:1 two-arm, phase II, open label pharmacodynamic study will recruit 47 men with high risk, localised prostate cancer who are planned to undergo radical prostatectomy. Participants who are randomised to receive the study treatment will be treated with LEE011 400 mg daily for 21 days for one cycle. The primary endpoint is the frequency of a 50% reduction in Ki-67 proliferation index from the pretreatment prostate biopsy compared to that present in prostate cancer tissue from radical prostatectomy. Secondary and tertiary endpoints include pharmacodynamic assessment of CDK4/6 cell cycle progression via E2F levels, apoptotic cell death by cleaved caspase-3, changes in serum and tumour levels of Prostate Specific Antigen (PSA), pathological regression, safety via incidence of adverse events and exploratory biomarker analysis.

Ethics and dissemination

The protocol was approved by a central ethics review committee (St Vincent’s Hospital HREC) for all participating sites (HREC/17/SVH/294). Results will be disseminated in peer-reviewed journals and at scientific conferences.

Drug supply

Novartis.

Protocol version

2.0, 30 May 2019

Trial registration number

Australian New Zealand Clinical Trials Registry (ACTRN12618000354280).
Dance PREEMIE, a Dance PaRticipation intervention for Extremely prEterm children with Motor Impairment at prEschool age: an Australian feasibility trial protocol
Authors: Cameron Kate L , McGinley Jennifer L , Allison Kim , Fini Natalie A , Cheong Jeanie L Y , Spittle Alicia J
Published: January 2020

Introduction

Children born extremely preterm (EP: <28 weeks gestation) and/or extremely low birth weight (ELBW: <1000 g) are at increased risk of motor impairment compared with children born at term. Children with motor impairment have lower rates of physical activity (PA) participation compared with their typically developing peers. PA participation is an important outcome for children with motor impairment, however, there is limited evidence available to support interventions that improve PA participation in this population. The aim of this study is to assess the feasibility, including the recruitment and retention, acceptability and fidelity, of a preschool dance participation intervention for children born EP/EBLW with motor impairment called Dance PaRticipation intervention for Extremely prEterm children with Motor Impairment at prEschool age.

Methods and analysis

This feasibility case series trial will recruit EP/ELBW children with motor impairment (n=10) from the Victorian Infant Collaborative Study 2016/2017 cohort, a prospective longitudinal cohort study. Up to 10 community-based dance teachers will be recruited and provided with physiotherapy-led training and support to facilitate the participation of EP/ELBW children in community dance classes. A mixed-methods approach (quantitative and qualitative) will be used to analyse the primary aim, to determine the feasibility of the intervention from the perspectives of families and dance teachers.

Ethics and dissemination

This study is approved by the Human Research Ethics Committees of The Royal Children’s Hospital and The Royal Women’s Hospital, Melbourne. Study outcomes will be disseminated through conference presentations, peer-reviewed publications and social media.

Trial registration number

ACTRN12619001266156
Therapeutic potential of FLANC, a novel primate-specific long non-coding RNA in colorectal cancer
Authors: Pichler Martin , Rodriguez-Aguayo Cristian , Nam Su Youn , Dragomir Mihnea Paul , Bayraktar Recep , Anfossi Simone , Knutsen Erik , Ivan Cristina , Fuentes-Mattei Enrique , Lee Sang Kil , Ling Hui , Catela Ivkovic Tina , Huang Guoliang , Huang Li , Okugawa Yoshinaga , Katayama Hiroyuki , Taguchi Ayumu , Bayraktar Emine , Bhattacharya Rajat , Amero Paola , He William Ruixian , Tran Anh M , Vychytilova-Faltejskova Petra , Klec Christiane , Bonilla Diana L , Zhang Xinna , Kapitanovic Sanja , Loncar Bozo , Gafà Roberta , Wang Zhihui , Cristini Vittorio , Hanash Samir M , Bar-Eli Menashe , Lanza Giovanni , Slaby Ondrej , Goel Ajay , Rigoutsos Isidore , Lopez-Berestein Gabriel , Calin George Adrian
Published: January 2020

Objective

To investigate the function of a novel primate-specific long non-coding RNA (lncRNA), named FLANC, based on its genomic location (co-localised with a pyknon motif), and to characterise its potential as a biomarker and therapeutic target.

Design

FLANC expression was analysed in 349 tumours from four cohorts and correlated to clinical data. In a series of multiple in vitro and in vivo models and molecular analyses, we characterised the fundamental biological roles of this lncRNA. We further explored the therapeutic potential of targeting FLANC in a mouse model of colorectal cancer (CRC) metastases.

Results

FLANC, a primate-specific lncRNA feebly expressed in normal colon cells, was significantly upregulated in cancer cells compared with normal colon samples in two independent cohorts. High levels of FLANC were associated with poor survival in two additional independent CRC patient cohorts. Both in vitro and in vivo experiments demonstrated that the modulation of FLANC expression influenced cellular growth, apoptosis, migration, angiogenesis and metastases formation ability of CRC cells. In vivo pharmacological targeting of FLANC by administration of 1,2-dioleoyl-sn-glycero-3-phosphatidylcholine nanoparticles loaded with a specific small interfering RNA, induced significant decrease in metastases, without evident tissue toxicity or pro-inflammatory effects. Mechanistically, FLANC upregulated and prolonged the half-life of phosphorylated STAT3, inducing the overexpression of VEGFA, a key regulator of angiogenesis.

Conclusions

Based on our findings, we discovered, FLANC as a novel primate-specific lncRNA that is highly upregulated in CRC cells and regulates metastases formation. Targeting primate-specific transcripts such as FLANC may represent a novel and low toxic therapeutic strategy for the treatment of patients.
Pseudodiastrophic dysplasia expands the known phenotypic spectrum of defects in proteoglycan biosynthesis
Authors: Byrne Alicia B , Mizumoto Shuji , Arts Peer , Yap Patrick , Feng Jinghua , Schreiber Andreas W , Babic Milena , King-Smith Sarah L , Barnett Christopher P , Moore Lynette , Sugahara Kazuyuki , Mutlu-Albayrak Hatice , Nishimura Gen , Liebelt Jan E , Yamada Shuhei , Savarirayan Ravi , Scott Hamish S
Published: January 2020

Background

Pseudodiastrophic dysplasia (PDD) is a severe skeletal dysplasia associated with prenatal manifestation and early lethality. Clinically, PDD is classified as a ‘dysplasia with multiple joint dislocations’; however, the molecular aetiology of the disorder is currently unknown.

Methods

Whole exome sequencing (WES) was performed on three patients from two unrelated families, clinically diagnosed with PDD, in order to identify the underlying genetic cause. The functional effects of the identified variants were characterised using primary cells and human cell-based overexpression assays.

Results

WES resulted in the identification of biallelic variants in the established skeletal dysplasia genes, B3GAT3 (family 1) and CANT1 (family 2). Mutations in these genes have previously been reported to cause ‘multiple joint dislocations, short stature, and craniofacial dysmorphism with or without congenital heart defects’ (‘JDSCD’; B3GAT3) and Desbuquois dysplasia 1 (CANT1), disorders in the same nosological group as PDD. Follow-up of the B3GAT3 variants demonstrated significantly reduced B3GAT3/GlcAT-I expression. Downstream in vitro functional analysis revealed abolished biosynthesis of glycosaminoglycan side chains on proteoglycans. Functional evaluation of the CANT1 variant showed impaired nucleotidase activity, which results in inhibition of glycosaminoglycan synthesis through accumulation of uridine diphosphate.

Conclusion

For the families described in this study, the PDD phenotype was caused by mutations in the known skeletal dysplasia genes B3GAT3 and CANT1, demonstrating the advantage of genomic analyses in delineating the molecular diagnosis of skeletal dysplasias. This finding expands the phenotypic spectrum of B3GAT3-related and CANT1-related skeletal dysplasias to include PDD and highlights the significant phenotypic overlap of conditions within the proteoglycan biosynthesis pathway.
Estimating the syphilis incidence and diagnosis rate in Japan: a mathematical modelling study
Authors: Echigoya Yuri , Yamaguchi Takayuki , Imamura Akifumi , Nishiura Hiroshi
Published: January 2020

Objectives

The reported number of syphilis cases is increasing in Japan. In this study, we aimed to estimate both the incidence of infection and diagnosis-and-reporting rate using a mathematical model that captures the time course of infection.

Methods

We analysed yearly notification data from 1961 to 2016 and stratified according to clinical stage and sex. We built a compartmental ordinary differential equations model to describe the natural epidemiological course of syphilis in which the incidence of infection and diagnosis-and-reporting rate were included as time-varying parameters that we estimated via the maximum likelihood method.

Results

From 2008 to 2016, the estimated number of new syphilis cases among men and women was 1070 (95% CI 1037 to 1104) and 302 (95% CI 287 to 318), respectively, which was increased from the previous period (1999–2007) with 269 (95% CI 256 to 282) and 71 (95% CI 64 to 78) cases, respectively. The diagnosis-and-reporting rate did not vary greatly over time. We estimated the number of undiagnosed syphilis cases from either incubating or early clinical (ie, primary or secondary) infections in 2016 to be 262 (95% CI 249 to 275) and 79 (95% CI 74 to 84) for men and women, respectively.

Conclusions

The recent increase in reported cases of syphilis is owing to an increase in the number of infections. We found no evidence of time-dependent improvement in detection or reporting.
Adjusting for the effect of missing or dominated plants in progeny and clonal trials of Eucalyptus
Authors: Ferreira Getúlio Caixeta , Aguiar Aurélio Mendes , de Lima Bruno Marco , Lima José Luis , Rezende Gabriel Dehon Sampaio Peçanha , Ramalho Magno Antonio Patto
Published: January 2020

The objective of this paper was to estimate the effect of either missing or dominated plants (those that developed poorly) in experiments evaluating progenies or clones of Eucalyptus. Additionally, it was to investigate whether the use of the area available per plant is a suitable strategy to mitigate the effect of missing plants. Lastly, it was to evaluate whether missing or dominated plants in the experiments affected the association between plant performance in a progeny trial (PT) and their respective clones in a clonal trial (CT). Five 5-year-old PTs and four 3-year-old CTs were used. The recorded trait was diameter at breast height (DBH). The area available per plant was used to carry out the adjustment, taking into consideration the absence of neighboring plants as well as dominated plants. It was found that with the level of missing plants below 20% in experiments, the adjustment using the area available per plant did not improve the efficiency of the selection of either PTs or CTs. The strategy of considering not only missing plants but also dominated plants is not beneficial for the adjustment.
Selection constraints determine preference for A/U-ending codons inTaxus contorta
Authors: Majeed Aasim , Kaur Harpreet , Bhardwaj Pankaj
Published: January 2020

Unequal utilization of synonymous codons is a well-known phenomenon among living organisms. This phenomenon plays a major role in the enhancement of the accuracy and efficiency of translation. Gymnosperms are rarely paid attention in this aspect. Understanding the degree of and determining the forces influencing codon usage bias (CUB) in Taxus contorta, an endangered Himalayan gymnosperm, will prove useful in interpreting the evolutionary characteristics of this species. Using RNAseq data, 93 790 assembled transcripts were clustered into 32 701 unigenes. Around 13 061 full-length sequences were utilized for the analysis of CUB. Compositional properties showed that GC-content ranged from 28.76% to 65.22%, with an average value of 44.28%, suggesting an AT-rich genome. The mean effective number of codons (ENC) value revealed that CUB is not strong in T. contorta. The preferred codons tended to be A/U ending, whereas the avoided codons tended to be G/C ending. A P2 index of 0.54 and a Mutation Responsive Index (MRI) value of –0.02 in addition to the results revealed by the neutrality, ENC, and parity plots showed that natural selection is a predominating factor governing CUB. Mutational pressure, gene length, hydropathiciy, aromaticity, and nucleotide composition influence CUB weakly.