bluuebunny/crossref_metadata_2025 huggingface dataset:
Unmasking of oestrogen‐dependent changes in left ventricular structure and function in aged female rats: a potential model for pre‐heart failure with preserved ejection fraction
Authors: Bustamante Moises , Garate‐Carrillo Alejandra , R. Ito Bruce , Garcia Ricardo , Carson Nancy , Ceballos Guillermo , Ramirez‐Sanchez Israel , Omens Jeffrey , Villarreal Francisco
Published: January 2019

Key points

Heart failure with preserved ejection fraction (HFpEF) is seen more frequently in older women; risk factors include age, hypertension and excess weight.

No female animal models of early stage remodelling (pre‐HFpEF) have examined the effects that the convergence of such factors have on cardiac structure and function.

In this study, we demonstrate that ageing can lead to the development of mild chamber remodelling, diffuse fibrosis and loss of diastolic function.

The loss of oestrogens further aggravates such changes by leading to a notable drop in cardiac output (while preserving normal ejection fraction) in the presence of diffuse fibrosis that is more predominant in endocardium and is accompanied by papillary fibrosis.

Excess weight did not markedly aggravate such findings.

This animal model recapitulates many of the features recognized in older, female HFpEF patients and thus, may serve to examine the effects of candidate therapeutic agents.

Two‐thirds of patients with heart failure with preserved ejection fraction (HFpEF) are older women, and risk factors include hypertension and excess weight/obesity. Pathophysiological factors that drive early disease development (before heart failure ensues) remain obscure and female animal models are lacking. The study evaluated the intersecting roles of ageing, oestrogen depletion and excess weight on altering cardiac structure/function. Female, 18‐month‐old, Fischer F344 rats were divided into an aged group, aged + ovariectomy (OVX) and aged + ovariectomy + 10% fructose (OVF) in drinking water (n = 8–16/group) to induce weight gain. Left ventricular (LV) structure/function was monitored by echocardiography. At 22 months of age, animals were anaesthetized and catheter‐based haemodynamics evaluated, followed by histological measures of chamber morphometry and collagen density. All aged animals developed hypertension. OVF animals increased body weight. Echocardiography only detected mild chamber remodelling with ageing while intraventricular pressure–volume loop analysis showed significant (P < 0.05) decreases vs. ageing in stroke volume (13% OVX and 15% for OVF), stroke work (34% and 52%) and cardiac output (29% and 27%), and increases in relaxation time (10% OVX) with preserved ejection fraction. Histology indicated papillary and interstitial fibrosis with ageing, which was higher in the endocardium of OVX and OVF groups. With ageing, ovariectomy leads to the loss of diastolic and global LV function while preserving ejection fraction. This model recapitulates many cardiovascular features present in HFpEF patients and may help understand the roles that ageing and oestrogen depletion play in early (pre‐HFpEF) disease development.
New Aspects of Immunogenic Tumors Within Different Fractional Operators
Authors: Ullah Malik Zaka , Al-Aidarous Eman S , Baleanu Dumitru
Published: January 2019

This paper presents a new mathematical formulation in fractional sense describing the asymptotic behavior of immunogenic tumor growth. The new model is investigated through different fractional operators with and without singular kernel. An efficient numerical technique to solve these equations is also suggested. Comparative results with experimental data verify that the fractional-order growth model covers the real data better than the integer model of tumor growth. Thus, more precise models can be provided by the fractional calculus (FC), which helps us to examine better the complex dynamics. Finally, numerical results confirming the theoretical analysis are provided.
Weighted Least Squares Approach for an Adaptive Aerodynamic Engineered Structure With Twist Transformation
Authors: Mou Fuzhao , Nejadkhaki Hamid Khakpour , Estes Aaron , Hall John F.
Published: January 2019

A design concept for a wind turbine blade with an adaptive twist transformation is presented. The design improves partial-load wind capture by adapting the twist distribution in relation to wind speed. Structural adaptability is enabled by actuating a series of compliant sections that are mounted on a relatively rigid spar. The sections are assumed to have a unique stiffness that is achievable through additive manufacturing technology. The authors' prior work employed an aerodynamic model to establish the theoretical blade twist distribution as a function of wind speed. The work in this paper focuses on a method to optimize the stiffness of each blade section that has been previously defined. A mathematical model is proposed to support design optimization. The model is parameterized in terms of actuator locations and the torsional stiffness ratios of each blade section. These parameters are optimized to allow the blade to adapt its twist distribution to match the prescribed configurations. The optimization is completed using a weighted-least squares approach that minimizes the error between the theoretical and practical design. The selected solution is based upon the configuration that maximizes production. Weights are assigned to bias the performance of the blade toward different operating regimes. Our results indicate that quadratically penalizing twist angle errors toward the blade tip increases power capture. A Rayleigh distribution is used to create three sets of wind data, which vary in average speed. These sets of data are used to evaluate the performance of the proposed blade and design technique.
Report: The University Health Clinic: Definition, educational practices and outcomes
Authors: Moore Keri Marie , Bacon Rachel , Bevitt Thomas , Bialocerkowski Andrea , Ciccone Natalie , Haworth Navine , Horstmanshof Louise , Milne Nikki , Naumann Fiona , Sanderson Brooke , Wells Cherie
Published: January 2019

Introduction: Increasingly, universities are allocating substantial resources and efforts towards developing their own student-led clinical services (SLCS) within university health clinics (UHCs). For that reason, under the umbrella of the Australian and New Zealand Association for Health Professional Educators (ANZAPHE), clinical educationalists from 12 Australian universities have come together as a hot topic action group (HTAG) to collaboratively explore and enhance learning outcomes from this setting. Context: SLCS within UHCs increase placement capacity to meet growing demand. Moreover, SLCS within UHCs have the potential to provide an outstanding learning opportunity through high-quality supervision and activities designed to develop clinical competencies. However, the benefits of providing clinical education experiences for health and medical students in this setting has not been formally assessed. Typically, SLCS within UHCs are developed through consultation between universities and local health providers and are purposefully designed clinical placements with a focus on clinical educational activities for pre-registration students. UHCs may be located on or off campus and offer SLCS or other services to university staff, students and/or the wider community. In SLCS, students’ delivery of health services is supervised by university employed health professionals. Scope: The work of the HTAG to date is presented in this paper, which defines the setting and outlines assumptions, aspirations, challenges and enablers. The next phase of work for the HTAG is to formally explore the educational value for health professional students’ of SLCS delivered in UHCs and to develop resources and a quality assurance framework to guide the evaluation of these services.
Can Australian medical students’ predictions of peers’ responses assist with gaining reliable results on course evaluations?
Authors: Bacchi Stephen , Guo Brad , Brown Stuart , Symonds Ian , Hudson Judith (Nicky)
Published: January 2019

Introduction: Student feedback is integral to continuous improvement of medical programmes. A key challenge with student course evaluations is gaining large enough response rates for results to be reliable. This study investigated whether student predictions of peer, rather than personal, responses could address this challenge. Method: An anonymous paper-based student experience of learning and teaching (SELT) survey was distributed to the Year 1–3 medical student cohorts. Students responded to 20 survey statements, using a 6-option Likert-type scale. Ten statements evaluated students’ personal perspectives of the course, while the other 10 statements asked students to predict the most common response by their year cohort. Mean scores between the individual opinion-based and prediction-based statements were compared. An iterative process involving random subsampling was conducted to enable calculation of the minimum required number of responses for a stable outcome for each statement. Results: Two hundred and fifty-nine students participated (response rate 81.7%). Three out of the 10 paired statements in the prediction-based survey accurately predicted the group opinion-based mean. For the remaining seven statement pairs, there were statistically significant (although small) differences in mean. The calculation of mean number of responses required for a stable outcome found that the prediction-based SELT required significantly fewer (189) responses than the opinion-based SELT (215) (95% CI 15.3–35.7, p < 0.001).Conclusions: A prediction-based style of course evaluation using a 6-option Likert-type scale approximated the results gained when asking for individual opinion and required fewer responses to achieve a stable outcome.
Characterization of the Rickettsia-like and Coxiella-like symbionts in the tick Dermacentor everestianus Hirst, 1926 (Acari: Ixodidae) from the Qinghai-Tibet Plateau
Authors: Li Ningxin , Li Sisi , Wang Duo , Yan Peng , Wang Wenying , Li Mengmeng , Yu Zhijun , Liu Jingze
Published: January 2019

The tick Dermacentor everestianus is widely distributed on the Tibetan Plateau of China, where adult ticks usually parasitize sheep, yaks and horses. D. everestianus is able to transmit many zoonotic pathogens, including Francisella tularensis, Anaplasma ovis and Rickettsia raoultii-like bacteria, and can cause great damage to animals and human health. However, the symbionts in D. everestianus have not yet been investigated, which has hindered our understanding of the relationships between this tick species and associated tick-borne pathogens. In the current study, the Rickettsia-like and Coxiella-like symbionts in D. everestianus were identified and characterized. The results indicated that both Rickettsia-like (RLS-Des) and Coxiella-like (CLS-Des) symbionts showed 100% infection rates and displayed vertical transmission in D. everestianus. The RLS-Des showed a relatively higher abundance than the CLS-Des in D. everestianus. No tissue specificity was found for the RLS-Des or CLS-Des. These symbionts can inhabit the ovaries, salivary glands, midguts, Malpighian tubules and testes of D. everestianus. During the development of D. everestianus, the density of the RLS-Des showed more obvious changes than did that of the CLS-Des. Dramatic changes in the density of the RLS-Des were detected in the midguts, ovaries, salivary glands and Malpighian tubules when female D. everestianus were engorged and detached from the host, which suggested the potential role of these symbionts in the reproduction and development of D. everestianus. The dynamic changes in the density of the CLS-Des during feeding and reproduction of D. everestianus suggest the involvement of the CLS-Des in the reproduction of D. everestianus.
Experiments and kinetic modeling of the ion energy distribution function at the substrate surface during magnetron sputtering of silver targets in radio frequency argon plasmas
Authors: Garofano Vincent , Montpetit Florence , Glad Xavier , Gangwar Reetesh Kumar , Stafford Luc
Published: January 2019

The quality of the films obtained by magnetron sputtering depends on numerous parameters, including the energy of the ions impinging on the substrate. The energy distribution functions of Ar and Ag ions during magnetron sputtering of a silver target in rf argon plasmas are hereby reported. Measurements were carried out by plasma sampling mass spectrometry at (i) various bias voltages on the surface of the target at constant pressure and (ii) various operating pressures at constant bias voltage. A distinct high-energy tail is observed for the sputtered silver ions (ionized in the plasma) in comparison to the argon gas ions. The results indicate that the sputtered Ag atoms are not completely thermalized by collisions with background gas atoms over the range of experimental conditions investigated. To confirm such assertion, a model has been developed for the ejection of Ag atoms from the target, their transport in the gas phase, and their acceleration in the sheath at the surface of the mass spectrometer. Since sputtering occurs at low impinging ion energies, the energy distribution function of the extracted atoms cannot be represented by the usual Sigmund–Thomson distribution. It is rather assumed to be characterized by a bi-Maxwellian distribution, with one population related to the direct “classical” sputtering and the other one to indirect “2-step etching.” During the transport of Ag neutrals, both ionization and thermalization processes are considered. Finally, the rf sheath near the entry of the mass spectrometer oscillates at a period close to the transit time of the ions passing through it. This induces a complex energy gain also implemented in the model. An excellent agreement between the latter and experimental measurements is obtained. The results are used to probe the effect of the bias voltage and pressure on the fitting parameters, namely, the dc and rf components of the voltage drop in the sheath, the mean energy of the sputtered atoms, and the relative importance of the sputtered populations.
Seamless fill of deep trenches by chemical vapor deposition: Use of a molecular growth inhibitor to eliminate pinch-off
Authors: Talukdar Tushar K. , Girolami Gregory S. , Abelson John R.
Published: January 2019

Attempts to fill deep trenches by chemical vapor deposition often result in a “bread-loaf” profile, an overhang near the trench opening that arises whenever the growth rate is slightly higher near the opening than deeper in the feature. Continued growth leads to premature pinch-off at the opening, which leaves an undesirable void or seam along the centerline. Bread-loaf profiles can form even under superconformal growth conditions, as the authors recently found for the growth of HfO2 from the precursor tetrakis(dimethylamino)hafnium and a forward-directed flux of H2O coreactant. The current paper describes a method that can reduce or eliminate the bread-loaf problem: addition of an isotropic flow of a reactant that inhibits growth near the trench opening but leaves the growth rate unchanged deeper in the trench. A Markov chain model for ballistic transport of the inhibitor inside trenches is developed to account for this behavior: the model reveals that suppression of a bread-loaf profile is best accomplished with growth inhibitors that have a high sticking probability (>0.1 per wall collision) and that are consumed during growth. Four molecules are investigated as potential inhibitors during HfO2 growth: tris(dimethylamino)silane, 3DMAS; methoxytrimethylsilane, MOTMS; hexafluoroacetylacetone, H(hfac); and acetylacetone, H(acac). The molecules 3DMAS and MOTMS inhibit growth but do so everywhere. As a result, they improve conformality, but are unable to eliminate the bread-loaf profile. In contrast, relatively small partial pressures (fluxes) of H(hfac) or H(acac) strongly inhibit HfO2 growth and do so selectively on the upper substrate surface and near trench openings. In conjunction with the use of a forward-directed water flux that affords superconformal growth, the use of H(hfac) or H(acac) enables seamless fill of HfO2 in trenches with aspect ratios as large as 10.
U.S. defenses look to thwart missiles early
Authors: Popkin Gabriel
Published: January 2019

Scientists worry about the cost and feasibility of "boost-phase" antimissile technologies.
Growth of legal pot farms drives smog worries
Authors: Plautz Jason
Published: January 2019

Colorado to launch study of potential air quality effects of indoor cannabis facilities.
Scientific societies worry about threat from Plan S
Authors: Brainard Jeffrey
Published: January 2019

Loss of subscription fees could mean having to cut services or sell journals to commercial publishers.
Pharmaceutical diversification via palladium oxidative addition complexes
Authors: Uehling Mycah R. , King Ryan P. , Krska Shane W. , Cernak Tim , Buchwald Stephen L.
Published: January 2019

Embedding palladium ahead of time

Palladium-catalyzed cross-coupling is one of the most widely applied reaction classes in pharmaceutical research. The metal is adept at connecting aromatic rings to one another or to nitrogen centers. However, functional complexity can obstruct the reaction, necessitating laborious ligand optimization. Uehling
et al.
mitigated this problem by isolating the stable product of palladium's reaction with a complex aryl halide ahead of time. Subjecting these compounds to downstream coupling reactions substantially improved yields.

Science
, this issue p.
405
Design and control of gas diffusion process in a nanoporous soft crystal
Authors: Gu Cheng , Hosono Nobuhiko , Zheng Jia-Jia , Sato Yohei , Kusaka Shinpei , Sakaki Shigeyoshi , Kitagawa Susumu
Published: January 2019

Flexibility in gas absorption

Soft materials such as porous coordination polymer (PCP) can exhibit temperature-dependent flexible motions of their internal pores that can assist in gas separation and storage. Gu
et al.
designed a copper-based PCP with a ligand that contains phenothiazine-5,5-dioxide. The entrances to the porous cages changed size with temperature, when these functional groups underwent flipping motions. The change in gate size could lead to high selectivity for gas absorption and enabled the separation of oxygen from argon and of ethylene from ethane as well as long-term gas storage under ambient conditions.

Science
, this issue p.
387
A Josephson relation for fractionally charged anyons
Authors: Kapfer M. , Roulleau P. , Santin M. , Farrer I. , Ritchie D. A. , Glattli D. C.
Published: January 2019

Probing the dynamics of anyons

A two-dimensional electron gas in the fractional quantum Hall regime has unusual excitations called anyons that carry only a fraction of the electron's charge. This fractional charge can be observed through a dynamical response to irradiation by microwaves, but such experiments require a combination of high magnetic fields with sensitive noise measurements and very low temperatures. Kapfer
et al.
observed this dynamical response in a GaAs/AlGaAs heterostructure hosting a high-mobility two-dimensional electron gas with fractional excitations of one-third and one-fifth of the electron's charge. The method may be of interest for use in topological quantum computing.

Science
, this issue p.
846
A hydrated crystalline calcium carbonate phase: Calcium carbonate hemihydrate
Authors: Zou Zhaoyong , Habraken Wouter J. E. M. , Matveeva Galina , Jensen Anders C. S. , Bertinetti Luca , Hood Matthew A. , Sun Chang-yu , Gilbert Pupa U. P. A. , Polishchuk Iryna , Pokroy Boaz , Mahamid Julia , Politi Yael , Weiner Steve , Werner Peter , Bette Sebastian , Dinnebier Robert , Kolb Ute , Zolotoyabko Emil , Fratzl Peter
Published: January 2019

Hydrous CaCO
3
gets a new structure

Calcium carbonate (CaCO
3
) forms important minerals on Earth and is a model system for understanding crystal nucleation. Three different structures of CaCO
3
are known, along with two structures that are hydrated. Zou
et al.
found a third hydrated CaCO
3
structure formed from amorphous CaCO
3
in the presence of magnesium ions. The discovery illustrates the importance of amorphous precursors for producing new materials.

Science
, this issue p.
396
E
-Olefins through intramolecular radical relocation
Authors: Kapat Ajoy , Sperger Theresa , Guven Sinem , Schoenebeck Franziska
Published: January 2019

Olefin shuffle for just a nickel

Controlling the geometry of carbon-carbon double bonds is a central component of chemical manufacturing. One useful trick is to shift hydrogen atoms around to interconvert C=C isomers selectively. However, this approach typically requires precious metals. Kapat
et al.
now report that more-abundant nickel can catalyze rapid conversion of terminal olefins into internal olefins with high selectivity for trans geometry. The odd-electron nickel complex relies on a radical mechanism to shuttle hydrogen to the terminal carbon from the saturated carbon adjacent to the double bond.

Science
, this issue p.
391
Structures and operating principles of the replisome
Authors: Gao Yang , Cui Yanxiang , Fox Tara , Lin Shiqiang , Wang Huaibin , de Val Natalia , Zhou Z. Hong , Yang Wei
Published: January 2019

Structures of the simplest replisome

The DNA replisome performs concerted parental-strand separation and DNA synthesis on both strands. Gao
et al.
report the cryo–electron microscopy structures of the minimum set of bacteriophage T7 proteins that can carry out leading- and lagging-strand synthesis at the replication fork (see the Perspective by Li and O'Donnell). Three key enzymes involved in DNA replication—DNA polymerase, helicase, and primase—were visualized in complex with substrate DNA, demonstrating their highly dynamic organizations on both strands. Comparison of prokaryotic and eukaryotic replisomes reveals evolutionarily conserved operating principles and provides a structural basis for understanding coordination among DNA replication, recombination, and repair.

Science
, this issue p.
eaav7003
; see also p.
814
Toward unrestricted use of public genomic data
Authors: Amann Rudolf I. , Baichoo Shakuntala , Blencowe Benjamin J. , Bork Peer , Borodovsky Mark , Brooksbank Cath , Chain Patrick S. G. , Colwell Rita R. , Daffonchio Daniele G. , Danchin Antoine , de Lorenzo Victor , Dorrestein Pieter C. , Finn Robert D. , Fraser Claire M. , Gilbert Jack A. , Hallam Steven J. , Hugenholtz Philip , Ioannidis John P. A. , Jansson Janet K. , Kim Jihyun F. , Klenk Hans-Peter , Klotz Martin G. , Knight Rob , Konstantinidis Konstantinos T. , Kyrpides Nikos C. , Mason Christopher E. , McHardy Alice C. , Meyer Folker , Ouzounis Christos A. , Patrinos Aristides A. N. , Podar Mircea , Pollard Katherine S. , Ravel Jacques , Muñoz Alejandro Reyes , Roberts Richard J. , Rosselló-Móra Ramon , Sansone Susanna-Assunta , Schloss Patrick D. , Schriml Lynn M. , Setubal João C. , Sorek Rotem , Stevens Rick L. , Tiedje James M. , Turjanski Adrian , Tyson Gene W. , Ussery David W. , Weinstock George M. , White Owen , Whitman William B. , Xenarios Ioannis
Published: January 2019

Publication interests should not limit access to public data
A Combination Antibiogram Evaluation for
Pseudomonas aeruginosa
in Respiratory and Blood Sources from Intensive Care Unit (ICU) and Non-ICU Settings in U.S. Hospitals
Authors: Puzniak Laura , DePestel Daryl D. , Srinivasan Arjun , Ye Gang , Murray John , Merchant Sanjay , DeRyke C. Andrew , Gupta Vikas
Published: January 2019

Pseudomonas aeruginosa
is an important pathogen associated with significant morbidity and mortality. U.S.
The Anthelmintic Drug Niclosamide Synergizes with Colistin and Reverses Colistin Resistance in Gram-Negative Bacilli
Authors: Domalaon Ronald , De Silva P. Malaka , Kumar Ayush , Zhanel George G. , Schweizer Frank
Published: January 2019

There is an urgent need for new therapies to overcome antimicrobial resistance especially in Gram-negative bacilli (GNB). Repurposing old U.S.
Staphylococcus aureus Biofilm-Conditioned Medium Impairs Macrophage-Mediated Antibiofilm Immune Response by Upregulating KLF2 Expression
Authors: Alboslemy Talib , Yu Bing , Rogers Tara , Kim Min-Ho
Published: January 2019

Staphylococcus aureus
infections associated with the formation of biofilms on medical implants or host tissue play a critical role in the persistence of chronic infections. One critical mechanism of biofilm infection that leads to persistent infection lies in the capacity of biofilms to evade the macrophage-mediated innate immune response.
Interaction of Gardnerella vaginalis and Vaginolysin with the Apical versus Basolateral Face of a Three-Dimensional Model of Vaginal Epithelium
Authors: Garcia Erin M. , Kraskauskiene Vita , Koblinski Jennifer E. , Jefferson Kimberly K.
Published: January 2019

Studies have implicated
Gardnerella vaginalis
as an important etiological agent in bacterial vaginosis (BV). It produces a cholesterol-dependent cytolysin, vaginolysin (VLY).
An Emerging Issue in Oncogenic Virology: the Role of Beta Human Papillomavirus Types in the Development of Cutaneous Squamous Cell Carcinoma
Authors: Rollison Dana E. , Viarisio Daniele , Amorrortu Rossybelle P. , Gheit Tarik , Tommasino Massimo
Published: January 2019

Evidence suggests that beta human papillomaviruses (HPVs), together with ultraviolet radiation, contribute to the development of cutaneous squamous cell carcinoma. Beta HPVs appear to be not the main drivers of carcinogenesis but rather facilitators of the accumulation of ultraviolet-induced DNA mutations.
Ectopic breast carcinoma presenting as sebaceous cyst left axilla
Authors: Jalali Uzma , Dhebri Alhad , Karip Eszter , Hunt Roger
Published: January 2019

A 43-year-old woman with a positive family history of breast cancer presented with a painless lump in her left axilla for 2 years. Clinical diagnosis was a left axillary sebaceous cyst as the lump was inseparable from the skin. The lesion was excised under local anaesthesia and reported as breast tissue widely infiltrated by an invasive ductal carcinoma (grade 2). The malignancy was not involving the epidermis but <1 mm away from deeper margins. Re-excision of the deeper tissue with an axillary sentinel lymph nodes biopsy was performed and deep margins were reported to be tumour-free with no nodal involvement.
Comparative effectiveness of rituximab, abatacept, and tocilizumab in adults with rheumatoid arthritis and inadequate response to TNF inhibitors: prospective cohort study
Authors: Gottenberg Jacques-Eric , Morel Jacques , Perrodeau Elodie , Bardin Thomas , Combe Bernard , Dougados Maxime , Flipo Rene-Marc , Saraux Alain , Schaeverbeke Thierry , Sibilia Jean , Soubrier Martin , Vittecoq Olivier , Baron Gabriel , Constantin Arnaud , Ravaud Philippe , Mariette Xavier
Published: January 2019

Objective

To compare the effectiveness and safety of three non-tumour necrosis factor (TNF) α inhibitors (rituximab, abatacept, and tocilizumab) in the treatment of rheumatoid arthritis.

Design

Population based prospective study.

Setting

53 university and 54 non-university clinical centres in France.

Participants

3162 adults (>18 years) with rheumatoid arthritis according to 1987 American College of Rheumatology criteria, enrolled in one of the three French Society of Rheumatology registries; who had no severe cardiovascular disease, active or severe infections, or severe immunodeficiency, with follow-up of at least 24 months.

Intervention

Initiation of intravenous rituximab, abatacept, or tocilizumab for rheumatoid arthritis.

Main outcome measure

The primary outcome was drug retention without failure at 24 months. Failure was defined as all cause death; discontinuation of rituximab, abatacept, or tocilizumab; initiation of a new biologic or a combination of conventional disease modifying antirheumatic drugs; or increase in corticosteroid dose >10 mg/d compared with baseline at two successive visits. Because of non-proportional hazards, treatment effects are presented as life expectancy difference without failure (LED
wf
), which measures the difference between average duration of survival without failure.

Results

Average durations of survival without failure were 19.8 months for rituximab, 15.6 months for abatacept, and 19.1 months for tocilizumab. Average durations were greater with rituximab (LED
wf
4.1, 95% confidence interval 3.1 to 5.2) and tocilizumab (3.5, 2.1 to 5.0) than with abatacept, and uncertainty about tocilizumab compared with rituximab was substantial (−0.7, −1.9 to 0.5). No evidence was found of difference between treatments for mean duration of survival without death, presence of cancer or serious infections, or major adverse cardiovascular events.

Conclusion

Among adults with refractory rheumatoid arthritis followed-up in routine practice, rituximab and tocilizumab were associated with greater improvements in outcomes at two years compared with abatacept.
Multicentre, open-label, randomised controlled clinical trial to assess the efficacy and safety of appropriate target values for lipid management in patients who have mild-to-moderate stenotic lesions with high-risk plaques in coronary arteries: study protocol
Authors: Matsuda Morihiro , Kada Akiko , Saito Akiko M , Hasegawa Koji
Published: January 2019

Introduction

To detect patients at high risk of developing myocardial infarction, plaque characteristics as well as the degree of stenosis in coronary arteries should be evaluated. However, unstable plaque or severe calcification detected via coronary artery CT (CACT) is not reflected in risk stratification according to current guidelines. It is hypothesised that patients with high-risk findings on CACT (even those without proven history of coronary artery diseases; CAD) should be strictly managed to lower their low-density lipoprotein cholesterol (LDL-C) levels to targets of secondary prevention. Currently, however, there is no evidence based on prospective randomised intervention studies to prove this hypothesis.

Methods and analysis

Patients with mild-to-moderate stenotic lesions with positive remodelling or severe calcification, but without any history of CAD, will be randomly allocated to group A (reduce LDL-C to <120~160 mg/dL according to the primary prevention criteria based on the Japan Atherosclerosis Society (JAS) Guideline for Prevention of Atherosclerotic Cardiovascular Diseases 2017) and group B (reduce LDL-C to <70 mg/dL according to the secondary prevention criteria for high risk based on the JAS Guideline). They will be strictly managed to achieve the LDL-C targets. We will follow-up and evaluate the composite endpoints consisting of major cardiovascular events (death from CAD, non-fatal myocardial infarction, operation for coronary revascularisation and stroke) and stenosis progression or new stenosis development for 3 years.

Ethics and dissemination

The study was approved by the National Hospital Organization Central Research Ethics Committee. The results of this study are scheduled to be published within 2 years after study completion via conference presentation or journal publication.

Trial registration number

UMIN000031136.
Dairy product consumption and development of cancer: an overview of reviews
Authors: Jeyaraman Maya M , Abou-Setta Ahmed M , Grant Laurel , Farshidfar Farnaz , Copstein Leslie , Lys Justin , Gottschalk Tania , Desautels Danielle , Czaykowski Piotr , Pitz Marshall , Zarychanski Ryan
Published: January 2019

Objectives

To provide a comprehensive systematic overview of current evidence from pooled analyses/meta-analyses and systematic reviews (PMASRs) pertaining to dairy consumption and incident cancer and/or all-cause or cancer-specific mortality.

Design

Overview of reviews.

Setting

Community setting.

Participants

The unit of analysis is PMASRs. A total of 42 PMASRs was included in this overview of reviews.

Interventions/exposures

Any dairy product consumption (eg, milk, yogurt, etc).

Primary and secondary outcomes measures

Primary outcome measure is development of any type of cancer. Secondary outcome measures are all-cause mortality and cancer-specific mortality.

Results

From 9693 citations identified, we included 42 PMASRs (52 study reports) published between 1991 and 2017. Thirty-one (74%) of these was pooled analyses/meta analyses, and only 11 (26%) were systematic reviews and meta-analyses. There was a wide variability in the type of study designs included within the other PMASRs, thus contributing to variable and, in instances, divergent estimates of cancer risk for several cancer subtypes. For example, only one systematic review and meta-analysis exclusively included prospective study designs. Most PMASRs were of low to moderate quality based on the Assessing the Methodological Quality of Systematic Reviews (AMSTAR) scores. The median AMSTAR score was 5 (IQR 2–7). Our overview identified conflicting evidence from PMASRs on association between dairy consumption and incident cancers or mortality. Heterogeneity in summary estimates reflected the inclusion of variable study designs and overall low methodological quality of individual PMASRs.

Conclusions

The association between dairy consumption and cancer risk has been explored in PMASRs with a variety of study designs and of low to moderate quality. To fully characterise valid associations between dairy consumption and risk of cancer and/or mortality rigorously conducted, PMASRs including only high-quality prospective study designs are required.

Trial registration number

CRD42017078463.
Reasoning under uncertainty
Authors: Aitken Colin , Mavridis Dimitris
Published: January 2019

Introduction

It is difficult to reason correctly when the information available is uncertain. Reasoning under uncertainty is also known as probabilistic reasoning.

Methods

We discuss probabilistic reasoning in the context of a medical diagnosis or prognosis. The information available are symptoms for the diagnosis or diagnosis for the prognosis. We show how probabilities of events are updated in the light of new evidence (conditional probabilities/Bayes’ theorem). A resolution is explained in which the support of the information for the diagnosis or prognosis is measured by the comparison of two probabilities, a statistic also known as the likelihood ratio.

Results

The likelihood ratio is a continuous measure of support that is not subject to the discrete nature of statistical significance where a result is either classified as ‘significant’ or ‘not significant’. It updates prior beliefs about diagnoses or prognoses in a coherent manner and enables proper consideration of successive pieces of information.

Discussion

Probabilistic reasoning is not innate and relies on good education. Common mistakes include the ‘prosecutor’s fallacy’ and the interpretation of relative measures without consideration of the actual risks of the outcome, for example, interpretation of a likelihood ratio without taking into account the prior odds.
Responsible use of antibiotics on sheep farms: application at farm level
Authors: Lovatt Fiona , Duncan Jennifer , Hinde Davinia
Published: January 2019

There is currently global concern over rising levels of antibiotic resistance among commensal and pathogenic bacteria in human and animal populations. Unless urgent action is taken by the medical and veterinary professions, it is thought that we will enter a postantibiotic era in which bacterial diseases that were readily treatable with antibiotics will kill once again. Consequently, antibiotic use in both the human and animal health industries has come under intense scrutiny. Long‐held ideas and accepted behavioural norms have rightly been challenged. Progress in the agricultural industries has developed apace with the establishment of the Responsible Use of Medicines in Agriculture Alliance Targets Task Force in December 2016 and Defra's call for the implementation of sector‐specific targets on the use of antibiotics. This article describes how veterinary surgeons and sheep farmers can work together to plan, prevent and protect against three specific disease management issues – infectious lameness, enzootic abortion of ewes and neonatal bacterial infections – by replacing, refining and reducing the use of antibiotics on farm, based on guidelines drawn up by the Sheep Veterinary Society.
International Endocervical Adenocarcinoma Criteria and Classification (IECC): correlation with adverse clinicopathological features and patient outcome
Authors: Hodgson Anjelica , Olkhov-Mitsel Ekaterina , Howitt Brooke E , Nucci Marisa R , Parra-Herran Carlos
Published: January 2019

Aims

The International Endocervical Adenocarcinoma Criteria and Classification (IECC) was recently proposed as an improved method for categorising endocervical adenocarcinoma (EA) into human papillomavirus (HPV)–associated adenocarcinomas (HPVAs) and non-HPV-associated adenocarcinomas (NHPVAs). Such categorisation correlates with patient age and tumour size; however, its association with patient outcome remains to be established.

Methods

Institutional cases of EA with histological material available were selected. Three gynaecological pathologists independently classified all tumours according to the IECC with consensus review used when necessary. Clinicopathologic variables were recorded for each case.

Results

Of a total of 87 EAs, 71 (82%) were classified as HPVA and 16 (18%) as NHPVA. Among HPVA, most were usual type (51/71, 72%) followed by mucinous not otherwise specified (10/71, 14%) and invasive stratified mucin-producing carcinoma (ISMC, 8/71, 11%). Most NHPVAs were of gastric type (12/16, 71%) followed by clear cell and mesonephric (two each, 12%). Compared with HPVAs, NHPVAs were significantly associated with older age (p<0.001), larger horizontal extent (p=0.013), greater depth of invasion (p=0.003), lymphovascular space invasion (p<0.001), advanced stage (p<0.001) and invasive pattern C (p<0.001). On univariate analysis, worse disease-free survival (DFS) and disease-specific survival (DSS) correlated with NHPVA group. Among the HPVA subtypes, ISMC showed worse DFS and DSS compared with other HPVA types.

Conclusions

The simple morphological approach of the IECC appears to be prognostically valuable. NHPVA (in particular gastric type) and ISMC (a recently recognised subset of HPVA) have an adverse outcome and their recognition following the IECC is important. We provide further evidence to replace the current WHO classification with the IECC.
Short-term risk of major adverse cardiovascular events or congestive heart failure in patients with psoriatic arthritis or psoriasis initiating a biological therapy: a meta–analysis of randomised controlled trials
Authors: Champs Bénédicte , Degboé Yannick , Barnetche Thomas , Cantagrel Alain , Ruyssen-Witrand Adeline , Constantin Arnaud
Published: January 2019

Objective

The objective was to investigate the short-term risk of major adverse cardiovascular events (MACEs) or congestive heart failure (CHF) in patients with psoriatic arthritis (PsA) or psoriasis initiating a biological therapy.

Methods

Screening for the study was carried out using MEDLINE, Cochrane and Embase, from the inception of the database to December 2017. Randomised controlled trials (RCTs) of anti-tumour necrosis factor (TNF), anti-interleukin (IL)12/23, anti-IL23 and anti-IL17 agents for the treatment of PsA or psoriasis were included. Two investigators independently extracted MACEs or CHF data reported during the placebo-controlled phase. The primary outcome measures were the incidence of MACEs or CHF.

Results

Of 753 references screened, 62 articles were selected, and 12 articles were added by manual searches. Accordingly 77 RCTs were included in the meta-analysis (MA) (10 174 patient-years (P-Y)). No significant difference was observed in MACE incidences in patients receiving anti-TNF, anti-IL12/23, anti-IL23 or anti-IL17 agents in comparison to the placebo. However, 10 MACEs were observed in the anti-IL12/23 group (1150 P-Y) compared with 1 in the placebo group (652 P-Y), with 0.01 −0.00 to 0.02 event/P-Y risk difference, which is not statistically significant. This trend was not observed in the anti-IL23 group. No significant difference was observed in CHF incidence in patients receiving biological agents in comparison to placebo.

Conclusion

This MA of 77 RCTs did not reveal any significant change in the short-term risk of MACE or CHF in patients with PsA or psoriasis initiating a biological therapy.
Indicator condition-guided HIV testing with an electronic prompt in primary healthcare: a before and after evaluation of an intervention
Authors: Cayuelas Redondo Laia , Ruíz Marina , Kostov Belchin , Sequeira Ethel , Noguera Pablo , Herrero Maria Alba , Menacho Ignacio , Barba Olga , Clusa Thaïs , Rifa Benet , González de la Fuente Eva María , González Redondo Eva , García Felipe , Sisó Almirall Antoni , León Agathe
Published: January 2019

Objective

Indicator condition (IC)-guided HIV testing is a strategy for the diagnosis of patients with HIV. The aim of this study was to assess the impact on the proportion of HIV tests requested after the introduction of an electronic prompt instructing primary healthcare (PHC) physicians to request an HIV test when diagnosing predefined IC.

Methods

A prospective interventional study was conducted in 2015 in three PHC centres in Barcelona to assess the number of HIV test requests made during the implementation of an electronic prompt. Patients aged 18–65 years without HIV infection and with a new diagnosis of predefined IC were included. The results were compared with preprompt (2013) and postprompt data (2016).

Results

During the prompt period, 832 patients presented an IC (median age 41.6 years [IQR 30–54], 48.2% female). HIV tests were requested in 296 individuals (35, 6%) and blood tests made in 238. Four HIV infections were diagnosed (positivity rate 1.7%, 95% CI 0.5% to 4.4%). The number of HIV tests requested based on IC increased from 12.6% in 2013 to 35.6% in 2015 (p<0.001) and fell to 17.9% after removal of the prompt in 2016 (p<0.001). Younger patient age (OR 0.97, 95% CI 0.96 to 0.98), birth outside Spain (OR 1.53, 95% CI 1.06 to 2.21) and younger physician age (OR 0.97, 95% CI 0.96 to 0.99) were independent predictive factors for an HIV test request during the prompt period. The electronic prompt (OR 3.36, 95% CI 2.70 to 4.18) was the factor most closely associated with HIV test requests. It was estimated that 10 (95% CI 3.0 to 26.2) additional new cases would have been diagnosed if an HIV test had been performed in all patients presenting an IC.

Conclusions

A significant increase in HIV test requests was observed during the implementation of the electronic prompt. The results suggest that this strategy could be useful in increasing IC-guided HIV testing in PHC centres.
Quantifying subclinical trauma associated with calving difficulty, vigour, and passive immunity in newborn beef calves
Authors: Pearson Jennifer M , Homerosky Elizabeth R , Caulkett Nigel A , Campbell John R , Levy Michel , Pajor Edmond A , Windeyer M Claire
Published: January 2019

This cross‐sectional study quantifies subclinical trauma associated with calving difficulty, calf vigour, and passive immunity (PI) in newborn beef calves. The degree of calving difficulty was categorised as: unassisted, easy assist (one or two people manually pulling to deliver the calf) and difficult assist (more than two people pulling, a fetal extractor (ie, calf jack), or caesarean section). Vigour assessment occurred at 10 minutes and blood sampling at 24 hours after birth in 77 beef calves. The measured blood parameters associated with trauma were creatine kinase (CK), aspartate aminotransferase (AST), and haptoglobin. Serum IgG concentration was measured, and an IgG concentration at least 24 g/l was considered as adequate PI. Calving difficulty was associated with elevated levels of CK (P=0.002) and AST (P=0.01), weak suckle reflex (P=0.001), abnormal mucous membrane colour (P<0.0001), and decreased odds of adequate PI (P=0.004). Elevated levels of CK and AST were associated with abnormal mucous membrane colour, incomplete tongue withdrawal and weak suckle reflex at birth (P<0.001). An incomplete tongue withdrawal (P=0.005) and weak suckle reflex (P=0.02) were associated with decreased IgG concentrations. Abnormal mucous membrane colour, incomplete tongue withdrawal, and a weak suckle reflex were associated with decreased odds of having adequate PI (P<0.05). Haptoglobin was not associated with any of the parameters measured. Subclinical trauma was associated with calving difficulty, decreased vigour and decreased odds of having adequate PI. Understanding the impacts of a traumatic birth may aid the development of management strategies for compromised newborn beef calves.
Liver mitochondrial respiratory plasticity and oxygen uptake evoked by cobalt chloride in rats with low and high resistance to extreme hypobaric hypoxia
Authors: Kurhaluk Natalia , Lukash Oleksaner , Nosar Valentina , Portnychenko Alla , Portnichenko Volodymyr , Wszedybyl-Winklewska Magdalena , Winklewski Pawel J.
Published: January 2019

High-altitude intolerance and consequently high-altitude sickness, is difficult to predict. Liver is an essential organ in glucose and lipid metabolism, and may play key role in the adaptation to high altitude. In response to extreme high altitude, mitochondrial respiration exhibits changes in substrate metabolism, mitochondrial electron transport chain activity, and respiratory coupling. We determined the cobalt chloride (CoCl2) effects on liver mitochondrial plasticity and oxygen uptake in rats with low resistance (LR) and high resistance (HR) to extreme hypobaric hypoxia. The polarographic method proposed by Chance and Williams was used as a simple and effective tool to trace mitochondrial functionality and oxygen consumption. HR rats had more efficient processes of NADH- and FAD-generated mitochondrial oxidation. CoCl2promoted more efficient NADH-generated and diminished less efficient FAD-generated mitochondrial respiratory reactions in HR rats. CoCl2diminished both aerobic and anaerobic processes in LR rats. Glutamate and pyruvate substrates of NADH-generated mitochondrial pathways were highly affected by CoCl2. Red blood cells acted as cobalt depots in HR and LR rats. We have unveiled several mechanisms leading to differentiated mitochondrial respiratory responses to hypobaric hypoxia in LR and HR rats. Our study strongly supports the existence of adaptive liver mitochondrial plasticity to extreme hypoxia.
Weakly exceptional singularities of log del Pezzo surfaces
Authors: Kim In-Kyun , Won Joonyeong
Published: January 2019

We complete the computation of global log canonical thresholds, or equivalently alpha invariants, of quasi-smooth well-formed complete intersection log del Pezzo surfaces of amplitude 1 in weighted projective spaces. As an application, we prove that they are weakly exceptional. And we investigate the super-rigid affine Fano 3-folds containing a log del Pezzo surface as boundary.
Generalization of uniqueness theorem for meromorphic mappings sharing hyperplanes
Authors: Quang Si Duc
Published: January 2019

In this paper, by introducing a new method in estimating the counting function of the auxiliary function, we prove a new generalization of uniqueness theorems for meromorphic mappings into [Formula: see text] which share few hyperplanes regardless of multiplicities. Our result improves the previous results in this topic. Moreover, our proof is simpler than the previous proofs.