bluuebunny/crossref_metadata_2025 huggingface dataset:
Comorbidity of dementia and age-related macular degeneration calls for clinical awareness: a meta-analysis
Authors: Rong Shi Song , Lee Bo Yee , Kuk Andrew K , Yu Xin Ting , Li Suki S , Li Jian , Guo Yanjun , Yin Yilin , Osterbur David L , Yam Jason C S , Cheung Carol Y , Chen Li Jia , Wong Tien Y , Ng Danny Siu-Chun
Published: April 2019

Aim

To determine the association between dementia and age-related macular degeneration (AMD) using meta-analysis.

Methods

We searched in the MEDLINE, EMBASE, Web of Knowledge, PsycInfo and Cochrane database of systematic reviews for studies published from March 1959 to March 2018. We included cross-sectional, case–control and cohort studies that evaluated the association of dementia/Alzheimer's disease (AD) with AMD (as outcome) and the association of AMD with dementia/AD (as outcome). Studies that compared cognitive functions between AMD and controls were also included. The summary outcomes, namely odds ratio (OR), relative risk, mean differences and corresponding 95% CIs, were estimated using random effects models. We performed sensitivity analysis based on study quality and individual study effect to control for potential biases.

Results

Among 2159 citation records, we identified 21 studies consisting of 7 876 499 study subjects for meta-analysis. Patients with dementia (padjusted≤0.017, OR≥1.24, I2≤9%) or AD (p=0.001, ORunadjusted=2.22, I2=50%) were at risk for AMD, particularly for late AMD (padjusted<0.001, OR=1.37, I2=0). AMD was also significantly associated with increased risk of AD/cognitive impairment (padjusted=0.037, OR=2.42, I2=38%). Moreover, patients with AMD had poorer cognitive functions when compared with controls, including Mini-Mental State Examination (p<0.001, I2≤79%) and Trail Making Test A (p<0.001, I2=0). Sensitivity analysis and Egger’s test indicated our results were less likely biased.

Conclusions

A significant association between dementia/AD and AMD calls for greater clinical awareness. The cost-effectiveness of routine screening for the other condition in patients with primary diagnosis of dementia/AD or AMD requires further study.
Excess risk of lower extremity amputations in people with type 1 diabetes compared with the general population: amputations and type 1 diabetes
Authors: Ólafsdóttir Arndís Finna , Svensson Ann-Marie , Pivodic Aldina , Gudbjörnsdottir Soffia , Nyström Thomas , Wedel Hans , Rosengren Annika , Lind Marcus
Published: April 2019

Objective

This study investigates how the excess risk of lower extremity amputations (amputations) in people with type 1 diabetes mellitus (DM) differs from the general population by diabetes duration, glycemic control, and renal complications.

Research design and methods

We analyzed data from people with type 1 DM from the Swedish National Diabetes Register without prior amputation from January 1998 to December 2013. Each person (n=36 872) was randomly matched with five controls by sex, age, and county (n=184 360) from the population without diabetes. All were followed until first amputation, death or end of follow-up.

Results

The overall adjusted HR for all amputation was 40.1 (95% CI 32.8 to 49.1) for type 1 DM versus controls. HR increased with longer diabetes duration. The incidence of amputation/1000 patient-years was 3.18 (95% CI 2.99 to 3.38) for type 1 DM and 0.07 (95% CI 0.05 to 0.08) for controls. The incidence decreased from 1998–2001 (3.09, 95% CI 2.56 to 3.62) to 2011–2013 (2.64, 95% CI 2.31 to 2.98). The HR for major amputations was lower than for minor amputations and decreased over the time period (p=0.0045). Worsening in glycemic control among patients with diabetes led to increased risk for amputation with an HR of 1.80 (95% CI 1.72 to 1.88) per 10 mmol/mol (1%) increase in hemoglobin A1c.

Conclusions

Although the absolute risk of amputation is relatively low, the overall excess risk was 40 times that of controls. Excess risk was substantially lower for those with good glycemic control and without renal complications, but excess risk still existed and is greatest for minor amputations.
Co-prescription patterns of cardiovascular preventive treatments: a cross-sectional study in the Aragon worker’ health study (Spain)
Authors: Aguilar-Palacio Isabel , Malo Sara , Lallana MªJesús , Feja Cristina , González Juan , Moreno-Franco Belén , Rabanaque MªJosé
Published: April 2019

Objectives

To identify cardiovascular disease (CVD) preventive treatments combinations, among them and with other drugs, and to determine their prevalence in a cohort of Spanish workers.

Design

Cross-sectional study.

Setting

Aragon Workers’ Health Study (AWHS) cohort in Spain.

Participants

5577 workers belonging to AWHS cohort. From these subjects, we selected those that had, at least, three prescriptions of the same therapeutic subgroup in 2014 (n=4605).

Primary and secondary outcome measures

Drug consumption was obtained from the Aragon Pharmaceutical Consumption Registry (Farmasalud). In order to know treatment utilisation, prevalence analyses were conducted. Frequent item set mining techniques were applied to identify drugs co-prescription patterns. All the results were stratified by sex and age.

Results

42.3% of men and 18.8% of women in the cohort received, at least, three prescriptions of a CVD preventive treatment in 2014. The most prescribed CVD treatment were antihypertensives (men: 28.2%, women 9.2%). The most frequent association observed among CVD preventive treatment was agents acting on the renin-angiotensin system and lipid-lowering drugs (5.1% of treated subjects). Co-prescription increased with age, especially after 50 years old, both in frequency and number of associations, and was higher in men. Regarding the association between CVD preventive treatments and other drugs, the most frequent pattern observed was lipid-lowering drugs and drugs used for acid related disorders (4.2% of treated subjects).

Conclusions

There is an important number of co-prescription patterns that involve CVD preventive treatments. These patterns increase with age and are more frequent in men. Mining techniques are a useful tool to identify pharmacological patterns that are not evident in the individual clinical practice, in order to improve drug prescription appropriateness.
Exploring the impacts of the 2012 Health and Social Care Act reforms to commissioning on clinical activity in the English NHS: a mixed methods study of cervical screening
Authors: Hammond Jonathan , Mason Thomas , Sutton Matt , Hall Alex , Mays Nicholas , Coleman Anna , Allen Pauline , Warwick-Giles Lynsey , Checkland Kath
Published: April 2019

Objectives

Explore the impact of changes to commissioning introduced in England by the Health and Social Care Act 2012 (HSCA) on cervical screening activity in areas identified empirically as particularly affected organisationally by the reforms.

Methods

Qualitative followed by quantitative methods. Qualitative: semi-structured interviews (with NHS commissioners, managers, clinicians, senior administrative staff from Clinical Commissioning Groups (CCGs), local authorities, service providers), observations of commissioning meetings in two metropolitan areas of England. Quantitative: triple-difference analysis of national administrative data. Variability in the expected effects of HSCA on commissioning was measured by comparing CCGs working with one local authority with CCGs working with multiple local authorities. To control for unmeasured confounders, differential changes over time in cervical screening rates (among women, 25–64 years) between CCGs more and less likely to have been affected by HSCA commissioning organisational change were compared with another outcome—unassisted birth rates—largely unaffected by HSCA changes.

Results

Interviewees identified that cervical screening commissioning and provision was more complex and ‘fragmented’, with responsibilities less certain, following the HSCA. Interviewees predicted this would reduce cervical screening rates in some areas more than others. Quantitative findings supported these predictions. Areas where CCGs dealt with multiple local authorities experienced a larger decline in cervical screening rates (1.4%) than those dealing with one local authority (1.0%). Over the same period, unassisted deliveries decreased by 1.6% and 2.0%, respectively, in the two groups.

Conclusions

Arrangements for commissioning and delivering cervical screening were disrupted and made more complex by the HSCA. Areas most affected saw a greater decline in screening rates than others. The fact that this was identified qualitatively and then confirmed quantitatively strengthens this finding. The study suggests large-scale health system reforms may have unintended consequences, and that complex commissioning arrangements may be problematic.
Visual impairment and objectively measured physical activity and sedentary behaviour in US adolescents and adults: a cross-sectional study
Authors: Smith Lee , Jackson Sarah E , Pardhan Shahina , López-Sánchez Guillermo Felipe , Hu Liang , Cao Chao , Vancampfort Davy , Koyanagi Ai , Stubbs Brendon , Firth Joseph , Yang Lin
Published: April 2019

Objectives

To compare levels of physical activity and sedentary time in a representative sample of US adolescents and adults with and without visual impairment.

Design

Cross-sectional analyses were carried out using data from the National Health and Nutrition Examination Survey.

Participants

The study population consisted of 6001 participants (adolescents n=1766, adults n=4235). The present analysis aggregated data from 2003 to 2004 and 2005–2006.

Measures

Objective physical activity and sedentary behaviour assessment was conducted over 7 days. Distance visual acuity was measured for each eye in all participants 12 years and older. Participants’ vision was categorised as: normal vision, uncorrected refractive error, non-refractive visual impairment. We estimated the sex-specific linear associations between presenting vision and objectively measured physical activity and sedentary patterns using adjusted generalised linear models in adolescents and adults.

Results and conclusions

Adolescents with uncorrected refractive error and non-refractive visual impairment did not accumulate higher levels of sedentary time or lower levels of moderate-to-vigorous physical activity (MVPA) compared with those with normal vision. We observed no association between vision status and accelerometer measured MVPA in adults aged 20–49 years. We observed more time spent sedentary among females 20–49 years old with non-refractive visual impairment compared with those presenting normal vision (mean difference 329.8 min/week, 95% CI: 12.5 to 647.0). Adults 50 years and older with non-refractive visual impairment appeared to accumulate less lifestyle physical activity, particularly in women (mean difference −82.8 min/week, 95% CI: −147.8 to −17.8). Adult women with non-refractive visual impairment have lower levels of lifestyle physical activity and higher levels of sedentary time than those with normal vision. Taken together, these findings highlight the need for interventions to promote physical activity and reduce sedentary time in adult populations with visual impairment, specifically adult women.
Opportunities and challenges of a novel cardiac output response to stress (CORS) test to enhance diagnosis of heart failure in primary care: qualitative study
Authors: Charman Sarah , Okwose Nduka , Maniatopoulos Gregory , Graziadio Sara , Metzler Tamara , Banks Helen , Vale Luke , MacGowan Guy A , Seferović Petar M , Fuat Ahmet , Deaton Christi , Mant Jonathan , Hobbs Richard F D , Jakovljevic Djordje G
Published: April 2019

Objective

To explore the role of the novel cardiac output response to stress (CORS), test in the current diagnostic pathway for heart failure and the opportunities and challenges to potential implementation in primary care.

Design

Qualitative study using semistructured in-depth interviews which were audio recorded and transcribed verbatim. Data from the interviews were analysed thematically using an inductive approach.

Setting

Newcastle upon Tyne, UK.

Participants

Fourteen healthcare professionals (six males, eight females) from primary (general practitioners (GPs), nurses, healthcare assistant, practice managers) and secondary care (consultant cardiologists).

Results

Four themes relating to opportunities and challenges surrounding the implementation of the new diagnostic technology were identified. These reflected that the adoption of CORS test would be an advantage to primary care but the test had barriers to implementation which include: establishment of clinical utility, suitability for immobile patients and cost implication to GP practices.

Conclusion

The development of a simple non-invasive clinical test to accelerate the diagnosis of heart failure in primary care maybe helpful to reduce unnecessary referrals to secondary care. The CORS test has the potential to serve this purpose; however, factors such as cost effectiveness, diagnostic accuracy and seamless implementation in primary care have to be fully explored.
Exploring standardisation, monitoring and training of medical devices in assisted vaginal birth studies: protocol for a systematic review
Authors: Hotton Emily J , Renwick Sophie , Barnard Katie , Lenguerrand Erik , Wade Julia , Draycott Tim , Crofts Joanna F , Blencowe Natalie S
Published: April 2019

Introduction

Assisted vaginal birth (AVB) can markedly improve maternal and neonatal outcomes arising from complications in the second stage of labour. Historically, both forceps and ventouse devices have been used to assist birth; however, they are not without risk and are associated with complications, such as cephalohaematoma, retinal haemorrhage and perineal trauma. As new devices are developed to overcome the limitations of existing techniques, it is necessary to establish their efficacy and effectiveness within randomised controlled trials (RCTs). A major challenge of evaluating complex interventions (ie, invasive procedures/devices used to assist vaginal birth) is ensuring they are delivered as intended. It can be difficult to standardise intervention delivery and monitor fidelity, and account for the varying expertise of clinicians (accoucher expertise). This paper describes the protocol for a systematic review aiming to investigate the reporting of device standardisation, monitoring and training in trials evaluating complex interventions, using AVB as a case study.

Methods and analysis

Relevant keywords and subject headings will be used to conduct a comprehensive search of MEDLINE, Embase, Cochrane Central Register of Controlled Trials, Cumulative Index of Nursing and Allied Health Literature and ClinicalTrials.gov, for RCTs and pilot/feasibility studies evaluating AVB. Abstracts will be screened and full-text articles of eligible studies reviewed for inclusion. Information relating to the following categories will be extracted: standardisation of device use (ie, descriptions of operative steps, including mandatory/flexible parameters), monitoring of intervention delivery (ie, intervention fidelity, confirming that an intervention is delivered as intended) and accoucher expertise (ie, entry criteria for participation, training programmes and previous experience with the device). Risk of bias of included studies will be assessed.

Ethics and dissemination

Ethical approval is not required because primary data will not be collected. Findings will be disseminated by publishing in a peer-reviewed journal and presentations at relevant conferences.
Designing and evaluating provider results-based financing for tuberculosis care in Georgia: a realist evaluation protocol
Authors: Marchal Bruno , Giralt Ariadna Nebot , Sulaberidze Lela , Chikovani Ivdity , Abejirinde Ibukun-Oluwa Omolade
Published: April 2019

Introduction

In 2016, Georgian researchers and policymakers were developing a policy to improve the performance of the national tuberculosis (TB) control programme. The research programme ‘Designing and Evaluating Provider Results-Based Financing for Tuberculosis Care in Georgia: Understanding Costs, Mechanisms of Effect and Impact (Results4TB)’ was initiated to inform the policy formulation phase, document the policy implementation and assess the effectiveness, cost-effectiveness and the processes of change. To achieve this, the research team intends to combine an impact evaluation, a cost-effectiveness study and a realist evaluation (RE) within an overarching theory-informed design. This protocol is the RE component of the programme.

Methods

A realist methodological approach will be adopted to guide the research design and evaluation. RE answers the question of ‘what works in which conditions for whom?’ and starts with the development of an initial programme theory (IPT). The IPT will feed into other phases of the realist research cycle (study design, data collection, data analysis and synthesis and theory refinement). Data will be collected in a multiple embedded case study design (five intervention and three control sites) through document reviews, in-depth interviews, non-participant observations and context mapping at facility and national levels. Additional data from other research components (cost-effectiveness and impact evaluation) will aid data triangulation.

Ethics and dissemination

The Institutional Review Boards of the National Centre for Disease Control and Public Health in Georgia (ref. IRB # 2018–019) and the Institute of Tropical Medicine, Antwerp (ref. IRB #- 1240/18) have granted ethical approval to the study.

Trial registration number

ISRCTN14667607
Hung up on mobile phones
Authors: Chapman Simon
Published: April 2019

Uncertainty about potential health risk
Emergency!
Authors: Howell David , Montgomery Hugh , Marshall Richard , Goldsack Neil
Published: April 2019

In the eighth part of our series,
Neil Goldsack, Richard Marshall, Hugh Montgomery,
and
David Howell
instruct you how to deal with patients who have had a cardiac arrest
Child and adolescent psychiatry
Authors: Goldin Jonathon
Published: April 2019

Childhood psychiatric problems are less intractable than their adult counterparts. Jonathon Goldin reviews the branch of psychiatry with development on its side
Thalidomide--a regret of the past, but a hope for the future?
Authors: Muggleton Ellis
Published: April 2019

Ellis Muggleton examines the chequered history of one of this century's most controversial drugs
Brooks' node
Authors: Brooks Philip
Published: April 2019

Philip Brooks
gains first hane experiance of a health scare but lives to tell the tale
Optimization of the lubrication system in a turbocharged engine
Authors: Lee Cho-Yu , Veera Dani Joseph , Chen Huan-Yuan , Chang Jui-Hung , Hung Kao-Ruei
Published: April 2019

Lubricating the engine reciprocating components effectively against various engine speeds is significant for a proper lubrication system. This paper presents the lubrication system optimization of a twin cylinder 700 c.c. turbocharged engine. A couple of modifications were tested including correction of ducts misalignment, consistence diameter of ducts and replacement of a low flow resistance oil cooler. Compared to the base engine, experimental results prove that differential pressure (DP) between the oil pump and main oil gallery has been decreased to a minimum 19% and maximum 54% at engine speed between 2000 and 7000 rpm. The lower the pressure drop, the lower the flow resistance. Thus, mechanical loss has also been improved.
Effect of nanosecond and femtosecond pulse laser on the formation of WS2 nanostructures and field emission characteristics
Authors: Koinkar Pankaj , Sasaki Kohei , Furube Akihiro , Murai Kei-Ichiro , Moriga Toshihiro , Shinde Manish , Rane Sunit , Bhopale Somnath , More Mahendra A.
Published: April 2019

The pulse laser ablation is a simple and direct method used for the generation of nanostructures in liquid environment. In this paper, formation of tungsten sulfide [Formula: see text] nanostructures has been carried out using nanosecond (ns) and femtosecond (fs) laser ablation with ablation time 120 min. In addition, the field emission studies were performed of the prepared sample. The characterization techniques such as the transmission electron microscopy (TEM), X-ray diffraction (XRD) and UV-visible spectroscopy have been used to confirm the surface morphology as well as structural details. It is observed that the laser pulse regime plays a vital role on the size reduction of [Formula: see text] nanostructure. The X-ray spectra reveal the formation of [Formula: see text] nanoparticles for ns laser ablation, while [Formula: see text] nanosheets for fs laser ablation. The TEM images indicate that the transformation of [Formula: see text] microsheet into nanosheet of the size about 15–200 nm for the sample treated with ns laser and fs laser ablation. Also, the results clearly shows the improvement in the field emission characteristics for laser ablated [Formula: see text] nanosheets. The enhanced field emission characteristics is attributed to the formation and separation of few layer [Formula: see text] nanosheets. The [Formula: see text] nanostructures may have great potential for the applications in optoelectronic devices.
Fire-Resistance of Eccentrically Loaded Rectangular Concrete-Filled Steel Tubular Slender Columns Incorporating Interaction of Local and Global Buckling
Authors: Kamil Ghanim Mohammed , Liang Qing Quan , Hadi Muhammad N. S.
Published: April 2019

A mathematical model using the fiber approach is presented in this paper for quantifying the strength and fire-resistance of eccentrically loaded slender concrete-filled steel tubular (CFST) columns with rectangular sections incorporating the interaction of local and global buckling. The model utilizes the thermal simulator to ascertain the temperature distribution in cross-sections, and the nonlinear global buckling analysis to predict the interaction responses of local and global buckling of loaded CFST slender columns to fire effects. The initial geometric imperfection, air gap between the concrete and steel tube, tensile concrete strength, deformations caused by preloads, and temperature-dependent material behavior are included in the formulation. The computational theory, modeling procedure and numerical solution algorithms are described. The computational model is verified by existing experimental and numerical results. The structural responses and fire-resistance of CFST columns of rectangular sections exposed to fire are investigated. The mathematical model proposed is demonstrated to be an efficient computer simulator for the fire-performance of slender CFST columns loaded eccentrically.
Radial basis function neural networks of Hankel translates as universal approximators
Authors: Marrero Isabel
Published: April 2019

Radial basis function neural networks (RBFNNs) of Hankel translates of order [Formula: see text] with a continuous activation function [Formula: see text] for which the limit [Formula: see text] exists are shown to possess the universal approximation property in spaces of continuous and of [Formula: see text]-integrable functions, [Formula: see text], on (compact subsets of) [Formula: see text] if, and only if, [Formula: see text] is not an even polynomial. This extends to the class of RBFNNs under consideration a result already known for RBFNNs of standard translates.
Near-optimal Linear Decision Trees for k-SUM and Related Problems
Authors: Kane Daniel M. , Lovett Shachar , Moran Shay
Published: April 2019

We construct near-optimal linear decision trees for a variety of decision problems in combinatorics and discrete geometry. For example, for any constant
k
, we construct linear decision trees that solve the
k
-SUM problem on
n
elements using
O
(
n
log
2
n
) linear queries. Moreover, the queries we use are comparison queries, which compare the sums of two
k
-subsets; when viewed as linear queries, comparison queries are 2
k
-sparse and have only { −1,0,1} coefficients. We give similar constructions for sorting sumsets A+B and for solving the SUBSET-SUM problem, both with optimal number of queries, up to poly-logarithmic terms.

Our constructions are based on the notion of “inference dimension,” recently introduced by the authors in the context of active classification with comparison queries. This can be viewed as another contribution to the fruitful link between machine learning and discrete geometry, which goes back to the discovery of the VC dimension.
The Association between DRD3 Ser9Gly Polymorphism and Depression Severity in Parkinson’s Disease
Authors: Zhi Yan , Yuan Yongsheng , Si Qianqian , Wang Min , Shen Yuting , Wang Lina , Zhang Hui , Zhang Kezhong
Published: April 2019

More and more evidence suggests that dopamine receptor D3 gene (DRD3) plays an important role in the clinical manifestations and the treatment of Parkinson’s disease (PD). DRD3 Ser9Gly polymorphism is the most frequently studied variant point. Our aim was to investigate the potential effect of DRD3 Ser9Gly polymorphism on modulating resting-state brain function and associative clinical manifestations in PD patients. We consecutively recruited 61 idiopathic PD patients and 47 healthy controls (HC) who were evaluated by clinical scales, genotyped for variant Ser9Gly in DRD3, and underwent resting-state functional magnetic resonance imaging. Based on DRD3 Ser9Gly polymorphism, PD patients and HCs were divided into four subgroups. Then, two-way analysis of covariance (ANCOVA) was applied to investigate main effects and interactions of PD and DRD3 Ser9Gly polymorphism on the brain function via amplitude of low-frequency fluctuations (ALFF) approach. The association between DRD3 Ser9Gly-modulated significantly different brain regions, and clinical manifestations were detected by Spearman’s correlations. PD patients exhibited decreased ALFF values in the right inferior occipital gyrus, lingual gyrus, and fusiform gyrus. A significant difference in the interaction of “groups × genotypes” was observed in the right medial frontal gyrus. The ALFF value of the cluster showing significant interactions was positively correlated with HAMD-17 scores (r=0.489, p=0.011) and anhedonia scores (r=0.512, p=0.008) in PD patients with the Ser/Gly or Gly/Gly genotypes. Therefore, D3 gene Ser9Gly polymorphism might be associated with the severity of depression characterized by anhedonia in PD patients.
Percutaneous Valvular Closure Followed by TAV-in-TAV Intervention during a Single Procedure in order to Treat a Severe Paravalvular Leak after Performing TAVI in a Bicuspid Aortic Stenosis
Authors: Tzimas Georgios , Eeckhout Eric , Antiochos Panagiotis , Roguelov Christan , Fournier Stephane , Harbaoui Brahim , Monney Pierre , Muller Olivier
Published: April 2019

In an era where transcatheter aortic valve implantation (TAVI) indications and utilization are expanding beyond high-risk patients, paravalvular leak remains the intervention’s Achilles heel. Effective reduction of paravalvular leak is important in order to ensure an optimal clinical outcome. We present here the first case report in which percutaneous valvular closure using Amplatzer plugs followed by a TAV-in-TAV intervention during the same procedure managed to resolve a severe paravalvular leak with haemodynamic instability, after TAVI for a bicuspid aortic stenosis.
Software Defect Prediction via Attention-Based Recurrent Neural Network
Authors: Fan Guisheng , Diao Xuyang , Yu Huiqun , Yang Kang , Chen Liqiong
Published: April 2019

In order to improve software reliability, software defect prediction is applied to the process of software maintenance to identify potential bugs. Traditional methods of software defect prediction mainly focus on designing static code metrics, which are input into machine learning classifiers to predict defect probabilities of the code. However, the characteristics of these artificial metrics do not contain the syntactic structures and semantic information of programs. Such information is more significant than manual metrics and can provide a more accurate predictive model. In this paper, we propose a framework called defect prediction via attention-based recurrent neural network (DP-ARNN). More specifically, DP-ARNN first parses abstract syntax trees (ASTs) of programs and extracts them as vectors. Then it encodes vectors which are used as inputs of DP-ARNN by dictionary mapping and word embedding. After that, it can automatically learn syntactic and semantic features. Furthermore, it employs the attention mechanism to further generate significant features for accurate defect prediction. To validate our method, we choose seven open-source Java projects in Apache, using F1-measure and area under the curve (AUC) as evaluation criteria. The experimental results show that, in average, DP-ARNN improves the F1-measure by 14% and AUC by 7% compared with the state-of-the-art methods, respectively.
Interventions to Increase Blood Donation among Ethnic/Racial Minorities: A Systematic Review
Authors: Makin Jennifer K. , Francis Kate L. , Polonsky Michael J. , Renzaho Andre M. N.
Published: April 2019

Ethnic/racial minorities are under-represented in blood donor populations in most developed countries. This is of particular concern where minorities differ from a country’s majority population in terms of blood or tissue typing, especially where type matching is required for effective management of rare disorders such as sickle-cell disease that require multiple transfusions. This systematic review assessed the effectiveness of interventions to increase blood donation among ethnic/racial minority populations in developed countries. We searched MEDLINE, EMBASE, CINAHL, and ProQuest on 20 March 2017 with no date restrictions and supplemented this with searches on Google Scholar, blood collection agency websites, reference lists of included studies, and a forward search of citations of included studies. We included intervention studies designed to increase recruitment and/or retention of adult, ethnic/racial minority blood donors in developed countries. The review identified eight studies reported in nine publications. Six were conducted in the USA with African Americans. Four studies reported on multifaceted, community-based interventions; three reported on one-off information and educational video interventions, presented face-to-face, or delivered via post or e-mail. The level of evidence for efficacy was low, and the majority of studies were assessed as having some risk of bias related to one or more methodological issues. All eight studies reported positive outcomes in blood donation and/or intention to donate. Seven trials found that the intervention increased presentation for donation, and three found an increase in the percentage of new donors from the ethnic minority targeted. The review findings demonstrate that it is possible to design and implement effective interventions to motivate individuals from ethnic/racial minority groups to donate blood. One-off interventions may be as effective as multifaceted, community-based interventions. There was insufficient evidence to recommend particular interventions, and future research should empirically assess alternative interventions using robust study designs.
Effect of N-Acetyl Cysteine on Intracerebroventricular Colchicine Induced Cognitive Deficits, Beta Amyloid Pathology, and Glial Cells
Authors: Joy Teresa , Rao Muddanna S. , Madhyastha Sampath , Pai Keshav
Published: April 2019

Among the many factors responsible for the cognitive decline in Alzheimer’s disease, beta amyloid protein and plaque formation is crucial. This amyloid pathology is associated with activation of glial cells and oxidative stress but whether oxidative stress activates beta amyloid protein in the neurons is not clear. Further the expression of microglia is also known to vary during pathogenesis of beta amyloid plaques. The aim of the present study is to evaluate the antioxidant effect of NAC on amyloid pathology and cognition and also to investigate the link between amyloid pathology and glial cells activation. Intracerebroventricular colchicine in rats known mimics human AD in many aspects including memory loss, oxidative stress, and hyper phosphorylation of tau protein. The animal groups consisted of age matched control, sham operated, AD, and NAC treated in AD models of rats. Cognitive function was evaluated in active avoidance test; beta amyloid protein, beta amyloid plaques, astrocytes, and microglia cells were quantified using immunohistochemistry in hippocampal and prefrontal cortices. Colchicine has resulted in significant cognitive loss, increased intraneuronal beta amyloid protein expression, increased reactive astrocytes, and activated microglia in all the regions of the hippocampus and prefrontal cortices. The antioxidant NAC has reversed the cognitive deficits and inhibited microglia activation but failed to inhibit BAP expression and astrocytosis. Intraneuronal BAP accumulation is deleterious and known to adversely affect cognition, but in this study in spite of intraneuronal BAP accumulation, the cognition is restored. It can be postulated that NAC might have reversed the effect of intraneuronal beta amyloid protein by acting on some downstream compensatory mechanisms which needs to be explored.
Response of RPC‐Filled Circular Steel Tube Columns under Monotonic and Cyclic Axial Loading
Authors: Rong Qin , Zeng Yusheng , Guo Lanhui , Hou Xiaomeng , Zheng Wenzhong
Published: April 2019

Results from mechanical tests on thirteen reactive powder concrete‐ (RPC‐) filled circular steel tube (RFCT) columns under monotonic and cyclic axial loading are presented in this paper. The test variables include monotonic and cyclic loadings, confinement coefficient, and diameter of the steel tube. The test results show that the envelope curves of specimens under cyclic loading were similar to the load‐deformation curves of the specimens under monotonic loading. Confinement coefficient had a significant influence on the failure modes of RFCT columns. With an increase in confinement coefficient of 0.53 to 0.98, the failure mode transformed from shear failure to compressive failure for specimens under monotonic and cyclic loading. In the elastic stage, no confining effect was provided by the steel tube to the RPC since Poisson’s ratio of steel was larger than the transverse deformation coefficient of RPC. Beyond the elastic stage, the axial compressive strength and ultimate strain of RPC increased significantly due to the confining effect when compared to unconfined RPC. Stress of the steel tube and RPC was investigated by using an elastic‐plastic analytical model. Before yielding of the steel tube, stress development in the tube was faster in the longitudinal direction than in the hoop direction. The results of the experiment indicate that the compressive strength of RPC could be predicted by Mander’s model for confined concrete. Based on Mander’s model, an equation is extended to calculate the axial compressive strength of RFCT columns, and the predicted results are in good agreement with the test results. Based on comparative analysis of 180 RFCT columns axial compressive tests, the equation given by EC4 considering the confinement effect can be applied to predict the compressive strength of RFCT columns.
Amides Derived from Vanillic Acid: Coupling Reactions, Antimicrobial Evaluation, and Molecular Docking
Authors: Santos Oliveira Ana Júlia de Morais , de Castro Ricardo Dias , Pessôa Hilzeth de Luna Freire , Wadood Abdul , de Sousa Damião Pergentino
Published: April 2019

A series of amides derived from vanillic acid were obtained by coupling reactions using PyBOP ((Benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate) and DCC (Dicyclohexylcarbodiimide) coupling reagents. These were submitted to biological evaluation for species ofCandida,Staphylococcus, andPseudomonas. The microdilution method in broth was used for the antimicrobial testing to determine the Minimum Inhibitory Concentration (MIC) and to verify the likely mechanism of action for antifungal activity. The ten amides were obtained with yields ranging from 28.81 to 86.44%, and three compounds were novel. In the antibacterial evaluation, the amides (in their greatest concentrations) were bioactive againstStaphylococcus aureusstrain ATCC 25925. Meanwhile, all of the tested amides presented antifungal activity against at least one strain. The amide with best antifungal profile was compound7, which featured an MIC of 0.46μmol/mL, and a mechanism of action involving the plasma membrane and fungal cell wall. The presence of a methyl group in theparaposition of the aromatic ring is suggested which enhances the activity of the compound against fungi. Docking studies of the ten compounds using the protein 14α-demethylase as a biological target were also performed. The biological results presented good correlation with molecular docking studies demonstrating that a possible site of antifungal action for bioactive amides is the enzyme 14α-demethylase.
Association of Serum 25-Hydroxyl Vitamin D Deficiency and Age-Related Cataract: A Case-Control Study
Authors: Abdellah Marwa Mahmoud , Mohamed Mostafa Engy , Salama Eman Hassan , Roshdy Mohamed Eman
Published: April 2019

Purpose. To study the relation between the serum 25-hydroxyl vitamin D (OH D) level and the occurrence of age-related cataract in a case-control study. Patients and Methods. 325 cataract patients and 385 control individuals of both sexes were examined for the 25-OH D level using the chemiluminescent microparticle immunoassay (CMIA) technology. Results. Mean 25-OH D level in cataract patients was 7.6 ± 5.5 ± 11.2 ng/mL and median was 5.6 (2.6–31.9), while in the control group, mean 25-OH D level was 18.5 ± 9.6 ng/mL and median was 17.8 (3.4–37.8) (p value < 0.001). There was a statistically significant difference among the different types of cataracts with the lowest level in nuclear cataract. Conclusion. 25-OH D levels in all enrolled individuals were below the reference levels with a severe deficiency in cataract patients. These results might highlight the role of deficiency of 25-OH D in age-related cataract patients.
The Adverse Effects of Thyrotropin Absence on Pancreatic β Cell Function in Mice
Authors: Yang Yu , Chen Yu , Chen Jie , Zhang Danyu , Wang Jianhua , Mao Xiaodong , Wei Xiao , Li Xingjia , Ma Xianghua , Liu Chao , Wang Kun
Published: April 2019

Thyrotropin (TSH) is a modulator of glucose metabolism by binding to its receptor on pancreatic cells. We used thyrotropin receptor (TSHR) knockout mice (Tshr-/-) as a model of TSH deletion to study its function in pancreatic β cells. Tshr-/- mice had a similar body weight at birth compared with Tshr+/+ mice, but grew at a significantly slower rate until adulthood with adequate thyroxine supplementation. TSH deletion led to lower fasting and postprandial blood glucose, insulin secretion impairment, and atrophy of islets in adult mice. Transcription factors and markers of pancreatic β cell maturation, Pdx1, Nkx6.1, Glut2, and insulin, together with cell proliferation marker Ki67 showed no differences at the mRNA level between the two groups. However, the Bax/Bcl-2 ratio was remarkably elevated in Tshr-/- mice at both mRNA and protein levels. We hypothesized that pancreatic cell apoptosis, rather than abnormal cell proliferation and maturation, is associated with pancreatic dysfunction and glucose intolerance in the absence of TSH modulation.
Genome–Epigenome–Senescence: Is TET1 a Caretaker of p53-Injured Lung Cancer Cells?
Authors: Kondo Yutaka
Published: April 2019

The study by Filipczak and colleagues identified the interplay between mutant p53 proteins and methylcytosine dioxygenase ten-eleven translocation 1 (TET1) in lung cancers. p53 transversion mutations were closely associated with high TET1 expression, which prevented genomic instability–associated cellular senescence. Depletion of TET1 was synergistic with classical antitumor drugs, such as cisplatin or doxorubicin, providing an attractive rationale for targeted therapies against TET1 combined with antitumor drugs in patients with p53-mutant lung cancer.

See related article by Filipczak et al., p. 1758
Phase I Study of Intermittent High-Dose Lapatinib Alternating with Capecitabine for HER2-Positive Breast Cancer Patients with Central Nervous System Metastases
Authors: Morikawa Aki , de Stanchina Elisa , Pentsova Elena , Kemeny Margaret M. , Li Bob T. , Tang Kendrick , Patil Sujata , Fleisher Martin , Van Poznak Catherine , Norton Larry , Seidman Andrew D.
Published: April 2019

Purpose:

Lapatinib and capecitabine cross the blood–tumor barrier in breast cancer brain metastasis but have modest clinical efficacy. Administration of high-dose tyrosine kinase inhibitor has been evaluated in brain metastases and primary brain tumors as a strategy to improve drug exposure in the central nervous system (CNS). We derived a rational drug scheduling of intermittent high-dose lapatinib alternating with capecitabine based on our preclinical data and Norton–Simon mathematical modeling. We tested this intermittent, sequential drug schedule in patients with breast cancer with CNS metastasis.

Patients and Methods:

We conducted a phase I trial using an accelerated dose escalation design in patients with HER2-positive (HER2+) breast cancer with CNS metastasis. Lapatinib was given on day 1–3 and day 15–17 with capecitabine on day 8–14 and day 22–28 on an every 28-day cycle. Lapatinib dose was escalated, and capecitabine given as a flat dose at 1,500 mg BID. Toxicity and efficacy were evaluated.

Results:

Eleven patients were enrolled: brain only (4 patients, 36%), leptomeningeal (5 patients, 45%), and intramedullary spinal cord (2 patients, 18%). Grade 3 nausea and vomiting were dose-limiting toxicities. The MTD of lapatinib was 1,500 mg BID. Three patients remained on therapy for greater than 6 months.

Conclusions:

High-dose lapatinib is tolerable when given intermittently and sequentially with capecitabine. Antitumor activity was noted in both CNS and non-CNS sites of disease. This novel administration regimen is feasible and efficacious in patients with HER2+ breast cancer with CNS metastasis and warrants further investigation.
A First-in-Human Study and Biomarker Analysis of NKTR-214, a Novel IL2Rβγ-Biased Cytokine, in Patients with Advanced or Metastatic Solid Tumors
Authors: Bentebibel Salah-Eddine , Hurwitz Michael E. , Bernatchez Chantale , Haymaker Cara , Hudgens Courtney W. , Kluger Harriet M. , Tetzlaff Michael T. , Tagliaferri Mary A. , Zalevsky Jonathan , Hoch Ute , Fanton Christie , Aung Sandra , Hwu Patrick , Curti Brendan D. , Tannir Nizar M. , Sznol Mario , Diab Adi
Published: April 2019

NKTR-214 (bempegaldesleukin) is a novel IL2 pathway agonist, designed to provide sustained signaling through heterodimeric IL2 receptor βγ to drive increased proliferation and activation of CD8+ T and natural killer cells without unwanted expansion of T regulatory cells (Treg) in the tumor microenvironment. In this first-in-human multicenter phase I study, NKTR-214 administered as an outpatient regimen was well tolerated and showed clinical activity including tumor shrinkage and durable disease stabilization in heavily pretreated patients. Immune activation and increased numbers of immune cells were observed in the periphery across all doses and cycles with no loss of NKTR-214 activity with repeated administration. On-treatment tumor biopsies demonstrated that NKTR-214 promoted immune cell increase with limited increase of Tregs. Transcriptional analysis of tumor biopsies showed that NKTR-214 engaged the IL2 receptor pathway and significantly increased genes associated with an effector phenotype. Based on safety and pharmacodynamic markers, the recommended phase II dose was determined to be 0.006 mg/kg every three weeks.

Significance:

We believe that IL2- and IL2 pathway–targeted agents such as NKTR-214 are key components to an optimal immunotherapy treatment algorithm. Based on its biological activity and tolerability, NKTR-214 is being studied with approved immuno-oncology agents including checkpoint inhibitors.

See related commentary by Sullivan, p. 694.

This article is highlighted in the In This Issue feature, p. 681
Siglec-9 Regulates an Effector Memory CD8+ T-cell Subset That Congregates in the Melanoma Tumor Microenvironment
Authors: Haas Quentin , Boligan Kayluz Frias , Jandus Camilla , Schneider Christoph , Simillion Cedric , Stanczak Michal A. , Haubitz Monika , Seyed Jafari Seyed Morteza , Zippelius Alfred , Baerlocher Gabriela M. , Läubli Heinz , Hunger Robert E. , Romero Pedro , Simon Hans-Uwe , von Gunten Stephan
Published: April 2019

Emerging evidence suggests an immunosuppressive role of altered tumor glycosylation due to downregulation of innate immune responses via immunoregulatory Siglecs. In contrast, human T cells, a major anticancer effector cell, only rarely express Siglecs. However, here, we report that the majority of intratumoral, but not peripheral blood, cytotoxic CD8+ T cells expressed Siglec-9 in melanoma. We identified Siglec-9+ CD8+ T cells as a subset of effector memory cells with high functional capacity and signatures of clonal expansion. This cytotoxic T-cell subset was functionally inhibited in the presence of Siglec-9 ligands or by Siglec-9 engagement by specific antibodies. TCR signaling pathways and key effector functions (cytotoxicity, cytokine production) of CD8+ T cells were suppressed by Siglec-9 engagement, which was associated with the phosphorylation of the inhibitory protein tyrosine phosphatase SHP-1, but not SHP-2. Expression of cognate Siglec-9 ligands was observed on the majority of tumor cells in primary and metastatic melanoma specimens. Targeting the tumor-restricted, glycosylation-dependent Siglec-9 axis may unleash this intratumoral T-cell subset, while confining T-cell activation to the tumor microenvironment.
The Tumor Immune Microenvironment Drives a Prognostic Relevance That Correlates with Bladder Cancer Subtypes
Authors: Pfannstiel Carolin , Strissel Pamela L. , Chiappinelli Katherine B. , Sikic Danijel , Wach Sven , Wirtz Ralph M. , Wullweber Adrian , Taubert Helge , Breyer Johannes , Otto Wolfgang , Worst Thomas , Burger Maximilian , Wullich Bernd , Bolenz Christian , Fuhrich Nicole , Geppert Carol I. , Weyerer Veronika , Stoehr Robert , Bertz Simone , Keck Bastian , Erlmeier Franziska , Erben Philipp , Hartmann Arndt , Strick Reiner , Eckstein Markus
Published: April 2019

Muscle-invasive bladder cancer (MIBC) represents approximately two-thirds of invasive urothelial bladder cancers (UBC) and has high morbidity and mortality. Men are over 3-fold more frequently affected by UBC than women. Despite intensive efforts to improve patient treatment and outcome, two-thirds of patients with UBC will have a recurrence or disease progression within 5 years. We demonstrated that the quantity and spatial distribution of stromal tumor-infiltrating lymphocytes (sTIL) within the tumor immune microenvironment (TIME) predict stages of tumor inflammation, subtypes, and patient survival and correlate with expression of immune checkpoints in an analysis of 542 patients with MIBC. High sTILs indicated an inflamed subtype with an 80% 5-year DSS, and a lack of immune infiltrates identified an uninflamed subtype with a survival rate of less than 25%. A separate immune evading phenotype with upregulated immune checkpoints associated with poor survival. Within the TIME are tertiary lymphoid structures (TLS), which can mediate antitumor activity via immune cells. High TLS amounts and close tumor distance correlated significantly with an inflamed phenotype and favorable survival. The uninflamed and evasion phenotypes showed lowest TLS numbers, farthest tumor distances, and shortest survival. High inflammation also correlated with increased neoantigen load and mutational burden. Patients treated with adjuvant chemotherapy showed a favorable prognosis, which was dependent on high sTILs. Determination of sTILs and tumor subtypes may stratify therapy success and patient survival, and considering sTILs can easily be quantified using simple morphologic parameters, like hematoxylin and eosin, sTILs can be implemented for predicting patient survival in a routine manner.