bluuebunny/crossref_metadata_2025 huggingface dataset:
Neurourbanistik – ein methodischer Schulterschluss zwischen Stadtplanung und Neurowissenschaften
Authors: Adli M. , Berger M. , Brakemeier E.-L. , Engel L. , Fingerhut J. , Hehl R. , Heinz A. , Mayer H J. , Matussek T. , Mehran N. , Tolaas S. , Walter H. , Weiland U. , Stollmann J.
Published: September 2018

Hintergrund: Urbanisierung gehört zu den wichtigsten globalen Veränderungen, denen die Menschheit in den kommenden Jahrzehnten ausgesetzt sein wird. Diese Entwicklung ist rasant – und sie ist gesundheitsrelevant, mit weit reichenden Konsequenzen für unser psychisches Befinden. Einige stressassoziierte psychische Erkrankungen zeigen ein erhöhtes Auftreten bei Stadtbewohnern. Methode: Es ist daher höchste Zeit, den Einfluss von Stadtleben auf das psychische Wohlbefinden sowie die Rolle urbaner Stressoren besser zu verstehen. Hierzu ist ein methodischer Schulterschluss zwischen Architektur, Stadtplanung, Neurowissenschaften und Medizin notwendig, für den wir den Begriff der „Neurourbanistik“ vorschlagen. Neurourbanistik als neue akademische Perspektive kann dazu beitragen, angemessen und effektiv auf die Herausforderungen einer urbanisierten Welt zu reagieren. Die Themen neurourbanistischer Forschung umfassen dabei Grundlagenforschung, Epidemiologie und Public Health genauso wie experimentelle Stressforschung und Präventionsforschung. Ziel: Ziel ist, ein Lebensumfeld zu schaffen, welches die Resilienz und psychische Gesundheit von Stadtbewohnern und urbaner Gemeinschaften stärkt.
Impact of liquid metal embrittlement cracks on resistance spot weld static strength
Authors: DiGiovanni Christopher , Biro Elliot , Zhou Norman Y.
Published: September 2018

Advanced high strength steels used in automotive structural components are commonly protected using zinc coatings. However, the steel/zinc system creates the potential for liquid metal embrittlement (LME) during welding. Although LME cracks are known to form, limited research has found any detrimental impact of LME cracks on weld strength. In this work, a comparison of zinc coated and uncoated advanced high strength steel joints showed LME decreased strength in welds from transformation induced plasticity type microstructures and an 1100 MPa ultimate tensile strength by 43.6%. LME cracks were observed to propagate until final fracture. However, only cracks located in the periphery of the weld area were found contribute to a loss in strength.
The GCTx format and cmap{Py, R, M, J} packages: resources for optimized storage and integrated traversal of annotated dense matrices
Authors: Enache Oana M , Lahr David L , Natoli Ted E , Litichevskiy Lev , Wadden David , Flynn Corey , Gould Joshua , Asiedu Jacob K , Narayan Rajiv , Subramanian Aravind
Published: September 2018

Motivation

Facilitated by technological improvements, pharmacologic and genetic perturbational datasets have grown in recent years to include millions of experiments. Sharing and publicly distributing these diverse data creates many opportunities for discovery, but in recent years the unprecedented size of data generated and its complex associated metadata have also created data storage and integration challenges.

Results

We present the GCTx file format and a suite of open-source packages for the efficient storage, serialization and analysis of dense two-dimensional matrices. We have extensively used the format in the Connectivity Map to assemble and share massive datasets currently comprising 1.3 million experiments, and we anticipate that the format’s generalizability, paired with code libraries that we provide, will lower barriers for integrated cross-assay analysis and algorithm development.

Availability and implementation

Software packages (available in Python, R, Matlab and Java) are freely available at https://github.com/cmap. Additional instructions, tutorials and datasets are available at clue.io/code.

Supplementary information

Supplementary data are available at Bioinformatics online.
KeggExp: a web server for visual integration of KEGG pathways and expression profile data
Authors: Liu Xian , Han Mingfei , Zhao Chen , Chang Cheng , Zhu Yunping , Ge Changhui , Yin Ronghua , Zhan Yiqun , Li Changyan , Yu Miao , He Fuchu , Yang Xiaoming
Published: September 2018

Effective visualization is important for knowledge discovery when analysing expression profile data. However, existing tools for visually integrating expression profile data with KEGG pathway maps lack extensive interactive visualization operations. KeggExp simultaneously presents the pathway map of one pathway, dendrogram and heatmap of the genes in the pathway and scatter map of one gene; and also provides interactive operations for highlighting specific genes on the pathway map, including differentially-expressed genes, co-expressed genes selected from the heatmap and user-input genes. With KeggExp, researchers, including those without programming skills, can take advantage of its interactive operations to determine key genes or pathways when analysing expression profile data.

Availability and implementation

Freely available at http://www.fgvis.com/expressvis/KeggExp/. Language: JavaScript, python; Libraries: D3.js, Rxjs, Angular, Django, Django rest frame work, Scipy.

Supplementary information

Supplementary data are available at Bioinformatics online.
In vitro versus in vivo compositional landscapes of histone sequence preferences in eucaryotic genomes
Authors: Giancarlo Raffaele , Rombo Simona E , Utro Filippo
Published: September 2018

Motivation

Although the nucleosome occupancy along a genome can be in part predicted by in vitro experiments, it has been recently observed that the chromatin organization presents important differences in vitro with respect to in vivo. Such differences mainly regard the hierarchical and regular structures of the nucleosome fiber, whose existence has long been assumed, and in part also observed in vitro, but that does not apparently occur in vivo. It is also well known that the DNA sequence has a role in determining the nucleosome occupancy. Therefore, an important issue is to understand if, and to what extent, the structural differences in the chromatin organization between in vitro and in vivo have a counterpart in terms of the underlying genomic sequences.

Results

We present the first quantitative comparison between the in vitro and in vivo nucleosome maps of two model organisms (S. cerevisiae and C. elegans). The comparison is based on the construction of weighted k-mer dictionaries. Our findings show that there is a good level of sequence conservation between in vitro and in vivo in both the two organisms, in contrast to the abovementioned important differences in chromatin structural organization. Moreover, our results provide evidence that the two organisms predispose themselves differently, in terms of sequence composition and both in vitro and in vivo, for the nucleosome occupancy. This leads to the conclusion that, although the notion of a genome encoding for its own nucleosome occupancy is general, the intrinsic histone k-mer sequence preferences tend to be species-specific.

Availability and implementation

The files containing the dictionaries and the main results of the analysis are available at http://math.unipa.it/rombo/material.

Supplementary information

Supplementary data are available at Bioinformatics online.
The Enabling Reduction of Low-Grade Inflammation in Seniors (ENRGISE) Pilot Study: Screening Methods and Recruitment Results
Authors: Cauley Jane A , Manini Todd M , Lovato Laura , Talton Jennifer , Anton Steven D , Domanchuk Kathryn , Kennedy Kimberly , Stowe Cynthia L , Walkup Michael , Fielding Roger A , Kritchevsky Stephen B , McDermott Mary M , Newman Anne B , Ambrosius Walter T , Pahor Marco ,   ENRGISE Investigators
Published: September 2018

Background

The Enabling Reduction of Low-grade Inflammation in Seniors (ENRGISE) Pilot Study is a multicenter randomized clinical trial examining the feasibility of testing whether omega-3 fish oil (ω-3) and the angiotensin receptor blocker losartan alone or in combination can reduce inflammation and improve walking speed in older adults with mobility impairment. We describe recruitment methods and results.

Methods

Eligible participants were 70 years and older, had elevated interleukin-6 levels (2.5–30 pg/mL) and mobility impairment.

Results

Of those who responded to recruitment, 83% responded to mailings. A total of 5,424 telephone screens were completed; of these, 2,011 (37.1%) were eligible for further screening. The most common reasons for ineligibility at the telephone screens were lack of mobility impairment or use of angiotensin receptor blockers or angiotensin-converting enzyme inhibitors (n=1.789). Of the 1,305 initial screening visits, 1,087 participants had slow gait speed (<1 m/s). Of these, 701 (64%) had elevated interleukin-6 and were eligible for second screening visits. Of the 582 second screening visits, 335 (57.6%) were eligible to be randomized. A total of 289 participants (96% of goal) were randomized: 180 in the ω-3 stratum (240% of goal); 43 in the losartan (57% of goal), and 66 in the combination (44% of goal). The telephone screen and first screening visit to randomization ratio was 19 to 1 and 4.5 to 1, respectively. The estimated cost of recruitment per randomized participant was $1,782.

Conclusion

Recruitment for ω-3 exceeded goals, but goals for the losartan and combination strata were not met due to the high proportion of participants taking angiotensin receptor blockers or angiotensin-converting enzyme inhibitors.
The Association Between Physical Activity, Including Physical Activity Intensity, and Fear of Falling Differs by Fear Severity in Older Adults Living in the Community
Authors: Sawa Ryuichi , Asai Tsuyoshi , Doi Takehiko , Misu Shogo , Murata Shunsuke , Ono Rei
Published: September 2018

Objectives

Fear of falling (FoF) is common in older adults. Physical activity decreases as FoF increases. However, this association between physical activity and FoF may vary depending on activity intensity. The current study was performed to explore the associations between FoF and step count, light-intensity physical activity (LPA), and moderate/vigorous-intensity physical activity (MVPA) in community-dwelling older adults.

Methods

This cross-sectional observational study was held at a local community association center, with 242 older adults living independently in the community (mean age: 75.1 ± 5.4 years). FoF was defined using the Falls Efficacy Scale-International and categorized into three levels (low, moderate, and high). Physical activity was measured using a uniaxial accelerometer worn for 7 consecutive days, and by calculating daily step count, LPA, and MVPA, over this period.

Results

Step count and physical activity intensity showed significant linear trends across FoF severity (p < .01, respectively). High FoF decreased step count by approximately 2,000 steps/day. Further, high FoF was significantly associated with short durations of both LPA and MVPA. In addition, moderate FoF was associated with decreased LPA duration, even after adjustment for confounding variables.

Discussion

Physical activity decreased concomitantly with a rise in FoF severity. Moreover, the association between physical activity and FoF differed by physical activity intensity level in community-dwelling older adults. Further studies are needed to investigate the causal relationship between FoF and objective physical activity in this population.
Continuous learning, teamwork, and lessons for young scientists
Authors: Peterman Randall M
Published: September 2018

This paper describes my research on fish population dynamics, which has aimed to improve the information available for management and conservation. Through numerous collaborations, my research program addressed three main objectives. (1) Increase the understanding of spatial and temporal variation in productivity of fish populations. (2) Quantify uncertainties and risks in fishery systems and their implications for management and conservation. (3) Develop methods to reduce those uncertainties and risks. To help young scientists, I present 11 general lessons, as well as some specific advice, that emerged from that research. The general lessons include pursuing a path of continuous learning, going beyond your comfort zone to broaden your skills and knowledge, and collaborating with others. More specific advice for fisheries scientists includes evaluating the bias and precision of parameter estimation methods via Monte Carlo simulations, and considering multiple models of whole fishery systems. This paper also illustrates, with examples, how the understanding of some aspects of fish population dynamics has evolved, at least from the limited perspective of my own group's research.
Pharmacokinetics and safety of fidaxomicin in patients with inflammatory bowel disease and Clostridium difficile infection: an open-label Phase IIIb/IV study (PROFILE)
Authors: Högenauer Christoph , Mahida Yashwant , Stallmach Andreas , Marteau Philippe , Rydzewska Grazyna , Ivashkin Vladimir , Gargalianos-Kakolyris Panagiotis , Michon Ingrid , Adomakoh Nicholas , Georgopali Areti , Tretter Reiner , Karas Andreas , Reinisch Walter
Published: September 2018

Objectives

Inflammatory bowel disease (IBD) poses an increased risk for Clostridium difficile infection (CDI). Fidaxomicin has demonstrated non-inferiority to vancomycin for initial clinical cure of CDI in patients without IBD; however, lack of data has caused concerns regarding potential systemic absorption of fidaxomicin in patients with IBD.

Methods

The plasma pharmacokinetics (PK) of fidaxomicin and its primary metabolite OP-1118 were evaluated in a multicentre, open-label, single-arm, Phase IIIb/IV study enrolling patients with active IBD and CDI. Patients received fidaxomicin, 200 mg twice daily for 10 days. The primary and secondary endpoints were, respectively, plasma and stool PK of fidaxomicin and OP-1118 on Days 1, 5 and 10 of treatment. Other secondary endpoints included safety of fidaxomicin treatment (assessed until Day 180). ClinicalTrials.gov identifier: NCT02437591.

Results

Median Tmax of fidaxomicin and OP-1118 for the PK analysis set (PKAS; 24 patients) was 1–2 h across Days 1, 5 and 10. Cmax ranges were 1.2–154 ng/mL for fidaxomicin and 4.7–555 ng/mL for OP-1118 across Days 1, 5 and 10 (PKAS). The ranges of concentrations in stool were 17.8–2170 μg/g for fidaxomicin and 0–1940 μg/g for OP-1118. Sixty percent (15/25) of patients experienced treatment-emergent adverse events (TEAEs), none of which led to treatment discontinuation or death.

Conclusions

Maximum fidaxomicin and OP-1118 plasma concentrations observed in this study population suggest no increase in absorption, compared with patients without IBD. Incidence of TEAEs was similar to previous Phase III trials, suggesting that fidaxomicin is comparatively well tolerated in patients with IBD.
Impact of Pharmacy-Initiated Interventions on Influenza Vaccination Rates in Pediatric Solid Organ Transplant Recipients
Authors: Gattis Sara , Yildirim Inci , Shane Andi L , Serluco Staci , McCracken Courtney , Liverman Rochelle
Published: September 2018

Background

In solid organ transplant (SOT) recipients, influenza infection can lead to subsequent graft dysfunction and death. Vaccination is the most effective approach to preventing influenza infection; however, vaccination rates are low, and interventions to optimize vaccine coverage are needed. The purpose of this study was to evaluate if pharmacy-initiated screening and recommendations for influenza immunization improve the rate of vaccination in pediatric SOT recipients.

Methods

We performed a retrospective pre-post chart review of all kidney, liver, and heart transplant recipients followed by Children’s Healthcare of Atlanta/Emory University transplant services between September 1, 2011, and February 16, 2017. Influenza vaccination coverage and influenza rates before (2011–2013) and after (2014–2016) the implementation of pharmacy-driven vaccination in SOT recipients were assessed.

Results

A total of 822 patients were included; 101 (13%) of these patients were diagnosed with influenza, and 40 (5%) were hospitalized secondarily during the study period. Vaccination coverage increased over time (144 [36%] patients vaccinated in 2011 vs 430 [74%] in 2016; P < .001). Influenza diagnosis rates decreased between the 2 eras (P = .006). The median time in which 50% of the population was vaccinated decreased over time from 163 days in 2012 to 94 days in 2016 (P < .001).

Conclusion

Within the constraints of the pre-post study design, we observed a significant increase in influenza vaccination rates after implementation of a transplant pharmacy-initiated screening and vaccination program. The number of patients diagnosed with influenza and the time to vaccination decreased after our pharmacy intervention. All efforts should be made to increase compliance with influenza vaccination; pharmacy-initiated interventions can improve protection against influenza infection in pediatric SOT recipients.
Antimicrobial Dosing—Adult
Authors: Wilson John W. , Estes Lynn L.
Published: September 2018

The medical management of infectious diseases and antimicrobial therapy can be a daunting task for health care professionals. Although expansive textbooks and online resources are available, we believe that a more simplified, quick reference guide is needed for the day-to-day office and hospital clinical practice. This book is designed to provide information about infectious diseases and antimicrobial therapy in a format that is readily accessible and easily applicable to the clinical environment. Highlights of this book include simplified and thorough drug dosing recommendations for renal function and renal replacement therapies, drugs of choice for specific organisms (including bacteria, fungi, and viruses), and simplified antimicrobial and management recommendations for specific infectious syndromes.
Antimicrobial Dosing—Pediatric
Authors: Wilson John W. , Estes Lynn L.
Published: September 2018

This section contains tables and text covering pediatric and neonatal antimicrobial dosing for an extensive list of antimicrobials, vancomycin, and aminoglycosides. Adjustments needed for patients with renal impairment, infusion rates, and monitoring are also included.
Antimicrobial Agent Fundamentals
Authors: Wilson John W. , Estes Lynn L.
Published: September 2018

This section contains tables covering fundamentals for an extensive list of antimicrobials. Pharmacokinetics, drug levels, toxicity, clinical monitoring, antimicrobials, laboratory monitoring are reviewed.
Infectious Syndromes in Adults
Authors: Wilson John W. , Estes Lynn L.
Published: September 2018

This section contains tables and text covering an exhaustive group of infectious syndromes including respiratory tract infections, infective endocarditis, intravascular catheter-related infections, central nervous system infections, urinary tract infections, soft-tissue infections, osteomyelitis, gastrointestinal infections, tick-borne infections, tuberculosis, sexually transmitted diseases, HIV, hepatitis, and fungal and zoonotic infections. Vaccination schedules, travel medicine, and bioterrorism are also reviewed.
Fetal Cardiology
Authors: Archer Nick , Manning Nicky
Published: September 2018

This resource brings together information in an accessible single source to allow professionals from many different disciplines to have a sound understanding of the scope and limitations of fetal cardiac diagnosis and treatment. It will be of practical clinical value to all involved in fetal cardiac assessment or in the management of feto-maternal problems.
Introduction
Authors: Archer Nick , Manning Nicky
Published: September 2018

This chapter discusses the role of fetal cardiology, plus the scope and limitations of fetal cardiac evaluation.
History and examination
Authors: Archer Nick , Manning Nicky
Published: September 2018

This chapter discusses the importance of history and examination in assessment of the fetal cardiovascular system. It concerns both history (including an introduction, parental history, family history, and pregnancy history) and examination (including an introduction, and parental examination).
Three-vessel trachea view
Authors: Archer Nick , Manning Nicky
Published: September 2018

This chapter discusses the three-vessel trachea view, including discussion on the normal three-vessel trachea view and abnormalities of the three-vessel trachea view.
Other investigations
Authors: Archer Nick , Manning Nicky
Published: September 2018

This chapter considers other fetal cardiovascular investigations, including discussion on invasive testing, examination of sample, non-invasive testing, parental blood sampling, fetal electrocardiography, and magnetic resonance imaging.
Structural abnormalities
Authors: Archer Nick , Manning Nicky
Published: September 2018

This chapter explores structural abnormalities, including an introduction, classication of structural congenital heart disease, and detailed consideration of anomalies.
Left-sided abnormalities
Authors: Archer Nick , Manning Nicky
Published: September 2018

This chapter explores left-sided abnormalities, discussing venoatrial abnormalities (including partial anomalous pulmonary venous drainage, total anomalous pulmonary venous drainage, and left-sided SVC), atrioventricular abnormalities (mitral atresia and mitral hypoplasia), ventriculoarterial abnormalities (including aortic stenosis, aortic atresia, and hypoplastic le. heart syndrome), and arterial abnormalities (coarctation of the aorta, interrupted aortic arch, right aortic arch, aberrant subclavian artery, double aortic arch, persistent fifth aortic arch, vascular rings, and aorto-pulmonary window).
Right-sided abnormalities
Authors: Archer Nick , Manning Nicky
Published: September 2018

This chapter explores right-sided abnormalities, discussing the venoatrial junction (including both azygous/hemiazygous connections and abnormal systemic venous drainage), the atrioventricular junction (including tricuspid atresia and Ebstein’s anomaly/tricuspid valve dysplasia), and the ventriculoarterial junction (including pulmonary stenosis, pulmonary atresia with intact septum, tetralogy of Fallot, tetralogy of Fallot with absent pulmonary valve, pulmonary atresia with ventricular septal defect, and double outlet right ventricle), and arterial abnormalities.
Septal anomalies
Authors: Archer Nick , Manning Nicky
Published: September 2018

This chapter explores septal abnormalities, including discussion on atrial septal defects (including an introduction, secundum, and sinus venosus type), ventricular septal defects (including an introduction, perimembranous, inlet, outlet, muscular, apical, and doubly committed subarterial), and atrioventricular septal defects (including an introduction, partial, complete, and intermediate).
Miscellaneous abnormalities
Authors: Archer Nick , Manning Nicky
Published: September 2018

This chapter explores miscellaneous abnormalities, namely double inlet ventricle and disorders of laterality.
Abnormalities at a glance
Authors: Archer Nick , Manning Nicky
Published: September 2018

This chapter explores abnormalities at a glance, including discussion on abnormal appearances of the cardiac chambers, abnormal appearances of the great arteries, abnormal cardiac position, abnormal cardiac axis, abnormalities of the three-vessel trachea view, and abnormal cardiac rhythms.
Abnormal cardiac position
Authors: Archer Nick , Manning Nicky
Published: September 2018

This chapter explores abnormal cardiac positions, namely normal cardiac position and axis and abnormalities of cardiac position.
Fetal cardiac rhythm
Authors: Archer Nick , Manning Nicky
Published: September 2018

This chapter explores fetal cardiac rhythm, including identication of fetal cardiac rhythm, normal rhythms, fast abnormal rhythms, slow abnormal rhythms, and irregular rhythms.
Heart muscle disease
Authors: Archer Nick , Manning Nicky
Published: September 2018

This chapter explores heart muscle disease, including discussion on types of cardiomyopathy, assessment, and treatment.
Nuchal translucency and the heart
Authors: Archer Nick , Manning Nicky
Published: September 2018

This chapter explores nuchal translucency and the heart, including an introduction and discussion on the nuchal scan, nuchal translucency and the heart, and management.
The heart in the sick fetus
Authors: Archer Nick , Manning Nicky
Published: September 2018

This chapter explores the heart in the sick fetus, including an introduction, and discussion on both maternal causes and fetal causes.
Pregnancy management of fetal cardiac disease
Authors: Archer Nick , Manning Nicky
Published: September 2018

This chapter explores pregnancy management of fetal cardiac disease, including an introduction and discussion on diagnosis, counselling, management of pregnancy, fetal intervention, management of delivery, and future pregnancies.
Neurodevelopment and fetal cardiac disease
Authors: Archer Nick , Manning Nicky
Published: September 2018

This chapter explores neurodevelopment and fetal cardiac disease, including an introduction and discussion on haemodynamics, specific cardiac lesions, methods of assessment, prevention or limitation, and counselling.
Postnatal evaluation
Authors: Archer Nick , Manning Nicky
Published: September 2018

This chapter explores postnatal evaluation, including an introduction and discussion on history and examination, echocardiography, radiology, magnetic resonance imaging, electrocardiography, chromosome analysis and gene testing, metabolic investigation, and autopsy examination.
Basics of Clinical Research
Authors: Nakamura Rui , Khawaja Faiza , Castillo-Saavedra Laura , Fregni Felipe , Freedman Steven D , Pinna Fabio , Brunoni Andre
Published: September 2018

Chapter 1 explores the history, ethical issues, and importance of regulations in clinical research. The history of clinical research is long and fascinating, starting from dietary therapy, such as legumes and lemons, and advancing to modern-day drugs and regulations. Advances in medical treatments today have been achieved because of the application of knowledge gained from experiments conducted hundreds of years ago. The rules and regulations were required to address unethical issues and the misuse of the clinical research. The chapter asserts that the development of clinical research regulations may still be under development in terms of optimizing safety and the use of future drugs and medical devices.
Selection of the Research Question
Authors: Ueda Keiko , Merabet Lotfi B , Brunoni Andre , Fregni Felipe
Published: September 2018

Selecting a research question is the first step of any research project. This chapter discusses how to formulate a specific research question from a variety of scientific interests. The reader will learn that a good research question needs to consider several aspects, such as feasibility, innovation, and significance, and that merging all these aspects into one research question may be challenging. This chapter reviews the importance of generating a strong research question using the PICOT format: population (P), intervention (I), control (C), outcomes (O), and time (T). This chapter also discusses the selection of appropriate outcome variables—surrogates or clinical endpoints, based on the types of questions or study phase. The final goal of this chapter is to refine the researcher’s general idea into the process of shaping a strong research question that will be feasible, important, ethical, and answerable.
Study Population
Authors: Carvalho Sandra , Fregni Felipe , Brunoni Andre
Published: September 2018

Chapter 3 discusses the decision-making process of choosing the study population. This is critical given that any study’s main goal is to make inferences that go beyond the individuals under study and can be used to explain the phenomenon in the broader population with shared characteristics or conditions. In this chapter, the definition of the target population is discussed—i.e. the portion of the general population from which a researcher wants to draw robust conclusions or inferences. The sampling process according to the study phase is also summarized, focusing on phase II and III clinical trials, as phase I trials are especially designed to assess safety, while phase IV trials are open-label studies, usually assessing post-marketing safety. The internal and external validity of a study is also discussed, as well as sampling methods, both probabilistic (simple random, systematic, stratified, cluster, or multistage sampling) and non-probabilistic (convenience, consecutive, and snowball sampling).
Basic Study Designs
Authors: Gomez Alexandra , Fregni Felipe , Novak Vera , Brunoni Andre
Published: September 2018

This chapter on basic study designs provides an overview of the most common design methodologies used in interventional studies. The chapter discusses both the advantages and limitations of parallel group designs (placebo or active control comparison trial, factorial design), repeated measures design (cross-over or between-subjects design), and quasi-experimental designs. It provides examples and discusses designs that are used in specific settings (for example, rare diseases, phases of dug development, and interventions in real life, including large simple trials, N-of-1). The chapter ends with a case study that illustrates the in-depth application of the available options into practice.
Randomization
Authors: Ferreira Juliana C , Illigens Ben M. W. , Fregni Felipe
Published: September 2018

Chapter 5 gives the reader an overview of a major important feature in every randomized clinical trial: the process of randomization. This chapter describes the main features of randomization, its importance, advantages, and disadvantages. It also discusses the most common methods of randomization (simple randomization, blocked randomization, stratified randomization, adaptive randomization), as well as what the investigator should take into consideration when choosing among these options. In this scenario, the challenges of defining a method in clinical trials with small sample sizes are also discussed. Additionally, the chapter explores the consequences that may arise from lack of randomization, such as selection bias. It also focuses on defining allocation concealment and its importance to the appropriate conduction of a study. In this chapter, the reader is taken through the entire process—from choosing a suitable randomization option to ensuring the appropriate implementation of the selected method.
Blinding
Authors: Tomás Rita , Massaro Joseph , Imamura Rui , Fregni Felipe
Published: September 2018

This chapter 6 discusses the importance of blinding in clinical research. Adequate blinding (or masking) of treatment allocation from subjects, health-care providers, outcome assessors, and other study personnel is of utmost importance to the methodological quality of a study. This chapter discusses the different terminology in use, describes the different types of blinding that can occur, and how blinding can be accomplished. It examines the consequences of the lack of blinding, or unblinding, such as study biases and overestimation of effects. It also reviews how can the success of blinding be measured and addresses the challenges that certain research areas face in designing blinded studies.
Recruitment and Adherence
Authors: Suemoto Claudia Kimie , Lee Catherine , Fregni Felipe
Published: September 2018

This chapter summarizes common challenges in clinical research related to the recruitment and adherence of study participants, including errors that lead to decreased adherence, such as commission and omission errors. This chapter provides specific strategies for how to avoid and overcome these pitfalls. Those strategies include both individual “human” aspects and administrative algorithms that have been designed to improve recruitment and adherence and thus reduce the chance of dropouts and missing data. Furthermore, this chapter explains the principles of retention and attrition and highlights how to employ specific strategies in order to reach the targeted study population effectively. This includes both health-care-provider-based and community-based strategies.
Parametric Statistical Tests
Authors: Illigens Ben M. W. , Lopes Fernanda , Fregni Felipe , Brunoni Andre
Published: September 2018

Chapter 9 provides an introduction to statistical testing,alongside the most common parametric tests. It reviews the basis of hypothesis testing while highlighting important concepts such as chance, bias, and confounding. Additionally, this chapter discusses fundamental topics in basic statistics, including p-value, type I and type II errors, alpha (α‎), beta (β‎), and statistical significance. The reader is taken throughout the basics of the theoretical explanation of t-test, ANOVA and linear regression, together with the indications of appropriate use for each of them. Additionally, the reader will learn how to perform and interpret the output for these tests in statistical softwares (e.g., STATA and SPSS). This chapter also examines the concept of normality and central limit theorem (CLT), and how it applies to the evaluation of data distribution.
Non-Parametric Statistical Tests
Authors: Fregni Felipe , Lopes Fernanda , Matsubayashi Suely R
Published: September 2018

Chapter 10 introduces the most commonly used non-parametric tests, as well as the appropriate situations for their use. It also examines concepts of sample size, power, and validity when using these tests. In addition, this chapter discusses the major advantages and disadvantages of non-parametric tests, and how they compare to their optimal parametric alternatives. A brief theoretical explanation is provided for the main non-parametric tests, including Wilcoxon Sign Rank, Mann-Whitney, and Kruskal-Wallis. However, the main goal of this chapter is to provide a summary of how to use them correctly. Additionally, the reader will learn how to perform and interpret the output for these tests in statistical softwares (STATA and SPSS).
Sample Size Calculation
Authors: Qureshi Mohammad Azfar , Paulus Jessica K , Fregni Felipe
Published: September 2018

In this chapter the basic principles of sample size calculation are discussed. The chapter also reviews the impact of sample size calculation on the study results, the parameters needed, and ways this calculation can be performed by researchers. Over- and underestimation of sample size for any study can have significant effects for the study participants, thus ensuring its adequacy is of critical importance. Setting values for alpha (level of significance) and beta (power) should be informed by the specific research goals and study hypothesis. A priori effect size estimation is challenging and can be done in various ways, which are addressed in this chapter. The chapter concludes with examples and references of sources that can be used for sample size calculation.
Survival Analysis
Authors: Leite Jorge , Carvalho Sandra , Boodhwani Munir , Fregni Felipe
Published: September 2018

This chapter focuses on basic principles of survival analysis for the clinical investigator. Survival analysis is a specific type of standardized statistical analysis that focuses on assessing the time elapsed since the exposure/intervention to the occurrence of an event. Important concepts such as median survival time, cumulative probability of survival at specific time points by using Kaplan-Meier estimators, and the use of the use of log rank (Mantel–Cox) to compare survival functions are discussed. This chapter also discusses the concept of censoring, which happens when the event occurs outside the pre-specified time window, and how to develop hazard functions when there are several interrelated factors that can contribute to the increase or decrease of survival probability.
Non-Inferiority Design
Authors: Moyses Raquel Ajub , Angelim Valeriam , Evans Scott , Imamura Rui , Fregni Felipe
Published: September 2018

This chapter discusses an interesting alternative to superiority RCT: the non-inferiority RCT. Non-inferiority trials are increasingly being used since superiority of effect is not the only factor in choosing a treatment option for patients. A typical motivation for a non-inferiority trial is when it is worthwhile to sacrifice a small fraction of effect in exchange for other benefits, such as a decrease in side effects or a more convenient dosing scheme. This chapter discusses the motivation of non-inferiority designs and the differences as compared to equivalence and superiority trials. It reviews fundamental aspects like the assumptions of assay sensitivity and constancy; principles driving the choice of a non-inferiority margin and interim analysis; and how to handle missing data in this trial design. It also raises important concerns specific to non-inferiority trials, such as biocreep and the way non-inferiority trial results should be appropriately applied in a clinical setting.
Observational Studies
Authors: Djannatian Minou , Valim Clarissa , Brunoni Andre , Fregni Felipe
Published: September 2018

This chapter on observational studies provides an understanding of the main concepts in epidemiology, introduces common study designs, such as cross-sectional, case-control, and cohort studies, and outlines their importance for clinical research. The hallmark of epidemiological research is that it observes unexposed and exposed individuals under “real-life conditions” without intervening itself. The chapter emphasizes the important role of bias and confounding in interpreting results from such studies and explains how bias and confounding can be controlled. It furthermore discusses specific aspects of sample size determination that are relevant to observational studies. The chapter concludes with a brief review of the special nature of surgical research.
Confounders and Using the Method of Propensity Scores
Authors: Lin Chin , Imamura Rui , Fregni Felipe
Published: September 2018

This chapter explores the important issue of confounding in observational studies. The potential imbalances that result for not controlling assignment of treatment or exposure may lead to imbalance of variables that are associated with both treatment and intervention (or exposure) thus confounding results. Therefore, in this context, a potential relationship between an intervention and an outcome could be invalid. This chapter therefore explains basic definitions of confounding and presents some methods to control for confounders, highlighting the use of the propensity score, which is considered a robust method for this purpose. Different techniques of adjustment using propensity score (matching, stratification, regression, and weighting) are also discussed. This chapter concludes with a case discussion about confounding and how to address it.
The Business of Clinical Research
Authors: Compte Lívia Caroline Mariano , Leite Jorge , Brunoni Andre , Fregni Felipe
Published: September 2018

This chapter presents a series of important topics that should be considered and evaluated before conducting a clinical trial in which there is a collaboration between industry and academia. It discusses important topics such as the project budget and sources of funding. Additionally, this chapter highlights the advantages of the academia-industry partnership, potential conflicts of interest, and, in the advent of a conflict of interest, strategies to minimize its effects. Intellectual property, indemnifications, publication, and other specific issues are also presented as key elements in a clinical trial agreement. A clinical case is used to exemplify and discuss the practical aspects of this challenging negotiation.
Design and Analysis of Surveys
Authors: Martins Ana R , Henriques Inês C. R , Brunoni Andre , Fregni Felipe
Published: September 2018

This chapter discusses the most important aspects of designing, administrating, and analyzing surveys in clinical research. It highlights the different topics of the main stages of survey research. It reviews the design and planning phase, especially focusing on the definition of the survey research question. It discusses the process of instrument design, from planning and development to pre-test and validation, types of sampling, and methods for survey administration. It also reviews the importance of the data analysis plan and report. Furthermore, it refers to potential problems and pitfalls, as well as legal and ethical issues encountered when conducting surveys, and strategies to address them. Finally, it includes a case study and explores different questions to be addressed when using surveys in clinical research.
Assessing Risk and Adverse Events
Authors: Castillo-Saavedra Laura , Matsubayashi Suely Reiko , Khawaja Faiza , Ferguson John , Fregni Felipe , Imamura Rui
Published: September 2018

This chapter provides an overview of safety assessment in clinical trials, including challenges for designing and reporting studies measuring safety. Adverse events are undesirable, unfavorable, harmful, and unexpected effects resulting from a normal dosage of drug, medication, therapy, or any other intervention such as surgery. Monitoring of adverse events is critical to the patient’s safety (i.e., human subject’s protection) and data integrity in clinical trials. Moreover, this chapter reviews the regulatory aspects related to adverse events in clinical trials. Finally it presents a case discussion in which an unexpected adverse effect is detected and investigators need to determine whether this event is or is not related to the intervention and define a plan of action.
Manuscript Submission
Authors: Jimenez Alma Tamara Sanchez , Fregni Felipe
Published: September 2018

This chapter presents an overview of the process of manuscript submission. It also presents a summary of the basic format of a scientific paper, highlighting the important content of each section. The chapter discusses the following topics: (i) starting a manuscript submission; (ii) presenting the scientific data; (iii) writing a draft for journal review; (iv) choosing where to submit the research; and (v) what to expect after submitting a manuscript. In the course of the discussion, it also examines the current publication landscape, from open access versus subscription journals, with a trend of bias toward publication of more positive studies than negative ones.
AL amyloidosis: advances in diagnostics and treatment
Authors: Ryšavá Romana
Published: September 2018

AL amyloidosis (light chain; previously also called primary amyloidosis) is a systemic disease characterized by an amyloid deposition process affecting many organs, and which still has unsatisfactory survival of patients. The monoclonal light chains kappa (κ) or lambda (λ) or their fragments form the fibrils that deposit and accumulate in different tissues. Renal involvement is very frequent in AL amyloidosis and can lead to the development of nephrotic syndrome followed by renal failure in some cases. AL amyloidosis ultimately leads to destruction of tissues and progressive disease. With recent advances in the treatment, the importance of an early diagnosis of amyloidosis and correct assessment of its type is high. Histologic confirmation is based on Congo red detection of amyloid deposits in tissues but AL amyloidosis must also be distinguished from other systemic forms of amyloidoses with renal involvement, such as AA amyloidosis, amyloidosis with heavy chain deposition, fibrinogen Aα or ALECT2 (leukocyte chemotactic factor 2) deposition. Immunofluorescence (IF) plays a key role here. IF on formalin-fixed paraffin-embedded tissue after protease digestion, immunohistochemistry or laser microdissection with mass spectrometry should complete the diagnosis in unclear cases. Standard treatment with melphalan and prednisolone or with cyclophosphamide and dexamethasone has been replaced with newer drugs used for the treatment of multiple myeloma—bortezomib, carfilzomib and ixazomib or thalidomide, lenalidomide and pomalidomide. High-dose melphalan supported by autologous stem cell transplantation remains the therapeutic option for patients with low-risk status. These new treatment options prolong survival from months to years and improve the prognosis in a majority of patients.
The Application of Commercially Available Mobile Cigarette Topography Devices for E-cigarette Vaping Behavior Measurements
Authors: Mikheev Vladimir B , Buehler Stephanie S , Brinkman Marielle C , Granville Courtney A , Lane Timothy E , Ivanov Alexander , Cross Kandice M , Clark Pamela I
Published: September 2018

Introduction

The ability to reliably measure real-world vaping behavior is critical to understand exposures to potential toxins. Commercially available mobile topography devices were originally designed to measure cigarette puffing behavior. Information regarding how applicable these devices are to the measurement of electronic cigarette (e-cigarette) vaping topography is needed.

Methods

Clinical Research Support System (CReSS; Pocket) and Smoking Puff Analyzer Mobile (SPA-M) topography devices were tested against the calibrated laboratory-based smoking puff analyzer duplicator (SPA-D) device combined with an analytical smoking machine that generates programmable puffs with high precision. Puff topography of e-cigarettes was measured over a range of puff volumes (10–130 mL) at 2 and 5 s puff durations (using bell- and square-shaped puffs). “Real-world” topography data collected from 10 participants during 1 week of at-home vaping were also analyzed. Recording anomalies and limitations of the devices, such as accuracy of detection of the puff end, flow rate dropouts, unreported puffs, and abandoned vaping sessions for the CReSS, and multi-peak puffs for the SPA-M were defined.

Results

The accuracy of puff volumes and durations was determined for both devices. The error for SPA-M was generally within ±10%, whereas that for the CReSS varied more widely. The CReSS consistently underestimated puff duration at higher flow rates.

Conclusions

CReSS and SPA-M topography devices can be used for real-world e-cigarette topography measurements, but researchers have to be aware of the limitations. Both devices can provide accurate measurements only under certain puff parameter ranges. The SPA-M provided more accurate measurements under a wider range of puffing parameters than the CReSS. Summary data reported by both devices require thorough analysis of the raw data to avoid misleading data interpretation.

Implications

Results of this study provide researchers with valuable information about the capability of commercially available cigarette topography devices to measure real-world vaping behaviors. The differing measurement ranges of the two devices and puff recording limitations and anomalies should be taken into account during analysis and interpretation of real-world data.