bluuebunny/crossref_metadata_2025_split huggingface dataset:
How recent findings on the pharmacokinetics and pharmacodynamics of integrase inhibitors can inform clinical use
Authors: Elliot Emilie , Chirwa Mimie , Boffito Marta 
Published: October 2016

Purpose of review
This review of recent published literature and data presented at scientific meetings on integrase stand transfer inhibitors (InSTIs) examines how these findings may impact on their future clinical use.

Recent findings
Elvitegravir (EVG), raltegravir (RAL) and dolutegravir (DTG) are InSTIs recommended as first-line options for treatment naive patients by the European AIDS Clinical Society, British HIV Association, International AIDS Society-USA and DHHS. InSTIs have gained a leading role in the management of HIV-1 because of increased viral suppression and maintaining undetectability with fewer side-effects.
RAL 1200 mg once-daily (QD) has been shown to be noninferior to 400 mg BD, and the European Medicines Agency has approved QD RAL for review. RAL and DTG are not metabolized via cytochrome P450 (CYP) resulting in fewer drug interactions and less toxicity risk in patients receiving direct-acting antivirals and other coadministered medications.
EVG is currently available as a single tablet regimen and requires cobisistat, a pharmacokinetic booster and CYP3A inhibitor to allow QD dosing. EVG will soon be available in combination with tenofovir alfenamide, which is as efficacious as tenofovir disoproxil fumarate, but offers better renal and bone outcomes.
DTG has a high genetic barrier to resistance and has been the subject of a number of simplification and treatment failure trials and shown promise. There are some emerging reports of neuropsychiatric and gastrointestinal side-effects associated with DTG, which were not reported in clinical trials emphasizing the importance of real-life data.
Carbotegravir, a long-acting InSTI, is currently in the pipeline of development.

Summary
All three InSTIs have impressive data on efficacy, tolerability and safety. The unique differences of each InSTI's pharmacokinetics and pharmacodynamics lend themselves to various clinical scenarios, enabling us as clinicians to provide better patient-centred care.
HIV-associated neurocognitive disorder
Authors: Clifford David B. 
Published: October 2016

Purpose of review
HIV-associated neurocognitive disease is the most active topic for neuroAIDS investigations at present. Although impairment is mild in patients successfully treated with modern antiviral regimens, it remains an ongoing problem for HIV patients. It is important to update the emerging research concerning HIV-associated neurocognitive disease.

Recent findings
The virus enters the brain during acute infection, with evidence for abnormal functioning that may occur early and often persists. Direct relationships with ongoing viral infection continue to be monitored, but chronic inflammation often associated with monocytes and macrophages appears to be the most likely driver of cognitive dysfunction. Appreciation for cerebrovascular disease as a significant comorbidity that is associated with cognitive deficits is increasing. Neuroimaging is actively being developed to address detection and measurement of changes in the brain. Optimal combined antiretroviral treatment therapy has vastly improved neurologic outcomes, but so far has not been demonstrated to reverse the remaining mild impairment. Inflammatory and vascular mechanisms of cerebral dysfunction may need to be addressed to achieve better outcomes.

Summary
Ongoing research is required to improve neurological outcomes for persons living with HIV. It is likely that interventions beyond antiviral approaches will be required to control or reverse HIV-associated neurocognitive disease.
Persistent homology in graph power filtrations
Authors: Parks Allen D. , Marchette David J. 
Published: October 2016

The persistence of homological features in simplicial complex representations of big datasets in

R

n

resulting from Vietoris–Rips or Čech filtrations is commonly used to probe the topological structure of such datasets. In this paper, the notion of homological persistence in simplicial complexes obtained from power filtrations of graphs is introduced. Specifically, the
r
th complex,
r
≥ 1, in such a power filtration is the clique complex of the
r
th power
G

r

of a simple graph
G
. Because the graph distance in
G
is the relevant proximity parameter, unlike a Euclidean filtration of a dataset where regional scale differences can be an issue, persistence in power filtrations provides a scale-free insight into the topology of
G
. It is shown that for a power filtration of
G
, the girth of
G
defines an
r
range over which the homology of the complexes in the filtration are guaranteed to persist in all dimensions. The role of chordal graphs as trivial homology delimiters in power filtrations is also discussed and the related notions of ‘persistent triviality’, ‘transient noise’ and ‘persistent periodicity’ in power filtrations are introduced.
A comprehensive survey of genetic variation in 20,691 subjects from four large cohorts
Authors: Lindström Sara , Loomis Stephanie , Turman Constance , Huang Hongyan , Huang Jinyan , Aschard Hugues , Chan Andrew T. , Choi Hyon , Cornelis Marilyn , Curhan Gary , De Vivo Immaculata , Eliassen A. Heather , Fuchs Charles , Gaziano Michael , Hankinson Susan E. , Hu Frank , Jensen Majken , Kang Jae H. , Kabrhel Christopher , Liang Liming , Pasquale Louis R. , Rimm Eric , Stampfer Meir J. , Tamimi Rulla M. , Tworoger Shelley S. , Wiggs Janey L. , Hunter David J. , Kraft Peter 
Published: October 2016

ABSTRACTThe Nurses’ Health Study (NHS), Nurses’ Health Study II (NHSII), Health Professionals Follow Up Study (HPFS) and the Physicians Health Study (PHS) have collected detailed longitudinal data on multiple exposures and traits for approximately 310,000 study participants over the last 35 years. Over 160,000 study participants across the cohorts have donated a DNA sample and to date, 20,691 subjects have been genotyped as part of genome-wide association studies (GWAS) of twelve primary outcomes. However, these studies utilized six different GWAS arrays making it difficult to conduct analyses of secondary phenotypes or share controls across studies. To allow for secondary analyses of these data, we have created three new datasets merged by platform family and performed imputation using a common reference panel, the 1,000 Genomes Phase I release. Here, we describe the methodology behind the data merging and imputation and present imputation quality statistics and association results from two GWAS of secondary phenotypes (body mass index (BMI) and venous thromboembolism (VTE)).We observed the strongest BMI association for the FTO SNP rs55872725 (β=0.45, p=3.48×10−22), and using a significance level of p=0.05, we replicated 19 out of 32 known BMI SNPs. For VTE, we observed the strongest association for the rs2040445 SNP (OR=2.17, 95% CI: 1.79-2.63, p=2.70×10−15), located downstream of F5 and also observed significant associations for the known ABO and F11 regions. This pooled resource can be used to maximize power in GWAS of phenotypes collected across the cohorts and for studying gene-environment interactions as well as rare phenotypes and genotypes.
Genome-wide Analysis of Differential Transcriptional and Epigenetic Variability Across Human Immune Cell Types
Authors: Ecker Simone , Chen Lu , Pancaldi Vera , Bagger Frederik O. , Fernandez José Maria , Carrillo de Santa Pau Enrique , Juan David , Mann Alice L. , Watt Stephen , Casale Francesco Paolo , Sidiropoulos Nikos , Rapin Nicolas , Merkel Angelika ,   BLUEPRINT Consortium, Stunnenberg Henk , Stegle Oliver , Frontini Mattia , Downes Kate , Pastinen Tomi , Kuijpers Taco W. , Rico Daniel , Valencia Alfonso , Beck Stephan , Soranzo Nicole , Paul Dirk S. 
Published: October 2016

AbstractBackgroundA healthy immune system requires immune cells that adapt rapidly to environmental challenges. This phenotypic plasticity can be mediated by transcriptional and epigenetic variability.ResultsWe applied a novel analytical approach to measure and compare transcriptional and epigenetic variability genome-wide across CD14+CD16−monocytes, CD66b+CD16+neutrophils, and CD4+CD45RA+naïve T cells, from the same 125 healthy individuals. We discovered substantially increased variability in neutrophils compared to monocytes and T cells. In neutrophils, genes with hypervariable expression were found to be implicated in key immune pathways and to associate with cellular properties and environmental exposure. We also observed increased sex-specific gene expression differences in neutrophils. Neutrophil-specific DNA methylation hypervariable sites were enriched at dynamic chromatin regions and active enhancers.ConclusionsOur data highlight the importance of transcriptional and epigenetic variability for the neutrophils’ key role as the first responders to inflammatory stimuli. We provide a resource to enable further functional studies into the plasticity of immune cells, which can be accessed from:http://blueprint-dev.bioinfo.cnio.es/WP10/hypervariability.
Rare disruptive variants in the DISC1 Interactome and Regulome: association with cognitive ability and schizophrenia
Authors: Teng Shaolei , Thomson Pippa A. , McCarthy Shane E. , Kramer Melissa , Muller Stephanie , Lihm Jayon , Morris Stewart , Soares Dinesh , Hennah William , Harris Sarah , Camargo Luiz Miguel , Malkov Vladislav , McIntosh Andrew M , Millar J. Kirsty , Blackwood Douglas , Evans Kathryn L. , Deary Ian J. , Porteous David J. , McCombie W. Richard 
Published: October 2016

ABSTRACTSchizophrenia (SCZ), bipolar disorder (BD) and recurrent major depressive disorder (rMDD) are common psychiatric illnesses. All have been associated with lower cognitive ability, and show evidence of genetic overlap and substantial evidence of pleiotropy with cognitive function and neuroticism.Disrupted in schizophrenia 1(DISC1) protein directly interacts with a large set of proteins (DISC1 Interactome) that are involved in brain development and signaling. Modulation of DISC1 expression alters the expression of a circumscribed set of genes (DISC1 Regulome) that are also implicated in brain biology and disorder. Here, we report targeted sequencing of 59 DISC1 Interactome genes and 154 Regulome genes in 654 psychiatric patients and 889 cognitively-phenotyped control subjects, on whom we previously reported evidence for trait association from complete sequencing of the DISC1 locus. Burden analyses of rare and singleton variants predicted to be damaging were performed for psychiatric disorders, cognitive variables and personality traits. The DISC1 Interactome and Regulome showed differential association across the phenotypes tested. After family-wise error correction across all traits (FWERacross), an increased burden of singleton disruptive variants in the Regulome was associated with SCZ (FWERacrossP=0.0339). The burden of singleton disruptive variants in the DISC1 Interactome was associated with low cognitive ability at age 11 (FWERacrossP=0.0043). These results suggest that variants in the DISC1 Interactome effect the risk of psychiatric illness through altered expression of schizophrenia-associated genes. The biological impact of rare variants highlighted here merit further study.
Scaffolding of long read assemblies using long range contact information
Authors: Ghurye Jay , Pop Mihai , Koren Sergey , Chin Chen-Shan 
Published: October 2016

AbstractMotivationLong read technologies have made a revolution inde novogenome assembly by generating contigs of size orders of magnitude more than that of short read assemblies. Although the assembly contiguity has increased, it still does not span a chromosome or an arm of the chromosome, resulting in an unfinished chromosome level assembly. To address this problem, we develop a scalable and computationally efficient scaffolding method that can boost the contiguity of the assembly by a large extent using genome wide chromatin interaction data such as Hi-C. Particularly, we demonstrate an algorithm that uses Hi-C data for longer-range scaffolding ofde novolong read genome assemblies.ResultsWe tested our methods on two long read assemblies of different organisms. We compared our method with previously developed method and show that our approach performs better in terms of accuracy of scaffolding.AvailabilityThe software is available for free use and can be downloaded from here:https://github.com/machinegun/hi-c-scaffoldContactjchin@pacificbiosciences.com
Calcium Deficiency Triggers Phloem Remobilization of Cadmium in a Hyperaccumulating Species
Authors: Tian Shengke , Xie Ruohan , Wang Haixin , Hu Yan , Ge Jun , Liao Xingcheng , Gao Xiaoyu , Brown Patrick , Lin Xianyong , Lu Lingli 
Published: October 2016

AbstractUnderstanding cadmium (Cd) accumulation in plants is critical for the development of plant-based strategies for soil remediation and crop safety. Sedum alfredii is a nonbrassica plant species known to hyperaccumulate Cd. The characteristics of Cd uptake, distribution, and retranslocation affected by the Ca status were investigated at cellular levels in S. alfredii. Low Ca supply significantly increased Cd contents in shoots of S. alfredii, particularly in the young leaves. Micro x-ray fluorescence images confirmed that sequestration of Cd was greatly enhanced in the young leaves under Ca deficiency stress, with a significant amount of Cd localized in mesophyll cells, compared to the young leaves supplied with high Ca levels. Cd influx into protoplasts isolated from young leaves was significantly inhibited by the addition of Ca channel inhibitors, but not by pre-exposure to Ca deficiency. In stems, the Cd signal in vascular systems under low Ca levels was 10-fold higher than in those treated with higher Ca levels. A detailed investigation of vascular bundles revealed that an extremely high Cd signal induced by low Ca supply occurred in the phloem tissues, but not in the xylem tissues. Transfer of Cd pretreated plants to nutrient solutions at different Ca levels confirmed that a much higher amount of Cd was reallocated to the new growth tissues under low Ca stress compared to plants supplied with sufficient Ca. These results suggest that Ca deficiency triggered a highly efficient phloem remobilization of Cd in S. alfredii and subsequently enhanced Cd accumulation in its young leaves.
A conceptual safety-oriented job demands and resources model for the fire service
Authors: Smith Todd D. , Dyal Mari-Amanda 
Published: October 2016

Purpose
The purpose of this paper is to develop and present a safety-oriented job demands-resources (JD-R) model that supports the notion that excessive job demands in the fire service, when not controlled or countered, may increase firefighter burnout and diminish firefighter safety.

Design/methodology/approach
The approach for the present project includes a review of the JD-R literature and the presentation of a conceptual model specific to fire service organizations.

Findings
A conceptual model, relevant to fire service organizations was derived. The model argues that excessive job demands associated with workload, physical demands, emotional demands, and complexity can result in burnout if not controlled or countered. Safety-specific resources, including recovery, support, safety-specific transformational leadership and safety climate are theorized to buffer these effects and are suggested to enhance firefighter engagement. These effects are argued then to improve firefighter safety. Ultimately, the findings will help guide future research, intervention projects and workplace safety and health management programs and initiatives.

Originality/value
This paper and conceptual model extends the application of the JD-R model to fire service organizations. Further, the conceptual model supports the application of safety-specific job resources vs more traditional job resources as a means to enhance firefighter safety.
Does democratic transition spur financial development?
Authors: Ghardallou Wafa 
Published: October 2016

Purpose
The literature studying the effect of democratic political systems on financial development has found conflicting results. Besides, recent work has focused on the level effects of democracy on financial outcomes showing evidence of positive, negative and no direct impact. This paper aims to investigate the dynamic effects of democratic transition on financial development, namely, short run and long run effects.

Design/methodology/approach
The author wants to see whether financial development improves after a transition to a democratic system and, if it does, for how long. Using a panel data set of 48 events of democratic transitions, the paper relies on an event study and on the estimation of dynamic panel after controlling for other potential determinants.

Findings
The author finds that transition to a democratic system raises the development of the financial sector. Particularly, these positive effects occurred in the long run, i.e. about 5 years following the democratic transition. However, in the short run, the author finds that the move to democracy does not impact financial outcomes.

Originality/value
The author contributes by studying the role of political system change on financial development finding that democratic transition increases the development of the financial system. Further, the author contributes by finding that the move to democracy produces positive effect only in the long term.
Managing the challenges of pharmaceutical patent expiry: a case study of Lipitor
Authors: Chao Chon Kit , Hu Hao , Zhang Liming , Wu Jihong 
Published: October 2016

Purpose
The paper aims to study how global pharmaceutical companies such as Pfizer have managed the challenges of pharmaceutical patent expiry.

Design/methodology/approach
A case study method was applied. The best-selling brand drug over the past 10 years – Lipitor – was chosen as the case target.

Findings
For dealing with this, this paper describes all the details of the corresponding strategies of Pfizer before and after patent expiration of Lipitor. Before patent expiry, Pfizer undertook the activities of direct-to-consumer marketing, pricing strategy for competition, legal delay and me-too drug R&D. After patent expiry, Pfizer chose to carry out continuous marketing for brand, rebate strategy, authorized generics and change to over-the-counter. In addition, diversity and globalization strategy was applied before and after patent expiry.

Research limitations/implications
This research provides strong implication for managing pharmaceutical products before and after patent expiry.

Practical implications
It is strongly recommended for both brand and generic drug companies to design strategies to meet the challenges of pharmaceutical patent expiry.

Social implications
For the global pharmaceutical market, a conclusion can be drawn that, nowadays, the “patent cliff” is the most significant factor influencing decision-makers to consider futuristic policies. Further, it is also a considerably effective solution for reducing health-care costs for policymakers.

Originality/value
This paper contributes to the field of patent expiry management in high-tech industries such as pharmaceuticals.
Two cases of seborrheic keratosis with basal clear cells
Authors: Anan Takashi , Fukumoto Takaya , Kimura Tetsunori 
Published: October 2016

AbstractSeborrheic keratosis with basal clear cells (SKBCC) is an extremely rare histopathological variant of seborrheic keratosis that has histological similarities to melanoma in situ. We herein report two cases of SKBCC and provide the first description of the dermoscopic features of this condition, in addition to the histopathological findings. Both of the two lesions showed typical histological architectures of seborrheic keratosis with rows or focal clusters of monomorphic clear cells with abundant pale cytoplasm and small round nucleus in the basal layer. Immunohistochemical examination revealed that most clear cells were positive for high molecular weight cytokeratin (34βE12) in a peripheral pattern but were negative tor Melan‐A. Dermoscopy revealed typical features of ordinary seborrheic keratosis, while unfortunately did not reflect the presence of basal clear cells.
Analysis of Korean acne patients according to age groups based on two multicenter studies
Authors: Park Mi Youn , Kim Kyung Ho , Kang Hoon , Kye Young Chul , Kwon Hyuck Hoon , Kim Kwang Joong , Kim Nack In , Kim Myeung Nam , Ro Young Suck , Min Seonguk , Park Kui Young , Song Margaret , Ahn Kyu Joong , Ahn Hyo Hyun , Lee Mi Woo , Lee Weon Ju , Lee Jee Bum , Choi Yu Sung , Suh Dae Hun ,   The Korean Society for Acne Research
Published: October 2016

AbstractAlong with increasing public concerns on acne and its complications, increasing treatment options seem to lead more acne patients to clinics globally, including Korea. The aim of the present study was to investigate the number and distribution of acne patients according to age group by analyzing number and age of outpatients from several general hospitals in Korea. Two retrospective multicenter studies including 14 general hospitals for a maximum of 10 years were conducted by medical chart review of acne patients. During the last 10 years, total acne patients have increased by 60% in number and patients under the age of 19 years have doubled. Adult acne patients (aged >18 years) accounted for the biggest portion in total acne patients at over 80%. Although upper grade of elementary school patients (aged 10–12 years) accounted for the biggest portion among the childhood acne patients, children under 10 years have also increased rapidly by 73% during the last 10 years. Childhood acne patients (aged <13 years) accounted for 11% of total acne patients. We found that acne patients were increasing consistently and the portion of those aged under 19 years is getting bigger. Additionally, childhood acne patients have increased remarkably.
Increased circulating anti‐α6‐integrin autoantibodies in psoriasis and psoriatic arthritis but not in rheumatoid arthritis
Authors: Gál Brigitta , Dulic Sonja , Kiss Mária , Groma Gergely , Kovács László , Kemény Lajos , Bata‐Csörgő Zsuzsanna 
Published: October 2016

AbstractIn psoriatic skin, laminin integrity is altered, which could lead to insufficient laminin integrin interactions, leaving the α6‐integrin exposed and possibly accessible for autoantibody production. Therefore we investigated the presence of anti‐α6‐integrin autoantibodies in the serum of patients with psoriasis vulgaris (Ps), psoriatic arthritis (PsA) and rheumatoid arthritis (RA) in comparison with healthy donors. The level of circulating anti‐α6‐integrin antibodies was determined by enzyme‐linked immunoassay using α6‐integrin fragments. Antibodies against at least one recombinant fragment were found in approximately 30% of Ps and PsA patients. In contrast, in RA patients, the frequency of antibodies was similar to healthy controls. Our study shows the presence of anti‐α6‐integrin antibodies in Ps and PsA but not in RA, which could indicate ongoing abnormal processes in the skin. Anti‐α6‐integrin autoantibodies may contribute to the formation of micro‐wounds in the skin and to the characteristic wound‐healing phenotype in psoriasis.