bluuebunny/crossref_metadata_2025_split huggingface dataset:
Antifungal Drugs: The Current Armamentarium and Development of New Agents
Authors: Robbins Nicole , Wright Gerard D. , Cowen Leah E. 
Published: October 2016

ABSTRACT

Invasive fungal infections are becoming an increasingly important cause of human mortality and morbidity, particularly for immunocompromised populations. The fungal pathogens
Candida albicans
,
Cryptococcus neoformans
, and
Aspergillus fumigatus
collectively contribute to over 1 million human deaths annually. Hence, the importance of safe and effective antifungal therapeutics for the practice of modern medicine has never been greater. Given that fungi are eukaryotes like their human host, the number of unique molecular targets that can be exploited for drug development remains limited. Only three classes of molecules are currently approved for the treatment of invasive mycoses. The efficacy of these agents is compromised by host toxicity, fungistatic activity, or the emergence of drug resistance in pathogen populations. Here we describe our current arsenal of antifungals and highlight current strategies that are being employed to improve the therapeutic safety and efficacy of these drugs. We discuss state-of-the-art approaches to discover novel chemical matter with antifungal activity and highlight some of the most promising new targets for antifungal drug development. We feature the benefits of combination therapy as a strategy to expand our current repertoire of antifungals and discuss the antifungal combinations that have shown the greatest potential for clinical development. Despite the paucity of new classes of antifungals that have come to market in recent years, it is clear that by leveraging innovative approaches to drug discovery and cultivating collaborations between academia and industry, there is great potential to bolster the antifungal armamentarium.
Host-Microsporidia Interactions in
Caenorhabditis elegans
, a Model Nematode Host
Authors: Troemel Emily R. 
Published: October 2016

ABSTRACT

Microsporidia comprise a phylum of obligate intracellular pathogens related to fungi that infect virtually all animals. Recently, the nematode
Caenorhabditis elegans
has been developed as a convenient model for studying microsporidia infection in a whole-animal host through the identification and characterization of a natural microsporidian pathogen of this commonly studied laboratory organism. The
C. elegans
natural microsporidian pathogen is named
Nematocida parisii
, and it causes a lethal intestinal infection in
C. elegans
. Comparison of the genomes of
N. parisii
and its closely related species
Nematocida
sp. 1, together with the genomes of other microsporidian species, has provided insight into the evolutionary events that led to the emergence of the large, specialized microsporidia phylum. Cell biology studies of
N. parisii
infection in
C. elegans
have shown how
N. parisii
restructures host intestinal cells and, in particular, how it hijacks host exocytosis for nonlytic exit to facilitate transmission. Recent results also show how the host responds to infection with ubiquitin-mediated responses, and how a natural variant of
C. elegans
is able to clear
N. parisii
infection, but only during early life. Altogether, these studies provide insight into the mechanisms of microsporidia pathogenesis using a whole-animal host.
Target of Rapamycin (TOR) Regulates Growth in Response to Nutritional Signals
Authors: Weisman Ronit 
Published: October 2016

ABSTRACT
All organisms can respond to the availability of nutrients by regulating their metabolism, growth, and cell division. Central to the regulation of growth in response to nutrient availability is the target of rapamycin (TOR) signaling that is composed of two structurally distinct complexes: TOR complex 1 (TORC1) and TOR complex 2 (TORC2). The TOR genes were first identified in yeast as target of rapamycin, a natural product of a soil bacterium, which proved beneficial as an immunosuppressive and anticancer drug and is currently being tested for a handful of other pathological conditions including diabetes, neurodegeneration, and age-related diseases. Studies of the TOR pathway unraveled a complex growth-regulating network. TOR regulates nutrient uptake, transcription, protein synthesis and degradation, as well as metabolic pathways, in a coordinated manner that ensures that cells grow or cease growth in response to nutrient availability. The identification of specific signals and mechanisms that stimulate TOR signaling is an active and exciting field of research that has already identified nitrogen and amino acids as key regulators of TORC1 activity. The signals, as well as the cellular functions of TORC2, are far less well understood. Additional open questions in the field concern the relationships between TORC1 and TORC2, as well as the links with other nutrient-responsive pathways. Here I review the main features of TORC1 and TORC2, with a particular focus on yeasts as model organisms.
‘Omics’ biomarkers associated with chronic low back pain: protocol of a retrospective longitudinal study
Authors: Allegri Massimo , De Gregori Manuela , Minella Cristina E , Klersy Catherine , Wang Wei , Sim Moira , Gieger Christian , Manz Judith , Pemberton Iain K , MacDougall Jane , Williams Frances MK , Van Zundert Jan , Buyse Klaas , Lauc Gordan , Gudelj Ivan , Primorac Dragan , Skelin Andrea , Aulchenko Yurii S , Karssen Lennart C , Kapural Leonardo , Rauck Richard , Fanelli Guido 
Published: October 2016

IntroductionChronic low back pain (CLBP) produces considerable direct costs as well as indirect burdens for society, industry and health systems. CLBP is characterised by heterogeneity, inclusion of several pain syndromes, different underlying molecular pathologies and interaction with psychosocial factors that leads to a range of clinical manifestations. There is still much to understand in the underlying pathological processes and the non-psychosocial factors which account for differences in outcomes. Biomarkers that may be objectively used for diagnosis and personalised, targeted and cost-effective treatment are still lacking. Therefore, any data that may be obtained at the ‘-omics’ level (glycomics, Activomics and genome-wide association studies—GWAS) may be helpful to use as dynamic biomarkers for elucidating CLBP pathogenesis and may ultimately provide prognostic information too. By means of a retrospective, observational, case-cohort, multicentre study, we aim to investigate new promising biomarkers potentially able to solve some of the issues related to CLBP.Methods and analysisThe study follows a two-phase, 1:2 case–control model. A total of 12 000 individuals (4000casesand 8000controls) will be enrolled; clinical data will be registered, with particular attention to pain characteristics and outcomes of pain treatments. Blood samples will be collected to perform -omics studies. The primary objective is to recognise genetic variants associated with CLBP; secondary objectives are to study glycomics and Activomics profiles associated with CLBP.Ethics and disseminationThe study is part of the PainOMICS project funded by European Community in the Seventh Framework Programme. The study has been approved from competent ethical bodies and copies of approvals were provided to the European Commission before starting the study. Results of the study will be reviewed by the Scientific Board and Ethical Committee of the PainOMICS Consortium. The scientific results will be disseminated through peer-reviewed journals.Trial registration numberNCT02037789; Pre-results.
Incidence and risk factors for capecitabine-induced symptomatic cardiotoxicity: a retrospective study of 452 consecutive patients with metastatic breast cancer
Authors: Polk Anne , Shahmarvand Nahid , Vistisen Kirsten , Vaage-Nilsen Merete , Larsen Finn Ole , Schou Morten , Nielsen Dorte Lisbeth 
Published: October 2016

ObjectivesCase reports of capecitabine cardiotoxicity resemble those seen with intravenous 5-fluorouracil (5-FU) with chest pain as the predominant manifestation, but few studies of capecitabine cardiotoxicity are available. We aimed to determine the incidence of symptomatic cardiotoxicity from capecitabine in patients with breast cancer and to identify risk factors.MethodsWe reviewed medical records of consecutive women with breast cancer treated with capecitabine (1000 mg/m2two times per day) from 2002 to 2012 at one institution.Results22 of 452 patients (4.9%) (95% CI 2.9% to 6.9%) had symptoms of cardiotoxicity (chest pain: n=13, dyspnoea: n=9, palpitations: n=2). 11 patients had changes on ECG (atrial fibrillation: n=5, ST deviations: n=3, T-wave abnormalities: n=2 and QTc prolongation: n=1). 2 patients (0.4%) sustained acute myocardial infarction. 1 patient (0.2%) developed cardiac arrest with lethal outcome. 4 of 6 patients (66%) retreated with capecitabine had recurrent symptoms at retreatment. Cardiac comorbidity (p=0.001), hypercholesterolaemia (p=0.005) and current smoking (p=0.023) were risk factors for cardiotoxicity in univariate analyses and remained significant when adjusted for age. Patients with cardiac comorbidity were 5.5 times (95% CI 2.0 to 14.8) more likely to develop cardiotoxicity. In the subgroup of patients with apparently no cardiac comorbidity, the incidence of cardiotoxicity was lower (3.7%) and hypercholesterolaemia (p=0.035) and current smoking (p=0.020) were risk factors of cardiotoxicity.ConclusionsThe incidence of cardiotoxicity from capecitabine resembles that of intravenous 5-FU (≈5%). Cardiac comorbidity, hypercholesterolaemia and current smoking were associated with development of cardiotoxicity.
Parenting acceptance and commitment therapy: a randomised controlled trial of an innovative online course for families of children with cerebral palsy
Authors: Whittingham Koa , Sheffield Jeanie , Boyd Roslyn N 
Published: October 2016

IntroductionCerebral palsy (CP) impacts on the entire family in a manner that is long-term, complex and multifactorial. In addition, the quality of the parent–child relationship impacts on many and varied child outcomes, making the provision of easily accessible and evidence-based support to parents of children with CP a priority. This paper reports the protocol of a randomised controlled trial of an innovative and translatable online intervention, parenting acceptance and commitment therapy (PACT), for families of children with CP. We predict that participating in the PACT programme will be associated with improvements in the parent–child relationship, in child functioning and in adjustment and quality of life for both parent and child.Methods and analysisWe aim to recruit 66 parents of children (2–10 years old) diagnosed with CP to this study. Families will be randomly assigned to two groups: wait-list control and PACT. PACT is a parenting intervention grounded in acceptance and commitment therapy (ACT) and developed into an online course ‘PARENT101 Parenting with Purpose’ using the edX platform. All participants will be offered PACT before completion of the study. Assessments will take place at baseline, following completion of PACT and at 6-month follow-up (retention) and will focus on the parent–child relationship, parent and child adjustment and parent and child quality of life. Analysis will follow standard methods for randomised controlled trials using general linear models, specifically analysis of variance or analysis of covariance.Ethics and disseminationEthics approvals have been obtained through the Children's Health Queensland Hospital and Health Service Human Research Ethics Committee (HREC/15/QRCH/115) and The University of Queensland (2015001743). If efficacy is demonstrated, then the PARENT101 course has the potential to be disseminated widely in an accessible manner and at minimal cost. Further, the PACT framework may provide a blueprint for similar online courses with parents in a full range of contexts.Trial registration numberACTRN12616000351415; Pre-results.
An outcomes-based grading scale for the evaluation of cerebral aneurysms treated with flow diversion
Authors: Park Min S , Mazur Marcus D , Moon Karam , Nanaszko Michael J , Kestle John R W , Shah Lubdha M , Winegar Blair , Albuquerque Felipe C , Taussky Philipp , McDougall Cameron G 
Published: October 2016

ObjectDespite the popularity of flow-diverting stents for the treatment of cerebral aneurysms, there is no widely accepted scale for the characterization of results. We present an outcomes-based grading scale that considers factors related to failure of flow diversion.MethodsThe grading scale was developed using the results from consecutive patients at two institutions who were treated with flow diversion for a cerebral aneurysm. The initial treatment results were graded on patient, aneurysm, and treatment characteristics. A 6-point grading scale was developed based on these data.ResultsOne hundred and seventy-one patients were included in the patient cohort. When compared by multivariate analysis with patients without residuals, patients with aneurysm residuals were found to be older (age ≥60 years, p=0.01, OR 1.17, 95% CI 1.03 to 1.33), to have larger aneurysms (size ≥15 mm, p<0.01, OR 1.38, 95% CI 1.17 to 1.62), to have aneurysms with associated side branches (p=0.02, OR 1.17, 95% CI 1.03 to 1.33), and to have a post-treatment Raymond score of 2 or 3 (p=0.01, OR 1.28, 95% CI 1.06 to 1.56). Using the Raymond score (1–3) as the foundation for the grading scale, additional points (0 or 1) were given for the other three identified factors, creating a 6-point scale. We found that patients with residual aneurysms had statistically higher final tabulated scores (p<0.01).ConclusionsWe propose a novel straightforward outcomes-based scale to characterize results after flow diversion treatment of cerebral aneurysms. This scale may provide the basis for the common reporting of results in future studies.
New Strategies in Multiple Myeloma: Immunotherapy as a Novel Approach to Treat Patients with Multiple Myeloma
Authors: Neri Paola , Bahlis Nizar J. , Lonial Sagar 
Published: October 2016

Abstract
Multiple myeloma is a B-cell malignancy characterized by proliferation of monoclonal plasma cells in the bone marrow. Although new therapeutic options introduced in recent years have resulted in improved survival outcomes, multiple myeloma remains incurable for a large number of patients, and new treatment options are urgently needed. Over the last 5 years, there has been a renewed interest in the clinical potential of immunotherapy for the treatment of multiple myeloma. Clinical progression of myeloma is known to be associated with progressive immune dysregulation and loss of immune surveillance that contribute to disease progression in association with progressive genetic complexity, rendering signaling-based treatments less effective. A variety of strategies to reverse the multiple myeloma–induced immunosuppression has been developed either in the form of immunomodulatory drugs, checkpoint inhibitors, mAbs, engineered T cells, and vaccines. They have shown encouraging results in patients with relapsed refractory multiple myeloma and hold great promise in further improving patient outcomes in multiple myeloma. This review will summarize the major approaches in multiple myeloma immunotherapies and discuss the mechanisms of action and clinical activity of these strategies. Clin Cancer Res; 22(24); 5959–65. ©2016 AACR.
Association Between a Prolonged PR Interval and Outcomes of Cardiac Resynchronization Therapy
Authors: Friedman Daniel J. , Bao Haikun , Spatz Erica S. , Curtis Jeptha P. , Daubert James P. , Al-Khatib Sana M. 
Published: October 2016

Background:
A prolonged PR interval is common among cardiac resynchronization therapy (CRT) candidates; however, the association between PR interval and outcomes is unclear, and the data are conflicting.

Methods:
We conducted inverse probability weighted analyses of 26 451 CRT-eligible (ejection fraction ≤35, QRS ≥120 ms) patients from the National Cardiovascular Data Registry ICD Registry to assess the association between a prolonged PR interval (≥230 ms), receipt of CRT with defibrillator (CRT-D) versus implantable cardioverter defibrillator (ICD), and outcomes. We first tested the association between a prolonged PR interval and outcomes among patients stratified by device type. Next, we performed a comparative effectiveness analysis of CRT-D versus ICD among patients when stratified by PR interval. Using Medicare claims data, we followed up with patients up to 5 years for incident heart failure hospitalization or death.

Results:

Patients with a PR≥230 ms (15%; n=4035) were older and had more comorbidities, including coronary artery disease, atrial arrhythmias, diabetes mellitus, and chronic kidney disease. After risk adjustment, a PR≥230 ms (versus PR<230 ms) was associated with increased risk of heart failure hospitalization or death among CRT-D (hazard ratio, 1.23; 95% confidence interval, 1.14–1.31;
P
<0.001) but not ICD recipients (hazard ratio, 1.08; 95% confidence interval, 0.97–1.20;
P
=0.17) (
P
interaction
=0.043). CRT-D (versus ICD) was associated with lower rates of heart failure hospitalization or death among patients with PR<230 ms (hazard ratio, 0.79; 95% confidence interval, 0.73–0.85;
P
<0.001) but not PR≥230 ms (hazard ratio, 1.01; 95% confidence interval, 0.87–1.17;
P
=0.90) (
P
interaction
=0.0025).

Conclusions:
A PR≥230 ms is associated with increased rates of heart failure hospitalization or death among CRT-D patients. The real-world comparative effectiveness of CRT-D (versus ICD) is significantly less among patients with a PR≥230 ms in comparison with patients with a PR<230 ms.
Comparison of Vascular Responses Following New‐Generation Biodegradable and Durable Polymer‐Based Drug‐Eluting Stent Implantation in an Atherosclerotic Rabbit Iliac Artery Model
Authors: Nakazawa Gaku , Torii Sho , Ijichi Takeshi , Nagamatsu Hirofumi , Ohno Yohei , Kurata Fumi , Yoshikawa Ayako , Nakano Masataka , Shinozaki Norihiko , Yoshimachi Fuminobu , Ikari Yuji 
Published: October 2016

Background
Incomplete endothelialization is the primary substrate of late stent thrombosis; however, recent reports have revealed that abnormal vascular responses are also responsible for the occurrence of late stent failure. The aim of the current study was to assess vascular response following deployment of biodegradable polymer‐based Synergy (Boston Scientific) and Nobori (Terumo) drug‐eluting stents and the durable polymer‐based Resolute Integrity stent (Medtronic) in an atherosclerotic rabbit iliac artery model.

Methods and Results

A total of 24 rabbits were fed an atherogenic diet, and then a balloon injury was used to induce atheroma formation. Synergy, Nobori, and Resolute Integrity stents were randomly implanted in iliac arteries. Animals were euthanized at 28 days for scanning electron microscopic evaluation and at 90 days for histological analysis. The percentage of uncovered strut area at 28 days was lowest with Synergy, followed by Resolute Integrity, and was significantly higher with Nobori stents (Synergy 1.1±2.2%, Resolute Integrity 2.0±3.9%, Nobori 4.6±3.0%;
P
<0.001). At 90 days, inflammation score was lowest for Synergy (0.27±0.45), followed by Nobori (0.62±0.59), and was highest for Resolute Integrity (0.89±0.46,
P
<0.001). Foamy macrophage infiltration within neointima (ie, neoatherosclerosis) was significantly less with Synergy (0.62±0.82) compared with Nobori (0.85±0.74) and Resolute Integrity (1.39±1.32;
P
=0.034).

Conclusions
The biodegradable polymer‐coated thin‐strut Synergy drug‐eluting stent showed the fastest stent strut neointimal coverage and the lowest incidence of neoatherosclerosis in the current animal model.
Relationship between the Asian Westerly Jet Stream and Summer Rainfall over Central Asia and North China: Roles of the Indian Monsoon and the South Asian High
Authors: Wei Wei , Zhang Renhe , Wen Min , Yang Song 
Published: October 2016

AbstractDiagnostic analyses are performed to investigate the relationship between the upper-level Asian westerly jet stream (AWJS) and the associated rainfall pattern over the AWJS region in boreal summer on interannual time scales. Results show an out-of-phase rainfall variation over central Asia (CA) and north China (NC), which is closely related to the southeast–northwest (SE–NW) shift of the AWJS. The physical mechanisms on the relationship between the AWJS and the rainfall pattern are revealed by exploring the effects of the Indian summer monsoon (ISM) and the South Asian high (SAH). It is found that the SE–NW shifts of the AWJS and SAH associated with the ISM lead to the anomalous circulations over the midlatitudes in the AWJS region and cause rainfall anomalies over CA and NC. A weak ISM results in a southeastward shift of SAH, which is responsible for a southeastward shift of the AWJS. The anomalous atmospheric circulation associated with the southeastward located SAH produces anomalous updrafts (downdrafts) over the western (eastern) AWJS region, resulting in increased rainfall over CA and decreased rainfall over NC. It is proposed that the upper-level system SAH plays a crucial role in the teleconnection among the summer rainfall over the midlatitude AWJS region and ISM region.
Heat Waves in Southern China: Synoptic Behavior, Long-Term Change, and Urbanization Effects
Authors: Luo Ming , Lau Ngar-Cheung 
Published: October 2016

AbstractThe characteristics of heat waves (HWs) in southern China in 1979–2010 are studied by using both reanalysis and station datasets. Guangdong Province of China (GDPC) is taken as an example. It is found that the westward movement of the western North Pacific subtropical high (WNPSH) is the primary factor for large-scale HWs occurring in GDPC. When an HW occurs, a hot and dry atmospheric column prevails over southern China. The region is overlaid by anomalous subsidence, which leads to warming, and clear sky, which causes greater solar heating. HWs are accompanied by an anomalous high pressure center and anticyclone near the surface, with anomalous land–sea northwesterly flow, thus reducing sea–land moisture transport and drying the atmosphere over land. The evolution of the high pressure anomaly and high temperature is associated with the westward displacement of WNPSH, with a prominent positive anomaly in 500-hPa height migrating westward. All these features associated with HWs in GDPC coincide with high-temperature extremes in the whole region of southern China and parts of Indochina. Significant increases in HW frequency (+0.19 events decade−1), HW days (+2.86 days decade−1), the duration of the longest event (+0.38 days decade−1), and the hottest temperature of the hottest event (+0.23°C decade−1) are also observed. These upward trends are more prominent in the Pearl River delta (PRD) region, and urbanization contributes to nearly 50% of the increase in HW frequency in PRD. It is also noticed that HWs are commencing earlier and ending later, and urbanization may advance the timing of the onset of HW events.