bluuebunny/crossref_metadata_2025_split huggingface dataset:
Causes and mechanisms of isolated mitral regurgitation in the community: clinical context and outcome
Authors: Dziadzko Volha , Dziadzko Mikhail , Medina-Inojosa Jose R , Benfari Giovanni , Michelena Hector I , Crestanello Juan A , Maalouf Joseph , Thapa Prabin , Enriquez-Sarano Maurice 
Published: May 2019

Abstract

Aims
To define the hitherto unknown aetiology/mechanism distributions of mitral regurgitation (MR) in the community and the linked clinical characteristics/outcomes.

Methods and results
We identified all isolated, moderate/severe MR diagnosed in our community (Olmsted County, MN, USA) between 2000 and 2010 and classified MR aetiology/mechanisms. Eligible patients (n = 727) were 73 ± 18 years, 51% females, with ejection fraction (EF) 49 ± 17%. MR was functional (FMR) in 65%, organic (OMR) in 32% and 2% mixed. Functional MR was linked to left ventricular remodelling (FMR-v) 38% and isolated atrial dilatation (FMR-a) 27%. At diagnosis FMR-v vs. FMR-a, vs. OMR displayed profound differences (all P &lt; 0.0001) in age (73 ± 14, 80 ± 10, 68 ± 21years), male-sex (59, 33, 51%), atrial-fibrillation (28, 54, 13%), EF (33 ± 14, 57 ± 11, 61 ± 10%), and regurgitant-volume (38 ± 13, 37 ± 11, 51 ± 24 mL/beat). Dominant MR mechanism was Type I (normal valve-movement) 38%, Type II (excessive valve-movement) 25%, Type IIIa (diastolic movement-restriction) 3%, and Type IIIb (systolic movement-restriction) 34%. Outcomes were mediocre with excess-mortality vs. general-population in FMR-v [risk ratio 3.45 (2.98–3.99), P &lt; 0.0001] but also FMR-a [risk ratio 1.88 (1.52–2.25), P &lt; 0.0001] and OMR [risk ratio 1.83 (1.50–2.22), P &lt; 0.0001]. Heart failure was frequent, particularly in FMR-v (5-year 83 ± 3% vs. 59 ± 4% FMR-a, 40 ± 3% OMR, P &lt; 0.0001). Mitral surgery during patients’ lifetime was performed in 4% of FMR-v, 3% of FMR-a, and 37% of OMR.

Conclusion
Moderate/severe isolated MR in the community displays considerable aetiology/mechanism heterogeneity. Functional MR dominates, mostly FMR-v but FMR-a is frequent and degenerative MR dominates OMR. Outcomes are mediocre with excess-mortality particularly with FMR-v but FMR-a, despite normal EF incurs notable excess-mortality and frequent heart failure. Pervasive undertreatment warrants clinical trials of therapies tailored to specific MR cause/mechanisms.
Radiogenomics Consortium Genome-Wide Association Study Meta-Analysis of Late Toxicity After Prostate Cancer Radiotherapy
Authors: Kerns Sarah L , Fachal Laura , Dorling Leila , Barnett Gillian C , Baran Andrea , Peterson Derick R , Hollenberg Michelle , Hao Ke , Narzo Antonio Di , Ahsen Mehmet Eren , Pandey Gaurav , Bentzen Søren M , Janelsins Michelle , Elliott Rebecca M , Pharoah Paul D P , Burnet Neil G , Dearnaley David P , Gulliford Sarah L , Hall Emma , Sydes Matthew R , Aguado-Barrera Miguel E , Gómez-Caamaño Antonio , Carballo Ana M , Peleteiro Paula , Lobato-Busto Ramón , Stock Richard , Stone Nelson N , Ostrer Harry , Usmani Nawaid , Singhal Sandeep , Tsuji Hiroshi , Imai Takashi , Saito Shiro , Eeles Rosalind , DeRuyck Kim , Parliament Matthew , Dunning Alison M , Vega Ana , Rosenstein Barry S , West Catharine M L 
Published: May 2019

Abstract

Background
A total of 10%–20% of patients develop long-term toxicity following radiotherapy for prostate cancer. Identification of common genetic variants associated with susceptibility to radiotoxicity might improve risk prediction and inform functional mechanistic studies.

Methods
We conducted an individual patient data meta-analysis of six genome-wide association studies (n = 3871) in men of European ancestry who underwent radiotherapy for prostate cancer. Radiotoxicities (increased urinary frequency, decreased urinary stream, hematuria, rectal bleeding) were graded prospectively. We used grouped relative risk models to test associations with approximately 6 million genotyped or imputed variants (time to first grade 2 or higher toxicity event). Variants with two-sided Pmeta less than 5 × 10−8 were considered statistically significant. Bayesian false discovery probability provided an additional measure of confidence. Statistically significant variants were evaluated in three Japanese cohorts (n = 962). All statistical tests were two-sided.

Results
Meta-analysis of the European ancestry cohorts identified three genomic signals: single nucleotide polymorphism rs17055178 with rectal bleeding (Pmeta = 6.2 × 10−10), rs10969913 with decreased urinary stream (Pmeta = 2.9 × 10−10), and rs11122573 with hematuria (Pmeta = 1.8 × 10−8). Fine-scale mapping of these three regions was used to identify another independent signal (rs147121532) associated with hematuria (Pconditional = 4.7 × 10−6). Credible causal variants at these four signals lie in gene-regulatory regions, some modulating expression of nearby genes. Previously identified variants showed consistent associations (rs17599026 with increased urinary frequency, rs7720298 with decreased urinary stream, rs1801516 with overall toxicity) in new cohorts. rs10969913 and rs17599026 had similar effects in the photon-treated Japanese cohorts.

Conclusions
This study increases the understanding of the architecture of common genetic variants affecting radiotoxicity, points to novel radio-pathogenic mechanisms, and develops risk models for testing in clinical studies. Further multinational radiogenomics studies in larger cohorts are worthwhile.
The Effects of Ganglioside-Monosialic Acid in Taxane-Induced Peripheral Neurotoxicity in Patients with Breast Cancer: A Randomized Trial
Authors: Su Yanhong , Huang Jiajia , Wang Shusen , Unger Joseph M , Arias-Fuenzalida Jonathan , Shi Yanxia , Li Jibin , Gao Yongxiang , Shi Wei , Wang Xinyue , Peng Roujun , Xu Fei , An Xin , Xue Cong , Xia Wen , Hong Ruoxi , Zhong Yongyi , Lin Ying , Huang Heng , Zhang Anqin , Zhang Lehong , Cai Li , Zhang Jinxin , Yuan Zhongyu ,   South China Breast Cancer Group
Published: May 2019

Abstract

Background
Taxane-induced peripheral neuropathy (TIPN) is a dose-limiting adverse effect. Ganglioside-monosialic acid (GM1) functions as a neuroprotective factor. We assessed the effects of GM1 on the prevention of TIPN in breast cancer patients.

Methods
We conducted a randomized, double-blind, placebo-controlled trial including 206 patients with early-stage breast cancer planning to receive taxane-based adjuvant chemotherapy with a follow-up of more than 1 year. Subjects were randomly assigned to receive GM1 (80 mg, day −1 to day 2) or placebo. The primary endpoint was the Functional Assessment of Cancer Treatment Neurotoxicity subscale score after four cycles of chemotherapy. Secondary endpoints included neurotoxicity evaluated by National Cancer Institute Common Terminology Criteria for Adverse Events Version 4.0 and the Eastern Cooperative Oncology Group neuropathy scale. All statistical tests were two-sided.

Results
In 183 evaluable patients, the GM1 group reported better mean Functional Assessment of Cancer Treatment Neurotoxicity subscale scores than patients in the placebo group after four cycles of chemotherapy (43.27, 95% confidence interval [CI] = 43.05 to 43.49 vs 34.34, 95% CI = 33.78 to 34.89; mean difference = 8.96, 95% CI = 8.38 to 9.54, P < .001). Grade 1 or higher peripheral neurotoxicity in Common Terminology Criteria for Adverse Events v4.0 scale was statistically significantly lower in the GM1 group (14.3% vs 100.0%, P < .001). Additionally, the GM1 group had a statistically significantly lower incidence of grade 1 or higher neurotoxicity assessed by Eastern Cooperative Oncology Group neuropathy scale sensory neuropathy (26.4% vs 97.8%, P < .001) and motor neuropathy subscales (20.9% vs 81.5%, P < .001).

Conclusions
The treatment with GM1 resulted in a reduction in the severity and incidence of TIPN after four cycles of taxane-containing chemotherapy in patients with breast cancer.
First- and Continuing-Generation Students, Substance Use, and College Graduation
Authors: Swisher Raymond R , Dennison Christopher R 
Published: May 2019

AbstractGraduation from a four-year college is an important potential means of social mobility for those from lower socioeconomic backgrounds. For “first-generation” students, the path to a degree is often made more difficult by circumstances such as working long hours and living with parents, as well as an unfamiliar college environment. One concerning aspect of college life is the continuing prevalence of substance use, which has hampered graduation rates and led many universities to reconsider the impact that the party subculture has on student well-being. In this paper, we use data from The National Longitudinal Study of Adolescent to Adult Health to examine differences in substance use (binge drinking, marijuana use, other illicit drug use) and four-year college graduation across unique combinations of students defined by college generation, work, and residential statuses. Consistent with previous qualitative studies into the class-specific consequences of the college party subculture, substance use is generally found to be higher among continuing-generation students who are not working nor living with their parents. In addition, substance use appears to have little consequence for the graduation prospects of these most traditional continuing-generation students. In contrast, substance use is negatively associated with graduation for most other groups, particularly first-generation students or those working long hours.
Does removal of work stress explain improved sleep following retirement? The Finnish Retirement and Aging study
Authors: Myllyntausta Saana , Salo Paula , Kronholm Erkki , Pentti Jaana , Oksanen Tuula , Kivimäki Mika , Vahtera Jussi , Stenholm Sari 
Published: May 2019

Abstract

Study Objectives
Relief from work stress has been hypothesized to explain improvements in sleep duration and quality following retirement, but this has not been confirmed with longitudinal studies. By using repeat sleep data, we examined the role of removal of work-related stressors in changes in sleep at retirement.

Methods
The study population consisted of 2,053 participants from the Finnish Retirement and Aging study. Participants’ sleep duration, sleep difficulties (difficulties falling asleep, difficulties maintaining sleep, waking up too early in the morning, nonrestorative sleep), daytime tiredness, and sleep loss due to worry were assessed using surveys conducted once a year before and after retirement (average number of repeat surveys 3.5 [range 2–5] per participant). We used Poisson regression with generalized estimating equations to examine the associations between work-related stressors (job strain, low work time control, effort–reward imbalance, and organizational injustice) and changes in sleep at retirement.

Results
An increase in sleep duration and decrease in waking up too early in the morning, nonrestorative sleep, daytime tiredness, and sleep loss due to worry were observed shortly after retirement. No systematic associations across the work-related stressors and changes in sleep characteristics were observed. Higher number of work-related stressors before retirement was not associated with a greater magnitude of favorable changes in any of the postretirement sleep characteristics investigated.

Conclusions
This longitudinal study suggests that perceived sleep improves shortly after retirement and that these changes are mainly driven by factors other than relief from work stress.
Interleukin 33 Expression Induced by Aryl Hydrocarbon Receptor in Macrophages
Authors: Ishihara Yasuhiro , Haarmann-Stemmann Thomas , Kado Norman Y , Vogel Christoph F A 
Published: May 2019

Abstract
Polycyclic aromatic hydrocarbons (PAHs) contained in airborne particulate matter have been identified as a contributing factor for inflammation in the respiratory tract. Recently, interleukin-33 (IL-33) is strongly suggested to be associated with airway inflammation. Aryl hydrocarbon receptor (AhR) is a receptor for PAHs to regulate several metabolic enzymes, but the relationships between AhR and airway inflammation are still unclear. In this study, we examined the role of AhR in the expression of IL-33 in macrophages. THP-1 macrophages mainly expressed IL-33 variant 5, which in turn was strongly induced by the AhR agonists 2, 3, 7, 8-tetrachlorodibenzo-p-dioxin (TCDD) and kynurenine (KYN). AhR antagonist CH223191 suppressed the increase in IL-33 expression. Promoter analysis revealed that the IL-33 promoter has 2 dioxin response elements (DREs). AhR was recruited to both DREs after treatment with TCDD or KYN as assessed by gel shift and chromatin immunoprecipitation assays. A luciferase assay showed that one of the DREs was functional and involved in the expression of IL-33. Macrophages isolated from AhR-null mice expressed only low levels of IL-33 even in response to treatment with AhR ligands compared with wild-type cells. The treatment of THP-1 macrophages with diesel particulate matter and particle extracts increased the mRNA and protein expression of IL-33. Taken together, the results show that ligand-activated AhR mediates the induction of IL-33 in macrophages via a DRE located in the IL-33 promoter region. AhR-mediated IL-33 induction could be involved in the exacerbation and/or prolongation of airway inflammation elicited by toxic chemical substances.
Vaginoscopy “No Touch” Technique: A Feasible Alternative to Paracervical Block for in Office Hysteroscopy [34E]
Authors: Echeverri Natalia , Fiorentino Desiree G. , Ulker Ashley , Timmons Douglas B. , Ring Sarah , Carugno Jose Antonio 
Published: May 2019

INTRODUCTION:
Hysteroscopy allows direct visualization of the uterine cavity. Traditionally, in office hysteroscopy is performed using a speculum and tenaculum to hold the cervix. However, the emergence of smaller diameter hysteroscopes along with the vaginoscopy no touch technique without the need of speculum or tenaculum has contributed for the procedure to be done in the office setting without the use of analgesia. This study reviews our experience of in office hysteroscopy using the vaginoscopy "no touch" approach.

METHODS:
Retrospective chart review of 22 in office hysteroscopies performed without analgesia using the vaginoscopy “No touch” technique from June 1, 2017 to January 31, 2018. Patients received 200 mcg of oral Misoprostol 30 minutes before the procedure. Data gathered included age, body mass index, prior vaginal deliveries, and pain during the procedure. Success was measured as the ability to enter the endometrial cavity and perform the expected procedure.

RESULTS:
The median age 45 SD ±10.0 and BMI of 26.9 SD ±4.4. Hysteroscopic indications were: 2 (9.1%) postmenopausal bleeding, 5 (22.7%) retained IUD, 7 (31.8%) for suspected polyp, 8 (36.4%) for abnormal uterine bleeding. Of the 22 procedures, 18 were successful completed (80%). The median pain on VAS scale reported immediately after the procedure was 3.8 SD ±0.8 All four of the unsuccessful procedures were in postmenopausal females, two of which due to severe cervical stenosis. There were no complications.

CONCLUSION:
In office hysteroscopies using the vaginoscopy “no touch” technique is a feasible and safe procedure. We recommend adopting this innovative, painless technique.
Increased Gastric MIBG Activity as a Normal Variant
Authors: Bai Xia , Wang Xuemei , Zhuang Hongming 
Published: May 2019

Abstract
Although increased MIBG activity in the colon is a well-described and well-known normal variant, elevated MIBG activity in the stomach is rarely seen. We describe increased 123I-MIBG accumulation in the stomach in a 13-year-old girl who had recurrent metastatic neuroblastoma. The activity appeared to be a new MIBG-avid lesion on the planar images. However, the SPECT/CT images revealed that the activity was inside the gastric lumen without anatomical abnormality. On a follow-up 123I-MIBG scan acquired 3 months later, the stomach no longer had elevated MIBG activity, while the other abnormal activity on prior study remained the same.
Mapping Transcription Factor Networks By Comparing Tf Binding Locations To Tf Perturbation Responses
Authors: Kang Yiming , Patel Nikhil R. , Shively Christian , Recio Pamela Samantha , Chen Xuhua , Wranik Bernd J. , Kim Griffin , Mitra Robi , McIsaac R. Scott , Brent Michael R. 
Published: May 2019

ABSTRACTBackgroundA transcription-factor (TF) network map indicates the direct, functional targets of each TF -- the genes it regulates by binding to their cis-regulatory DNA. Data on the genomic binding locations of each TF and the transcriptional responses to perturbations of its activity, such as overexpressing it, could support TF network mapping. Systematic data sets of both types exist for yeast and for human K562 and HEK293 cells.ResultsIn previous data, most TF binding sites appear to be non-functional, so one cannot take the genes in whose promoters a TF binds as its direct, functional (DF) targets. Taking the genes that are both bound by a TF and responsive to a perturbation of it as its DF targets (intersection algorithm) is also not safe, as we show by deriving a new lower bound on the expected false discovery rate of the intersection algorithm. When there are many non-functional binding sites and many indirect targets, non-functional sites are expected to occur in the cis-regulatory DNA of indirect targets by chance. Dual threshold optimization, a new method for setting significance thresholds on binding and response data, improves the intersection algorithm, as does post-processing perturbation-response data with NetProphet 2.0. A comprehensive new data set measuring the transcriptional response shortly after inducing overexpression of a TF also helps, as does transposon calling cards, a new method for identifying TF binding locations.ConclusionsThe combination of dual threshold optimization and NetProphet greatly expands the high-confidence TF network map in both yeast and human. In yeast, measuring the response shortly after inducing TF overexpression and measuring binding locations by using transposon calling cards improve the network synergistically.
Structural basis of TFIIH activation for nucleotide excision repair
Authors: Kokic Goran , Chernev Aleksandar , Tegunov Dimitry , Dienemann Christian , Urlaub Henning , Cramer Patrick 
Published: May 2019

AbstractGenomes are constantly threatened by DNA damage, but cells can remove a large variety of DNA lesions by nucleotide excision repair (NER)1. Mutations in NER factors compromise cellular fitness and cause human diseases such as Xeroderma pigmentosum (XP), Cockayne syndrome and trichothiodystrophy2,3. The NER machinery is built around the multisubunit transcription factor IIH (TFIIH), which opens the DNA repair bubble, scans for the lesion, and coordinates excision of the damaged DNA single strand fragment1,4. TFIIH consists of a kinase module and a core module that contains the ATPases XPB and XPD5. Here we prepare recombinant human TFIIH and show that XPB and XPD are stimulated by the additional NER factors XPA and XPG, respectively. We then determine the cryo-electron microscopy structure of the human core TFIIH-XPA-DNA complex at 3.6 Å resolution. The structure represents the lesion-scanning intermediate on the NER pathway and rationalizes the distinct phenotypes of disease mutations. It reveals that XPB and XPD bind double- and single-stranded DNA, respectively, consistent with their translocase and helicase activities. XPA forms a bridge between XPB and XPD, and retains the DNA at the 5’-edge of the repair bubble. Biochemical data and comparisons with prior structures6,7 explain how XPA and XPG can switch TFIIH from a transcription factor to a DNA repair factor. During transcription, the kinase module inhibits the repair helicase XPD8. For DNA repair, XPA dramatically rearranges the core TFIIH structure, which reorients the ATPases, releases the kinase module and displaces a ‘plug’ element from the DNA-binding pore in XPD. This enables XPD to move by ~80 Å, engage with DNA, and scan for the lesion in a XPG-stimulated manner. Our results provide the basis for a detailed mechanistic analysis of the NER mechanism.
Multimodal frequency representations are embedded in modality-defined cortical sensory systems
Authors: Rahman Shoaibur , Barnes Kelly Anne , Crommett Lexi E. , Tommerdahl Mark , Yau Jeffrey M. 
Published: May 2019

AbstractSensory information is represented and elaborated in hierarchical cortical systems that are thought to be dedicated to individual sensory modalities. This traditional view of sensory cortex organization has been challenged by recent evidence of multimodal responses in primary and association sensory areas. Although it is indisputable that sensory areas respond to multiple modalities, it remains unclear whether these multimodal responses reflect selective information processing for particular stimulus features. Here, we used fMRI adaptation to identify brain regions that are sensitive to the temporal frequency information contained in auditory, tactile, and audiotactile stimulus sequences. A number of brain regions distributed over the parietal and temporal lobes exhibited frequency-selective temporal response modulation for both auditory and tactile stimulus events, as indexed by repetition suppression effects. A smaller set of regions responded to crossmodal adaptation sequences in a frequency-dependent manner. Despite an extensive overlap of multimodal frequency-selective responses across the parietal and temporal lobes, representational similarity analysis revealed a cortical “regional landscape” that clearly reflected distinct somatosensory and auditory processing systems that converged on modality-invariant areas. These structured relationships between brain regions were also evident in spontaneous signal fluctuation patterns measured at rest. Our results reveal that multimodal processing in human cortex can be feature-specific and that multimodal frequency representations are embedded in the intrinsically hierarchical organization of cortical sensory systems.Significance StatementA hallmark of traditional brain organization models is the segregation of signals from the different senses in modality-dedicated brain regions. Recent evidence showing multimodal activity in brain regions thought to be dedicated to a single modality have challenged the traditional sensory cortex model. Notably, few studies have explored the feature-specificity of multimodal responses found in sensory cortex. Here, we used fMRI adaptation to identify parietal and temporal cortex regions which exhibited sensitivity to both tactile and auditory frequency information. These univariate results demonstrate that multimodal processing in sensory cortex can be feature-specific. Using the same data, though, we found clear evidence of modality-based cortical organization estimated from multivariate response patterns and spontaneous BOLD signal fluctuations. Thus, our results reveal an embedding of feature-specific multimodal processing in traditionally-defined cortical systems.