bluuebunny/crossref_metadata_2025_split huggingface dataset:
Safety of Flibanserin in Women Treated With Antidepressants: A Randomized, Placebo-Controlled Study
Authors: Clayton Anita H. , Croft Harry A. , Yuan James , Brown Louise , Kissling Robert 
Published: December 2017

Abstract

Background
Depression is often associated with sexual dysfunction, and pharmacologic treatment for hypoactive sexual desire disorder can be considered in women receiving treatment for depression.

Aim
To evaluate the safety of flibanserin in women treated for depression with selective serotonin reuptake inhibitors or serotonin and norepinephrine reuptake inhibitors.

Methods
In this double-blinded, randomized, placebo-controlled trial, women with remitted or mild depression treated with selective serotonin reuptake inhibitors or serotonin and norepinephrine reuptake inhibitors who were not postmenopausal and were experiencing symptoms of hypoactive sexual desire disorder (ie, decreased sexual desire and related distress) received flibanserin 50 mg at bedtime (qhs) for 2 weeks and up-titrated to 100 mg qhs, flibanserin 100 mg qhs for the entire treatment period, or placebo for up to 12 weeks.

Outcomes
Safety assessment included adverse events and symptoms of depression and anxiety.

Results
73 patients were randomly assigned to flibanserin (both dose groups combined) and 38 to placebo. The sponsor terminated the study early at discontinuation of the development of flibanserin. Treatment duration was at least 8 weeks for 84.9% and 94.7% of patients in the flibanserin and placebo groups, respectively. The most common adverse events (incidence ≥ 2% in the flibanserin group and higher than that in the placebo group) included dry mouth (5.5% for flibanserin vs 2.6% for placebo), insomnia (5.5% vs 2.6%), back pain (4.1% vs 2.6%), and dizziness (4.1% vs 0.0%). There were no serious adverse events and no instances of suicidal ideation or behavior. The proportions of patients with symptom worsening in the flibanserin and placebo groups, respectively, were 6.9% and 21.6% for depression and 1.4% and 2.7% for anxiety. Remission of depression at study end point, as measured by the Quick Inventory of Depressive Symptomatology–Self Report, was experienced by 19.4% of flibanserin-treated patients and 10.8% of patients receiving placebo; remission of anxiety based on the Beck Anxiety Inventory was noted in 16.4% and 2.7% of patients, respectively.

Clinical Implications
The results of this study support the safety of flibanserin in premenopausal women being treated with a serotonergic antidepressant. No increased risks were observed when adding flibanserin to a stable selective serotonin reuptake inhibitor or serotonin and norepinephrine reuptake inhibitor treatment regimen.

Strengths and Limitations
This was a well-designed, randomized, placebo-controlled trial. The primary limitation was the early study discontinuation by the sponsor, which decreased the sample size and duration of treatment.

Conclusion
In this small trial, flibanserin 100 mg qhs was generally safe and well tolerated in premenopausal women with mild or remitted depression taking a serotonergic antidepressant.
Differences in Perceived and Physiologic Genital Arousal Between Women With and Without Sexual Dysfunction
Authors: Handy Ariel B. , Stanton Amelia M. , Pulverman Carey S. , Meston Cindy M. 
Published: December 2017

Abstract

Background
Many sexual psychophysiologic studies have failed to find differences in physiologic genital arousal between women with and those without sexual dysfunction. However, differences in self-reported (ie, perceived) measures of genital responses between these 2 groups of women have been noted.

Aims
To determine whether women with and without sexual dysfunction differ on measures of physiologic and perceived genital arousal based on type of analytic technique used, to explore differences in perceived genital arousal, and to assess the relation between physiologic and perceived genital arousal.

Methods
Data from 5 studies (N = 214) were used in this analysis. Women were categorized into 3 groups: women with arousal-specific sexual dysfunction (n = 40), women with decreased sexual function (n = 72), and women who were sexually functional (n = 102). Women viewed an erotic film while their physiologic genital arousal was measured using a vaginal photoplethysmograph. After watching the film, women completed a self-report measure of perceived genital arousal.

Outcomes
There were differences in vaginal pulse amplitude (VPA) levels and association of VPA with perceived genital sensations based on level of sexual function.

Results
Commonly used methods of analysis failed to identify significant differences in VPA among these groups of women. When VPA data were analyzed with hierarchical linear modeling, significant differences emerged. Notably, women with arousal-specific dysfunction exhibited lower VPA than sexually functional women at the beginning of the assessment. As the erotic film progressed, women with arousal-specific dysfunction became aroused at a faster rate than sexually functional women, and these 2 groups ultimately reached a similar level of VPA. Sexually functional women reported the highest levels of perceived genital responses among the 3 groups of women. No significant relation between VPA and perceived genital arousal emerged.

Clinical Translation
Women's perception of their genital responses could play a role in women's experience of sexual dysfunction and might be more clinically relevant for women with sexual dysfunction than genital blood flow.

Strengths and Limitations
This study's large sample is unique in sexual psychophysiology, and it strengthens the credibility of the findings. However, this study is limited in that arousal-specific dysfunction was determined with self-report measures, not by a clinician-administered assessment.

Conclusion
These findings suggest distinct response trajectories in women with and without sexual dysfunction, and although perceived genital responses are important for women who are experiencing problems with arousal, they do not seem to be related to objective measures of physiologic arousal.
Treatment of Paraphilic Disorders in Sexual Offenders or Men With a Risk of Sexual Offending With Luteinizing Hormone-Releasing Hormone Agonists: An Updated Systematic Review
Authors: Turner Daniel , Briken Peer 
Published: December 2017

Abstract

Background
Different pharmacologic agents are used in the treatment of paraphilic disorders in sexual offenders or men with a risk of sexual offending, with luteinizing hormone-releasing hormone (LHRH) agonists being the agents introduced more recently to treatment regimens.

Aim
To summarize the relevant literature concerning LHRH agonist treatment of paraphilic disorders in sexual offenders and update the previously published systematic review by Briken et al (J Clin Psychiatry 2003;64:890–897).

Methods
The PubMed and Google Scholar databases were searched for literature published from January 2003 through October 2017 using the following key words: LHRH agonists, GnRH agonists, antiandrogens AND paraphilia, pedophilia, sex offenders.

Outcomes
Evaluation of the effectiveness and side effects of LHRH agonist treatment of paraphilic disorders in sexual offenders.

Results
After screening for duplicates and applying specific selection criteria, the search yielded 24 eligible studies reporting on a sample of 256 patients. There is increasing evidence that LHRH agonists are more effective than steroidal antiandrogens in lowering paraphilic sexual thoughts and behaviors. Current research also is based on methods that might be less susceptible to faking (eg, eye-tracking, brain imaging, and viewing-time measures). Side effects occurring most frequently are fatigue, hot flashes, depressive mood, weight gain, high blood pressure, diabetes, gynecomastia, loss of erectile function, and loss of bone mineral density.

Clinical Implications
Although LHRH agonists seem to be the most effective drugs in the treatment of paraphilic fantasies and behaviors, they should be reserved for patients with a paraphilic disorder and the highest risk of sexual offending because of their extensive side effects.

Strengths and Limitations
This systematic review considers all types of research on LHRH agonist treatment in patients with paraphilic disorders, thereby providing a complete overview of the current state of research. However, most studies are case reports or observational studies and randomized controlled clinical trials have not been conducted or published.

Conclusions
LHRH agonists are a useful treatment when combined with psychotherapy in patients with a paraphilic disorder and the highest risk of sexual offending. However, throughout treatment, close monitoring of side effects is needed and ethical concerns must always be kept in mind.
Glucose Modulates Human Ventral Tegmental Activity in Response to Sexual Stimuli
Authors: Ulrich Martin , Stauß Philipp , Grön Georg 
Published: December 2017

AbstractBackgroundAttribution of salience to sexual stimuli is mediated by the dopaminergic midbrain, including the ventral tegmental area (VTA). The existence of glucose-sensing neurons in the VTA, as suggested by animal studies, offers the opportunity to modulate aberrant salience coding involved in sexual disorders such as sexual addiction. Recent neuroimaging work supported that VTA activity in humans can be modulated by intravenously infusing a small bolus of glucose. However, that study used appetitive food stimuli, leaving the possibility that glucose modulation of VTA-mediated salience coding might be bound to this class of stimuli.AimTo test whether glucose-modulatory effects generalize to food-unrelated stimuli despite being in the class of primary reinforcers.MethodsDuring functional imaging, 37 healthy men were exposed to images showing nude or clothed female upper bodies. At the end of the 1st quarter (∼6 minutes) of the experiment, 18 participants received a small amount of intravenously infused glucose.ResultsBefore glucose administration, VTA activity was higher for nude than for clothed female stimuli. After infusion of glucose, this pattern reversed such that VTA activity was higher for clothed than for nude female stimuli. The effect was at its maximum approximately 7 to 12 minutes after glucose infusion, changing back during the experiment’s 4th phase. In another 19 participants not treated with glucose, VTA activity was consistently higher for nude than for clothed female stimuli throughout the experiment.ConclusionThe present findings show that glucose modulates VTA-mediated salience coding of sexual stimuli. These results suggest that glucose might affect salience coding in a stimulus-general way. However, future studies are necessary to address the question of whether glucose modulation also affects the VTA’s salience coding of secondary reinforcers.
Initial assessment in the management of adult epistaxis: systematic review
Authors: Khan M , Conroy K , Ubayasiri K , Constable J , Smith M E , Williams R J , Kuhn I , Smith M , Philpott C 
Published: December 2017

AbstractBackground:The initial assessment of epistaxis patients commonly includes: first aid measures, observations, focused history taking, and clinical examinations and investigations. This systematic review aimed to identify evidence that informs how the initial assessment of these patients should be conducted.Method:A systematic review of the literature was performed using a standardised methodology and search strategy.Results:Seventeen articles were included. Factors identified were: co-morbidity, intrinsic patient factors, coagulation screening and ice pack use. Hypertension and anticoagulant use were demonstrated to adversely affect outcomes. Coagulation screening is useful in patients on anticoagulant medication. Four studies could not be accessed. Retrospective methodology and insufficient statistical analysis limit several studies.Conclusion:Sustained ambulatory hypertension, anticoagulant therapy and posterior bleeding may be associated with recurrent epistaxis, and should be recorded. Oral ice pack use may decrease severity and can be considered as first aid. Coagulation studies are appropriate for patients with a history of anticoagulant use or bleeding diatheses.
Amphiphilic nanocarrier-induced modulation of PLK1 and miR-34a leads to improved therapeutic response in pancreatic cancer
Authors: Gibori Hadas , Eliyahu Shay , Krivitsky Adva , Ben-Shushan Dikla , Epshtein Yana , Tiram Galia , Blau Rachel , Ofek Paula , Lee Joo Sang , Ruppin Eytan , Landsman Limor , Barshack Iris , Golan Talia , Merquiol Emmanuelle , Blum Galia , Satchi-Fainaro Ronit 
Published: December 2017

AbstractThe heterogeneity of pancreatic ductal adenocarcinoma (PDAC) suggests that successful treatment might rely on simultaneous targeting of multiple genes, which can be achieved by RNA interference-based therapeutic strategies. Here we show a potent combination of microRNA and siRNA delivered by an efficient nanocarrier to PDAC tumors. Using proteomic-microRNA profiles and survival data of PDAC patients from TCGA, we found a novel signature for prolonged survival. Accordingly, we used a microRNA-mimic to increase miR-34a together with siRNA to silence PLK1 oncogene. For in vivo dual-targeting of this combination, we developed a biodegradable amphiphilic polyglutamate amine polymeric nanocarrier (APA). APA-miRNA–siRNA polyplexes systemically administered to orthotopically inoculated PDAC-bearing mice showed no toxicity and accumulated at the tumor, resulting in an enhanced antitumor effect due to inhibition of MYC oncogene, a common target of both miR-34a and PLK1. Taken together, our findings warrant this unique combined polyplex’s potential as a novel nanotherapeutic for PDAC.
Momentum-resolved observations of the phonon instability driving geometric improper ferroelectricity in yttrium manganite
Authors: Bansal Dipanshu , Niedziela Jennifer L. , Sinclair Ryan , Garlea V. Ovidiu , Abernathy Douglas L. , Chi Songxue , Ren Yang , Zhou Haidong , Delaire Olivier 
Published: December 2017

AbstractMagnetoelectrics offer tantalizing opportunities for devices coupling ferroelectricity and magnetism but remain difficult to realize. Breakthrough strategies could circumvent the mutually exclusive origins of magnetism and ferroelectricity by exploiting the interaction of multiple phonon modes in geometric improper and hybrid improper ferroelectrics. Yet, the proposed instability of a zone-boundary phonon mode, driving the emergence of ferroelectricity via coupling to a polar mode, remains to be directly observed. Here, we provide previously missing evidence for this scenario in the archetypal improper ferroelectric, yttrium manganite, through comprehensive scattering measurements of the atomic structure and phonons, supported with first-principles simulations. Our experiments and theoretical modeling resolve the origin of the unusual temperature dependence of the polarization and rule out a reported double-step ferroelectric transition. These results emphasize the critical role of phonon anharmonicity in rationalizing lattice instabilities in improper ferroelectrics and show that including these effects in simulations could facilitate the design of magnetoelectrics.
ERK-mediated phosphorylation regulates SOX10 sumoylation and targets expression in mutant BRAF melanoma
Authors: Han Shujun , Ren Yibo , He Wangxiao , Liu Huadong , Zhi Zhe , Zhu Xinliang , Yang Tielin , Rong Yu , Ma Bohan , Purwin Timothy J. , Ouyang Zhenlin , Li Caixia , Wang Xun , Wang Xueqiang , Yang Huizi , Zheng Yan , Aplin Andrew E. , Liu Jiankang , Shao Yongping 
Published: December 2017

AbstractIn human mutant BRAF melanoma cells, the stemness transcription factor FOXD3 is rapidly induced by inhibition of ERK1/2 signaling and mediates adaptive resistance to RAF inhibitors. However, the mechanism underlying ERK signaling control of FOXD3 expression remains unknown. Here we show that SOX10 is both necessary and sufficient for RAF inhibitor-induced expression of FOXD3 in mutant BRAF melanoma cells. SOX10 activates the transcription of FOXD3 by binding to a regulatory element in FOXD3 promoter. Phosphorylation of SOX10 by ERK inhibits its transcription activity toward multiple target genes by interfering with the sumoylation of SOX10 at K55, which is essential for its transcription activity. Finally, depletion of SOX10 sensitizes mutant BRAF melanoma cells to RAF inhibitors in vitro and in vivo. Thus, our work discovers a novel phosphorylation-dependent regulatory mechanism of SOX10 transcription activity and completes an ERK1/2/SOX10/FOXD3/ERBB3 axis that mediates adaptive resistance to RAF inhibitors in mutant BRAF melanoma cells.
Linking soil biology and chemistry in biological soil crust using isolate exometabolomics
Authors: Swenson Tami L. , Karaoz Ulas , Swenson Joel M. , Bowen Benjamin P. , Northen Trent R. 
Published: December 2017

AbstractMetagenomic sequencing provides a window into microbial community structure and metabolic potential; however, linking these data to exogenous metabolites that microorganisms process and produce (the exometabolome) remains challenging. Previously, we observed strong exometabolite niche partitioning among bacterial isolates from biological soil crust (biocrust). Here we examine native biocrust to determine if these patterns are reproduced in the environment. Overall, most soil metabolites display the expected relationship (positive or negative correlation) with four dominant bacteria following a wetting event and across biocrust developmental stages. For metabolites that were previously found to be consumed by an isolate, 70% are negatively correlated with the abundance of the isolate’s closest matching environmental relative in situ, whereas for released metabolites, 67% were positively correlated. Our results demonstrate that metabolite profiling, shotgun sequencing and exometabolomics may be successfully integrated to functionally link microbial community structure with environmental chemistry in biocrust.
Non-canonical Wnt signaling regulates neural stem cell quiescence during homeostasis and after demyelination
Authors: Chavali Manideep , Klingener Michael , Kokkosis Alexandros G. , Garkun Yury , Felong Sylwia , Maffei Arianna , Aguirre Adan 
Published: December 2017

AbstractAdult neural stem cells (NSCs) reside in a specialized microenvironment, the subventricular zone (SVZ), which provides them with unique signaling cues to control their basic properties and prevent their exhaustion. While the signaling mechanisms that regulate NSC lineage progression are well characterized, the molecular mechanisms that trigger the activation of quiescent NSCs during homeostasis and tissue repair are still unclear. Here, we uncovered that the NSC quiescent state is maintained by Rho-GTPase Cdc42, a downstream target of non-canonical Wnt signaling. Mechanistically, activation of Cdc42 induces expression of molecules involved in stem cell identity and anchorage to the niche. Strikingly, during a demyelination injury, downregulation of non-canonical Wnt-dependent Cdc42 activity is necessary to promote activation and lineage progression of quiescent NSCs, thereby initiating the process of tissue repair.
Dynamic metal-ligand coordination for multicolour and water-jet rewritable paper
Authors: Ma Yun , She Pengfei , Zhang Kenneth Yin , Yang Huiran , Qin Yanyan , Xu Zihan , Liu Shujuan , Zhao Qiang , Huang Wei 
Published: December 2017

AbstractRewritable paper has recently become prevalent in both academic research and marketplace due to the potential environmental advantages, including forest conservation, pollution reduction, energy saving and resource sustainability. However, its real-life applications are limited by a lack of effective strategy to realize multicolour and water-jet printing on rewritable paper with long legible image-lasting times. Herein, we report an effective strategy to construct rewritable paper based on colour or luminescence switching induced by dynamic metal–ligand coordination. This type of rewritable paper can be conveniently utilized for multicolour water-jet printing by using aqueous solutions containing different metal salts as ink. In addition, the printed images on the water-jet rewritable paper can be retained for a long time (> 6 months), which shows great progress compared to previous work. We believe that this type of rewritable paper could be considered as a prototype for multicolour water-jet printing to meet the practical needs.
Metabolic rate evolves rapidly and in parallel with the pace of life history
Authors: Auer Sonya K. , Dick Cynthia A. , Metcalfe Neil B. , Reznick David N. 
Published: December 2017

AbstractMetabolic rates and life history strategies are both thought to set the “pace of life”, but whether they evolve in tandem is not well understood. Here, using a common garden experiment that compares replicate paired populations, we show that Trinidadian guppy (Poecilia reticulata) populations that evolved a fast-paced life history in high-predation environments have consistently higher metabolic rates than guppies that evolved a slow-paced life history in low-predation environments. Furthermore, by transplanting guppies from high- to low-predation environments, we show that metabolic rate evolves in parallel with the pace of life history, at a rapid rate, and in the same direction as found for naturally occurring populations. Together, these multiple lines of inference provide evidence for a tight evolutionary coupling between metabolism and the pace of life history.
Structural basis for DNA 3′-end processing by human tyrosyl-DNA phosphodiesterase 1
Authors: Flett Fiona J. , Ruksenaite Emilija , Armstrong Lee A. , Bharati Shipra , Carloni Roberta , Morris Elizabeth R. , Mackay C. Logan , Interthal Heidrun , Richardson Julia M. 
Published: December 2017

AbstractTyrosyl-DNA phosphodiesterase (Tdp1) is a DNA 3′-end processing enzyme that repairs topoisomerase 1B-induced DNA damage. We use a new tool combining site-specific DNA–protein cross-linking with mass spectrometry to identify Tdp1 interactions with DNA. A conserved phenylalanine (F259) of Tdp1, required for efficient DNA processing in biochemical assays, cross-links to defined positions in DNA substrates. Crystal structures of Tdp1–DNA complexes capture the DNA repair machinery after 3′-end cleavage; these reveal how Tdp1 coordinates the 3′-phosphorylated product of nucleosidase activity and accommodates duplex DNA. A hydrophobic wedge splits the DNA ends, directing the scissile strand through a channel towards the active site. The F259 side-chain stacks against the −3 base pair, delimiting the junction of duplexed and melted DNA, and fixes the scissile strand in the channel. Our results explain why Tdp1 cleavage is non-processive and provide a molecular basis for DNA 3′-end processing by Tdp1.