bluuebunny/crossref_metadata_2025 huggingface dataset:
Gene activation of SMN by selective disruption of lncRNA-mediated recruitment of PRC2 for the treatment of spinal muscular atrophy
Authors: Woo Caroline J. , Maier Verena K. , Davey Roshni , Brennan James , Li Guangde , Brothers John , Schwartz Brian , Gordo Susana , Kasper Anne , Okamoto Trevor R. , Johansson Hans E. , Mandefro Berhan , Sareen Dhruv , Bialek Peter , Chau B. Nelson , Bhat Balkrishen , Bullough David , Barsoum James
Published: February 2017

Significance

Autosomal recessive mutations or deletions of the gene
Survival Motor Neuron 1
(
SMN1
) cause spinal muscular atrophy, a neurodegenerative disorder. Transcriptional up-regulation of a nearly identical gene,
SMN2
, can functionally compensate for the loss of
SMN1
, resulting in increased SMN protein to ameliorate the disease severity. Here we demonstrate that the repressed state of
SMN2
is reversible by interrupting the recruitment of a repressive epigenetic complex in disease-relevant cell types. Using chemically modified oligonucleotides to bind at a site of interaction on a long noncoding RNA that recruits the repressive complex,
SMN2
is epigenetically altered to create a transcriptionally permissive state.
Optimizing virtual reality for all users through gaze-contingent and adaptive focus displays
Authors: Padmanaban Nitish , Konrad Robert , Stramer Tal , Cooper Emily A. , Wetzstein Gordon
Published: February 2017

Significance

Wearable displays are becoming increasingly important, but the accessibility, visual comfort, and quality of current generation devices are limited. We study optocomputational display modes and show their potential to improve experiences for users across ages and with common refractive errors. With the presented studies and technologies, we lay the foundations of next generation computational near-eye displays that can be used by everyone.
Mass spectrometry-based cross-linking study shows that the Psb28 protein binds to cytochrome
b
559
in Photosystem II
Authors: Weisz Daniel A. , Liu Haijun , Zhang Hao , Thangapandian Sundarapandian , Tajkhorshid Emad , Gross Michael L. , Pakrasi Himadri B.
Published: February 2017

Significance

Photosystem II (PSII) is a multisubunit membrane protein complex that catalyzes light-driven oxidation of water, supplying energy to nearly all life on Earth. Because of the challenging chemistry it performs, PSII undergoes frequent damage, prompting an intricate cycle of disassembly, repair, and reassembly. Psb28, a protein that binds transiently to the RC47 intermediate complex, protects PSII from light-induced damage. The location of Psb28 in PSII has not been determined. In this study, we used chemical cross-linking, mass spectrometry, and protein docking to demonstrate that Psb28 binds to cytochrome
b
559
. Our results allow us to propose a mechanism by which Psb28 exerts its protective effect on the vulnerable RC47 complex.
Genetic regulatory signatures underlying islet gene expression and type 2 diabetes
Authors: Varshney Arushi , Scott Laura J. , Welch Ryan P. , Erdos Michael R. , Chines Peter S. , Narisu Narisu , Albanus Ricardo D’O. , Orchard Peter , Wolford Brooke N. , Kursawe Romy , Vadlamudi Swarooparani , Cannon Maren E. , Didion John P. , Hensley John , Kirilusha Anthony ,   NISC Comparative Sequencing Program, Bonnycastle Lori L. , Taylor D. Leland , Watanabe Richard , Mohlke Karen L. , Boehnke Michael , Collins Francis S. , Parker Stephen C. J. , Stitzel Michael L. , Barnabas Beatrice B. , Bouffard Gerard G. , Brooks Shelise Y. , Coleman Holly , Dekhtyar Lyudmila , Guan Xiaobin , Han Joel , Ho Shi-ling , Legaspi Richelle , Maduro Quino L. , Masiello Catherine A. , McDowell Jennifer C. , Montemayor Casandra , Mullikin James C. , Park Morgan , Riebow Nancy L. , Rosarda Jessica , Schandler Karen , Schmidt Brian , Sison Christina , Smith Raymond , Stantripop Sirintorn , Thomas James W. , Thomas Pamela J. , Vemulapalli Meghana , Young Alice C.
Published: February 2017

Significance

The majority of genetic variants associated with type 2 diabetes (T2D) are located outside of genes in noncoding regions that may regulate gene expression in disease-relevant tissues, like pancreatic islets. Here, we present the largest integrated analysis to date of high-resolution, high-throughput human islet molecular profiling data to characterize the genome (DNA), epigenome (DNA packaging), and transcriptome (gene expression). We find that T2D genetic variants are enriched in regions of the genome where transcription Regulatory Factor X (RFX) is predicted to bind in an islet-specific manner. Genetic variants that increase T2D risk are predicted to disrupt RFX binding, providing a molecular mechanism to explain how the genome can influence the epigenome, modulating gene expression and ultimately T2D risk.
p53 regulates the cardiac transcriptome
Authors: Mak Tak W. , Hauck Ludger , Grothe Daniela , Billia Filio
Published: February 2017

Significance

The tumor suppressor Trp53 (p53) is a gene that regulates the expression of many genes. However, the role of p53 in the heart has not been well characterized. This work documents the important role for p53 in the heart as a master regulator of the cardiac transcriptome. The contribution of p53 to the maintenance of cardiac tissue homeostasis is complex under physiological conditions.
Strong signal increase in STED fluorescence microscopy by imaging regions of subdiffraction extent
Authors: Göttfert Fabian , Pleiner Tino , Heine Jörn , Westphal Volker , Görlich Dirk , Sahl Steffen J. , Hell Stefan W.
Published: February 2017

Significance

In stimulated emission depletion (STED) fluorescence microscopy, the diffraction resolution barrier is overcome by applying a doughnut-shaped light beam that transiently switches fluorescence off, confining molecular emission to subdiffraction-sized regions around the doughnut center. Unfortunately, the doughnut intensities required for high resolution exacerbate photobleaching. Our remedy, called MINFIELD, exploits the fact that fluorescence off-switching by STED does not require the high intensities of the doughnut crest. By recording subdiffraction-sized areas or volumes in the sample, molecular exposure to high intensities is avoided and photobleaching is reduced by more than 100-fold. Fluorescence analysis of cellular structures becomes possible in unprecedented detail. Providing larger signal and faster recording times, MINFIELD-STED microscopy should open a unique range of superresolution imaging applications in the life sciences.
Simulating the dynamics of the mechanochemical cycle of myosin-V
Authors: Mukherjee Shayantani , Alhadeff Raphael , Warshel Arieh
Published: February 2017

Significance

The free-energy landscape of the complete mechanochemical cycle of myosin-V is used in simulating the real-time features of the directional motion. The combination of Langevin dynamics simulations and time-dependent Monte Carlo simulations reproduces the observed trend in terms of stall force and force/velocity profile. The present study also addresses the role of the powerstroke and finds it to be the result of the complete free-energy landscape rather than the driving force of the energy conversion by the system.
The entrepreneurial state: service exports in healthcare and criminal justice
Authors: Lunt Neil
Published: February 2017

This article analyses an overlooked element of public service marketisation, examining overseas export activity within healthcare and criminal justice. It explores the drivers, strategies, opportunities and risks of such activities, and the differences across policy sector. Focussing on contrasting experiences is an opportunity to understand the complex and differentiated operational and structural environments within which this form of “public entrepreneurialism” is expressed. There is a gap in our understanding of such developments and their promotion within the context of austerity. The paper discusses the implications of the entrepreneurial state for public sector reputation.
Informality as illegality in Georgia’s anti-mafia campaign
Authors: Slade Gavin
Published: February 2017

The paper examines the anti-mafia laws in Georgia and links the decline of informality under Saakashvili with the use of punitive measures in a concerted effort to establish legal centrism over and above other extra-legal normative orders. The paper discusses the specific informal practice of the obshchak, or mutual aid fund, and how this evolved to become linked to organized crime, making it an object of criminalization. Finally, the paper argues that punitiveness, framed in terms of fighting the mafia, was a key element in tackling informality. However, far from banishing informality, pressure in the criminal justice system led to systemic punitive informal practices within the state.
Sensitivity of Rhizoctonia Isolates to Phenazine-1-Carboxylic Acid and Biological Control by Phenazine-Producing Pseudomonas spp.
Authors: Jaaffar Ahmad Kamil Mohd , Parejko James A. , Paulitz Timothy C. , Weller David M. , Thomashow Linda S.
Published: February 2017

Rhizoctonia solani anastomosis groups (AG)-8 and AG-2-1 and R. oryzae are ubiquitous in cereal-based cropping systems of the Columbia Plateau of the Inland Pacific Northwest and commonly infect wheat. AG-8 and R. oryzae, causal agents of Rhizoctonia root rot and bare patch, are most commonly found in fields in the low-precipitation zone, whereas R. solani AG-2-1 is much less virulent on wheat and is distributed in fields throughout the low-, intermediate-, and high-precipitation zones. Fluorescent Pseudomonas spp. that produce the antibiotic phenazine-1-carboxylic acid (PCA) also are abundant in the rhizosphere of crops grown in the low-precipitation zone but their broader geographic distribution and effect on populations of Rhizoctonia is unknown. To address these questions, we surveyed the distribution of PCA producers (Phz+) in 59 fields in cereal-based cropping systems throughout the Columbia Plateau. Phz+ Pseudomonas spp. were detected in 37 of 59 samples and comprised from 0 to 12.5% of the total culturable heterotrophic aerobic rhizosphere bacteria. The frequency with which individual plants were colonized by Phz+ pseudomonads ranged from 0 to 100%. High and moderate colonization frequencies of Phz+ pseudomonads were associated with roots from fields located in the driest areas whereas only moderate and low colonization frequencies were associated with crops where higher annual precipitation occurs. Thus, the geographic distribution of Phz+ pseudomonads overlaps closely with the distribution of R. solani AG-8 but not with that of R. oryzae or R. solani AG-2-1. Moreover, linear regression analysis demonstrated a highly significant inverse relationship between annual precipitation and the frequency of rhizospheres colonized by Phz+ pseudomonads. Phz+ pseudomonads representative of the four major indigenous species (P. aridus, P. cerealis, P. orientalis, and P. synxantha) suppressed Rhizoctonia root rot of wheat when applied as seed treatments. In vitro, mean 50% effective dose values for isolates of AG-8 and AG-2-1 from fields with high and low frequencies of phenazine producers did not differ significantly, nor was there a correlation between virulence of an isolate and sensitivity to PCA, resulting in rejection of the hypothesis that tolerance in Rhizoctonia spp. to PCA develops in nature upon exposure to Phz+ pseudomonads.
Virulence Structure Within Populations of Pseudoperonospora cubensis in the United States
Authors: Thomas Anna , Carbone Ignazio , Lebeda Aleš , Ojiambo Peter S.
Published: February 2017

Cucurbit downy mildew (CDM), caused by the obligate oomycete Pseudoperonospora cubensis, has resurged around the world during the past three decades. A new pathotype or genetic recombinant of P. cubensis have been suggested as possible reasons for the resurgence of CDM in the United States in 2004. In total, 22 isolates collected between 2004 and 2014, mainly in the eastern United States, were tested for their compatibility with a set of 15 cucurbit host types. The virulence structure within these isolates was evaluated on a set of 12 differential genotypes from eight genera. All isolates were highly compatible with the susceptible cultivar of Cucumis sativus, whereas the least compatibility was observed with Luffa cylindrica and Momordica charantia. Based on the compatibility with the differential host set, five pathotypes (1, 3, 4, 5, and 6) were identified among the 22 isolates examined. Pathotypes 1 and 3 had not been previously described in the United States and isolates of these two new pathotypes were also compatible with ‘Poinsett 76’, a cultivar of C. sativus known to be resistant to CDM prior to 2004. Virulence within the pathogen population was expressed based on virulence factors, virulence phenotypes, and virulence complexity. The number of virulence factors ranged from two to eight, indicating a complex virulence structure, with 77% of the isolates having five to eight virulence factors. Thirteen virulence phenotypes were identified; the mean number of virulence factors per isolate and mean number of virulence factors per virulence phenotype was 5.05 and 5.23, respectively, indicating that complex isolates and phenotypes contributed equally to the complex virulence structure of P. cubensis. Gleason and Shannon indices of diversity were 3.88 and 2.32, respectively, indicating a diverse virulence structure of P. cubensis within the United States population. The diverse virulence and high virulence complexity within the pathogen population indicate that host resistance alone in available cucurbit cultivars will not be effective to control CDM. An integrated approach involving a combination of fungicide application and introduction of cultivars with new resistance genes will be required for effective management of CDM.
Borderline Tuberculoid Leprosy Masquerading as Granuloma Annulare: A Clinical and Histological Pitfall
Authors: Zhu Tian Hao , Kamangar Faranak , Silverstein Marc , Fung Maxwell A.
Published: February 2017

Introduction:

Leprosy is a chronic granulomatous disease caused byMycobacterium leprae, an intracellular acid-fast bacillus that tends to infect the skin and peripheral nerves. Because of the wide array of cutaneous manifestation, diagnosis is not always straightforward, especially in nonendemic regions of the world such as the United States.

Case Report:

The authors report an unusual case of borderline tuberculoid leprosy in an 80-year-old white woman from California. Clinical examination revealed multiple nonscaly annular plaques, with central clearing and absence of lesional anesthesia, distributed over the trunk and extremities initially clinically diagnosed as granuloma annulare (GA). After 2 years of unsuccessful treatment with topical corticosteroid, biopsy revealed a palisaded and interstitial granulomatous infiltrate with necrobiosis, without discrete granulomas, compatible with GA. However, the presence of perineural lymphocytes in the reticular dermis prompted a Fite stain, which revealed acid-fast bacilli within the Schwann cells of a small peripheral nerve, pathognomonic for leprosy.

Conclusion:

This is the first reported case of leprosy masquerading both clinically and histologically as GA. Dermatopathologists should be aware of the possibility of leprosy given the presence of perineural lymphocytes amidst any pattern of granulomatous infiltrate and obtain a Fite stain.
Microscopy of Common Nail Cosmetics
Authors: Zimmer Katelyn A. , Clay Tiffany , Vidal Claudia I. , Chaudhry Sofia , Hurley Maria Y.
Published: February 2017

Nail clipping specimens are commonly submitted for the microscopic evaluation of nail disease; however, there may be missing clinical history regarding nail polish or other adornments present on the nail at the time of specimen retrieval. For this study, 6 types of nail cosmetics were chosen and applied to the nail plate of a volunteer. After a period of at least 24 hours, the nail plates with adornments and a control nail plate were clipped and placed in formalin. Specimens were processed using a standard nail protocol. All of the specimens, except the sticker appliqué, survived the fixation process. The glitter nail polish was the only specimen found to be polarizable. None of the specimens that survived fixation were found to be PAS-positive. Cosmetic nail enhancements are easily differentiated from the nail plate microscopically; nail cosmetics appear as a distinct layer of inorganic material lying atop the nail plate. There were 2 main microscopic patterns noted on the specimens: those with 2 layers and those with 3 layers.
Pathological Sampling of Basal Cell Carcinoma Re-excision Specimens: How Much is Enough?
Authors: Mesbah Ardakani Nima , Harvey Nathan Tobias , Mansford Vanessa , Wood Benjamin Andrew
Published: February 2017

Basal cell carcinoma (BCC) is the most common cutaneous malignancy, comprising approximately 75%–80% of all skin cancers. Surgical excision is the most common first line treatment modality, with the intent of obtaining clear margins. If the initial excision is incomplete or inadequate, a re-excision will often be performed in an attempt to achieve histological clearance. The pathological examination of these specimens requires a balance between the need for adequate assessment and efficient use of laboratory resources. In this study, we sought to systematically compare different approaches to the pathological sampling of these specimens in the hope of providing an evidential basis for a rational approach. Seventy-four BCC re-excision specimens were entirely sampled and retrospectively examined to determine the rate of detection of residual BCC which would have been achieved using different sampling methodologies. Residual BCC was identified in 37 specimens (50%). Limited transverse sections through the centre of the ellipse resulted in a sensitivity for detection of residual BCC of 78% (or 85% if only “significant” residual tumor is considered). By including the entire scar or the remainder of the specimen except the polar pieces, the sensitivity improved to 95% and 97%, respectively. Only one case showed residual tumor in the apical sections alone, with tumor extending to the new surgical margin in that case. We hope that this data may help laboratories develop sampling protocols appropriate to their own cost–benefit analyses and patient populations.
Putative Intravascular Myofibroma Mimicking a Vascular Malformation With Phleboliths
Authors: Klufas Daniel M. , Que Syril Keena T. , Rothe Marti , Makkar Hanspaul S. , Murphy Michael J.
Published: February 2017

Myofibroma is a rare, benign myofibroblastic tumor that commonly presents at birth or in early infancy, usually as a painless, slow-growing, solitary, nodular mass. We present a case of a 40-year-old woman with a painful, solitary, myofibroma on the right elbow. The unique features of this case include age and gender of the patient, site, pain on presentation, tumor morphology, and putative intravascular nature of the tumor.
Eccrine Syringofibroadenoma in Association With Acquired Epidermodysplasia Verruciformis
Authors: Tan Timothy , Guitart Joan , Liu Luzheng Lisa , Brieva Joaquin C. , Amin Sapna , Rani Monica , Gerami Pedram , Yazdan Pedram
Published: February 2017

A 75-year-old man with human immunodeficiency virus infection and numerous biopsy-proven warts for 10 years, refractory to cryosurgery, cimetidine, and topical imiquimod, presented with numerous pink to hypopigmented verrucous papules and plaques involving the face, trunk, buttocks, and groin. Laboratory evaluation revealed a CD4 T-cell count of 62 cells per microliter and human immunodeficiency virus viral load of <117 copies per milliliter. Biopsy of a plaque groin lesion was performed. Histopathology revealed vertically oriented anastomosing strands of basaloid epithelium arising from multiple points along the epidermis in a background fibrovascular stroma. Ductal differentiation was identified. Areas of epidermis showed compact orthokeratosis, coarse hypergranulosis, and keratinocytes with abundant steel-blue–gray cytoplasm, indicative of viral cytopathic changes. Cytologic atypia was not identified. Human papillomavirus (HPV) genotyping of this lesion was positive for types 5 and 14. Overall, the findings were consistent with epidermodysplasia verruciformis in association with eccrine syringofibroadenoma (ESFA). The patient was subsequently treated with acitretin and showed clinical improvement. ESFA is an uncommon benign adnexal tumor with unknown pathogenesis. Although its association with HPV has rarely been reported, ESFA in the setting of acquired epidermodysplasia verruciformis has not been described. The development of ESFA in this case may be the result of HPV-induced cellular transformation.
Processing Adipose-Rich Mohs Samples: A Comparative Study of Effectiveness of Pretreatment With Liquid Nitrogen Versus Flash Freezing Spray
Authors: Reserva Jeave , Kozel Zachary , Krol Cindy , Speiser Jodi , Adams William , Tung Rebecca
Published: February 2017

Processing of adipose-rich Mohs micrographic surgery (MMS) specimens poses challenges that may preclude complete margin evaluation. In this setting, the value of additional freezing methods using various cooling agents has not been previously investigated. The aim of this study is to compare the frozen section quality of high-adipose Mohs specimens processed without additional cooling treatments versus those pretreated with 1,1,1,2-tetrafluoroethane (TFE) or liquid nitrogen (LN2). A set of 3 sections were each taken from 24 adipose-rich Mohs micrographic surgery specimens. A section from each set was subjected to either no additional cooling treatment (control), two 10-second pulse sprays of 1,1,1,2-tetrafluoroethane, or three 2-second pulse sprays of LN2. After staining, 2 blinded raters evaluated slide quality based on the presence or absence of the following features: margin completeness, nuclear clearing, epidermal or adipose folding, holes, or venetian blind-like artifacts. Pretreatment of the sample with LN2 produced a significantly (P < 0.001) greater number of high-quality slides (19/24) compared to pretreatment with 1,1,1,2-tetrafluoroethane (1/24) and no additional treatment (0/24). The adjunctive use of LN2 spray before tissue embedding circumvents the challenges of processing “thick” (high-adipose) specimens and facilitates the production of high-quality frozen section slides during Mohs micrographic surgery.
Alpha–Melanocyte-stimulating Hormone Induces Vasodilation and Exerts Cardioprotection Through the Heme-Oxygenase Pathway in Rat Hearts
Authors: Vecsernyes Miklos , Szokol Miklos , Bombicz Mariann , Priksz Daniel , Gesztelyi Rudolf , Fulop Gabor Aron , Varga Balazs , Juhasz Bela , Haines David , Tosaki Arpad
Published: February 2017

Alpha–melanocyte-stimulating hormone (α-MSH) is a protein with known capacity for protection against cardiovascular ischemia–reperfusion (I/R) injury. This investigation evaluates the capacity of α-MSH to mitigate I/R effects in an isolated working rat heart model and determine the dependency of these alterations on the activity of heme oxygenase-1 (HO-1, hsp-32), a heat shock protein that functions as a major antioxidant defense molecule. Healthy male Sprague Dawley rats were used for all experiments. After treatment with selected doses of α-MSH, echocardiographic examinations were performed on live, anesthetized animals. Hearts were harvested from anesthetized rats pretreated with α-MSH and/or the HO-1 inhibitor SnPP, followed by cardiac function assessment on isolated working hearts, which were prepared using the Langendorff protocol. Induction of global ischemia was performed, followed by during reperfusion assessment of cardiac functions. Determination of incidence of cardiac arrhythmias was made by electrocardiogram. Major outcomes include echocardiographic data, suggesting that α-MSH has mild effects on systolic parameters, along with potent antiarrhythmic effects. Of particular significance was the specificity of dilatative effects on coronary vasculature, and similar outcomes of aortic ring experiments, which potentially allow different doses of the compound to be used to selectively target various portions of the vasculature for dilation.
G Protein Coupled Receptor-mediated Transactivation of Extracellular Proteases
Authors: Schafer Allison E. , Blaxall Burns C.
Published: February 2017

G protein-coupled receptors (GPCRs) comprise the largest family of receptors in humans. Traditional activation of GPCRs involves binding of a ligand to the receptor, activation of heterotrimeric G proteins and induction of subsequent signaling molecules. It is now known that GPCR signaling occurs through G protein-independent pathways including signaling through β-arrestin and transactivation of other receptor types. Generally, transactivation occurs when activation of one receptor leads to the activation of another receptor(s). GPCR-mediated transactivation is an essential component of GPCR signaling, as activation of other receptor types, such as receptor tyrosine kinases, allows GPCRs to expand their signal transduction and affect various cellular responses. Several mechanisms have been identified for receptor transactivation downstream of GPCRs, one of which involves activation of extracellular proteases, such as a disintegrin and metalloprotease, and matrix metalloproteases . These proteases cleave and release ligands that are then able to activate their respective receptors. A disintegrin and metalloprotease, and matrix metalloproteases can be activated via various mechanisms downstream of GPCR activation, including activation via second messenger, direct phosphorylation, or direct G protein interaction. Additional understanding of the mechanisms involved in GPCR-mediated protease activation and subsequent receptor transactivation could lead to identification of new therapeutic targets.
Bioequivalence of a New Oral Levosulpiride Formulation Compared With a Standard One in Healthy Volunteers
Authors: De Gregori Simona , Cipollina Laura , De Silvestri Annalisa , Ventura Marianna , Michelini Roberta , Morosini Monica , Montagna Michela , Tinelli Carmine , Regazzi Mario , Molinaro Mariadelfina , Imberti Roberto
Published: February 2017

Background:

A monocentric, single-dose, open-label, 2-way, crossover randomized study was conducted by the San Matteo Phase I Clinical Trial Unit and Experimental Therapy (Pavia, Italy) to assess the bioequivalence and the systemic tolerability of a new oral formulation of levosulpiride (tablet 25 mg: test) versus a commercially available formulation on the Italian market (tablet 25 mg: reference).

Methods:

Thirty-five healthy adult volunteers, men (n = 19) and women (n = 16), aged between 18 and 55 years were screened and 32 of them were enrolled in the study. After having signed the written informed consent, each subject received a single oral dose of Test or Reference product with 250 mL of natural mineral water, in fasting conditions, interspersed with a 6-day washout period Blood samples were collected up to 36 hours after drug administration: the drug plasma levels were determined by high-performance liquid chromatography coupled with electrospray ionization tandem mass spectrometry. The pharmacokinetic parameters included peak plasma concentration (Cmax), time corresponding to Cmax (tmax), area under the plasma concentration–time curve from zero to infinity (AUC0
–∞) or to the last sampling time assessment (AUC0–36), the elimination rate constant (ke), and the terminal half-life (t1/2). Safety was measured by pre- and post-treatment specific biochemical investigations, physical examination, electrocardiogram, occurrence of adverse events, and any information on patients' withdrawal.

Results:

The geometric mean ratio Test/Reference (90% confidence interval) for levosulpiride was 103.0% (95.8–110.8) for AUC0–36, 103.6% (95.9–111.9) for AUC0–∞, and 104.3% (94.9–114.6) for Cmax. ke and t1/2 were 0.07 (SD: 0.02) and 9 hours (8–12) for both the formulations. Clearance (L/h) was 29.6 (±13.5) and 30.7 (±14.2) for the test and the reference product, respectively.

Conclusions:

Because the acceptance criteria required by the drug regulatory agency (European Medicines Agency, EMA) for bioequivalence prescribe limits of 80%–120% for untransformed data and 80%–125% for “ln” transformed data, we can confirm that the 2 formulations are bioequivalent, in terms of the rate and extent of absorption.
Pharmacodynamic effects of the fetal estrogen estetrol in postmenopausal women: results from a multiple-rising-dose study
Authors: Coelingh Bennink Herjan J.T. , Verhoeven Carole , Zimmerman Yvette , Visser Monique , Foidart Jean-Michel , Gemzell-Danielsson Kristina
Published: February 2017

Objective:

Estetrol (E4) is an estrogen produced exclusively by the human fetal liver during pregnancy. In this study the pharmacodynamic effects of escalating doses of E4 in postmenopausal women were investigated.

Methods:

This was a partly randomized, open-label, multiple-rising-dose study in 49 postmenopausal women. Participants were randomized to receive either 2 mg E4 or 2 mg estradiol-valerate (E2 V) for 28 days. Subsequent dose-escalation groups were (non-randomized): 10, 20 and 40 mg E4. Blood samples were collected regularly for measuring endocrine and hemostasis variables, lipids and lipoproteins, fasting glucose and bone turnover markers.

Results:

Estetrol treatment resulted in a decrease of follicle-stimulating hormone and luteinizing hormone and an increase of sex-hormone binding globulin. Changes in hemostasis variables were small. A lowering effect on low-density lipoprotein cholesterol was accompanied with an increase in high-density lipoprotein cholesterol and no or minimal changes in triglycerides. The considerable decrease in osteocalcin levels in the three highest E4 dose groups and the small decrease in C-telopeptide levels were comparable to the E2 V control group and suggest a preventive effect on bone loss. All changes observed were dose-dependent.

Conclusions:

In this study, estetrol treatment showed dose-dependent estrogenic effects on endocrine parameters, bone turnover markers, and lipids and lipoproteins. The effect on triglycerides was small as were the effects on hemostatic variables. These results support the further investigation of estetrol as a candidate for hormone therapy. Quantitatively, the effects of 10 mg estetrol were similar to the study comparator 2 mg estradiol valerate.
Association of sleep disturbance and sexual function in postmenopausal women
Authors: Kling Juliana M. , Manson JoAnn E. , Naughton Michelle J. , Temkit M’hamed , Sullivan Shannon D. , Gower Emily W. , Hale Lauren , Weitlauf Julie C. , Nowakowski Sara , Crandall Carolyn J.
Published: February 2017

Objective:

Sleep disturbance and sexual dysfunction are common in menopause; however, the nature of their association is unclear. The present study aimed to determine whether sleep characteristics were associated with sexual activity and sexual satisfaction.

Methods:

Sexual function in the last year and sleep characteristics (past 4 wk) were assessed by self-report at baseline for 93,668 women age 50 to 79 years enrolled in the Women's Health Initiative (WHI) Observational Study (OS). Insomnia was measured using the validated WHI Insomnia Rating Scale. Sleep-disordered breathing (SDB) risk was assessed using questions adapted from the Berlin Questionnaire. Using multivariate logistic regression, we examined cross-sectional associations between sleep measures and two indicators of sexual function: partnered sexual activity and sexual satisfaction within the last year.

Results:

Fifty-six percent overall reported being somewhat or very satisfied with their current sexual activity, and 52% reported partnered sexual activity within the last year. Insomnia prevalence was 31%. After multivariable adjustment, higher insomnia scores were associated with lower odds of sexual satisfaction (yes/no) (odds ratio [OR] 0.92, 95% CI, 0.87-0.96). Short sleep duration (<7-8 h) was associated with lower odds of partnered sexual activity (yes/no) (≤5 h, OR 0.88, 95% CI, 0.80-0.96) and less sexual satisfaction (≤5 h, OR 0.88, 95% CI, 0.81-0.95).

Conclusions:

Shorter sleep durations and higher insomnia scores were associated with decreased sexual function, even after adjustment for potential confounders, suggesting the importance of sufficient, high-quality sleep for sexual function. Longitudinal investigation of sleep and its impact on sexual function postmenopause will clarify this relationship.
Use of a novel fractional CO2 laser for the treatment of genitourinary syndrome of menopause: 1-year outcomes
Authors: Sokol Eric R. , Karram Mickey M.
Published: February 2017

Objectives:

To assess safety and efficacy of a fractional CO2 laser therapy for the treatment of genitourinary syndrome of menopause (GSM) with follow-up to 1 year posttreatment.

Methods:

Women presenting with GSM and meeting inclusion criterion were enrolled. Visual Analog Scales were used to grade vaginal pain, burning, itching, dryness, dyspareunia, and dysuria. Dilators were used to rate vaginal elasticity at baseline and at each follow-up visit. Before each treatment and at follow-up, Vaginal Health Index scoring and Female Sexual Function Index questionnaires were completed. Women received three vaginal laser treatments spaced 6 weeks apart. Participant satisfaction was measured on 5-point Likert scales (1 = very dissatisfied, 5 = very satisfied).

Results:

Of 30 women (mean age 58.6 ± 8.8 years), three were lost to follow-up at 3 months and six at 1 year. None were discontinued or withdrew due to an adverse event. Average improvement in Visual Analog Scale scores for all symptom categories was statistically significant at 3 months and remained so through 1 year, except dysuria. Differences between data at 3 months and 1 year were not statistically significant, indicating persistence of positive outcomes. Average overall improvement in pain was 1.9 (±3.4), burning 1.9 (±3.1), itching 1.4 (±1.9), dryness 5.9 (±2.8), dyspareunia 4.9 (±3.3), and dysuria 0.9 (±3.1). Improvement in average Vaginal Health Index and Female Sexual Function Index scores was also statistically significant (P < 0.0001). Of 19 women undergoing dilator examination at 1 year, 18 (94.8%) were comfortable with the same or larger dilator size. Twenty-two of 24 women (92%) were satisfied or extremely satisfied with the treatment at 1 year.

Conclusions:

Based on study data up to 1 year, the fractional CO2 laser may be an effective and safe treatment for women suffering from symptoms of GSM, although additional studies with larger populations and placebo control is needed to confirm these results.
Patient acceptability and satisfaction with a low-dose solubilized vaginal estradiol softgel capsule, TX-004HR
Authors: Kingsberg Sheryl A. , Kroll Robin , Goldstein Irwin , Kushner Harvey , Bernick Brian , Graham Shelli , Mirkin Sebastian , Constantine Ginger D.
Published: February 2017

Objective:

TX-004HR is an investigational, muco-adhesive, vaginal, softgel capsule containing low-dose, solubilized, 17β-estradiol designed to treat postmenopausal vulvar and vaginal atrophy (VVA) and improve user experience without an applicator and less mess.

Methods:

As part of the 12-week, placebo-controlled, double-blind, phase 3 REJOICE trial evaluating the efficacy/safety of 4-, 10-, and 25-μg TX-004HR in 764 postmenopausal women with VVA, a five-question product survey was administered. Pearson correlation coefficients were used to evaluate correlations between clinical endpoints (vaginal physiology, dyspareunia, and vaginal dryness) and patient acceptability and satisfaction.

Results:

Majority of the women receiving TX-004HR or placebo reported that the product was easy to use (85.4%-92.1%) and rated ease of capsule insertion as “good” to “excellent” (75.0%-82.6%). A significantly greater percentage of women reported being “very satisfied” or “satisfied” with TX-004HR (68.6%-76.3%) than with placebo (56.8%, P < 0.05 for all). A greater percentage of women “somewhat” or “very much” preferred TX-004HR over their previous treatment versus those taking placebo (P < 0.05). Significantly more women receiving TX-004HR (72.8%-80.5%) versus placebo (62.5%, P < 0.05) would “probably” or “definitely” consider using the product again. Dyspareunia and vaginal dryness reductions were correlated with higher product satisfaction and the percentage of women who would consider re-using TX-004HR.

Conclusions:

TX-004HR had a high level of product acceptability, and more women were satisfied with TX-004HR, preferred it over their previous treatment, and would consider using it again versus placebo. Women may find TX-004HR to be a more acceptable product than current options to treat their dyspareunia associated with postmenopausal VVA.
Resolution of Primary Lymphedema: A Case Report
Authors: Goss Jeremy A. , Maclellan Reid A. , Beijnen Usha E. A. , Greene Arin K.
Published: February 2017

Primary lymphedema is a rare, progressive disease that typically affects the lower extremity. The condition is not curable, and the limb enlarges over time because of subcutaneous fibroadipose deposition. We present a patient with clinical and radiographical evidence of resolution of primary lymphedema. This observation may provide greater insight into the pathophysiology of the disease.
Pharmacoepidemiologic analyses of opioid use among OEF/OIF/OND veterans
Authors: Hudson Teresa J. , Painter Jacob T. , Martin Bradley C. , Austen Mark A. , Williams James S. , Fortney John C. , Sullivan Mark D. , Edlund Mark J.
Published: February 2017

There is a great deal of concern about opioid use in veterans, particularly those who served in Afghanistan (OEF) and Iraq (OIF and OND). The current study provides a detailed pharmacoepidemiologic analysis of opioid use among OEF/OIF/OND veterans from FY09 to FY12. Data from 3 data repositories from the Veterans Health Administration (VHA) were used to describe demographic, clinical, and medication characteristics associated with opioid use among OEF/OIF/OND veterans and among those with TBI. Logistic regression models were used to identify risks associated with chronic opioid use in FY12. Approximately 23% of all OEF/OIF/OND veterans and 35% of those with TBI received any opioid medications. Most received moderate doses ranging from 26 to 30 mg morphine equivalent dose daily. Median days of opioid use for all OEF/OIF/OND veterans were 30 to 40 days. Factors associated with chronic use in both groups included young age, male sex, white race, being married, and living in rural areas. A diagnosis of PTSD (odds ratio [OR] = 1.22, P < 0.0001), major depressive disorder (OR = 1.14, P < 0.0001), and tobacco use disorder (OR = 1.18, P < 0.0001) were strongly associated with chronic opioid use. Back pain was also strongly associated with chronic use (OR = 2.50, P < 0.0001). As pain severity increased the odds of chronic opioid use also increased: mild pain (OR = 3.76, P < 0.0001), moderate pain (OR = 6.80, P < 0.0001), and severe pain (OR = 8.49, P < 0.0001). Opioid use among OEF/OIF/OND veterans is characterized by moderate doses that are used over relatively long periods of time by a minority of veterans.
Treatment Duration With Long-Acting Injectable Antipsychotics After In-hospital Initiation
Authors: Rittmannsberger Hans , Rosenleitner Jan , Malsiner-Walli Gertraud , Werl Regina , Rittmannsberger Barbara , Yazdi Kurosch
Published: February 2017

Purpose

Long-acting injectable (LAI) antipsychotics are recommended especially for patients with multiple admissions and poor adherence. The empirical basis of this strategy is a matter of debate.

Methods

In a retrospective cohort study extending over 6 years, all patients admitted for inpatient treatment with a diagnosis of psychotic disorders according to International Statistical Classification of Diseases and Related Health Problems, 10th Revision (F2) were screened for treatment episodes with a new start of an LAI. Indication for LAI treatment was based primarily on previous medication default. All-cause discontinuation was used as a measure of treatment efficiency. Patients with early dropout (termination of LAI treatment within 6 months) were compared with patients with longer treatment (treatment >6 months) for sociodemographic and treatment variables using bivariate and multivariate analyses.

Results

A total of 194 treatment episodes with new start of LAIs were identified. Almost one half dropped out within 6 months (early dropout: n = 95 [49%]; mean duration, 2.2 months). Termination of treatment was mainly due to patients’ refusal to continue. However, almost a third of patients (61; 31.4%) had a treatment duration of more than 2 years. In a multivariate Cox regression model, longer treatment duration was associated with older age (P = 0.05), not being single (P = 0.04), fewer admissions during the year preceding the index episode (P = 0.02), and better ratings for adherence at the index episode (P = 0.03).

Conclusions

There are both more patients than expected leaving the treatment early and more patients than expected staying for long periods, even among patients with a history of poor adherence.
NIACE score for hepatocellular carcinoma patients treated by surgery or transarterial chemoembolization
Authors: Adhoute Xavier , Pénaranda Guillaume , Raoul Jean Luc , Bollon Emilie , Pol Bernard , Letreut Yves P. , Perrier Hervé , Bayle Olivier , Monnet Olivier , Beaurain Patrick , Muller Cyril , Hardwigsen Jean , Lefolgoc Gaëlle , Castellani Paul , Bronowicki Jean P. , Bourlière Marc
Published: February 2017

Background and aims

Hepatocellular carcinoma (HCC) prognostic scores could be useful in addition to the Barcelona Clinic Liver Cancer (BCLC) system to clarify patient prognosis and guide treatment decision. The NIACE (tumor Nodularity, Infiltrative nature of the tumor, serum Alpha-fetoprotein level, Child–Pugh stage, ECOG performance status) score distinguishes different prognosis groups among BCLC A, B, and C HCC patients. Our aims are to evaluate the NIACE score and its additive value in two HCC cohorts treated either by surgery or by chemoembolization, and then according to the BCLC recommendations.

Patients and methods

This was a retrospective multicenter study with two BCLC A, B, and C HCC cohorts treated either by surgery (n=207) or by chemoembolization (n=168) carried out between 2008 and 2013. We studied survival time according to the baseline NIACE score and compared it with the Cancer of the Liver Italian Program score and the BCLC system.

Results

The NIACE score differentiates between subgroups of patients with different prognosis within each BCLC class. Among BCLC A patients treated by surgery and BCLC B patients treated by chemoembolization, the NIACE score differentiates between two subgroups with a significant difference in survival time: 68 (55–81) months versus 35 (21–56) months (P=0.0004) and 20 (17–24) months versus 13 (7–17) months (P=0.0008), respectively. Among those subgroups, the NIACE score has a significantly better prognostic value than the BCLC system or the Cancer of the Liver Italian Program score.

Conclusion

In this study, among HCC patients treated according to the BCLC recommendations, the NIACE score predicts more accurately than any other system the survival time.
Development and validation of a prognostic model for acute-on-chronic hepatitis B liver failure
Authors: Gao Fangyuan , Sun Le , Ye Xieqiong , Liu Yao , Liu Huimin , Geng Mingfan , Li Xiaoshu , Yang Xue , Li Yuxin , Wang Rui , Chen Jialiang , Wan Gang , Jiang Yuyong , Wang Xianbo
Published: February 2017

Aim

The CANONIC study proposed the Chronic Liver Failure Consortium acute-on-chronic liver failure (CLIF-C ACLF) prognostic model at the European Association for the Study of the Liver-CLIF diagnosis. This study aimed to develop and validate a prognostic model for predicting the short-term mortality of hepatitis B virus (HBV) ACLF as defined by the Asia-Pacific Association for the Study of the Liver.

Patients and methods

A retrospective cohort of 381 HBV ACLF patients and a prospective cohort of 192 patients were included in this study. Independent predictors of disease progression were determined using univariate and multivariate Cox proportional hazard regression analysis, and a regression model for predicting prognosis was established. Patient survival was estimated by Kaplan–Meier analysis and subsequently compared by log-rank tests. The area under the receiver operating characteristic curve was used to compare the performance of various current prognostic models.

Results

Our model was constructed with five independent risk factors: hepatic encephalopathy, international normalized ratio, neutrophil–lymphocyte ratio, age, and total bilirubin, termed as the HINAT ACLF model, which showed the strongest predictive values compared with CLIF-C ACLF, CLIF-C Organ Failure, Sequential Organ Failure Assessment, CLIF-Sequential Organ Failure Assessment, Model for End-stage Liver Disease, Model for End-stage Liver Disease-sodium, and Child–Turcotte–Pugh scores; this model reduced the corresponding prediction error rates at 28 and 90 days by 16.4–54.5% after ACLF diagnosis in both the derivation cohort and the validation cohorts.

Conclusion

The HINAT ACLF model can accurately predict the short-term mortality of patients with HBV ACLF as defined by Asia-Pacific Association for the Study of the Liver.
Usefulness of the prediction method based on a logarithmic model for functional recovery in stroke patients: in case of using the motor-Functional Independence Measure score
Authors: Kimura Yosuke , Yamada Minoru , Hamanaka Koji , Tanaka Naoki , Muroh Yasushi
Published: February 2017

Predicting functional recovery is important for the rehabilitation of stroke patients. This study aimed to examine the predictive validity of motor items of Functional Independence Measure (motor-FIM) using the prediction method based on a logarithmic model. This prospective observational cohort study included 111 patients with subacute stroke (mean age: 67.0±13.8 years). The motor-FIM score was assessed at admission, 1 month after admission, and at discharge. We calculated the predictive value of motor-FIM scores at discharge using a logarithmic model, which used only motor-FIM scores at admission and 1 month after admission. The relationship between the actual motor-FIM score at discharge and the predictive value was assessed with the intraclass correlation coefficient. The motor-FIM score at admission, 1 month after admission, and at discharge, and the predictive value were 41.9±15.0, 52.3±18.4, 66.0±18.8, and 65.1±21.2, respectively. The predictive value was highly correlated with the actual motor-FIM score at discharge (intraclass correlation coefficient=0.89). Our results suggest that we can use the prediction method based on a logarithmic model for predicting the motor-FIM score at discharge. This may be useful for designing rehabilitation programs for patients with subacute stroke.