bluuebunny/crossref_metadata_2025_split huggingface dataset:
Long-term clinical outcome of femtosecond laser-assisted lamellar keratectomy with phototherapeutic keratectomy in anterior corneal stromal dystrophy
Authors: Lee Jonghyun , Kim Jin Hyoung , Lee Doh , Chang Ji Woong , Shin Joo Youn , Seo Ji Won , Seo Min Hwan , Moon Nam Ju 
Published: June 2017

PurposeTo evaluate long-term outcome of femtosecond laser-assisted lamellar keratectomy (FLK) with phototherapeutic keratectomy (PTK) in patients with anterior corneal stromal dystrophies.MethodsA total of 10 eyes from seven patients who underwent FLK were included. The patients had suffered from recurrent corneal erosion or visual disturbance in anterior corneal dystrophies (five Avellino dystrophies and two lattice dystrophies). Planar-shaped lamellar keratectomy was performed using femtosecond laser. The amount of corneal excision was determined by the depth of corneal opacity. Additional PTK with mitomycin C application was performed for smoothening of corneal cut surface. The patients were evaluated with following parameters: uncorrected visual acuity, best-corrected visual acuity (BCVA), mean anterior keratometric value, corneal irregularity, corneal high-order aberrations (HOA) and the recurrence of corneal erosion.ResultsMean duration of follow-up was 64 months (2.5–9.5 years). The BCVA improved more than two lines of Snellen chart at last visit. The changes of keratometric values were within ±1 D in eight out of 10 eyes. Corneal irregularities in central 5 mm cornea and the values of total corneal HOA in central 6 mm cornea decreased by 0.3–3.1 D and 0.01–2.2 µm, respectively. Corneal erosion did not recur in any of those patients during follow-up and corneal dystrophy did not recur in eight out of 10 eyes.ConclusionIn anterior corneal stromal dystrophies, FLK with PTK can be an effective surgical option to improve VA through decreasing corneal irregularities and HOA, while minimising corneal curvature changes.
Impact of social service and public health spending on teenage birth rates across the USA: an ecological study
Authors: Sipsma Heather L , Canavan Maureen , Gilliam Melissa , Bradley Elizabeth 
Published: June 2017

ObjectiveTo examine whether greater state-level spending on social and public health services such as income, education and public safety is associated with lower rates of teenage births in USA.DesignEcological study.SettingUSA.Participants50 states.Primary outcome measureOur primary outcome measure was teenage birth rates. For analyses, we constructed marginal models using repeated measures to test the effect of social spending on teenage birth rates, accounting for several potential confounders.ResultsThe unadjusted and adjusted models across all years demonstrated significant effects of spending and suggested that higher spending rates were associated with lower rates of teenage birth, with effects slightly diminishing with each increase in spending (linear effect: B=−0.20; 95% CI −0.31 to 0.08; p<0.001 and quadratic effect: B=0.003; 95% CI 0.002 to 0.005; p<0.001).ConclusionHigher state spending on social and public health services is associated with lower rates of teenage births. As states seek ways to limit healthcare costs associated with teenage birth rates, our findings suggest that protecting existing social service investments will be critical.
Protocol for a randomised controlled trial evaluating the effects of providing essential medicines at no charge: the Carefully seLected and Easily Accessible at No Charge Medicines (CLEAN Meds) trial
Authors: Persaud Nav , Lee Taehoon , Ahmad Haroon , Li Winny , Taglione Michael Sergio , Rajakulasingam Yathavan , Umali Norman , Boozary Andrew , Glazier Richard H , Gomes Tara , Hwang Stephen W , Jüni Peter , Law Michael , Mamdani Muhammad M , Manns Braden , Martin Danielle , Morgan Steve , Oh Paul , Pinto Andrew David , Shah Baiju R , Sullivan Frank M , Thorpe Kevin E , Tu Karen , Laupacis Andreas 
Published: June 2017

IntroductionCost-related non-adherence to medicines is common in low-income, middle-income and high-income countries such as Canada. Medicine non-adherence is associated with poor health outcomes and increased mortality. This randomised trial will test the impact of a carefully selected list of essential medicines at no charge (compared with usual medicine access) in primary care patients reporting cost-related non-adherence.Methods and analysisThis is an open-label, parallel two-arm, superiority, individually randomised controlled trial conducted in three primary care sites (one urban, two rural) in Ontario, Canada, that was codesigned by a community guidance panel. Adult patients (≥18 years) who report cost-related non-adherence to medicines are eligible to participate in the study. Participants will be randomised to receive free and convenient access to a carefully selected list of 125 essential medicines (based on the WHO’s Model List of Essential Medicines) or usual means of medicine access. Care for patients in both groups will otherwise be unchanged. The primary outcome of this trial is adherence to appropriately prescribed medicines. Secondary outcomes include medicine adherence, appropriate prescribing, blood pressure, haemoglobin A1c, low-density lipoprotein cholesterol, patient-oriented outcomes and healthcare costs. All participants will be followed for at least 12 months.Ethics and disseminationEthics approval was obtained in all three participating sites. Results of the main trial and secondary outcomes will be submitted for publication in a peer-reviewed journal and discussed with members of the public and decision makers.Trial registration numberNCT02744963.
The impact of interventions to improve the quality of prescribing and use of antibiotics in primary care patients with respiratory tract infections: a systematic review protocol
Authors: Martínez-González Nahara Anani , Coenen Samuel , Plate Andreas , Colliers Annelies , Rosemann Thomas , Senn Oliver , Neuner-Jehle Stefan 
Published: June 2017

IntroductionRespiratory tract infections (RTIs) are the most common reason for primary care (PC) consultations and for antibiotic prescribing and use. The majority of RTIs have a viral aetiology however, and antibiotic consumption is ineffective and unnecessary. Inappropriate antibiotic use contributes greatly to antibiotic resistance (ABR) leading to complications, increased adverse events, reconsultations and costs. Improving antibiotic consumption is thus crucial to containing ABR, which has become an urgent priority worldwide. We will systematically review the evidence about interventions aimed at improving the quality of antibiotic prescribing and use for acute RTI.Methods and analysisWe will include primary peer-reviewed and grey literature of studies conducted on in-hours and out-of-hours PC patients (adults and children): (1) randomised controlled trials (RCTs), quasi-RCTs and/or cluster-RCTs evaluating the effectiveness, feasibility and acceptability of patient-targeted and clinician-targeted interventions and (2) RCTs and other study designs evaluating the effectiveness of public campaigns and regulatory interventions. We will search MEDLINE (EBSCOHost), EMBASE (Elsevier), the Cochrane Library (Wiley), CINHAL (EBSCOHost), PsychINFO (EBSCOHost), Web of Science, LILACS (Latin American and Caribbean Literature on Health Sciences), TRIP (Turning Research Into Practice) and opensgrey.eu without language restriction. We will also search the reference lists of included studies and relevant reviews. Primary outcomes include the rates of (guideline-recommended) antibiotics prescribed and/or used. Secondary outcomes include immediate or delayed use of antibiotics, and feasibility and acceptability outcomes. We will assess study eligibility and risk of bias, and will extract data. Data permitting, we will perform meta-analyses.Ethics and disseminationThis is a systematic review protocol and so formal ethical approval is not required. We will not collect confidential, personal or primary data. The findings of this review will be disseminated at national and international scientific meetings.Trial registration numberPROSPERO trial (CRD42017035305).
Graphs of systoles on hyperbolic surfaces
Authors: Sanki Bidyut , Gadgil Siddhartha 
Published: June 2017

Given a hyperbolic surface, the set of all closed geodesics whose length is minimal forms a graph on the surface, in fact a so-called fat graph, which we call the systolic graph. We study which fat graphs are systolic graphs for some surface (we call these admissible).There is a natural necessary condition on such graphs, which we call combinatorial admissibility. Our first main result is that this condition is also sufficient.It follows that a sub-graph of an admissible graph is admissible. Our second major result is that there are infinitely many minimal non-admissible fat graphs (in contrast, for instance, to the classical result that there are only two minimal non-planar graphs).
Effect of eye position during human visual-vestibular integration of heading perception
Authors: Crane Benjamin T. 
Published: June 2017

Visual and inertial stimuli provide heading discrimination cues. Integration of these multisensory stimuli has been demonstrated to depend on their relative reliability. However, the reference frame of visual stimuli is eye centered while inertia is head centered, and it remains unclear how these are reconciled with combined stimuli. Seven human subjects completed a heading discrimination task consisting of a 2-s translation with a peak velocity of 16 cm/s. Eye position was varied between 0° and ±25° left/right. Experiments were done with inertial motion, visual motion, or a combined visual-inertial motion. Visual motion coherence varied between 35% and 100%. Subjects reported whether their perceived heading was left or right of the midline in a forced-choice task. With the inertial stimulus the eye position had an effect such that the point of subjective equality (PSE) shifted 4.6 ± 2.4° in the gaze direction. With the visual stimulus the PSE shift was 10.2 ± 2.2° opposite the gaze direction, consistent with retinotopic coordinates. Thus with eccentric eye positions the perceived inertial and visual headings were offset ~15°. During the visual-inertial conditions the PSE varied consistently with the relative reliability of these stimuli such that at low visual coherence the PSE was similar to that of the inertial stimulus and at high coherence it was closer to the visual stimulus. On average, the inertial stimulus was weighted near Bayesian ideal predictions, but there was significant deviation from ideal in individual subjects. These findings support visual and inertial cue integration occurring in independent coordinate systems. NEW & NOTEWORTHY In multiple cortical areas visual heading is represented in retinotopic coordinates while inertial heading is in body coordinates. It remains unclear whether multisensory integration occurs in a common coordinate system. The experiments address this using a multisensory integration task with eccentric gaze positions making the effect of coordinate systems clear. The results indicate that the coordinate systems remain separate to the perceptual level and that during the multisensory task the perception depends on relative stimulus reliability.
The visual encoding of purely proprioceptive intermanual tasks is due to the need of transforming joint signals, not to their interhemispheric transfer
Authors: Arnoux Léo , Fromentin Sebastien , Farotto Dario , Beraneck Mathieu , McIntyre Joseph , Tagliabue Michele 
Published: June 2017

To perform goal-oriented hand movement, humans combine multiple sensory signals (e.g., vision and proprioception) that can be encoded in various reference frames (body centered and/or exo-centered). In a previous study (Tagliabue M, McIntyre J. PLoS One 8: e68438, 2013), we showed that, when aligning a hand to a remembered target orientation, the brain encodes both target and response in visual space when the target is sensed by one hand and the response is performed by the other, even though both are sensed only through proprioception. Here we ask whether such visual encoding is due 1) to the necessity of transferring sensory information across the brain hemispheres, or 2) to the necessity, due to the arms’ anatomical mirror symmetry, of transforming the joint signals of one limb into the reference frame of the other. To answer this question, we asked subjects to perform purely proprioceptive tasks in different conditions: Intra, the same arm sensing the target and performing the movement; Inter/Parallel, one arm sensing the target and the other reproducing its orientation; and Inter/Mirror, one arm sensing the target and the other mirroring its orientation. Performance was very similar between Intra and Inter/Mirror (conditions not requiring joint-signal transformations), while both differed from Inter/Parallel. Manipulation of the visual scene in a virtual reality paradigm showed visual encoding of proprioceptive information only in the latter condition. These results suggest that the visual encoding of purely proprioceptive tasks is not due to interhemispheric transfer of the proprioceptive information per se, but to the necessity of transforming joint signals between mirror-symmetric limbs. NEW & NOTEWORTHY Why does the brain encode goal-oriented, intermanual tasks in a visual space, even in the absence of visual feedback about the target and the hand? We show that the visual encoding is not due to the transfer of proprioceptive signals between brain hemispheres per se, but to the need, due to the mirror symmetry of the two limbs, of transforming joint angle signals of one arm in different joint signals of the other.
Prevention and reversal of latent sensitization of dorsal horn neurons by glial blockers in a model of low back pain in male rats
Authors: Zhang Juanjuan , Mense Siegfried , Treede Rolf-Detlef , Hoheisel Ulrich 
Published: June 2017

In an animal model of nonspecific low back pain, recordings from dorsal horn neurons were made to investigate the influence of glial cells in the central sensitization process. To induce a latent sensitization of the neurons, nerve growth factor (NGF) was injected into the multifidus muscle; the manifest sensitization to a second NGF injection 5 days later was used as a read-out. The sensitization manifested in increased resting activity and in an increased proportion of neurons responding to stimulation of deep somatic tissues. To block microglial activation, minocycline was continuously administered intrathecally starting 1 day before or 2 days after the first NGF injection. The glia inhibitor fluorocitrate that also blocks astrocyte activation was administrated 2 days after the first injection. Minocycline applied before the first NGF injection reduced the manifest sensitization after the second NGF injection to control values. The proportion of neurons responsive to stimulation of deep tissues was reduced from 50% to 17.7% ( P < 0.01). No significant changes occurred when minocycline was applied after the first injection. In contrast, fluorocitrate administrated after the first NGF injection reduced significantly the proportion of neurons with deep input (15.8%, P < 0.01). A block of glia activation had no significant effect on the increased resting activity. The data suggest that blocking microglial activation prevented the NGF-induced latent spinal sensitization, whereas blocking astrocyte activation reversed it. The induction of spinal neuronal sensitization in this pain model appears to depend on microglia activation, whereas its maintenance is regulated by activated astrocytes. NEW & NOTEWORTHY Activated microglia and astrocytes mediate the latent sensitization induced by nerve growth factor in dorsal horn neurons that receive input from deep tissues of the low back. These processes may contribute to nonspecific low back pain.
Characterization of MK-4166, a Clinical Agonistic Antibody That Targets Human GITR and Inhibits the Generation and Suppressive Effects of T Regulatory Cells
Authors: Sukumar Selvakumar , Wilson Douglas C. , Yu Ying , Wong Jerelyn , Naravula Saraswathi , Ermakov Grigori , Riener Romina , Bhagwat Bhagyashree , Necheva Antoaneta S. , Grein Jeff , Churakova Tatyana , Mangadu Ruban , Georgiev Peter , Manfra Denise , Pinheiro Elaine M. , Sriram Venkataraman , Bailey Wendy J. , Herzyk Danuta , McClanahan Terrill K. , Willingham Aarron , Beebe Amy M. , Sadekova Svetlana 
Published: June 2017

Abstract
GITR is a T-cell costimulatory receptor that enhances cellular and humoral immunity. The agonist anti-mouse GITR antibody DTA-1 has demonstrated efficacy in murine models of cancer primarily by attenuation of Treg-mediated immune suppression, but the translatability to human GITR biology has not been fully explored. Here, we report the potential utility of MK-4166, a humanized GITR mAb selected to bind to an epitope analogous to the DTA-1 epitope, which enhances the proliferation of both naïve and tumor-infiltrating T lymphocytes (TIL). We also investigated the role of GITR agonism in human antitumor immune responses and report here the preclinical characterization and toxicity assessment of MK-4166, which is currently being evaluated in a phase I clinical study. Expression of human GITR was comparable with that of mouse GITR in tumor-infiltrating Tregs despite being drastically lower in other human TILs and in many human peripheral blood populations. MK-4166 decreased induction and suppressive effects of Tregs in vitro. In human TIL cultures, MK-4166 induced phosphorylation of NFκB and increased expression of dual specificity phosphatase 6 (DUSP6), indicating that MK-4166 activated downstream NFκB and Erk signaling pathways. Furthermore, MK-4166 downregulated FOXP3 mRNA in human tumor infiltrating Tregs, suggesting that, in addition to enhancing the activation of TILs, MK-4166 may attenuate the Treg-mediated suppressive tumor microenvironment. Cancer Res; 77(16); 4378–88. ©2017 AACR.
Arl13b Promotes Gastric Tumorigenesis by Regulating Smo Trafficking and Activation of the Hedgehog Signaling Pathway
Authors: Shao Jia , Xu Linlin , Chen Limin , Lu Quqin , Xie Xinsheng , Shi Wei , Xiong Huanting , Shi Chao , Huang Xuan , Mei Jinhong , Rao Hai , Lu Hua , Lu Nonghua , Luo Shiwen 
Published: June 2017

Abstract
Inhibitors of the Hedgehog (Hh) pathway transducer Smoothened (Smo) have been approved for cancer treatment, but Smo mutations often lead to tumor resistance and it remains unclear how Smo is regulated. In this study, we identified the small GTPase Arl13b as a novel partner and regulator of Smo. Arl13b regulated Smo stability, trafficking, and localization, which are each crucial for Hh signaling. In gastric cancer cells, Arl13b stimulated proliferation, migration, and invasion in vitro and in vivo. In clinical specimens of gastric cancer, Arl13b expression correlated strongly with tumor size and depth of invasion; patients with high levels of Arl13b had a poor prognosis. Our results show how Arl13b participates in Hh pathway activation in gastric cancer. Cancer Res; 77(15); 4000–13. ©2017 AACR.
Competition between DNA Methylation, Nucleotide Synthesis, and Antioxidation in Cancer versus Normal Tissues
Authors: Cao Sha , Zhu Xiwen , Zhang Chi , Qian Hong , Schuttler Heinz-Bernd , Gong Jianping , Xu Ying 
Published: June 2017

Abstract
Global DNA hypomethylation occurs in many cancer types, but there is no explanation for its differential occurrence or possible impact on cancer cell physiology. Here we address these issues with a computational study of genome-scale DNA methylation in 16 cancer types. Specifically, we identified (i) a possible determinant for global DNA methylation in cancer cells and (ii) a relationship between levels of DNA methylation, nucleotide synthesis, and intracellular oxidative stress in cells. We developed a system of kinetic equations to capture the metabolic relations among DNA methylation, nucleotide synthesis, and antioxidative stress response, including their competitions for methyl and sulfur groups, based on known information about one-carbon metabolism and trans-sulfuration pathways. We observed a kinetic-based regulatory mechanism that controls reaction rates of the three competing processes when their shared resources are limited, particularly when the nucleotide synthesis rates or oxidative states are high. The combination of this regulatory mechanism and the need for rapid nucleotide synthesis, as well as high production of glutathione dictated by cancer-driving forces, led to the nearly universal observations of reduced global DNA methylation in cancer. Our model provides a natural explanation for differential global DNA methylation levels across cancer types and supports the observation that more malignant cancers tend to exhibit reduced DNA methylation levels. Insights obtained from this work provide useful information about the complexities of cancer due to interplays among competing, dynamic biological processes. Cancer Res; 77(15); 4185–95. ©2017 AACR.
Comprehensive Evaluation of Protein Coding Mononucleotide Microsatellites in Microsatellite-Unstable Colorectal Cancer
Authors: Kondelin Johanna , Gylfe Alexandra E. , Lundgren Sofie , Tanskanen Tomas , Hamberg Jiri , Aavikko Mervi , Palin Kimmo , Ristolainen Heikki , Katainen Riku , Kaasinen Eevi , Taipale Minna , Taipale Jussi , Renkonen-Sinisalo Laura , Järvinen Heikki , Böhm Jan , Mecklin Jukka-Pekka , Vahteristo Pia , Tuupanen Sari , Aaltonen Lauri A. , Pitkänen Esa 
Published: June 2017

Abstract
Approximately 15% of colorectal cancers exhibit microsatellite instability (MSI), which leads to accumulation of large numbers of small insertions and deletions (indels). Genes that provide growth advantage to cells via loss-of-function mutations in microsatellites are called MSI target genes. Several criteria to define these genes have been suggested, one of them being simple mutation frequency. Microsatellite mutation rate, however, depends on the length and nucleotide context of the microsatellite. Therefore, assessing the general impact of mismatch repair deficiency on the likelihood of mutation events is paramount when following this approach. To identify MSI target genes, we developed a statistical model for the somatic background indel mutation rate of microsatellites to assess mutation significance. Exome sequencing data of 24 MSI colorectal cancers revealed indels at 54 million mononucleotide microsatellites of three or more nucleotides in length. The top 105 microsatellites from 71 genes were further analyzed in 93 additional MSI colorectal cancers. Mutation significance and estimated clonality of mutations determined the most likely MSI target genes to be the aminoadipate-semialdehyde dehydrogenase AASDH and the solute transporter SLC9A8. Our findings offer a systematic profiling of the somatic background mutation rate in protein-coding mononucleotide microsatellites, allowing a full cataloging of the true targets of MSI in colorectal cancer. Cancer Res; 77(15); 4078–88. ©2017 AACR.