bluuebunny/crossref_metadata_2025 huggingface dataset:
Assertion, Nonepistemic Values, and Scientific Practice
Authors: Franco Paul L.
Published: August 2016

This article motivates a shift in certain strands of the debate over legitimate roles for nonepistemic values in scientific practice from investigating what is involved in taking cognitive attitudes like acceptance toward an empirical hypothesis to looking at a social understanding of assertion, the act of communicating that hypothesis. I argue that speech act theory’s account of assertion as a type of doing makes salient legitimate roles nonepistemic values can play in scientific practice. The article also shows how speech act theory might provide a framework for fruitfully extending aspects of the social and pragmatic turns in the philosophy of science.
Differential selection on pollen and pistil traits in relation to pollen
competition in the context of a sexual conflict over timing of stigma
receptivity
Authors: Lankinen Åsa , Strandh Maria
Published: August 2016

Sexual conflict and its evolutionary consequences are understudied in plants, but the theory of sexual conflict may help explain how selection generates and maintains variability. Here, we investigated selection on pollen and pistil traits when pollen arrives sequentially to partially receptive pistils in relation to pollen competition and a sexual conflict over timing of stigma receptivity in the mixed-mating annual Collinsia heterophylla (Plantaginaceae). In this species the conflict is generated by early fertilizing pollen that reduces seed production, which is counteracted by delaying receptivity in the recipient. We performed sequential two-donor pollinations at early floral developmental stages involving two pollen deposition schedules (with or without a time lag of 1 day), using only outcross or self and outcross pollen. We investigated pollen and pistil traits in relation to siring success (male fitness) and seed production (female fitness). In contrast to previous findings in receptive pistils in C. heterophylla and in other species, last arriving pollen donors showed highest siring success in partially receptive pistils. The last male advantage was weaker when self pollen was the first arriving donor. Two measures of germination rate (early and late) and pollen tube growth rate of first arriving donors were important for siring success in crosses with a time lag, while only late germination rate had an effect in contemporary crosses. Curiously, late stigma receptivity was negatively related to seed production in our contemporary crosses, which was opposite to expectation. Our results in combination with previous studies suggest that pollen and pistil traits in C. heterophylla are differentially advantageous depending on stage of floral development and varying pollen deposition schedules. Variation in success of these traits over floral development time may result from sexually antagonistic selection.
LoFtool: a gene intolerance score based on loss-of-function variants in 60 706 individuals
Authors: Fadista João , Oskolkov Nikolay , Hansson Ola , Groop Leif
Published: August 2016

Motivation

Depletion of loss-of-function (LoF) mutations may provide a rank of genic functional intolerance and consequently susceptibility to disease.

Results

Here we have studied LoF mutations in 60 706 unrelated individuals and show that the most intolerant quartile of ranked genes is enriched in rare and early onset diseases and explains 87% of de novo haploinsufficient OMIM mutations, 17% more than any other gene scoring tool. We detected particular enrichment in expression of the depleted LoF genes in brain (odds ratio = 1.5; P-value = 4.2e−07). By searching for de novo haploinsufficient mutations putatively associated with neurodevelopmental disorders in four recent studies, we were able to explain 81% of them. Taken together, this study provides a novel gene intolerance ranking system, called LoFtool, which may help in ranking genes of interest based on their LoF intolerance and tissue expression.

Availability and implementation

The LoFtool gene scores are available in the Supplementary data.

Supplementary information

Supplementary data are available at Bioinformatics online.
Molecular Mechanisms of Anesthetic Neurotoxicity: A Review of the Current Literature
Authors: Jackson William M. , Gray Christy D.B. , Jiang Danye , Schaefer Michele L. , Connor Caroline , Mintz Cyrus D.
Published: August 2016

Data from epidemiologic studies and animal models have raised a concern that exposure to anesthetic agents during early postnatal life may cause lasting impairments in cognitive function. It is hypothesized that this is due to disruptions in brain development, but the mechanism underlying this toxic effect remains unknown. Ongoing research, particularly in rodents, has begun to address this question. In this review we examine currently postulated molecular mechanisms of anesthetic toxicity in the developing brain, including effects on cell death pathways, growth factor signaling systems, NMDA and GABA receptors, mitochondria, and epigenetic factors. The level of evidence for each putative mechanism is critically evaluated, and we attempt to draw connections between them where it is possible to do so. Although there are many promising avenues of research, at this time no consensus can be reached as to a definitive mechanism of injury.
Mechanisms for Research Support
Authors: Houck Philipp , Hache Manon , Busse Jennifer
Published: August 2016

During the second day of the Pediatric Anesthesia NeuroDevelopment Assessment (PANDA) symposium 2016, 3 invited speakers focused on future directions for the PANDA group. This session, entitled “The Way Forward,” included 3 talks on how other groups have organized through public-private partnerships (ACTTION), obtained NIH funding, and how to better communicate a research message. Dr Robert H. Dworkin spoke on the mission of the Analgesic, Anesthetic, and Addiction Clinical Trial Translations, Innovations, Opportunities and Networks (ACTTION), which is a public-private partnership with the United States Food and Drug Administration that pushes forward research related to pain and analgesics. Dr Tracy King discussed National Institute of Health funding for future studies in neurocognitive development after exposure to anesthetics. Dr Sharon Hertz discussed how the PANDA group might better craft their message to the public regarding effects of analgesics on neurocognitive development. Through their talks, the above speakers provided a clear route for the way forward in regard to research, funding, and messaging for the PANDA group.
Use of Anesthesia for Imaging Studies and Interventional Procedures in Children
Authors: Huang Yolanda Y. , Li Lucy , Monteleone Matthew , Ferrari Lynne , States Lisa J. , Riviello James J. , Kernie Steven G. , Mencin Ali A. , Gupta Sumit , Sun Lena S.
Published: August 2016

Ongoing investigation from the Pediatric Anesthesia NeuroDevelopment Assessment (PANDA) study hopes to examine the long-term effect on cognitive and language development of a single anesthetic exposure in children undergoing inguinal hernia repair. The fifth PANDA Symposium, held in April 2016, continued the mission of previous symposia to examine evidence from basic science and clinical studies on potential neurotoxic effects of anesthetics on developing brain. At the 2016 Symposium, a panel of specialists from nonsurgical pediatric disciplines including anesthesiology, radiology, neurology, gastroenterology, oncology, cardiology, and critical care reviewed use of anesthesia in their practices, including how concern over possible neurodevelopmental effects of early childhood anesthetic exposure has changed discussion with patients and families regarding risks and benefits of imaging studies and interventional procedures involving sedation or anesthesia. This paper summarizes presentations from nonsurgical pediatric specialists at the 2016 PANDA Symposium.
Analysis of MRI Utilization in Pediatric Patients
Authors: Huang Yolanda Y. , Ing Caleb , Li Gouhua , Sun Lena S.
Published: August 2016

Introduction:

Although animal studies have consistently demonstrated long-term neurocognitive deficits following early anesthetic exposure under certain conditions, risk in human children remains unknown. Magnetic resonance imaging (MRI) in young patients often requires anesthesia to facilitate image acquisition. We studied MRI utilization in a pediatric population, and associated use of anesthesia for ambulatory MRI.

Materials and Methods:

Data were obtained from the New York State Inpatient Database and State Ambulatory Surgery and Services Database on MRI performed in children under the age of 18 years from 2005 to 2011. Demographic characteristics of children who underwent inpatient or ambulatory MRI were evaluated. A subset of ambulatory MRI patients was assessed to evaluate associated use of anesthesia.

Results:

Overall, 2% of pediatric inpatient discharges (55,036/2,779,507), and 0.5% of pediatric ambulatory encounters (4670/943,520), had MRI performed. Inpatient MRI utilization did not change over time. Ambulatory MRI utilization decreased by 55.2%, from 8.07 per 1000 encounters in 2005 to 2006 to 3.62 per 1000 encounters in 2007 to 2011 (P<0.001). Associated use of anesthesia for ambulatory MRI in children aged below 1 year, 1 to below 6 years, 6 to below 12 years, and 12 to below 18 years, was 91.1%, 83.6%, 74.6%, and 47.5%, respectively.

Conclusions:

Significant percentages of MRI in children are associated with use of anesthesia, particularly in younger children, a population potentially more vulnerable to anesthetic neurotoxicity. Discussion of risks and benefits of anesthesia for MRI in children among physicians, patients, and families is recommended.
Auditory Distraction and Acclimatization to Hearing Aids
Authors: Dawes Piers , Munro Kevin J.
Published: August 2016

Objective:

It is widely recognized by hearing aid users and audiologists that a period of auditory acclimatization and adjustment is needed for new users to become accustomed to their devices. The aim of the present study was to test the idea that auditory acclimatization and adjustment to hearing aids involves a process of learning to “tune out” newly audible but undesirable sounds, which are described by new hearing aid users as annoying and distracting. It was hypothesized that (1) speech recognition thresholds in noise would improve over time for new hearing aid users, (2) distractibility to noise would reduce over time for new hearing aid users, (3) there would be a correlation between improved speech recognition in noise and reduced distractibility to background sounds, (4) improvements in speech recognition and distraction would be accompanied by self-report of reduced annoyance, and (5) improvements in speech recognition and distraction would be associated with higher general cognitive ability and more hearing aid use.

Design:

New adult hearing aid users (n = 35) completed a test of aided speech recognition in noise (SIN) and a test of auditory distraction by background sound amplified by hearing aids on the day of fitting and 1, 7, 14, and 30 days post fitting. At day 30, participants completed self-ratings of the annoyance of amplified sounds. Daily hearing aid use was measured via hearing aid data logging, and cognitive ability was measured with the Wechsler Abbreviated Scale of Intelligence block design test. A control group of experienced hearing aid users (n = 20) completed the tests over a similar time frame.

Results:

At day 30, there was no statistically significant improvement in SIN among new users versus experienced users. However, levels of hearing loss and hearing aid use varied widely among new users. A subset of new users with moderate hearing loss who wore their hearing aids at least 6 hr/day (n = 10) had significantly improved SIN (by ~3-dB signal to noise ratio), compared with a control group of experienced hearing aid users. Improvements in SIN were associated with more consistent HA use and more severe hearing loss. No improvements in the test of auditory distraction by background sound were observed. Improvements in SIN were associated with self-report of background sound being less distracting and greater self-reported hearing aid benefit. There was no association between improvements in SIN and cognitive ability or between SIN and auditory distraction.

Conclusions:

Improvements in SIN were accompanied by self-report of background sounds being less intrusive, consistent with auditory acclimatization involving a process of learning to “tune out” newly audible unwanted sounds. More severe hearing loss may afford the room for improvement required to show better SIN performance with time. Consistent hearing aid use may facilitate acclimatization to hearing aids and better SIN performance.
Revisiting Tension Band Fixation for Difficult Patellar Fractures
Authors: Hambright Dustin S. , Walley Kempland C. , Hall Amber , Appleton Paul T. , Rodriguez Edward K.
Published: August 2016

Patella fractures with comminution, osteoporotic bone, and/or previously failed fixation are exceedingly difficult to reduce and fix. Moreover, the risk of symptomatic constructs and patients who are poorly compliant with postoperative activity restrictions can make these complex fracture patterns an even more challenging scenario. Although there is an array of techniques described for comminuted patella fractures, there lacks an accepted surgical technique for these difficult cases. In this clinical series, we describe an enhancement to the traditional tension band construct that uses additional wires and multiple tension bands to gather and fix comminuted fracture patterns in nontransverse planes, bolster osteoporotic bone, and secure fractures in patients undergoing a revision and/or have potential to be poorly compliant with postoperative activity restrictions. The clinical outcomes of 27 patients demonstrate high rates of bony union, functional range of motion, and low rates of both infection and failure. In conclusion, using the basic principles of tension band wiring remains highly versatile, useful, and economical in approaching difficult patella fractures.
Adiposity, breast density, and breast cancer risk: epidemiological and biological considerations
Authors: Soguel Ludivine , Durocher Francine , Tchernof André , Diorio Caroline
Published: August 2016

Excess total body fat and abdominal adipose tissue are recognized risk factors for metabolic diseases but also for some types of cancers, including breast cancer. Several biological mechanisms in connection with local and systemic effects of adiposity are believed to be implicated in breast cancer development, and may involve breast fat. Breast adipose tissue can be studied through mammography by looking at breast density features such as the nondense area mainly composed of fat, or the percent breast density, which is the proportion of fibroglandular tissue in relation to fat. The relation between adiposity, breast density features, and breast cancer is complex. Studies suggest a paradoxical association as adiposity and absolute nondense area correlate positively with each other, but in contrast to adiposity, absolute nondense area seems to be associated negatively with breast cancer risk. As breast density is one of the strongest risk factors for breast cancer, it is therefore critical to understand how these factors interrelate. In this review, we discuss these relations by first presenting how adiposity measurements and breast density features are linked to breast cancer risk. Then, we used a systematic approach to capture the literature to review the relation between adiposity and breast density features. Finally, the role of adipose tissue in carcinogenesis is discussed briefly from a biological perspective.
Immune Monitoring of Patients Treated With a Whole-Cell Melanoma Vaccine Engineered to Express 4-1BBL
Authors: Engelstein Roni , Merims Sharon , Eisenberg Galit , Cohen Jonathan , Frank Stephen , Hamburger Tamar , Frankenburg Shoshana , Ron Ilan , Isacson Ruth , Grenader Tal , Steinberg Hanna , Cohen Cyrille J. , Peretz Tamar , Lotem Michal
Published: August 2016

CD8 lymphocytes are mandatory mediators of tumor regression. To enhance their specific antitumor activity, we aimed to improve a melanoma cell-based vaccine by transfecting it with 4-1BB ligand, a costimulatory and immune modulatory molecule. Thirty-four American Joint Committee on Cancer (AJCC) stage IIB–IV patients were vaccinated with a melanoma antigen-rich cell line engineered to express HLA-A2 and 4-1BBL (M20/A2/BBL). Twelve serially recruited patients were monitored for interferon γ expression and CD107a mobilization before and after vaccination. Thirty-three patients remained alive, with an estimated mean overall survival of 26.2 months. No grade 3–4 adverse events were encountered. Immune monitoring detected an increase in circulating antimelanoma CD8 T cells in 9 of 12 patients, which were significantly stimulated by the parental melanoma, reflecting a relevant antitumor response. The results from this study show that the costimulatory 4-1BB ligand fortifies an antigen-rich melanoma cell line with enhanced antigen-specific stimulation of CD8 T cells. The use of a costimulatory molecule as part of a vaccine confers a selective increase of T-cell subsets with antimelanoma reactivity, which in some cases were characterized for their epitope specificity.
Melanocytoma-like melanoma may be the missing link between benign and malignant uveal melanocytic lesions in humans and dogs: a comparative study
Authors: Zoroquiain Pablo , Mayo-Goldberg Erin , Alghamdi Sarah , Alhumaid Sulaiman , Perlmann Eduardo , Barros Paulo , Mayo Nancy , Burnier Miguel N.
Published: August 2016

The cutoff presented in the current classification of canine melanocytic lesions by Wilcock and Pfeiffer is based on the clinical outcome rather than morphological concepts. Classification of tumors based on morphology or molecular signatures is the key to identifying new therapies or prognostic factors. Therefore, the aim of this study was to analyze morphological findings in canine melanocytic lesions based on classic malignant morphologic principles of neoplasia and to compare these features with human uveal melanoma (HUM) samples. In total, 64 canine and 111 human morphologically malignant melanocytic lesions were classified into two groups (melanocytoma-like or classic melanoma) based on the presence or absence of M cells, respectively. Histopathological characteristics were compared between the two groups using the χ
2-test, t-test, and multivariate discriminant analysis. Among the 64 canine tumors, 28 (43.7%) were classic and 36 (56.3%) were melanocytoma-like melanomas. Smaller tumor size, a higher degree of pigmentation, and lower mitotic activity distinguished melanocytoma-like from classic tumors with an accuracy of 100% for melanocytoma-like lesions. From the human series, only one case showed melanocytoma-like features and had a low risk for metastasis characteristics. Canine uveal melanoma showed a morphological spectrum with features similar to the HUM counterpart (classic melanoma) and overlapped features between uveal melanoma and melanocytoma (melanocytoma-like melanoma). Recognition that the subgroup of melanocytoma-like melanoma may represent the missing link between benign and malignant lesions could help explain the progression of uveal melanoma in dogs; these findings can potentially be translated to HUM.
Discrimination and Acculturation Stress: A Longitudinal Study of Children's Well-Being from Prenatal Development to 5 Years of Age
Authors: Zeiders Katharine H. , Umaña-Taylor Adriana J. , Jahromi Laudan B. , Updegraff Kimberly A. , White Rebecca M. B.
Published: August 2016

Objective:

To examine whether cumulative family discrimination and acculturation stress (prenatally to 24 months postpartum) among Mexican-origin adolescent mothers and their mother-figures predicted children's socio-emotional functioning and academic achievement at 5 years of age, and the role of maternal depressive symptoms and mother–child interactions in the association.

Method:

Mexican-origin families (N = 204) with an adolescent mother, a child, and a mother-figure participated in a 6-wave longitudinal study (2007–2013). Families were recruited and interviewed during the adolescent mother's pregnancy; adolescent mothers, mother-figures, and children were then assessed annually for the next 5 years using a combination of interview-based survey and observational methods. Maternal reports of children's socio-emotional behaviors (measured using the Child Behavior Checklist) and children's academic achievement (assessed with the Woodcock Johnson III Tests of Achievement/Bateria III Woodcock-Muñoz) were used.

Results:

Structural equation modeling revealed that greater cumulative family discrimination and acculturation stress from pregnancy to 24 months postpartum predicted higher adolescent mothers' depressive symptoms, greater mother–child intrusive interactions, and less mother sensitivity at 36 months postpartum. Maternal depressive symptoms were positively related to children's CBCL symptoms at 60 months postpartum. Greater cumulative discrimination and acculturation stressors directly predicted children's lower Woodcock Johnson/Bateria test scores after accounting for socio-economic status.

Conclusion:

Mexican-origin adolescent mothers' and mother figures' cumulative discrimination and acculturation stress from pregnancy through children's second birthday predicted children's socio-emotional and academic achievement at age 5. Overall, the findings underscore the cumulative impact of these stressors on well-being in a population with substantial public health significance.
Application of Palpebral Spring in Asian Patients With Paralytic Lagophthalmos
Authors: Chan Richie Chiu-Lung , Chan Jimmy Yu-Wai
Published: August 2016

Purpose:

Literature on palpebral springs is scarce, and even more so for the Asian population. In this study, the authors evaluated their experience with palpebral spring placement for paralytic lagophthalmos in an Asian population. The authors report the unique challenges encountered due to the distinctive features in Asian eyelids and how they overcome them. To the best of our knowledge, this is the first report on the application of palpebral springs in Asians.

Methods:

All patients treated for paralytic lagophthalmos in the Department of Surgery, Queen Mary Hospital, from November 2013 to December 2015, were included in this study. The authors retrieved and analyzed the demographic data, preoperative assessment details, and treatment outcomes.

Results:

A total of 17 patients were recruited. The median interval between facial palsy occurrence and surgery was 66 months. Preoperatively, vertical palpebral fissure was 12.3 ± 1.7 mm with margin reflex distance 1 of 3.7 ± 0.3 mm and margin reflex distance 2 of 8.6 ± 1.6 mm. Lagophthalmos before surgery was 9.6 ± 2.3 mm. After the palpebral spring surgeries, vertical palpebral fissure was reduced to 9.1 ± 1.4 mm. margin reflex distance 1 is slightly reduced (3.3 ± 0.8 mm) and margin reflex distance 2 improved to 5.8 ± 1.0 mm. Lagophthalmos reduced significantly to 0.8 ± 1.3 mm. Seven patients required revision procedures.

Conclusions:

Palpebral spring is a safe and effective treatment for Asian patients with paralytic lagophthalmos. However, surgeons should be aware of the unique challenges associated with the anatomy of Asian eyelids. Special adaptation of the procedure is required to optimize the outcome.
The evolution and outcome of surveillance of Barrett’s oesophagus over four decades in a UK District General Hospital
Authors: Royston Christine , Caygill Christine , Charlett Andre , Bardhan Karna Dev
Published: August 2016

Introduction

We present the long-term outcome of Barrett’s oesophagus (BO) at a District General Hospital set against the increasing numbers of patients with gastro-oesophageal reflux disease (GORD).

Methods

Data were collected prospectively over 37 years. Comparison of GORD without Barrett’s (NoBO) versus BO was performed from 1/1/1977 to 31/12/2001 when the NoBO database closed and outcomes of all cases of BO diagnosed until 31/12/2011 and followed up until 31/12/2013 have been reported.

Results

During the period 1977–2001 the number of GORD NoBO cases was 11 610, and that of BO cases was 764 (6.2% of all GORD); total number of BO cases in 1977–2011 was 1468. NoBO patients were younger than BO patients: 52.2 versus 61.6 years. There was a male predominance in both groups: NoBO 55% and BO 62% (P<0.0001). The prevalence of oesophageal adenocarcinoma (OAC) was 87/1468 (5.9%) BO cases. Its incidence was 54/1381 (3.9%); the mean interval between the diagnosis of BO and incident OAC was 9 years (range 13 months–25.4 years); there was one OAC per 192 patient-years of follow-up (0.52% per year). Mortality was significantly lower in 37 patients under endoscopic surveillance at the time OAC was diagnosed (51 vs. 88% P=0.0141) partly because of older age and comorbidity of the other 17, in whom serial endoscopy was contraindicated. A proportional hazards model to allow for age estimated that the hazard rate ratio was lower in the surveillance group; however, this difference did not reach statistical significance (0.64, 95% confidence interval 0.30–1.48, P=0.08). Excluding prevalent cancers from both groups, mortality in BO was double that in NoBO (47 vs. 24%).

Conclusion

These 37 years of observation suggest, but do not confirm, that endoscopic surveillance may reduce the risk of death from OAC. Modern technology is likely to yield better results, but larger prospective studies are needed to confirm the benefits.
Efficacy and Toxicity of Intrathecal Liposomal Cytarabine in First-line Therapy of Childhood Acute Lymphoblastic Leukemia
Authors: Levinsen Mette , Harila-Saari Arja , Grell Kathrine , Jonsson Olafur Gisli , Taskinen Mervi , Abrahamsson Jonas , Vettenranta Kim , Åsberg Ann , Risteli Juha , Heldrup Jesper , Schmiegelow Kjeld
Published: August 2016

We investigated efficacy and toxicity of replacing conventional triple (cytarabine, methotrexate, and hydrocortisone) intrathecal therapy (TIT) with liposomal cytarabine during maintenance therapy among 40 acute lymphoblastic leukemia patients. Twenty-eight of 29 patients in the TIT arm received TIT and 9/11 in the liposomal cytarabine arm received liposomal cytarabine. Arachnoiditis occurred in all initial 5 patients given liposomal cytarabine and intrathecal prednisolone succinate. Subsequently liposomal cytarabine was given with systemic dexamethasone. Neurotoxicity occurred at 6/27 liposomal cytarabine administrations with concomitant dexamethasone (22%). More liposomal cytarabine-treated patients experienced neurotoxicity in relation to intrathecal therapy during at least 1 cycle compared with TIT-treated patients (6/9 [67%] vs. 3/28 [11%], P=0.002). Apart from intermittent lower extremity sensory pain in 1 liposomal cytarabine-treated patient, no permanent adverse neurological sequelae were observed. In intention-to-treat analysis, projected 5-year event-free survival (pEFS-5y) was borderline higher for patients in the liposomal cytarabine arm compared with the TIT arm (1.0 vs. 0.69, P=0.046). However, pEFS-5y and projected 5-year relapse-free survival did not differ signficantly between patients treated with liposomal cytarabine or TIT (1.0 vs. 0.73, P=0.10; 1.0 vs. 0.76, P=0.12). Larger prospective trials are needed to explore whether liposomal cytarabine should be used as first-line prevention of relapse.
Focal Nodulary Hyperplasia of the Liver Due to Congenital Portosystemic Shunt: A Rare Condition Mimicking Hepatocellulary Carcinoma
Authors: Yazal Erdem Arzu , Emir Suna , Demir Haci A. , Özyörük Derya , Çetin İlker , Turan Aynur , Karakuş Esra
Published: August 2016

Congenital portosystemic shunts are rare vascular malformations that lead to several complications including liver tumors, pulmonary hypertension, and metabolic encephalopathy. We describe a rare case of a 17-year-old girl with an extrahepatic portosystemic shunt presenting recurrent syncope episodes and a liver mass mimicking hepatocellulary carcinoma.
Central Corneal Thickness Reproducibility among Ten Different Instruments
Authors: Pierro Luisa , Iuliano Lorenzo , Gagliardi Marco , Ambrosi Alessandro , Rama Paolo , Bandello Francesco
Published: August 2016

Purpose

To assess agreement between one ultrasonic (US) and nine optical instruments for the measurement of central corneal thickness (CCT), and to evaluate intra- and inter-operator reproducibility.

Methods

In this observational cross-sectional study, two masked operators measured CCT thickness twice in 28 healthy eyes. We used seven spectral-domain optical coherence tomography (SD-OCT) devices, one time-domain OCT, one Scheimpflug camera, and one US-based instrument. Inter- and intra-operator reproducibility was evaluated by intraclass correlation coefficient (ICC), coefficient of variation (CV), and Bland-Altman test analysis. Instrument-to-instrument reproducibility was determined by ANOVA for repeated measurements. We also tested how the devices disagreed regarding systemic bias and random error using a structural equation model.

Results

Mean CCT of all instruments ranged from 536 ± 42 μm to 577 ± 40 μm. An instrument-to-instrument correlation test showed high values among the 10 investigated devices (correlation coefficient range 0.852–0.995; p values <0.0001 in all cases). The highest correlation coefficient values were registered between 3D OCT-2000 Topcon—Spectral OCT/SLO Opko (0.995) and Cirrus HD-OCT Zeiss—RS-3000 Nidek (0.995), whereas the lowest were seen between SS-1000 CASIA and Spectral OCT/SLO Opko (0.852). ICC and CV showed excellent inter- and intra-operator reproducibility for all optic-based devices, except for the US-based device. Bland-Altman analysis demonstrated low mean biases between operators.

Conclusions

Despite highlighting good intra- and inter-operator reproducibility, we found that a scale bias between instruments might interfere with thorough CCT monitoring. We suggest that optimal monitoring is achieved with the same operator and the same device.
A Case Report of Postmortem Radiography of Acute, Fatal Abdominal Distension After Binge Eating
Authors: Usui Akihito , Kawasumi Yusuke , Ishizuka Yuya , Hosokai Yoshiyuki , Ikeda Tomoya , Saito Haruo , Funayama Masato
Published: August 2016

This case report describes a woman who developed fatal gastric dilatation after binge eating. She called an ambulance because of stomach pain. When she arrived at the hospital, she did not look seriously ill. However, she rapidly became unconscious and collapsed immediately after she was laid on the examination table in a supine position. Postmortem chest x-ray and computed tomography showed right shift of the mediastinum and raised left diaphragm caused by massive gastric distension. Computed tomography showed no visible inferior vena cava. We think that her sudden deterioration was caused by movement of her stomach contents. Radiographic images provided some clues to the cause of her rapid collapse and death.
TFEB-amplified Renal Cell Carcinomas
Authors: Argani Pedram , Reuter Victor E. , Zhang Lei , Sung Yun-Shao , Ning Yi , Epstein Jonathan I. , Netto George J. , Antonescu Cristina R.
Published: August 2016

Renal cell carcinomas (RCCs) with the t(6;11)(p21;q12) chromosome translocation are low-grade RCC which often occur in young patients. They typically feature an unusual biphasic morphology characterized by nests of larger epithelioid cells surrounding intraluminal collections of smaller cells clustered around basement membrane material. The t(6;11)(p21;q12) translocation fuses the Alpha (MALAT1) gene with the TFEB transcription factor gene, resulting in upregulated expression of intact native TFEB that drives the aberrant expression of melanocytic markers which is a hallmark of this distinctive neoplasm. We now report 8 cases of RCC, which demonstrate TFEB gene amplification (6 without TFEB rearrangement, 2 with concurrent TFEB rearrangement) and demonstrate downstream consequences of TFEB overexpression. Like the unamplified t(6;11) RCC, all TFEB-amplified RCC were associated with aberrant melanocytic marker expression. However, several differences between TFEB-amplified RCC and the usual unamplified t(6;11) RCC are evident. First, TFEB-amplified RCC occurred in older patients (median age, 64.5 y) compared with unamplified t(6;11) RCC (median age, 31 y). Second, the morphology of TFEB-amplified RCC is not entirely distinctive, frequently featuring nests of high-grade epithelioid cells with eosinophilic cytoplasm associated with pseudopapillary formation and necrosis, or true papillary formations. These patterns raise the differential diagnosis of high-grade clear cell and papillary RCC. Third, TFEB and melanocytic marker expression was more variable within the TFEB-amplified RCC. TFEB protein expression by immunohistochemistry was detectable in 6 of 8 cases. While all 8 cases expressed melan-A, only 5 of 8 expressed cathepsin K and only 3 of 8 expressed HMB45. Fourth, the TFEB-amplified RCC were associated with a more aggressive clinical course; 3 of 8 cases presented with advanced stage or metastatic disease, 2 subsequently developed metastatic disease, whereas the other 3 cases had minimal/no follow-up. Our results are corroborated by scant data reported on 6 TFEB-amplified RCC in the literature, gleaned from 1 case report, 1 abstract, and 4 individual cases identified within 2 genomic studies of large cohorts of RCC. In summary, TFEB-amplified RCC represent a distinct molecular subtype of high-grade adult RCC associated with aggressive clinical behavior, variable morphology, and aberrant melanocytic marker expression.
Cost-Effectiveness Analysis of Anticholinergics Versus Botox for Urgency Urinary Incontinence: Results From the Anticholinergic Versus Botox Comparison Randomized Trial
Authors: Visco Anthony G. , Zyczynski Halina , Brubaker Linda , Nygaard Ingrid , Xu Xiao , Lukacz Emily S. , Paraiso Marie Fidela , Greer Jerod , Rahn David D. , Meikle Susan F. , Honeycutt Amanda A.
Published: August 2016

Objectives

This study aimed to compare the cost-effectiveness of Botox and anticholinergic (AC) medications for the management of urgency urinary incontinence (UUI).

Methods

Cost and effectiveness data were analyzed from participants in the Anticholinergic versus Botox Comparison randomized trial of daily AC medication versus 100 U of intradetrusor Botox injection. Societal costs included the following: treatment costs, patient costs, and medical and nonmedical utilization during the 6-month trial. Quality-adjusted life-years (QALYs) were calculated based on questionnaire-derived utility measures and annualized based on data collected at baseline through 6 months. We also estimated the average direct costs for each treatment through 9 months — the duration of time when approximately half the Botox participants maintained adequate symptom control.

Results

Data were analyzed on the 231 women who completed a 6-month follow-up in the Anticholinergic versus Botox Comparison trial (119 AC and 112 Botox). The mean reduction in UUI episodes per day was not significantly different per group. The cumulative mean direct costs through the first 6 months also were similar: $1339 for the AC group and $1266 for the Botox group with AC costs exceeding Botox costs after 5 months. Both groups had considerable QALY gains. Annualizing the 6-month trial results to a 12-month measure, the AC and Botox groups averaged 0.702 and 0.707 QALYs, respectively. Estimates through 9 months favored Botox, showing that AC participants incurred a higher cost per month of adequate symptoms control ($305) compared with Botox participants ($207).

Conclusions

Botox and AC medications have similar costs and effectiveness in the first 6 months of UUI treatment. If costs and outcomes are considered through 9 months, Botox may have significantly lower costs but similar UUI symptom control as AC.
Baclofen in the Therapeutic of Sequele of Traumatic Brain Injury: Spasticity
Authors: Pérez-Arredondo Adán , Cázares-Ramírez Eduardo , Carrillo-Mora Paul , Martínez-Vargas Marina , Cárdenas-Rodríguez Noemí , Coballase-Urrutia Elvia , Alemón-Medina Radamés , Sampieri Aristides , Navarro Luz , Carmona-Aparicio Liliana
Published: August 2016

Traumatic brain injury (TBI) is an alteration in brain function, caused by an external force, which may be a hit on the skull, rapid acceleration or deceleration, penetration of an object, or shock waves from an explosion. Traumatic brain injury is a major cause of morbidity and mortality worldwide, with a high prevalence rate in pediatric patients, in which treatment options are still limited, not available at present neuroprotective drugs. Although the therapeutic management of these patients is varied and dependent on the severity of the injury, general techniques of drug types are handled, as well as physical and surgical. Baclofen is a muscle relaxant used to treat spasticity and improve mobility in patients with spinal cord injuries, relieving pain and muscle stiffness. Pharmacological support with baclofen is contradictory, because disruption of its oral administration may cause increased muscle tone syndrome and muscle spasm, prolonged seizures, hyperthermia, dysesthesia, hallucinations, or even multisystem organ failure. Combined treatments must consider the pathophysiology of broader alterations than only excitation/inhibition context, allowing the patient's reintegration with the greatest functionality.
Frameshift and wild-type proteins are highly similar because the genetic code and genomes were optimized for frameshift tolerance
Authors: Wang Xiaolong , Dong Quanjiang , Chen Gang , Zhang Jianye , Liu Yongqiang , Cai Yujia
Published: August 2016

Frameshift protein sequences encoded by alternative reading frames of coding genes have been considered meaningless, and frameshift mutations have been considered of little importance for the molecular evolution of coding genes and proteins. However, functional frameshifts have been found widely existing. It was puzzling how a frameshift protein kept its structure and functionality while its amino-acid sequence was changed substantially. Here we show that frame similarities between frameshifts and wild types are higher than random similarities and are defined at the genetic code, gene, and genome levels. In the standard genetic code, frameshift codon substitutions are more conservative than random substitutions. The frameshift tolerability of the standard genetic code ranks in the top 2.0-3.5% of alternative genetic codes, showing that the genetic code is nearly optimal for frameshift tolerance. Furthermore, frameshift-resistant codons (codon pairs) appear more frequently than expected in many genes and certain genomes, showing that the frameshift optimality is reflected not only in the genetic code but more importantly, in its allowance of further optimizing the frameshift tolerance of a particular gene or genome, which shed light on the role of frameshift mutations in molecular and genomic evolution.
Untangling the Components of Phenotypic Plasticity in Nonlinear Reaction Norms of Drosophila Mediopunctata Pigmentation
Authors: Rocha Felipe Bastos , Klaczko Louis Bernard
Published: August 2016

Phenotypic plasticity may evolve as a generalist strategy to cope with environmental heterogeneity. Empirical studies, however, rarely find results confirming this prediction. This may be related to constraints imposed by the genetic architecture underlying plasticity variation. Three components of plasticity are central to characterize its variation: the intensity of response, the direction of response and the total amount of change. Reaction norm functions are a key analytical tool in plasticity studies. The more complex they are, the more plasticity components will vary independently, requiring more parameters to be described. Experimental studies are continuously collecting results showing that actual reaction norms are often nonlinear. This demands an analytical framework – yet to be developed – capable of straightforwardly untangling plasticity components. In Drosophila mediopunctata, the number of dark spots on the abdomen decreases as a response to increasing developmental temperatures. We have previously described a strong association between reaction norm curvature and across-environment mean values in homozygous strains. Here, we describe seven new reaction norms of heterozygous genotypes and further the investigation on the genetic architecture of this trait’s plasticity, testing three competing models from the literature – Overdominance, Epistasis and Pleiotropy. We use the curves of localized slopes of each reaction norm – Local Plasticity functions – to characterize the plastic response intensity and direction, and introduce a Global Plasticity parameter to quantify their total amount of change. Uncoupling plasticity components allowed us to discard the Overdominance model, weaken the Epistasis model and strengthen the support for the Pleiotropy model. Furthermore, this approach allows the elaboration of a coherent developmental model for the pigmentation of D. mediopunctata where genetic variation at one single feature explains the patterns of plasticity and overall expression of the trait. We claim that Global Plasticity and Local Plasticity may prove instrumental to the understanding of adaptive reaction norm evolution
Laboratory strains ofAedes aegyptiare Competent to Brazilian Zika virus
Authors: Costa-da-Silva André Luis , Ioshino Rafaella Sayuri , Araújo Helena Rocha Corrêa , Kojin Bianca Burini , Zanotto Paolo Marinho de Andrade , Oliveira Danielle Bruna Leal , Melo Stella Rezende , Durigon Edison Luiz , Capurro Margareth Lara
Published: August 2016

Since the Zika outbreaks are unprecedented human threat in relation to congenital malformations and neurological/autoimmune complications as well as its high potential to spread in regions presenting the vectors, improvements in mosquito control is a top priority. Thus,Aedes aegyptilaboratory strains will be fundamental to support studies in different research fields implicated on Zika-mosquito interactions which are the basis for the development of innovative control methods. In this sense, we determined the main infection aspects of the Brazilian Zika strain in referenceAedes aegyptilaboratory mosquitoes.

We orally exposed Rockefeller, Higgs and Rexville mosquitoes to a Brazilian ZIKV (ZIKVBR) and qRT-PCR was applied to determine the infection and dissemination rates, and viral levels in mosquito tissues as well as in the saliva. The ZIKVBRkinetics was monitored during the infection in Rockefeller mosquitoes. Rockefeller strain was the most susceptible at 7 days post-infection but all strains presented similar infection levels at 14 days post-infection. Although variations in the saliva detection rates were observed, we confirmed that ZIKVBRwas present in saliva from Rockefeller, Higgs and Rexville females at detectable levels at 14 days post-infection. The ZIKVBRkinetics in Rockefeller mosquitoes showed that the virus could be detected in the heads at 4 days post-infection but was more consistently detected late in infection. The viral levels peaked at 11 days post-infection in the mosquito bodies, remaining stable until 14 days post-infection, in contrast to the heads, where the mean viral levels only peaked at 14 days post-infection.

Our study presents the first evaluation on how Brazilian Zika virus behaves in referenceAedes aegyptistrains and shed light on how the infection evolves over time. Vector competence and basic hallmarks of the ZIKVBRdevelopment were revealed in laboratory mosquitoes. This study provides additional information to accelerate studies focusing on ZIKV-mosquito interactions.
CRISPR/Cas9 gene drives in genetically variable and non-randomly mating wild populations
Authors: Drury Douglas W. , Siniard Dylan J. , Zentner Gabriel E. , Wade Michael J.
Published: August 2016

Synthetic gene drives based on CRISPR/Cas9 have the potential to control, alter or suppress populations of crop pests and disease vectors, but it is unclear how they will function in wild populations. Using genetic data from four populations of the flour beetleTribolium castaneum, we show that most populations harbor genetic variants in Cas9 target sites, some of which would render them immune to drive (ITD). We show that even a rare ITD allele can reduce or eliminate the efficacy of CRISPR/Cas9-based synthetic gene. This effect is equivalent to and accentuated by mild inbreeding, which is a characteristic of many diseasevectoring arthropods. We conclude that designing such a drive will require characterization of genetic variability and the mating system within and among targeted populations.
Interacting networks of resistance, virulence and core machinery genes identified by genome-wide epistasis analysis
Authors: Skwark Marcin J. , Croucher Nicholas J , Puranen Santeri , Chewapreecha Claire , Pesonen Maiju , Xu Ying ying , Turner Paul , Harris Simon R. , Parkhill Julian , Bentley Stephen D. , Aurell Erik , Corander Jukka
Published: August 2016

Recent advances in the scale and diversity of population genomic datasets for bacteria now provide the potential for genome-wide patterns of co-evolution to be studied at the resolution of individual bases. The major human pathogenStreptococcus pneumoniaerepresents the first bacterial organism for which densely enough sampled population data became available for such an analysis. Here we describe a new statistical method, genomeDCA, which uses recent advances in computational structural biology to identify the polymorphic loci under the strongest co-evolutionary pressures. Genome data from over three thousand pneumococcal isolates identified 5,199 putative epistatic interactions between 1,936 sites. Over three-quarters of the links were between sites within thepbp2x,pbp1aandpbp2bgenes, the sequences of which are critical in determining non-susceptibility to beta-lactam antibiotics. A network-based analysis found these genes were also coupled to that encoding dihydrofolate reductase, changes to which underlie trimethoprim resistance. Distinct from these resistance genes, a large network component of 384 protein coding sequences encompassed many genes critical in basic cellular functions, while another distinct component included genes associated with virulence. These results have the potential both to identify previously unsuspected protein-protein interactions, as well as genes making independent contributions to the same phenotype. This approach greatly enhances the future potential of epistasis analysis for systems biology, and can complement genome-wide association studies as a means of formulating hypotheses for experimental work.

Author Summary

Epistatic interactions between polymorphisms in DNA are recognized as important drivers of evolution in numerous organisms. Study of epistasis in bacteria has been hampered by the lack of both densely sampled population genomic data, suitable statistical models and powerful inference algorithms for extremely high-dimensional parameter spaces. We introduce the first model-based method for genome-wide epistasis analysis and use the largest available bacterial population genome data set on Streptococcus pneumoniae (the pneumococcus) to demonstrate its potential for biological discovery. Our approach reveals interacting networks of resistance, virulence and core machinery genes in the pneumococcus, which highlights putative candidates for novel drug targets. Our method significantly enhances the future potential of epistasis analysis for systems biology, and can complement genome-wide association studies as a means of formulating hypotheses for experimental work.