bluuebunny/crossref_metadata_2025_split huggingface dataset:
Advances in pediatric antimicrobial agents development
Authors: Wood James B. , Cravens Lauryn B. , Creech C. Buddy 
Published: November 2018

Purpose of review
Rising rates of multidrug-resistant organisms has necessitated the development of novel antimicrobials. In this review, we will highlight agents that have recently received licensure and those that are in clinical development.

Recent findings
In recent years, development of novel antimicrobial agents has accelerated. Although most studies have targeted the adult population, studies in pediatric patients are underway. Adequately powered clinical trials are needed to establish the safety and role of these new drugs.

Summary
The recent development of novel antimicrobials to combat multidrug-resistant organisms is encouraging; however, more studies in the pediatric population are needed.
Role of Immunohistochemistry to Distinguish Grade 3 Endometrioid Carcinoma and Uterine Serous Carcinoma
Authors: Zaidi Ariba , Gupta Parikshaa , Gupta Nalini , Rajwanshi Arvind , Rai Bhavana , Gainder Shalini 
Published: November 2018

Aim:
The categorization of endometrial carcinomas into endometrioid and serous categories has prognostic implications but many-a-times, it is difficult to categorize based solely on morphology. The present study was conducted to determine an appropriate immunohistochemical panel to distinguish grade 3 endometrioid carcinoma from serous carcinoma.

Experimental Design:
This study was a retrospective and a prospective study including 63 cases of endometrial carcinoma diagnosed on morphology as either grade 3 endometrioid (n=29) or serous endometrial carcinomas (n=34). Immunohistochemistry (IHC) was performed using tissue microarrays for 8 immunomarkers on 60 cases.

Results:
The mean age of presentation was not significantly different for both types of carcinomas and the most common presentation was postmenopausal bleeding (93% of the total cases, P=0.66). Obesity (P=0.038), lymph nodal involvement (P=0.044), and stage at presentation (P=0.042) were found to be significantly different among the 2 types of carcinomas. Estrogen and progesterone receptor (ER, PR) positivity was more common (47.6% and 28.2%, respectively) in endometrioid carcinomas as compared with serous. Mutation type (diffuse or null) p53 staining was a powerful predictor of serous carcinomas. IMP3 and p16 were found to be positive in most cases of serous carcinoma (64.1% and 79.5%, respectively). Vimentin and β-catenin were found to be of limited utility. On the basis of IHC, 21 cases could be categorized as grade 3 endometrioid carcinomas and 39 as type 2 carcinomas (serous and clear cell carcinoma).

Conclusions:
The most appropriate IHC panel to differentiate endometrioid and serous endometrial carcinomas includes ER, PR, IMP3, p53, and p16.
A Spoonful of Lead: A 10-Year Look at Spices as a Potential Source of Lead Exposure
Authors: Hore Paromita , Alex-Oni Kolapo , Sedlar Slavenka , Nagin Deborah 
Published: November 2018

Context:
While lead-based paint and occupational lead hazards remain the primary sources of lead exposures among New York City's lead-poisoned children and men, respectively, these are not the only possible lead sources. Certain consumer products are often implicated. Between 2008 and 2017, the New York City Department of Health and Mental Hygiene tested more than 3000 samples of consumer products during lead poisoning case investigations and surveys of local stores, and of these, spices were the most frequently tested (almost 40% of the samples).

Objectives:
To describe spice samples—types, origin, lead concentrations, and the implication of findings for public health programs and global food safety regulations.

Design:
Descriptive study of lead contamination in spices systematically collected as part of lead poisoning investigations.

Setting and Participants:
A total of 1496 samples of more than 50 spices from 41 countries were collected during investigations of lead poisoning cases among New York City children and adults and local store surveys.

Results:
More than 50% of the spice samples had detectable lead, and more than 30% had lead concentrations greater than 2 ppm. Average lead content in the spices was significantly higher for spices purchased abroad than in the United States. The highest concentrations of lead were found in spices purchased in the countries Georgia, Bangladesh, Pakistan, Nepal, and Morocco.

Conclusions:
Certain commonly used spices, particularly those purchased abroad in Georgia, Bangladesh, Pakistan, Nepal, and Morocco, can have very high lead levels, which can contribute to lead body burden. This underscores the need to develop comprehensive interventions that educate consumers and initiate intergovernmental efforts for stricter global food regulations.
Using Medicaid Data to Improve Childhood Lead Poisoning Prevention Program Outcomes and Blood Lead Surveillance
Authors: Bruce Shelley A. , Christensen Krista Y. , Coons Marjorie J. , Havlena Jeffrey A. , Meiman Jon G. , Walsh Reghan O. 
Published: November 2018

Context:
Wisconsin-specific data revealed that not all Medicaid providers were testing children appropriately for blood lead levels and not all blood lead tests were reported to the Department of Health Services, Childhood Lead Poisoning Prevention Program. The Medicaid program requires blood lead screening for all Medicaid-enrolled children at specific ages. Wisconsin state law requires reporting of all blood lead test results. Projects were implemented to encourage appropriate testing for Medicaid-enrolled children and improve blood lead surveillance.

Methods:
Medicaid billing data were linked to blood lead data to identify Medicaid-enrolled children who had not received the required tests. Medicaid provider report cards were distributed annually from 2006 to 2011 to inform providers of their compliance with federal testing requirements and of the names of children within their practice who had not been tested. Blood lead tests billed to Medicaid but not in the blood lead database were identified and billing providers were contacted to obtain the test report.

Results:
The number of children tested increased from 81 834 children per year in 2006 to 106 003 children per year in 2010. Testing of Medicaid-enrolled children increased by 31% from 2006 to 2010. The percentage of Medicaid-enrolled children receiving an age-appropriate test increased from 46% in 2004 to a high of 55% in 2010. There were 9035 blood lead tests identified in the Medicaid billing data that had not been reported from 2007 to 2015. There were 468 billing providers who had unreported tests. All sites with unreported tests were contacted, 84% of test results were obtained, and 14% of test records could not be retrieved. Outpatient clinics accounted for the majority of all unreported tests (72%) and irretrievable test records (74%).

Discussion:
Childhood lead poisoning prevention programs can effectively utilize Medicaid data to increase testing and improve blood lead surveillance. Primary health care providers should ensure that Medicaid-enrolled children in their care receive the age-appropriate tests. Many Wisconsin health care providers lack awareness of blood lead test reporting requirements. Outpatient clinics account for the largest proportion of unreported tests and highest priority should be given working with these sites to improve reporting practices.
Dynamic Frailty Before Kidney Transplantation: Time of Measurement Matters
Authors: Chu Nadia M. , Deng Arlinda , Ying Hao , Haugen Christine E. , Garonzik Wang Jacqueline M. , Segev Dorry L. , McAdams-DeMarco Mara A. 
Published: November 2018

Background.
Frail kidney transplant (KT) recipients have higher risk of adverse post-KT outcomes. Yet, there is interest in measuring frailty at KT evaluation and then using this information for post-KT risk stratification. Given long wait times for KT, frailty may improve or worsen between evaluation and KT. Patterns, predictors, and post-KT adverse outcomes associated with these changes are unclear.

Methods.
Five hundred sixty-nine adult KT candidates were enrolled in a cohort study of frailty (November 2009-September 2017) at evaluation and followed up at KT. Patterns of frailty transitions were categorized as follows: (1) binary state change (frail/nonfrail), (2) 3-category state change (frail/intermediate/nonfrail), and (3) raw score change (−5 to 5). Adjusted Cox proportional hazard and logistic regression models were used to test whether patterns of frailty transitions were associated with adverse post-KT outcomes.

Results.
Between evaluation and KT, 22.0% became more frail, while 24.4% became less frail. Black race (relative risk ratio, 1.98; 95% confidence interval [CI], 1.07-3.67) was associated with frail-to-nonfrail transition, and diabetes (relative risk ratio, 2.56; 95% CI, 1.22-5.39) was associated with remaining stably frail. Candidates who became more frail between 3-category states (hazard ratio, 2.27; 95% CI, 1.11-4.65) and frailty scores (hazard ratio, 2.36; 95% CI, 1.12-4.99) had increased risk of post-KT mortality and had higher odds of length of stay ≥2 weeks (3-category states: odds ratio, 2.02; 95% CI, 1.20-3.40; frailty scores: odds ratio, 1.92; 95% CI, 1.13-3.25).

Conclusions.
Almost half of KT candidates experienced change in frailty between evaluation and KT, and those transitions were associated with mortality and longer length of stay. Monitoring changes in frailty from evaluation to admission may improve post-KT risk stratification.
CD44v6 expression is a novel predictive marker of therapy response and poor prognosis in gastric cancer patients
Authors: Pereira Carla , Ferreira Daniel , Lemos Carolina , Martins Diana , Mendes Nuno , Almeida Daniela , Granja Pedro , Carneiro Fátima , Almeida Raquel , Almeida Gabriela M , Oliveira Carla 
Published: November 2018

AbstractLate diagnosis, modest treatment options and lack of predictive markers of therapy response dictate the poor overall survival (OS) of ∼1 year in most gastric cancer (GC) patients. We hypothesized that the level of CD44v6 expression in tumor cells could predict therapy response and prognosis in GC patients.We analyzed a surgical tumor series of GC patients for the extension of CD44v6 membranous immuno-expression, clinical-pathological features, patient survival, and response to therapy. By integrating this information, we assessed the value of CD44v6 expression to predict benefit from current treatment regimens and prognosis in GC patients. We used GC cell lines and mouse xenografts to assess and/validate the biological impact of CD44v6 expression in GC cells behavior.We demonstrated that GC patients whose tumors present higher levels of CD44v6 membranous expression benefit from adding chemotherapy to surgery as opposed to those without CD44v6 expression. Moreover, patients bearing CD44_high tumors presented worse OS than those bearing CD44_absent/low tumors, consolidating the role of CD44v6 expression as an independent factor of poor prognosis in this disease. Finally, ourin vitroand patients’ data pinpoints the CD44v6+ cell population as the driver of tumor recurrence following conventional chemotherapy, in heterogeneous tumors composed by CD44v6- and CD44v6+ cells.Our study pioneers the identification of CD44v6 as a potential predictive marker of response to conventional chemotherapy, and consolidates CD44v6 as an independent marker of poor prognosis in GC. Overall, our data strongly supports selection of patients with high CD44v6 expressing tumors for conventional chemotherapy with or without surgery, regardless of the TNM stage.
Insect egg size and shape evolve with ecology, not developmental rate
Authors: Church Samuel H. , Donoughe Seth , de Medeiros Bruno A. S. , Extavour Cassandra G. 
Published: November 2018

1AbstractThe evolution of organism size is hypothesized to be predicted by a combination of development, morphological constraints, and ecological pressures. However, tests of these predictions using phylogenetic methods have been limited by taxon sampling. To overcome this limitation, we generated a database of more than ten thousand observations of insect egg size and shape from the entomological literature and combined them with published genetic and novel life-history datasets. This enabled us to perform phylogenetic tests of long-standing predictions in size evolution across hexapods. Here we show that across eight orders of magnitude in egg volume variation, the relationship between egg shape and size itself evolves, such that predicted universal patterns of scaling do not adequately explain egg shape diversity. We test the hypothesized relationship between size and development, and show that egg size is not correlated with developmental rate across insects, and that for many insects egg size is not correlated with adult body size either. Finally, we show that the evolution of parasitism and aquatic oviposition both help to explain the diversification of egg size and shape across the insect evolutionary tree. Our study challenges assumptions about the evolutionary constraints on egg morphology, suggesting that where eggs are laid, rather than universal mathematical allometric constants, underlies egg size and shape evolution.
Does juvenile Baltic sturgeon (Acipenser oxyrinchus) smell the enemy?
Authors: Ruiz Maria Cámara , Santo Carlos Espírito , Mai Alfons , Gessner Jorn , Wuertz Sven 
Published: November 2018

SUMMARYAtlantic sturgeon (Acipenser oxyrinchus), also known as Baltic sturgeon, is considered extinct in German waters. Fish-rearing for conservation purposes still relies on classical hatchery technology producing fish not well suited for facing life in the wild, lacking behavioural skills such as foraging or anti-predation. Predation is hence a major source of mortality in newly stocked individuals. The aim of this study was to evaluate if naïve Baltic sturgeon juveniles were able to smell and recognize a common predator, sander (Sander lucioperca). Over a period of 30 days, three tanks from each group of Baltic sturgeon were attached to a rearing tank with sander (sander unit) and, as a control, carp (carp unit). Morphology of the dorsal scutes, distribution within the tank, stress (glucose, lactate and cortisol) and gene expression of brain plasticity and cognition were studied in comparison to the control group (carp unit). No significant differences were observed in any of the parameters measured. Thus, we conclude that naïve Baltic sturgeon is not able to innately recognize potential predators and future studies should focus on implementing predator odour together with chemical alarm substances.
Excitatory GABAergic signalling is associated with acquired benzodiazepine resistance in status epilepticus
Authors: Burman Richard J. , Selfe Joshua S. , Lee John Hamin , van den Burg Maurits , Calin Alexandru , Codadu Neela K. , Wright Rebecca , Newey Sarah E. , Parrish R. Ryley , Katz Arieh A. , Wilmshurst Joanne M. , Akerman Colin J. , Trevelyan Andrew J. , Raimondo Joseph V. 
Published: November 2018

AbstractStatus epilepticus (SE) is defined as a state of unrelenting seizure activity. Generalised convulsive SE is associated with a rapidly rising mortality rate, and thus constitutes a medical emergency. Benzodiazepines, which act as positive modulators of chloride (Cl-) permeable GABAA receptors, are indicated as first-line treatment, but this is ineffective in many cases. We found that 48% of children presenting with SE were unresponsive to benzodiazepine treatment, and critically, that the duration of SE at the time of treatment is an important predictor of non-responsiveness. We therefore investigated the cellular mechanisms that underlie acquired benzodiazepine resistance, using rodent organotypic and acute brain slices. Removing Mg2+ ions leads to an evolving pattern of epileptiform activity, and eventually to a persistent state of repetitive discharges that strongly resembles clinical EEG recordings of SE. We found that diazepam loses its antiseizure efficacy and conversely exacerbates epileptiform activity during this stage of SE-like activity. Interestingly, a low concentration of the barbiturate phenobarbital had a similar exacerbating effect on SE-like activity, whilst a high concentration of phenobarbital was effective at reducing or preventing epileptiform discharges. We then show that the persistent SE-like activity is associated with a reduction in GABAA receptor conductance and Cl- extrusion capability. We explored the effect on intraneuronal Cl- using both gramicidin, perforated-patch clamp recordings and Cl- imaging. This showed that during SE-like activity, reduced Cl- extrusion capacity was further exacerbated by activity-dependent Cl- loading, resulting in a persistently high intraneuronal Cl-. Consistent with these results, we found that optogenetic stimulation of GABAergic interneurons in the SE-like state, actually enhanced epileptiform activity in a GABAAR dependent manner. Together our findings describe a novel potential mechanism underlying benzodiazepine-resistant SE, with relevance to how this life-threatening condition should be managed in the clinic.
An agent-based framework for improving wildlife disease surveillance: A case study of chronic wasting disease in Missouri white-tailed deer
Authors: Belsare Aniruddha V. , Gompper Matthew E. , Keller Barbara , Sumners Jason , Hansen Lonnie , Millspaugh Joshua J. 
Published: November 2018

AbstractEpidemiological surveillance for important wildlife diseases often relies on samples obtained from hunter-harvested animals. A problem, however, is that although convenient and cost-effective, hunter-harvest samples are not representative of the population due to heterogeneities in disease distribution and biased sampling. We developed an agent-based modeling framework that i) simulates a deer population in a user-generated landscape, and ii) uses a snapshot of the in silico deer population to simulate disease prevalence and distribution, harvest effort and sampling as per user-specified parameters. This framework can incorporate real-world heterogeneities in disease distribution, hunter harvest and harvest-based sampling, and therefore can be useful in informing wildlife disease surveillance strategies, specifically to determine population-specific sample sizes necessary for prompt detection of disease. Application of this framework is illustrated using the example of chronic wasting disease (CWD) surveillance in Missouri’s white-tailed deer (Odocoileus virginianus) population. We show how confidence in detecting CWD is grossly overestimated under the unrealistic, but standard, assumptions that sampling effort and disease are randomly and independently distributed. We then provide adjusted sample size recommendations based on more realistic assumptions. These models can be readily adapted to other regions as well as other wildlife disease systems.
Early detection of retinal alteration by visible and near-infrared optical co-herence tomography (vnOCT) in a dexamethasone-induced ocular hypertension mouse model
Authors: Song Weiye , Fu Sipei , Song Shangshang , Zhang Sui , Zhang Lei , Ness Steven , Desai Manishi , Yi Ji 
Published: November 2018

ABSTRACTPurposeTo apply a novel visible and near-infrared optical coherence tomography (vnOCT) in the dexa-methasone-induced ocular hypertension mouse model, and test the capability of four optical markers, peri-papillary retinal nerve fiber layer (RNFL) thickness, total retinal blood flow, VN ratio and hemoglobin oxygen saturation (sO2), in detecting retinal ganglion cell (RGC) damage in association with ocular hyper-tension.MethodsTwelve mice (C57BL/6J) were separated into a control (n=6) and a dexamethasone group (n=6) receiving twice daily saline or dexamethasone eye drops, respectively, for 7 weeks. Intraocular pressure (IOP) measurements were taken at baseline and weekly. Optical measurements by vnOCT were longitudinally taken at baseline, 4 weeks and 7 weeks. Following week 7, ex vivo RGC counting was performed by immunostaining.ResultsThe dexamethasone group showed a measurable rise in IOP by week 2. Despite the IOP differences between the dexamethasone and control groups, there was not a statistical difference in RNFL thickness or total blood flow over 7 weeks. The dexamethasone group did show an increase in retinal arteriovenous sO2 difference (A-V sO2) that was significant at week 4 and 7. The RNFL VN ratio showed a significant decrease at week 4 and 7 in dexamethasone group associated with a decreased RGC count.ConclusionsRNFL VN ratio and A-V sO2 are capable of detecting early retinal alterations in the dexamethasone-induced ocular hypertension mouse model. Data analysis suggests VN ratio and A-V sO2 are corralated with RGC loss secondary to ocular hypertension, while being independent of IOP.
Genetic combination risk for schizophrenia
Authors: Oishi Kengo , Niitsu Tomihisa , Kanahara Nobuhisa , Hashimoto Tasuku , Komatsu Hideki , Sasaki Tsuyoshi , Takase Masayuki , Sato Yasunori , Iyo Masaomi 
Published: November 2018

Summary ParagraphSchizophrenia is a highly hereditary mental disease1 related to abnormal dopaminergic activities.2,3 To elucidate the mechanisms underlying schizophrenia’s development, genomic studies have sought to identify the pathogenic genetic polymorphisms. Large-scale genome-wide association studies (GWAS) have reported potential candidate loci that contribute to schizophrenia’s development.4,5 The risk genetic profiles are not yet established. Here we show that the combination of three functional single nucleotide polymorphisms (SNPs) related to the key factors of dopaminergic signaling can be used to predict the risk of schizophrenia’s development, though none of the SNPs is known to be associated by itself. These functional SNPs were reported to demonstrate directional influences in their parent gene activity, perhaps characterizing the integrated properties of dopaminergic signaling. Interestingly, the risk combination presented here included the major genotype as well as the minor polymorphisms, suggesting a possible association of unaffected activities of some dopamine-related genes with the disease development. The phenotype speculated based on the allelic status seemed consistent with the conventional pathophysiological hypotheses, although recently developed predictive methods, such as the polygenic risk score, could miss this potent pathogenic role of carrying a normal genotype by evaluating only minor polymorphisms. Our results demonstrate the presence of a subtype in schizophrenia with the favored genetic background related to dopamine signaling. Our findings indicate the possibility that the combinations could characterize integrated biological functions (including neurotransmission) and therefore identify individuals with a disease risk. The biological microenvironment indicated by the functional SNPs could bring an insight to elucidate the pathogenic mechanisms of developing schizophrenia. Furthermore, we believe that our approach will contribute to the development of innovative means to predict disease risks even for other multi-factorial diseases and then, the following preventive medicine.