Retinal vein occlusion (RVO) is the second most common retinal vascular disorder that affected 16.4 million people worldwide in 2008. The last decade has seen new epidemiological data on RVO, enabling us to provide a contemporary estimation of RVO epidemiology.

Globally, progress in Maternal and Child Health (MCH) has been inconsistent, with several evidence showing both between and within country disparities in several RMNCH outcome measures. In this study, we aim to meta-analyse existing literature on association between three major equity stratifiers and a selection of RMNCH indicators.

Since the approval of medical abortion in Cambodia in 2010, the proportion of women reporting an abortion has increased. We describe the characteristics and contraceptive outcomes of women seeking medical abortion compared to surgical abortion at four reproductive health clinics in Cambodia.

To design and validate a computer application for the diagnosis of shoulder locomotor system pathology.

Nanocarriers for medical applications must work reliably within organisms, independent of the individual differences in the blood proteome. Variation in the blood proteome, such as immunoglobulin levels, is a result of environmental, nutrition, and constitution conditions. This variation, however, should not influence the behavior of nanocarriers in biological media. The composition of the protein corona is investigated to understand the influence varying immunoglobulin levels in the blood plasma have on the interactions with nanocarriers. Specifically, the composition of the nanocarriers' coronas is analyzed after incubation in plasma with normal or elevated immunoglobulin G (IgG) levels, and cellular uptake is monitored in cell lines containing different immunoglobulin receptors. Here, it is reported that upon doubling the IgG concentration in plasma, the IgG fraction in the protein corona increases by a factor of 40 independent of the nanocarrier material. This results in a significant increase in uptake in cells exhibiting IgG binding receptors. Furthermore, precoating nanocarriers with clusterin successfully prevents dominant IgG-adsorption and additionally reduces cellular internalization, after incubation with IgG-enriched plasma. Therefore, precoating nanocarriers may be utilized as a powerful method to reduce the influence of individual variations in blood composition on the protein corona.

Altered expression of many genes and proteins is essential for cancer development and progression. Recently, the affected expression of metadherin (MTDH), also known as AEG-1 (Astrocyte Elevated Gene 1) and Lyric, has been implicated in various aspects of cancer progression and metastasis. Elevated expression of MTDH/AEG-1 has been reported in many cancers including breast, prostate, liver, and esophageal cancers, whereas its expression is low or absent in non-malignant tissues. These expression studies suggest that MTDH may represent a potential tumor associated antigen. MTDH also regulates multiple signaling pathways including PI3K/Akt, NF-κB, Wnt/β-catenin, and MAPK which cooperate to promote the tumorigenic and metastatic potential of transformed cells. Several microRNA have also been found to be associated with the increased MTDH expression in different cancers. Increased MTDH levels were linked to the tumor chemoresistance making it an attractive novel therapeutic target. In this review, we summarize data on MTDH function in various cancers.

The blood-brain barrier (BBB) limits passage of substances between general circulation and the brain extracellular fluid, maintaining homeostasis in neural tissues and providing a defense against potential toxins. However, the protection provided by the BBB often prevents conventional chemotherapeutics from reaching brain tumors which makes brain cancers one of the most difficult cancers to treat (1). Traditionally, high-throughput testing of compound permeability through the BBB in vitro has been limited to assay of radio- or fluorophore-labeled compounds as they pass a cell monolayer growing on a permeable support system. Unfortunately, the labels themselves may negatively impact the assay, and the ability to determine resulting tumor cytotoxicity must be studied independently. The present study demonstrates proof-of-concept of a three-dimensional (3D) model to study label-free BBB transport as well as the resulting brain tumor cytotoxicity by combining two commercially available products: Corning® HTS Transwell®-96 tissue culture system and Corning 96-well spheroid microplates. Transwells are permeable support systems commonly used for drug transport and migration/invasion studies (2, 3). Corning spheroid microplates are cell culture microplates with round well-bottom geometry coated with Corning Ultra-low Attachment surface, enabling the formation of a single multicellular tumor spheroid centered in each well in a highly reproducible manner. By replacing the standard flat-bottom Transwell receiver plate with a Corning spheroid microplate, the resulting system-which can be tailored to any number of cell types and screening applications-enables a more comprehensive assay to study drug transport across the BBB and the resulting 3D glioma spheroid toxicity in an easy-to-use 3D high-throughput assay.

Enteroaggregative Escherichia coli (EAEC) infections are one of the most frequent causes of persistent diarrhea in children, immunocompromised patients and travelers worldwide. The most prominent colonization factors of EAEC are aggregative adherence fimbriae (AAF). EAEC prototypical strain 042 harbors the AAF/II fimbriae variant, which mediates adhesion to intestinal epithelial cells and participates in the induction of an inflammatory response against this pathogen. However, the mechanism and the cell receptors implicated in eliciting this response have not been fully characterized. Since previous reports have shown that TLR4 recognize fimbriae from different pathogens, we evaluated the role of this receptor in the response elicited against EAEC by intestinal cells. Using a mutual antagonist against TLR2 and TLR4 (OxPAPC), we observed that blocking of these receptors significantly reduces the secretion of the inflammatory marker IL-8 in response to EAEC and AAF/II fimbrial extract in HT-29 cells. Using a TLR4-specific antagonist (TAK-242), we observed that the secretion of this cytokine was significantly reduced in HT-29 cells infected with EAEC or incubated with AAF/II fimbrial extract. We evaluated the participation of AAF/II fimbriae in the TLR4-mediated secretion of 38 cytokines, chemokines, and growth factors involved in inflammation. A reduction in the secretion of IL-8, GRO, and IL-4 was observed. Our results suggest that TLR4 participates in the secretion of several inflammation biomarkers in response to AAF/II fimbriae.

Background: Sepsis is a time critical disease and outcomes strongly depend on time to initiation of appropriate treatment in hospital. A range of studies have assessed sepsis recognition in hospital settings, whereas little is known about sepsis recognition in the community. The decision-making of parents in seeking medical care may substantially impact survival of children with sepsis. An improved understanding of the parental perspective in recognizing sepsis is urgently needed to inform the design of education campaigns and consideration of using parental concerns as a trigger in sepsis screening tools. Aim: To review the literature on parental concerns in the diagnosis of sepsis in children. Methods: A literature review on parental concerns in pediatric sepsis was performed accessing publications in PubMed, CINAHL and Medline published between 1990 and 2018. In addition, we compared guidelines and online institutional sepsis recognition tools and assessed whether parental concerns were used for screening. Results: Out of 188 articles reviewed, 11 met the criteria. One article was found prospectively assessing the diagnostic performance of parental concern in children evaluated for infection, indicating high positive (16.4) and negative likelihood ratio (0.23) for sepsis/meningitis in presence of parental concerns. The role of parental concern was listed as a sign assisting recognition of sepsis in four studies reporting original data, and six reviews commented on parental concern listed as a factor upon diagnosis of sepsis. When comparing selected examples of institutional sepsis pathways available online, parental concern was variably listed as a criterion to prompt evaluation for sepsis. Conclusions: Despite some guidelines emphasizing the role of parental concern in recognizing sepsis, there is a paucity of data in the field. An improved understanding of whether parental concerns adds diagnostic value to sepsis recognition at acceptable sensitivity and specificity is urgently needed. Future prospective studies should assess whether including parental concerns in sepsis screening tools benefits the assessment resulting in early diagnosis and treatment of children with sepsis.

Using data from the Canadian Integrated Program for Antimicrobial Resistance Surveillance (CIPARS), we aimed to describe trends in antimicrobial use (AMU) in broiler chickens and turkeys, to compare AMU across species, to compare with trends in antimicrobial resistance (AMR), and to assess the effects of various AMU/AMR units of measurement (metrics and indicators) on data integration. Data on AMU and AMR in enteric bacteria, collected from 2013 to 2017 from broiler chickens (n = 143 flocks) and turkeys (n = 145) were used. In broiler chickens, the total AMU in milligrams/population correction unit (mg/PCUBr) decreased by 6%, the number (n) of defined daily doses for animals using Canadian standards (nDDDvetCA) per 1,000 broiler chicken-days decreased by 12%, and nDDDvetCA/PCU decreased by 6%. In turkeys, the mg/PCUTk decreased by 1%, whereas the nDDDvetCA/1,000 turkey-days and the nDDDvetCA/PCU increased by 1 and 5%, respectively. The types of antimicrobial classes used in both species were similar. Using the frequency of flocks reporting use (i.e., number of flocks reporting use/number of flocks participating) as a measurement, the use of certain antimicrobials changed over time (e.g., Broilers, decreased cephalosporin use, virginiamycin use, emerging use of lincomycin-spectinomycin, and avilamycin; Turkeys: increased trimethoprim-sulfonamides and macrolide use). The trends in resistance to specific antimicrobials paralleled the frequency and quantity of use (e.g., ceftriaxone use decreased-ceftriaxone resistance decreased, and gentamicin use increased-gentamicin resistance increased) in some situations, but not others (decreased fluoroquinolone use-increased ciprofloxacin resistance). AMR data were summarized using the AMR indicator index (AMR Ix). The most notable AMR Ix trend was the decrease in ceftriaxone AMR Ix among Escherichia coli (0.19 to 0.07); indicative of the success of the poultry industry action to eliminate the preventive use of third generation cephalosporins. Other trends observed were the increase in ciprofloxacin AMR Ix among Campylobacter from 0.23 to 0.41 and gentamicin AMR Ix among E. coli from 0.11 to 0.22, suggestive of the persistence/emergence of resistance related to previous and current AMU not captured in our surveillance timeframe. These data highlight the necessity of multiple AMU and AMR indicators for monitoring the impact of stewardship activities and interventions.

Background: The business world has long recognized the power of defining discrete audiences within a target population. However, market segmentation's full potential has not been applied to the public health context. While some broad elements of market segmentation (e.g., age, geography) are considered, a nuanced look at behavioural and psychographic segmentation, which could greatly enhance the possibility of lasting behaviour change, is often missing.   Segmentation, and the associated mindset which acknowledges the multi-dimensional differences between people, allows service providers, implementers, policymakers, and government officials to target initiatives and lead to a greater likelihood of lasting behavioural change. This paper investigates what segmentation is, how it has been applied to voluntary medical male circumcision (VMMC), how it can be applied in development, and the challenges in both measuring and adopting segmentation as part of program design. Methods: We performed a detailed search of peer-reviewed literature using PubMed, ProQuest, ScienceDirect, Google Scholar, and the abstract directories of the International AIDS Society (IAS) published between January 2015 and September 2018. We also accessed articles from business databases such as the Harvard Business Review.   Results: Results from a VMMC-focused intervention that successfully designed and delivered segmentation-based programs in two countries demonstrated that it is possible to adapt private sector approaches. However, within the sector of global development that is most familiar with segmentation, these efforts rarely go beyond basic demographic segments. Conclusions: Existing published material tends not to measure the impact of segmentation itself, but the impact of the intervention to which segmentation was applied, which makes it challenging for the development sector to invest in the approach without evidence that it works. Nonetheless, the experiences of segmentation and demand creation for VMMC do highlight the opportunity for better integrating this approach in HIV prevention and in global development and measurement initiatives.

Telomeres located at the ends of linear chromosomes play important roles in the maintenance of life. Rap1, a component of the shelterin telomere protein complex, interacts with multiple proteins to perform various functions; further, formation of shelterin requires Rap1 binding to other components such as Taz1 and Poz1, and telomere tethering to the nuclear envelope (NE) involves interactions between Rap1 and Bqt4, a nuclear membrane protein. Although Rap1 is a hub for telomere protein complexes, the regulatory mechanisms of its interactions with partner proteins are not fully understood. Here, we show that Rap1 is phosphorylated by casein kinase 2 (CK2) at multiple sites, which promotes interactions with Bqt4 and Poz1. Among the multiple CK2-mediated phosphorylation sites of Rap1, phosphorylation at Ser496 was found to be crucial for both Rap1-Bqt4 and Rap1-Poz1 interactions. These mechanisms mediate proper telomere tethering to the NE and the formation of the silenced chromatin structure at chromosome ends.

Soft tissue sarcomas (STSs) are aggressive tumors with few efficient systemic therapies. Poly(ADP-ribose) polymerase-1 (PARP1) inhibitors represent an emerging therapeutic option in tumors with genomic instability. The genomics of STSs is complex in more than half of cases, suggesting a high level of inherent DNA damage and genomic instability. Thus, STSs could be efficiently targeted with PARP inhibitors. Promising preclinical results have been reported, but few data are available regarding PARP1 expression in clinical samples. We examined PARP1 mRNA expression in 1464 clinical samples of STS, including 1432 primary tumors and 32 relapses, and searched for correlations with clinicopathological features, including metastasis-free survival (MFS). Expression was heterogeneous across the samples, not different between primary and secondary tumors, and was correlated to PARP1 DNA copy number. In the 1432 primary tumors, the 'PARP1-high' samples were associated with younger patients, more frequent locations at the extremities, superficial trunk and head and neck, more leiomyosarcomas and other STSs and less liposarcomas and myxofibrosarcomas, more grade 3, more high-risk CINSARC tumors, and more 'chromosomically instable' tumors. They were associated with shorter MFS, independently of other significant prognostic features, including the CINSARC signature. We found a strong involvement of genes overexpressed in the 'PARP1-high' samples in cell cycle, DNA replication, and DNA repair. PARP1 expression refines the prediction of MFS in STSs, and similar expression exists in secondary and primary tumors, supporting the development of PARP1 inhibitors.

One of the limitations of somatic cell nuclear transfer (SCNT) strategy to generate genetically modified offspring is the low birth rate. Placental dysfunction is one of the causes of abortion. Circular RNA (circRNA) is noncoding RNA which functions as microRNA (miRNA) sponges in biological processes.

Background. Effective treatment methods are needed for moderate/severely impairment chronic stroke. Objective. The questions were the following: (1) Is there need for long-dose therapy or is there a mid-treatment plateau? (2) Are the observed gains from the prior-studied protocol retained after treatment? Methods. Single-blind, stratified/randomized design, with 3 applied technology treatment groups, combined with motor learning, for long-duration treatment (300 hours of treatment). Measures were Arm Motor Ability Test time and coordination-function (AMAT-T, AMAT-F, respectively), acquired pre-/posttreatment and 3-month follow-up (3moF/U); Fugl-Meyer (FM), acquired similarly with addition of mid-treatment. Findings. There was no group difference in treatment response (P ≥ .16), therefore data were combined for remaining analyses (n = 31; except for FM pre/mid/post, n = 36). Pre-to-Mid-treatment and Mid-to-Posttreatment gains of FM were statistically and clinically significant (P < .0001; 4.7 points and P < .001; 5.1 points, respectively), indicating no plateau at 150 hours and benefit of second half of treatment. From baseline to 3moF/U: (1) FM gains were twice the clinically significant benchmark, (2) AMAT-F gains were greater than clinically significant benchmark, and (3) there was statistically significant improvement in FM (P < .0001); AMAT-F (P < .0001); AMAT-T (P < .0001). These gains indicate retained clinically and statistically significant gains at 3moFU. From posttreatment to 3moF/U, gains on FM were maintained. There were statistically significant gains in AMAT-F (P = .0379) and AMAT-T P = .003.

Total laryngectomy is the standard of care for advanced laryngeal/hypopharyngeal cancer. Effective voice rehabilitation is mandatory and tracheo-oesophageal speech (TES) has progressively gained approval. In 2011, we evaluated quality of life (QoL) and satisfaction after TES rehabilitation, demonstrating its efficacy in highly motivated subjects. The aim of the present study was to investigate whether those results are maintained over time within the same selected cohort. 15 of 24 patients were left with a minimum 12 year-follow up after voice prosthesis (VP) implantation. Short Form 36-Item Health Survey (SF-36) for QoL assessment and a study-specific structured questionnaire for evaluation of TES-related satisfaction were employed. The 9/24 patients who dropped out from the follow-up were excluded from the original count and the former results were recalculated. A control group of subjects with minor ENT diseases was used for SF-36 analysis. Many SF-36 items (RP, BP, SF, RE) significantly improved over time, approaching the results of the control group. VP duration also increased (6.3 ± 3.1 against 3.0 ± 1.8 months). TES-related satisfaction items did not change in a statistically significant way. Three patients (20.0%) would not have chosen the same kind of voice restoration: these subjects are those more distant from our institution (230 km and 462 km, respectively, against a mean distance of 15.4 ± 13.8 km for other patients). With the present work, we highlight how the striking results of TES can not only be maintained over time (i.e. TES-related satisfaction), but also substantially improve (i.e. QoL). An integrated, widespread network of centres for VP management is needed to optimise patient follow-up and allow studies on larger series.

Deciphering the potential of noncoding loci to influence gene regulation has been the subject of intense research, with important implications in understanding genetic underpinnings of human diseases. Massively parallel reporter assays (MPRAs) can measure regulatory activity of thousands of DNA sequences and their variants in a single experiment. With increasing number of publically available MPRA data sets, one can now develop data-driven models which, given a DNA sequence, predict its regulatory activity. Here, we performed a comprehensive meta-analysis of several MPRA data sets in a variety of cellular contexts. We first applied an ensemble of methods to predict MPRA output in each context and observed that the most predictive features are consistent across data sets. We then demonstrate that predictive models trained in one cellular context can be used to predict MPRA output in another, with loss of accuracy attributed to cell-type-specific features. Finally, we show that our approach achieves top performance in the Fifth Critical Assessment of Genome Interpretation "Regulation Saturation" Challenge for predicting effects of single-nucleotide variants. Overall, our analysis provides insights into how MPRA data can be leveraged to highlight functional regulatory regions throughout the genome and can guide effective design of future experiments by better prioritizing regions of interest.

Inflamed tissue is characterized by low availability of oxygen and nutrients. Yet CD4+ T helper lymphocytes persist over time in such tissue and probably contribute to the chronicity of inflammation. This study was undertaken to analyze the metabolic adaptation of these cells to the inflamed environment.

After meal ingestion, a series of coordinated hormone responses occur concomitantly with changes in perceived appetite. It is not known whether interindividual variability in appetite exists in response to a meal.

Bayesian molecular dating is widely used to study evolutionary timescales. This procedure usually involves phylogenetic analysis of nucleotide sequence data, with fossil-based calibrations applied as age constraints on internal nodes of the tree. An alternative approach is tip-dating, which explicitly includes fossil data in the analysis. This can be done, for example, through the joint analysis of molecular data from present-day taxa and morphological data from both extant and fossil taxa. In the context of tip-dating, an important development has been the fossilized birth-death process, which allows non-contemporaneous tips and sampled ancestors while providing a model of lineage diversification for the prior on the tree topology and internal node times. However, tip-dating with fossils faces a number of considerable challenges, especially, those associated with fossil sampling and evolutionary models for morphological characters. We conducted a simulation study to evaluate the performance of tip-dating using the fossilized birth-death model. We simulated fossil occurrences and the evolution of nucleotide sequences and morphological characters under a wide range of conditions. Our analyses of these data show that the number and the maximum age of fossil occurrences have a greater influence than the degree of among-lineage rate variation or the number of morphological characters on estimates of node times and the tree topology. Tip-dating with the fossilized birth-death model generally performs well in recovering the relationships among extant taxa but has difficulties in correctly placing fossil taxa in the tree and identifying the number of sampled ancestors. The method yields accurate estimates of the ages of the root and crown group, although the precision of these estimates varies with the probability of fossil occurrence. The exclusion of morphological characters results in a slight overestimation of node times, whereas the exclusion of nucleotide sequences has a negative impact on inference of the tree topology. Our results provide an overview of the performance of tip-dating using the fossilized birth-death model, which will inform further development of the method and its application to key questions in evolutionary biology.