SA-15 Antibiotic Resistance Microbial Infection in Five Dogs in Bali

Antimicrobial Resistance is a global public health problem that is influenced by the use of antimicrobial agents in humans, animals and elsewhere. Abuse of antibiotics has increased the prevalence of human and animal microbioma resistance genes over the last 75 years (Pal et al, 2016). Antibiotic resistance occurs when bacteria are able to reduce or eliminate the effectiveness of drugs, chemicals or other agents designed to cure or prevent infection. Thus bacteria survive and continue to multiply causing more harm (Bisht et al 2009). A strain is resistant against an antibiotic if its minimal inhibitory concentration (MIC) is higher than for the corresponding parental wild-type strain (Martinez et al, 2015;Bengtsson-palme, 2017). As well as humans, pet animal like dogs that have certain medical conditions that are often prescribed antibiotics have a higher risk of infection with antibiotic resistant bacteria. Antibiotic resistance in dog or other pet animal causes very adverse effects such as treatment failure with antibiotics that can cause severe infections, complications,  increased mortality. Antibiotic resistance leads to extended treatment time leading to increased medical expenses. Another impact that is considered very dangerous is the zoonotic potential of resistant microbes that can be transmitted to humans. Infections that do not respond to antibiotics appropriately, should be suspected of having an antibiotic resistant microbial infection. Actibiotic sensitivity test is necessary in the selection and use of appropriate antibiotics for therapy

Clinical effectiveness and cost-effectiveness of pegvisomant for the treatment of acromegaly: a systematic review and economic evaluation

Background: Acromegaly, an orphan disease usually caused by a benign pituitary tumour, is characterised by hyper-secretion of growth hormone (GH) and insulin-like growth factor I (IGF-1). It is associated with reduced life expectancy, cardiovascular problems, a variety of insidiously progressing detrimental symptoms and metabolic malfunction. Treatments include surgery, radiotherapy and pharmacotherapy. Pegvisomant (PEG) is a genetically engineered GH analogue licensed as a third or fourth line option when other treatments have failed to normalise IGF-1 levels. Methods: Evidence about effectiveness and cost-effectiveness of PEG was systematically reviewed. Data were extracted from published studies and used for a narrative synthesis of evidence. A decision analytical economic model was identified and modified to assess the cost-effectiveness of PEG. Results: One RCT and 17 non-randomised studies were reviewed for effectiveness. PEG substantially reduced and rapidly normalised IGF-1 levels in the majority of patients, approximately doubled GH levels, and improved some of the signs and symptoms of the disease. Tumour size was unaffected at least in the short term. PEG had a generally safe adverse event profile but a few patients were withdrawn from treatment because of raised liver enzymes. An economic model was identified and adapted to estimate the lower limit for the cost-effectiveness of PEG treatment versus standard care. Over a 20 year time horizon the incremental cost-effectiveness ratio was pound81,000/QALY and pound212,000/LYG. To reduce this to pound30K/QALY would require a reduction in drug cost by about one third. Conclusion: PEG is highly effective for improving patients' IGF-1 level. Signs and symptoms of disease improve but evidence is lacking about long term effects on improved signs and symptoms of disease, quality of life, patient compliance and safety. Economic evaluation indicated that if current standards (UK) for determining cost-effectiveness of therapies were to be applied to PEG it would be considered not to represent good value for money

SentiBench - a benchmark comparison of state-of-the-practice sentiment analysis methods

In the last few years thousands of scientific papers have investigated sentiment analysis, several startups that measure opinions on real data have emerged and a number of innovative products related to this theme have been developed. There are multiple methods for measuring sentiments, including lexical-based and supervised machine learning methods. Despite the vast interest on the theme and wide popularity of some methods, it is unclear which one is better for identifying the polarity (i.e., positive or negative) of a message. Accordingly, there is a strong need to conduct a thorough apple-to-apple comparison of sentiment analysis methods, \textit{as they are used in practice}, across multiple datasets originated from different data sources. Such a comparison is key for understanding the potential limitations, advantages, and disadvantages of popular methods. This article aims at filling this gap by presenting a benchmark comparison of twenty-four popular sentiment analysis methods (which we call the state-of-the-practice methods). Our evaluation is based on a benchmark of eighteen labeled datasets, covering messages posted on social networks, movie and product reviews, as well as opinions and comments in news articles. Our results highlight the extent to which the prediction performance of these methods varies considerably across datasets. Aiming at boosting the development of this research area, we open the methods' codes and datasets used in this article, deploying them in a benchmark system, which provides an open API for accessing and comparing sentence-level sentiment analysis methods

Modified Pilates as an adjunct to standardphysiotherapy care for urinaryincontinence: a mixed methods pilot for arandomised controlled trial

Background Urinary incontinence (UI) is a distressing condition affecting at least 5 million women in England and Wales. Traditionally, physiotherapy for UI comprises pelvic floor muscle training, but although evidence suggests this can be effective it is also recognised that benefits are often compromised by patient motivation and commitment. In addition, there is increasing recognition that physical symptoms alone are poor indicators of the impact of incontinence on individuals’ lives. Consequently, more holistic approaches to the treatment of UI, such as Modified Pilates (MP) have been recommended. This study aimed to provide preliminary findings about the effectiveness of a 6-week course of MP classes as an adjunct to standard physiotherapy care for UI, and to test the feasibility of a randomised controlled trial (RCT) design. Methods The study design was a single centre pilot RCT, plus qualitative interviews. 73 women referred to Women’s Health Physiotherapy Services for UI at Colchester Hospital University NHS Foundation Trust were randomly assigned to two groups: a 6-week course of MP classes in addition to standard physiotherapy care (intervention) or standard physiotherapy care only (control). Main outcome measures were self-reported UI, quality of life and self-esteem at baseline (T1), completion of treatment (T2), and 5 months after randomisation (T3). Qualitative interviews were conducted with a subgroup at T2 and T3. Due to the nature of the intervention blinding of participants, physiotherapists and researchers was not feasible. Results Post-intervention data revealed a range of benefits for women who attended MP classes and who had lower symptom severity at baseline: improved self-esteem (p = 0.032), decreased social embarrassment (p = 0.026) and lower impact on normal daily activities (p = 0.025). In contrast, women with higher symptom severity showed improvement in their personal relationships (p = 0.017). Qualitative analysis supported these findings and also indicated that MP classes could positively influence attitudes to exercise, diet and wellbeing. Conclusions A definitive RCT is feasible but will require a large sample size to inform clinical practice. Trial registration ISRCTN74075972 Registered 12/12/12 (Retrospectively registered)

miR-337-3p and Its Targets STAT3 and RAP1A Modulate Taxane Sensitivity in Non-Small Cell Lung Cancers

NSCLC (non-small cell lung cancer) often exhibits resistance to paclitaxel treatment. Identifying the elements regulating paclitaxel response will advance efforts to overcome such resistance in NSCLC therapy. Using in vitro approaches, we demonstrated that over-expression of the microRNA miR-337-3p sensitizes NCI-H1155 cells to paclitaxel, and that miR-337-3p mimic has a general effect on paclitaxel response in NSCLC cell lines, which may provide a novel adjuvant strategy to paclitaxel in the treatment of lung cancer. By combining in vitro and in silico approaches, we identified STAT3 and RAP1A as direct targets that mediate the effect of miR-337-3p on paclitaxel sensitivity. Further investigation showed that miR-337-3p mimic also sensitizes cells to docetaxel, another member of the taxane family, and that STAT3 levels are significantly correlated with taxane resistance in lung cancer cell lines, suggesting that endogenous STAT3 expression is a determinant of intrinsic taxane resistance in lung cancer. The identification of a miR-337-3p as a modulator of cellular response to taxanes, and STAT3 and RAP1A as regulatory targets which mediate that response, defines a novel regulatory pathway modulating paclitaxel sensitivity in lung cancer cells, which may provide novel adjuvant strategies along with paclitaxel in the treatment of lung cancer and may also provide biomarkers for predicting paclitaxel response in NSCLC

Gene Expression in Human Hippocampus from Cocaine Abusers Identifies Genes which Regulate Extracellular Matrix Remodeling

The chronic effects of cocaine abuse on brain structure and function are blamed for the inability of most addicts to remain abstinent. Part of the difficulty in preventing relapse is the persisting memory of the intense euphoria or cocaine “rush”. Most abused drugs and alcohol induce neuroplastic changes in brain pathways subserving emotion and cognition. Such changes may account for the consolidation and structural reconfiguration of synaptic connections with exposure to cocaine. Adaptive hippocampal plasticity could be related to specific patterns of gene expression with chronic cocaine abuse. Here, we compare gene expression profiles in the human hippocampus from cocaine addicts and age-matched drug-free control subjects. Cocaine abusers had 151 gene transcripts upregulated, while 91 gene transcripts were downregulated. Topping the list of cocaine-regulated transcripts was RECK in the human hippocampus (FC = 2.0; p<0.05). RECK is a membrane-anchored MMP inhibitor that is implicated in the coordinated regulation of extracellular matrix integrity and angiogenesis. In keeping with elevated RECK expression, active MMP9 protein levels were decreased in the hippocampus from cocaine abusers. Pathway analysis identified other genes regulated by cocaine that code for proteins involved in the remodeling of the cytomatrix and synaptic connections and the inhibition of blood vessel proliferation (PCDH8, LAMB1, ITGB6, CTGF and EphB4). The observed microarray phenotype in the human hippocampus identified RECK and other region-specific genes that may promote long-lasting structural changes with repeated cocaine abuse. Extracellular matrix remodeling in the hippocampus may be a persisting effect of chronic abuse that contributes to the compulsive and relapsing nature of cocaine addiction

Evolutionary Modeling of Rate Shifts Reveals Specificity Determinants in HIV-1 Subtypes

A hallmark of the human immunodeficiency virus 1 (HIV-1) is its rapid rate of evolution within and among its various subtypes. Two complementary hypotheses are suggested to explain the sequence variability among HIV-1 subtypes. The first suggests that the functional constraints at each site remain the same across all subtypes, and the differences among subtypes are a direct reflection of random substitutions, which have occurred during the time elapsed since their divergence. The alternative hypothesis suggests that the functional constraints themselves have evolved, and thus sequence differences among subtypes in some sites reflect shifts in function. To determine the contribution of each of these two alternatives to HIV-1 subtype evolution, we have developed a novel Bayesian method for testing and detecting site-specific rate shifts. The RAte Shift EstimatoR (RASER) method determines whether or not site-specific functional shifts characterize the evolution of a protein and, if so, points to the specific sites and lineages in which these shifts have most likely occurred. Applying RASER to a dataset composed of large samples of HIV-1 sequences from different group M subtypes, we reveal rampant evolutionary shifts throughout the HIV-1 proteome. Most of these rate shifts have occurred during the divergence of the major subtypes, establishing that subtype divergence occurred together with functional diversification. We report further evidence for the emergence of a new sub-subtype, characterized by abundant rate-shifting sites. When focusing on the rate-shifting sites detected, we find that many are associated with known function relating to viral life cycle and drug resistance. Finally, we discuss mechanisms of covariation of rate-shifting sites

Identifying Alternative Hyper-Splicing Signatures in MG-Thymoma by Exon Arrays

BACKGROUND: The vast majority of human genes (>70%) are alternatively spliced. Although alternative pre-mRNA processing is modified in multiple tumors, alternative hyper-splicing signatures specific to particular tumor types are still lacking. Here, we report the use of Affymetrix Human Exon Arrays to spot hyper-splicing events characteristic of myasthenia gravis (MG)-thymoma, thymic tumors which develop in patients with MG and discriminate them from colon cancer changes. METHODOLOGY/PRINCIPAL FINDINGS: We combined GO term to parent threshold-based and threshold-independent ad-hoc functional statistics with in-depth analysis of key modified transcripts to highlight various exon-specific changes. These denote alternative splicing in MG-thymoma tumors compared to healthy human thymus and to in-house and Affymetrix datasets from colon cancer and healthy tissues. By using both global and specific, term-to-parent Gene Ontology (GO) statistical comparisons, our functional integrative ad-hoc method allowed the detection of disease-relevant splicing events. CONCLUSIONS/SIGNIFICANCE: Hyper-spliced transcripts spanned several categories, including the tumorogenic ERBB4 tyrosine kinase receptor and the connective tissue growth factor CTGF, as well as the immune function-related histocompatibility gene HLA-DRB1 and interleukin (IL)19, two muscle-specific collagens and one myosin heavy chain gene; intriguingly, a putative new exon was discovered in the MG-involved acetylcholinesterase ACHE gene. Corresponding changes in spliceosome composition were indicated by co-decreases in the splicing factors ASF/SF(2) and SC35. Parallel tumor-associated changes occurred in colon cancer as well, but the majority of the apparent hyper-splicing events were particular to MG-thymoma and could be validated by Fluorescent In-Situ Hybridization (FISH), Reverse Transcription-Polymerase Chain Reaction (RT-PCR) and mass spectrometry (MS) followed by peptide sequencing. Our findings demonstrate a particular alternative hyper-splicing signature for transcripts over-expressed in MG-thymoma, supporting the hypothesis that alternative hyper-splicing contributes to shaping the biological functions of these and other specialized tumors and opening new venues for the development of diagnosis and treatment approaches

Molecular mechanisms of cell death: recommendations of the Nomenclature Committee on Cell Death 2018.

Over the past decade, the Nomenclature Committee on Cell Death (NCCD) has formulated guidelines for the definition and interpretation of cell death from morphological, biochemical, and functional perspectives. Since the field continues to expand and novel mechanisms that orchestrate multiple cell death pathways are unveiled, we propose an updated classification of cell death subroutines focusing on mechanistic and essential (as opposed to correlative and dispensable) aspects of the process. As we provide molecularly oriented definitions of terms including intrinsic apoptosis, extrinsic apoptosis, mitochondrial permeability transition (MPT)-driven necrosis, necroptosis, ferroptosis, pyroptosis, parthanatos, entotic cell death, NETotic cell death, lysosome-dependent cell death, autophagy-dependent cell death, immunogenic cell death, cellular senescence, and mitotic catastrophe, we discuss the utility of neologisms that refer to highly specialized instances of these processes. The mission of the NCCD is to provide a widely accepted nomenclature on cell death in support of the continued development of the field