Learning Priors for Bayesian Computations in the Nervous System

Our nervous system continuously combines new information from our senses with information it has acquired throughout life. Numerous studies have found that human subjects manage this by integrating their observations with their previous experience (priors) in a way that is close to the statistical optimum. However, little is known about the way the nervous system acquires or learns priors. Here we present results from experiments where the underlying distribution of target locations in an estimation task was switched, manipulating the prior subjects should use. Our experimental design allowed us to measure a subject's evolving prior while they learned. We confirm that through extensive practice subjects learn the correct prior for the task. We found that subjects can rapidly learn the mean of a new prior while the variance is learned more slowly and with a variable learning rate. In addition, we found that a Bayesian inference model could predict the time course of the observed learning while offering an intuitive explanation for the findings. The evidence suggests the nervous system continuously updates its priors to enable efficient behavior

Identification of a novel splice variant form of the influenza a virus m2 ion channel with an antigenically distinct ectodomain

Segment 7 of influenza A virus produces up to four mRNAs. Unspliced transcripts encode M1, spliced mRNA2 encodes the M2 ion channel, while protein products from spliced mRNAs 3 and 4 have not previously been identified. The M2 protein plays important roles in virus entry and assembly, and is a target for antiviral drugs and vaccination. Surprisingly, M2 is not essential for virus replication in a laboratory setting, although its loss attenuates the virus. To better understand how IAV might replicate without M2, we studied the reversion mechanism of an M2-null virus. Serial passage of a virus lacking the mRNA2 splice donor site identified a single nucleotide pseudoreverting mutation, which restored growth in cell culture and virulence in mice by upregulating mRNA4 synthesis rather than by reinstating mRNA2 production. We show that mRNA4 encodes a novel M2-related protein (designated M42) with an antigenically distinct ectodomain that can functionally replace M2 despite showing clear differences in intracellular localisation, being largely retained in the Golgi compartment. We also show that the expression of two distinct ion channel proteins is not unique to laboratory-adapted viruses but, most notably, was also a feature of the 1983 North American outbreak of H5N2 highly pathogenic avian influenza virus. In identifying a 14th influenza A polypeptide, our data reinforce the unexpectedly high coding capacity of the viral genome and have implications for virus evolution, as well as for understanding the role of M2 in the virus life cycle

Epitope mapping of avian influenza m2e protein: different species recognise various epitopes

Published: June 30, 2016A common approach for developing diagnostic tests for influenza virus detection is the use of mouse or rabbit monoclonal and/or polyclonal antibodies against a target antigen of the virus. However, comparative mapping of the target antigen using antibodies from different animal sources has not been evaluated before. This is important because identification of antigenic determinants of the target antigen in different species plays a central role to ensure the efficiency of a diagnostic test, such as competitive ELISA or immunohistochemistry-based tests. Interest in the matrix 2 ectodomain (M2e) protein of avian influenza virus (AIV) as a candidate for a universal vaccine and also as a marker for detection of virus infection in vaccinated animals (DIVA) is the rationale for the selection of this protein for comparative mapping evaluation. This study aimed to map the epitopes of the M2e protein of avian influenza virus H5N1 using chicken, mouse and rabbit monoclonal or monospecific antibodies. Our findings revealed that rabbit antibodies (rAbs) recognized epitope 6EVETPTRN13 of the M2e, located at the N-terminal of the protein, while mouse (mAb) and chicken antibodies (cAbs) recognized epitope 10PTRNEWECK18, located at the centre region of the protein. The findings highlighted the difference between the M2e antigenic determinants recognized by different species that emphasized the importance of comparative mapping of antibody reactivity from different animals to the same antigen, especially in the case of multi-host infectious agents such as influenza. The findings are of importance for antigenic mapping, as well as diagnostic test and vaccine development.Noor Haliza Hasan, Esmaeil Ebrahimie, Jagoda Ignjatovic, Simson Tarigan, Anne Peaston, Farhid Hemmatzade

Management of intra-abdominal infections : recommendations by the WSES 2016 consensus conference

This paper reports on the consensus conference on the management of intra-abdominal infections (IAIs) which was held on July 23, 2016, in Dublin, Ireland, as a part of the annual World Society of Emergency Surgery (WSES) meeting. This document covers all aspects of the management of IAIs. The Grading of Recommendations Assessment, Development and Evaluation recommendation is used, and this document represents the executive summary of the consensus conference findings.Peer reviewe

Reduced costs with bisoprolol treatment for heart failure - An economic analysis of the second Cardiac Insufficiency Bisoprolol Study (CIBIS-II)

Background Beta-blockers, used as an adjunctive to diuretics, digoxin and angiotensin converting enzyme inhibitors, improve survival in chronic heart failure. We report a prospectively planned economic analysis of the cost of adjunctive beta-blocker therapy in the second Cardiac Insufficiency BIsoprolol Study (CIBIS II). Methods Resource utilization data (drug therapy, number of hospital admissions, length of hospital stay, ward type) were collected prospectively in all patients in CIBIS . These data were used to determine the additional direct costs incurred, and savings made, with bisoprolol therapy. As well as the cost of the drug, additional costs related to bisoprolol therapy were added to cover the supervision of treatment initiation and titration (four outpatient clinic/office visits). Per them (hospital bed day) costings were carried out for France, Germany and the U.K. Diagnosis related group costings were performed for France and the U.K. Our analyses took the perspective of a third party payer in France and Germany and the National Health Service in the U.K. Results Overall, fewer patients were hospitalized in the bisoprolol group, there were fewer hospital admissions perpatient hospitalized, fewer hospital admissions overall, fewer days spent in hospital and fewer days spent in the most expensive type of ward. As a consequence the cost of care in the bisoprolol group was 5-10% less in all three countries, in the per them analysis, even taking into account the cost of bisoprolol and the extra initiation/up-titration visits. The cost per patient treated in the placebo and bisoprolol groups was FF35 009 vs FF31 762 in France, DM11 563 vs DM10 784 in Germany and pound 4987 vs pound 4722 in the U.K. The diagnosis related group analysis gave similar results. Interpretation Not only did bisoprolol increase survival and reduce hospital admissions in CIBIS II, it also cut the cost of care in so doing. This `win-win' situation of positive health benefits associated with cost savings is Favourable from the point of view of both the patient and health care systems. These findings add further support for the use of beta-blockers in chronic heart failure

A prenylated dsRNA sensor protects against severe COVID-19

INTRODUCTION Interferons (IFNs) are cytokines that are rapidly deployed in response to invading pathogens. By initiating a signaling cascade that stimulates the expression of hundreds of genes, IFNs create an antiviral state in host cells. Because IFNs heavily influence COVID-19 outcomes, and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) replication can be inhibited by the antiviral state, it is important to understand how the individual antiviral effectors encoded by IFN-stimulated genes (ISGs) inhibit SARS-CoV-2. RATIONALE We hypothesized that IFN-stimulated antiviral effectors can inhibit SARS-CoV-2, and that variation at the loci encoding these defenses underlies why some people are more susceptible to severe COVID-19. RESULTS We used arrayed ISG expression screening to reveal that 2′-5′-oligoadenylate synthetase 1 (OAS1) consistently inhibited SARS-CoV-2 in different contexts. Using CRISPR-Cas9, we found that endogenous OAS1 makes a substantial contribution to the antiviral state by recognizing short stretches of double-stranded RNA (dsRNA) and activating RNase L. We globally mapped where OAS1 binds to SARS-CoV-2 viral RNAs and found that OAS1 binding is remarkably specific, with two conserved stem loops in the SARS-CoV-2 5′-untranslated region (UTR) constituting the principal viral target. OAS1 expression was readily detectable at the sites of infection in individuals who died of COVID-19, and specific OAS1 alleles are known to be associated with altered susceptibility to infection and severe disease. It had previously been reported that alleles containing a common splice-acceptor single nucleotide polymorphism in OAS1 (Rs10774671) were associated with less severe COVID-19. We determined that people with at least one allele with a G at this position could express a prenylated form of OAS1 (p46), whereas other individuals could not. Using a series of mutants, we found that C-terminal prenylation was necessary for OAS1 to initiate a block to SARS-CoV-2. Furthermore, confocal microscopy revealed that prenylation targeted OAS1 to perinuclear structures rich in viral dsRNA, whereas non-prenylated OAS1 was diffusely localized and unable to initiate a detectable block to SARS-CoV-2 replication. The realization that prenylation is essential for OAS1-mediated sensing of SARS-CoV-2 allowed us to examine the transcriptome of infected patients and investigate whether there was a link between the expression of prenylated OAS1 and SARS-CoV-2 disease progression. Analysis of the OAS1 transcripts from 499 hospitalized COVID-19 patients revealed that expressing prenylated OAS1 was associated with protection from severe COVID-19. Because prenylated OAS1 was so important in human cases, we wanted to determine whether horseshoe bats, the likely source of SARS-CoV-2, possessed the same defense. When we examined the genomic region where the prenylation signal should reside, retrotransposition of a long terminal repeat sequence had ablated this signal, preventing the expression of prenylated anti-CoV OAS1 in these bats. CONCLUSION C-terminal prenylation targets OAS1 to intracellular sites rich in viral dsRNA, which are likely the SARS-CoV-2 replicative organelles. Once in the right place, OAS1 binds to dsRNA structures in the SARS-CoV-2 5′-UTR and initiates a potent block to SARS-CoV-2 replication. Thus, the correct targeting of OAS1 and the subsequent inhibition of SARS-CoV-2 likely underpins the genetic association of alleles containing a G at Rs10774671 with reduced susceptibility to infection and severe disease in COVID-19. Moreover, the conspicuous absence of this antiviral defense in horseshoe bats potentially explains why SARS-CoV-2 is so sensitive to this defense in humans

WSES Jerusalem guidelines for diagnosis and treatment of acute appendicitis

Acute appendicitis (AA) is among the most common cause of acute abdominal pain. Diagnosis of AA is challenging; a variable combination of clinical signs and symptoms has been used together with laboratory findings in several scoring systems proposed for suggesting the probability of AA and the possible subsequent management pathway. The role of imaging in the diagnosis of AA is still debated, with variable use of US, CT and MRI in different settings worldwide. Up to date, comprehensive clinical guidelines for diagnosis and management of AA have never been issued. In July 2015, during the 3rd World Congress of the WSES, held in Jerusalem (Israel), a panel of experts including an Organizational Committee and Scientific Committee and Scientific Secretariat, participated to a Consensus Conference where eight panelists presented a number of statements developed for each of the eight main questions about diagnosis and management of AA. The statements were then voted, eventually modified and finally approved by the participants to The Consensus Conference and lately by the board of co-authors. The current paper is reporting the definitive Guidelines Statements on each of the following topics: 1) Diagnostic efficiency of clinical scoring systems, 2) Role of Imaging, 3) Non-operative treatment for uncomplicated appendicitis, 4) Timing of appendectomy and in-hospital delay, 5) Surgical treatment 6) Scoring systems for intra-operative grading of appendicitis and their clinical usefulness 7) Non-surgical treatment for complicated appendicitis: abscess or phlegmon 8) Pre-operative and post-operative antibiotics.Peer reviewe

Measurement of compartment pressure of the rectus sheath during intra-abdominal hypertension in rats

OBJECTIVE: To investigate whether the compartment pressure of the rectus sheath (CPRS) reflects the intra-abdominal pressure (IAP) under various conditions of intra-abdominal hypertension (IAH). DESIGN AND SETTING: Prospective experimental study with in vivo pressure measurements at the Institute for Clinical and Experimental Surgery, University of Saarland. ANIMALS: Sprague-Dawley rats. INTERVENTIONS: Stepwise increase and decrease in IAP with continuous measurement of the correspondent CPRS. MEASUREMENTS AND RESULTS: Physiological IAP (2 mmHg) and CPRS (6 mmHg) showed a statistically significant difference. Stepwise elevation in IAP was associated with a simultaneous increase in CPRS. Accordingly, stepwise decompression of IAP resulted in a stepwise decrease in CPRS. Under both conditions Bland-Altman analysis comparing IAP to correspondent CPRS showed a very good agreement for IAP at or above 12 mmHg. In addition, closure of the overlaying subcutaneous tissue and skin did not affect CPRS or its correlation with IAP. CONCLUSIONS: CPRS accurately reflects IAP for IAP of 12 mmHg or higher. Thus CPRS measurements may represent a novel approach for diagnosis and monitoring of IAH