Intense human-animal interaction and limited capacity for the surveillance of zoonoses as drivers for Hepatitis E virus infections among animals and humans in Lao PDR

Purpose: In Lao People's Democratic Republic (PDR), overlapping habitats of the population and livestock create a propitious environment for zoonoses. Insufficient hygienic measures in slaughterhouses and in rural settings further increase the risk for zoonotic transmission. Limited laboratory capacity as well as lack of background knowledge prevent timely control of disease oubreaks. Here, we assess the occurrence and transmission of Hepatits E virus (HEV), as well as public awareness of zoonoses. Methods & Materials: In 2015 and 2016, samples were collected from ruminants in rural areas (n=211), as well as from slaughterhouse workers (n=129) and slaughter pigs (n=290) in Lao PDR. Using commercial ELISAs, presence of antibodies (IgG, IgM and IgA) against HEV was assessed. Fecal shedding of HEV by animals was investigated using a generic real-time PCR. Detected viruses were characterized by Sanger sequencing if feasible. Using a standardized questionnaire, data on risk factors for zoonotic pathogen transmission and awareness on zoonoses were captured. Much emphasis was placed on collaborating with local actors and on strengthening laboratory capacities. Results: Anti-HEV antibodies were detected in 13% of ruminants in rural settings and in 46% of slaughter pigs. 7% of the ruminants and 2% of the pigs shed HEV that were thus far not characterizable. While anti-HEV antibody seroprevalence was of 33% in people exposed to pigs, only 15% of the non-exposed control group were seropositive (p= 0.001). Awareness of zoonoses among farmers and slaughterhouse workers was low. Wearing protective equipment was associated with a decrease in anti-HEV antibody detection (p=0.024). Limiting the consumption and use of groundwater and cooking of meat further reduced the risk for HEV infection in a domestic context. Conclusion: We could show that people who are exposed to livestock and pigs are at higher risk for contracting HEV than the general population. Although shedding rates were relatively low, animals may represent an infection source that can be controlled by applying personal protective equipment. Building the capacity for the detection and prevention of infectious diseases and increasing awareness about zoonoses in developing countries is a prerequisite for combating infectious disease outbreaks in future

Clinical Experience with Off-Label Intrathecal Administration of Selected Antibiotics in Adults:An Overview with Pharmacometric Considerations

Drain-associated intracerebral infections are life-threatening emergencies. Their treatment is challenging due to the limited penetration of antibiotics to the site of infection, resulting in potentially inadequate exposure. The emergence of multidrug-resistant pathogens might force the use of off-label intrathecal (IT) doses of antibiotics. We reviewed the literature on general aspects determining intrathecal dosing regimen, using pharmacometric knowledge. We summarised clinical experience with IT doses of antibiotics that are usually not used intrathecally, as well as the outcome of the cases and concentrations reached in the cerebrospinal fluid (CSF). Factors determining the IT regimen are the size of the ventricle system and the CSF drainage volume. With regard to pharmacometrics, pharmacokinetic/pharmacodynamic indices are likely similar to those in non-cerebral infections. The following number (N) of cases were described: benzylpenicillin (&gt;50), ampicillin (1), ceftazidime (2), cephaloridine (56), ceftriaxone (1), cefotiam (1), meropenem (57), linezolid (1), tigecycline (15), rifampicin (3), levofloxacin (2), chloramphenicol (3) and daptomycin (8). Many side effects were reported for benzylpenicillin in the 1940–50s, but for the other antibiotics, when administered correctly, all side effects were minor and reversible. These data might help when choosing an IT dosing regimen in case there is no alternative option due to antimicrobial resistance.</p

Livestock diseases threatening smallholder farmers in Lao people's Democratic Republic

Purpose: In Lao People's Democratic Republic, uncontrolled animal trade, lack of animal containment and limited access to veterinary services are a growing-ground for virus spread. Foot-and-Mouth Disease (FMD) and several avian viruses are enzootic and threaten subsistence farmers. We assessed the (sero-)prevalence of several livestock viruses, and evaluated the knowledge, attitude, and practice of smallholder farmers towards FMD. Methods & Materials: In 2018, sera were collected from 394 domestic ruminants and screened using an ELISA that differentiates between infected and vaccinated animals. Questionnaires (n = 101) were statistically explored to identify knowledge gaps and risk factors related to FMD. In addition, oral and cloacal swabs, collected from 619 backyard poultry in 2011, 2014 and 2015, were tested by PCR for Newcastle disease (NDV), Influenza A, Coronavirus (CoV) and Chicken Anemia Virus (CAV). 206 poultry sera were screened by ELISA for the presence of anti-NDV and –Influenza A antibodies. Statistical and phylogenetic analyses revealed the viral infection patterns. Results: Although most farmers had very limited knowledge about FMD, many could correctly enumerate the symptoms and observed outbreaks recently. This was confirmed by our laboratory analysis: overall 37.1% of the animals were seropositive and 72.3% of the farms had at least one seropositive animal. Approx. 90% of the farmers reported that FMD negatively affects livestock trade and health. Moreover, we found high positivity rates of CoV and CAV RNA in cloacal and oral swabs (CoV: 38.3% and 6.2%; CAV: 16.1% and 1.7%). Younger animals were more likely to shed both, CoV and CAV, and similar virus strains co-circulated in chickens and ducks. Despite serological evidence of NDV and influenza A circulation (86.9% and 1.9%), viral RNA was detected in none of the swabs. Conclusion: A large proportion of the Lao population relies on subsistence livestock production which is, as shown here, severely compromised by the circulating viruses. To secure their livelihoods, vaccination programmes should target all susceptible hosts and achieve a high coverage throughout the country. These campaigns should be complemented by community-based sensitization to raise the awareness about prevention strategies, such as quarantine and trade restrictions

Prevalence of antibodies against canine distemper virus among red foxes in Luxembourg.

Canine distemper virus (CDV) has a wide host spectrum, and during the past years, distemper has been observed in species that were previously not considered to be susceptible. In this study, we investigated the prevalence of CDV-specific antibodies in red foxes (Vulpes vulpes) sampled between May and November 1997. About 9 to 13% of the Luxembourg red fox population is positive for antibodies against CDV. Thus a sizeable proportion of red foxes has been exposed to CDV in the wild. The significance of CDV in red foxes is discussed

Which patients benefit from model-informed precision dosing of beta-lactam antibiotics and ciprofloxacin at the ICU?

Objectives: Antibiotic dosing is not optimal in the ICU. Our recent trial investigated the effect of model-informed precision dosing (MIPD) of beta-lactam antibiotics and ciprofloxacin and showed no significant differences in clinical outcomes in all patients. This study aimed to identify subgroups of patients in which the MIPD of these antibiotics could be beneficial for clinical outcomes. Methods: We analysed data from the DOLPHIN randomized controlled trial, which compared MIPD to standard dosing of beta-lactam antibiotics and ciprofloxacin in 388 ICU patients. We divided patients into subgroups based on baseline characteristics and assessed the effect of MIPD on 28-day mortality, 6-month mortality, change in sequential organ failure assessment (delta-SOFA), and ICU length of stay (LOS). Results: We found a lower 28-day mortality in patients with a SOFA below 8 randomized to MIPD (OR 0.40; 95% CI 0.17–0.88). However, patients with a higher SOFA show an increased 28-day mortality (OR 1.94; 95% CI 1.07–3.59) in the MIPD group. ICU LOS was increased in patients receiving MIPD with a SOFA below 8 (IRR 1.36; 95% CI 1.01–1.83) and those receiving MIPD for ceftriaxone (IRR 1.76; 95% CI 1.24–2.51). Patients receiving a dose recommendation within 24 hours show a trend towards decreased ICU LOS (IRR 0.77; 95% CI 0.52–1.16) and higher delta-SOFA (estimate -1.19; 95% CI -2.98–0.60). Conclusions: ICU patients with a SOFA below 8 using MIPD had an increased ICU LOS but a lower 28-day mortality. Fast dose recommendations using MIPD of beta-lactam antibiotics and ciprofloxacin needs to be investigated in ICU patients.</p

Supergravity and the jet quenching parameter in the presence of R-charge densities

Following a recent proposal, we employ the AdS/CFT correspondence to compute the jet quenching parameter for N=4 Yang-Mills theory at nonzero R-charge densities. Using as dual supergravity backgrounds non-extremal rotating branes, we find that the presence of the R-charges generically enhances the jet quenching phenomenon. However, at fixed temperature, this enhancement might or might not be a monotonically increasing function of the R-charge density and depends on the number of independent angular momenta describing the solution. We perform our analysis for the canonical as well as for the grand canonical ensemble which give qualitatively similar results.Comment: 18 pages, 2 figures; v3: clarifying comments added, references added, version to appear in JHE

Population plasma and urine pharmacokinetics and the probability of target attainment of fosfomycin in healthy male volunteers

Purpose: A population pharmacokinetic model of fosfomycin was developed in healthy volunteers after intravenous administration, and different dosing regimens were evaluated in terms of the probability of target attainment for Escherichia coli using both plasma and urinary pharmacokinetic/pharmacodynamic targets. Methods: Eight healthy men received fosfomycin as both intermittent 8 g q8h and continuous infusion 1 g/h with a loading dose of 8 g in a crossover study design. Dense sampling was conducted during both regimens. Population pharmacokinetic modelling was performed using NONMEM. Monte Carlo simulations were conducted to evaluate the Probability of Target Attainment (PTA) of different dosing regimens using bactericidal (AUC24h/MIC of 83 and 75%T&gt;MIC) and bacteriostatic (AUC24h/MIC of 25) plasma targets and bacteriostatic (AUC24h/MIC of 3994) urine target. Results: A total of 176 plasma and 86 urine samples were available for PK analysis. A two-compartment model with a urine compartment best described the data. Glomerular filtration rate (GFR) showed a significant correlation with renal clearance and was implemented in the final model. Simulation results show that the dose of 4 g q8h reached 100% of PTA using bactericidal and bacteriostatic targets for MIC up to 16 mg/L. Conclusion: For the clinical breakpoint of 32 mg/L, the standard dosing regimen (4 g q8h) might not be sufficient to reach the bactericidal target. Higher dosing of 8 g q8h as an intermittent infusion or 0.75 g/h as a continuous infusion might be required. Continuous infusion resulted in better attainment of the %T&gt;MIC target than intermittent infusion.</p

Predicted enhanced human propensity of current avian-like H1N1 swine influenza virus from China

Influenza A virus (IAV) subtypes against which little or no pre-existing immunity exists in humans represent a serious threat to global public health. Monitoring of IAV in animal hosts is essential for early and rapid detection of potential pandemic IAV strains to prevent their spread. Recently, the increased pandemic potential of the avian-like swine H1N1 IAV A/swine/Guangdong/104/2013 has been suggested. The virus is infectious in humans and the general population seems to lack neutralizing antibodies against this virus. Here we present an in silico analysis that shows a strong human propensity of this swine virus further confirming its pandemic potential. We suggest mutations which would further enhance its human propensity. We also propose conserved antigenic determinants which could serve as a component of a prepandemic vaccine. The bioinformatics tool, which can be used to further monitor the evolution of swine influenza viruses towards a pandemic virus, are described here and are made publically available (http://www.vin.bg.ac.rs/180/tools/iav-mon.php; http://www.biomedprotection.com/iav-mon.php)