The Mare Reproductive Loss Syndrome and the Eastern Tent Caterpillar: A Toxicokinetic/Statistical Analysis With Clinical, Epidemiologic, and Mechanistic Implications

During 2001, central Kentucky experienced acute transient epidemics of early and late fetal losses, pericarditis, and unilateral endophthalmitis, collectively referred to as mare reproductive loss syndrome (MRLS). A toxicokinetic/statistical analysis of experimental and field MRLS data was conducted using accelerated failure time (AFT) analysis of abortions following administration of Eastern tent caterpillars (ETCs; 100 or 50 g/day or 100 g of irradiated caterpillars/day) to late-term pregnant mares. In addition, 2001 late-term fetal loss field data were used in the analysis. Experimental data were fitted by AFT analysis at a high (P \u3c .0001) significance. Times to first abortion (“lag time”) and abortion rates were dose dependent. Lag times decreased and abortion rates increased exponentially with dose. Calculated dose × response data curves allow interpretation of abortion data in terms of “intubated ETC equivalents.” Analysis suggested that field exposure to ETCs in 2001 in central Kentucky commenced on approximately April 27, was initially equivalent to approximately 5 g of intubated ETCs/day, and increased to approximately 30 g/day at the outbreak peak. This analysis accounts for many aspects of the epidemiology, clinical presentations, and manifestations of MRLS. It allows quantitative interpretation of experimental and field MRLS data and has implications for the basic mechanisms underlying MRLS. The results support suggestions that MRLS is caused by exposure to or ingestion of ETCs. The results also show that high levels of ETC exposure produce intense, focused outbreaks of MRLS, closely linked in time and place to dispersing ETCs, as occurred in central Kentucky in 2001. With less intense exposure, lag time is longer and abortions tend to spread out over time and may occur out of phase with ETC exposure, obscuring both diagnosis of this syndrome and the role of the caterpillars

PON1 and Neurodevelopment in Children from the CHAMACOS Study Exposed to Organophosphate Pesticides in Utero

BackgroundParaoxonase 1 (PON1) detoxifies oxon derivatives of some organophosphate (OP) pesticides, and its genetic polymorphisms influence enzyme activity and quantity. We previously reported that maternal urinary concentrations of dialkyl phosphate (DAP) metabolites, a marker of OP pesticide exposure, were related to poorer mental development and maternally reported symptoms consistent with pervasive developmental disorder (PDD) in 2-year-olds participating in the Center for the Health Assessment of Mothers and Children of Salinas (CHAMACOS) study.ObjectiveWe determined whether PON1 genotypes and enzyme measurements were associated with child neurobehavioral development and whether PON1 modified the association of in utero exposure to OPs (as assessed by maternal DAPs) and neurobehavior.MethodsWe measured DAP concentrations in maternal urine during pregnancy, PON1₁₉₂ and PON1₋₁₀₈ genotypes in mothers and children, and arylesterase (ARYase) and paraoxonase (POase) in maternal, cord, and 2-year-olds' blood. We assessed 353 2-year-olds on the Mental Development Index (MDI) and Psychomotor Development Index (PDI) of the Bayley Scales of Infant Development and queried their mothers on the Child Behavior Checklist to obtain a score for PDD.ResultsChildren with the PON1(-108T) allele had poorer MDI scores and somewhat poorer PDI scores. Children were less likely to display PDD when they or their mothers had higher ARYase activity and when their mothers had higher POase activity. The association between DAPs and MDI scores was strongest in children with PON1(-108T) allele, but this and other interactions between DAPs and PON1 polymorphisms or enzymes were not significant.ConclusionPON1 was associated with child neurobehavioral development, but additional research is needed to confirm whether it modifies the relation with in utero OP exposure

Chaotic systems in complex phase space

This paper examines numerically the complex classical trajectories of the kicked rotor and the double pendulum. Both of these systems exhibit a transition to chaos, and this feature is studied in complex phase space. Additionally, it is shown that the short-time and long-time behaviors of these two PT-symmetric dynamical models in complex phase space exhibit strong qualitative similarities.Comment: 22 page, 16 figure

De novo assembly and characterization of a maternal and developmental transcriptome for the emerging model crustacean Parhyale hawaiensis

<p>Abstract</p> <p>Background</p> <p>Arthropods are the most diverse animal phylum, but their genomic resources are relatively few. While the genome of the branchiopod <it>Daphnia pulex </it>is now available, no other large-scale crustacean genomic resources are available for comparison. In particular, genomic resources are lacking for the most tractable laboratory model of crustacean development, the amphipod <it>Parhyale hawaiensis</it>. Insight into shared and divergent characters of crustacean genomes will facilitate interpretation of future developmental, biomedical, and ecological research using crustacean models.</p> <p>Results</p> <p>To generate a transcriptome enriched for maternally provided and zygotically transcribed developmental genes, we created cDNA from ovaries and embryos of <it>P. hawaiensis</it>. Using 454 pyrosequencing, we sequenced over 1.1 billion bases of this cDNA, and assembled them <it>de novo </it>to create, to our knowledge, the second largest crustacean genomic resource to date. We found an unusually high proportion of C2H2 zinc finger-containing transcripts, as has also been reported for the genome of the pea aphid <it>Acyrthosiphon pisum</it>. Consistent with previous reports, we detected trans-spliced transcripts, but found that they did not noticeably impact transcriptome assembly. Our assembly products yielded 19,067 unique BLAST hits against <b>nr </b>(E-value cutoff e-10). These included over 400 predicted transcripts with significant similarity to <it>D. pulex </it>sequences but not to sequences of any other animal. Annotation of several hundred genes revealed <it>P. hawaiensis </it>homologues of genes involved in development, gametogenesis, and a majority of the members of six major conserved metazoan signaling pathways.</p> <p>Conclusions</p> <p>The amphipod <it>P. hawaiensis </it>has higher transcript complexity than known insect transcriptomes, and trans-splicing does not appear to be a major contributor to this complexity. We discuss the importance of a reliable comparative genomic framework within which to consider findings from new crustacean models such as <it>D. pulex </it>and <it>P. hawaiensis</it>, as well as the need for development of further substantial crustacean genomic resources.</p

Engineered Toxins “Zymoxins” Are Activated by the HCV NS3 Protease by Removal of an Inhibitory Protein Domain

The synthesis of inactive enzyme precursors, also known as “zymogens,” serves as a mechanism for regulating the execution of selected catalytic activities in a desirable time and/or site. Zymogens are usually activated by proteolytic cleavage. Many viruses encode proteases that execute key proteolytic steps of the viral life cycle. Here, we describe a proof of concept for a therapeutic approach to fighting viral infections through eradication of virally infected cells exclusively, thus limiting virus production and spread. Using the hepatitis C virus (HCV) as a model, we designed two HCV NS3 protease-activated “zymogenized” chimeric toxins (which we denote “zymoxins”). In these recombinant constructs, the bacterial and plant toxins diphtheria toxin A (DTA) and Ricin A chain (RTA), respectively, were fused to rationally designed inhibitor peptides/domains via an HCV NS3 protease-cleavable linker. The above toxins were then fused to the binding and translocation domains of Pseudomonas exotoxin A in order to enable translocation into the mammalian cells cytoplasm. We show that these toxins exhibit NS3 cleavage dependent increase in enzymatic activity upon NS3 protease cleavage in vitro. Moreover, a higher level of cytotoxicity was observed when zymoxins were applied to NS3 expressing cells or to HCV infected cells, demonstrating a potential therapeutic window. The increase in toxin activity correlated with NS3 protease activity in the treated cells, thus the therapeutic window was larger in cells expressing recombinant NS3 than in HCV infected cells. This suggests that the “zymoxin” approach may be most appropriate for application to life-threatening acute infections where much higher levels of the activating protease would be expected

Geographical and temporal distribution of SARS-CoV-2 clades in the WHO European Region, January to June 2020

We show the distribution of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) genetic clades over time and between countries and outline potential genomic surveillance objectives. We applied three genomic nomenclature systems to all sequence data from the World Health Organization European Region available until 10 July 2020. We highlight the importance of real-time sequencing and data dissemination in a pandemic situation, compare the nomenclatures and lay a foundation for future European genomic surveillance of SARS-CoV-2

Impact of opioid-free analgesia on pain severity and patient satisfaction after discharge from surgery: multispecialty, prospective cohort study in 25 countries

Background: Balancing opioid stewardship and the need for adequate analgesia following discharge after surgery is challenging. This study aimed to compare the outcomes for patients discharged with opioid versus opioid-free analgesia after common surgical procedures.Methods: This international, multicentre, prospective cohort study collected data from patients undergoing common acute and elective general surgical, urological, gynaecological, and orthopaedic procedures. The primary outcomes were patient-reported time in severe pain measured on a numerical analogue scale from 0 to 100% and patient-reported satisfaction with pain relief during the first week following discharge. Data were collected by in-hospital chart review and patient telephone interview 1 week after discharge.Results: The study recruited 4273 patients from 144 centres in 25 countries; 1311 patients (30.7%) were prescribed opioid analgesia at discharge. Patients reported being in severe pain for 10 (i.q.r. 1-30)% of the first week after discharge and rated satisfaction with analgesia as 90 (i.q.r. 80-100) of 100. After adjustment for confounders, opioid analgesia on discharge was independently associated with increased pain severity (risk ratio 1.52, 95% c.i. 1.31 to 1.76; P &lt; 0.001) and re-presentation to healthcare providers owing to side-effects of medication (OR 2.38, 95% c.i. 1.36 to 4.17; P = 0.004), but not with satisfaction with analgesia (beta coefficient 0.92, 95% c.i. -1.52 to 3.36; P = 0.468) compared with opioid-free analgesia. Although opioid prescribing varied greatly between high-income and low- and middle-income countries, patient-reported outcomes did not.Conclusion: Opioid analgesia prescription on surgical discharge is associated with a higher risk of re-presentation owing to side-effects of medication and increased patient-reported pain, but not with changes in patient-reported satisfaction. Opioid-free discharge analgesia should be adopted routinely

Occurrence and timing of withdrawal of life-sustaining measures in traumatic brain injury patients: a CENTER-TBI study

Funder: National Institute for Health Research (UK)Abstract: Background: In patients with severe brain injury, withdrawal of life-sustaining measures (WLSM) is common in intensive care units (ICU). WLSM constitutes a dilemma: instituting WLSM too early could result in death despite the possibility of an acceptable functional outcome, whereas delaying WLSM could unnecessarily burden patients, families, clinicians, and hospital resources. We aimed to describe the occurrence and timing of WLSM, and factors associated with timing of WLSM in European ICUs in patients with traumatic brain injury (TBI). Methods: The CENTER-TBI Study is a prospective multi-center cohort study. For the current study, patients with traumatic brain injury (TBI) admitted to the ICU and aged 16 or older were included. Occurrence and timing of WLSM were documented. For the analyses, we dichotomized timing of WLSM in early (< 72 h after injury) versus later (≥ 72 h after injury) based on recent guideline recommendations. We assessed factors associated with initiating WLSM early versus later, including geographic region, center, patient, injury, and treatment characteristics with univariable and multivariable (mixed effects) logistic regression. Results: A total of 2022 patients aged 16 or older were admitted to the ICU. ICU mortality was 13% (n = 267). Of these, 229 (86%) patients died after WLSM, and were included in the analyses. The occurrence of WLSM varied between regions ranging from 0% in Eastern Europe to 96% in Northern Europe. In 51% of the patients, WLSM was early. Patients in the early WLSM group had a lower maximum therapy intensity level (TIL) score than patients in the later WLSM group (median of 5 versus 10) The strongest independent variables associated with early WLSM were one unreactive pupil (odds ratio (OR) 4.0, 95% confidence interval (CI) 1.3–12.4) or two unreactive pupils (OR 5.8, CI 2.6–13.1) compared to two reactive pupils, and an Injury Severity Score (ISS) if over 41 (OR per point above 41 = 1.1, CI 1.0–1.1). Timing of WLSM was not significantly associated with region or center. Conclusion: WLSM occurs early in half of the patients, mostly in patients with severe TBI affecting brainstem reflexes who were severely injured. We found no regional or center influences in timing of WLSM. Whether WLSM is always appropriate or may contribute to a self-fulfilling prophecy requires further research and argues for reluctance to institute WLSM early in case of any doubt on prognosis

Cantharellus floccosus

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