Topology-Accelerated and Selective Cascade Depolymerization of Architecturally Complex Polyesters.

Despite considerable recent advances already made in developing chemically circular polymers (CPs), the current framework predominantly focuses on CPs with linear-chain structures of different monomer types. As polymer properties are determined by not only composition but also topology, manipulating the topology of the single-monomer-based CP systems from linear-chain structures to architecturally complex polymers could potentially modulate the resulting polymer properties without changing the chemical composition, thereby advancing the concept of monomaterial product design. To that end, here, we introduce a chemically circular hyperbranched polyester (HBPE), synthesized by a mixed chain-growth and step-growth polymerization of a rationally designed bicyclic lactone with a pendent hydroxyl group (BiLOH). This HBPE exhibits full chemical recyclability despite its architectural complexity, showing quantitative selectivity for regeneration of BiLOH, via a unique cascade depolymerization mechanism. Moreover, distinct differences in materials properties and performance arising from topological variations between HBPE, hb-PBiLOH, and its linear analogue, l-PBiLOH, have been revealed where generally the branched structure led to more favorable interchain interactions, and topology-amplified optical activity has also been observed for chiral (1S, 4S, 5S)-hb-PBiLOH. More intriguingly, depolymerization of l-PBiLOH proceeds through an unexpected, initial topological transformation to the HBPE polymer, followed by the faster cascade depolymerization pathway adopted by hb-PBiLOH. Overall, these results demonstrate that CP design can go beyond typical linear polymers, and rationally redesigned, architecturally complex polymers for their unique properties may synergistically impart advantages in topology-augmented depolymerization acceleration and selectivity for exclusive monomer regeneration.

Automated detection and classification of polioviruses from nanopore sequencing reads using piranha.

Widespread surveillance, rapid detection, and appropriate intervention will be critical for successful eradication of poliovirus. Using deployable next-generation sequencing (NGS) approaches, such as Oxford Nanopore Technologies' MinION, the time from sample to result can be significantly reduced compared to cell culture and Sanger sequencing. We developed piranha (poliovirus investigation resource automating nanopore haplotype analysis), a 'sequencing reads-to-report' solution to aid routine poliovirus testing of both stool and environmental samples and alleviate the bioinformatic bottleneck that often exists for laboratories adopting novel NGS approaches. Piranha can be used for efficient intratypic differentiation of poliovirus serotypes, for classification of Sabin-like polioviruses, and for detection of wild-type and vaccine-derived polioviruses. It produces interactive, distributable reports, as well as summary comma-separated values files and consensus poliovirus FASTA sequences. Piranha optionally provides phylogenetic analysis, with the ability to incorporate a local database, processing from raw sequencing reads to an interactive, annotated phylogeny in a single step. The reports describe each nanopore sequencing run with interpretable plots, enabling researchers to easily detect the presence of poliovirus in samples and quickly disseminate their results. Poliovirus eradication efforts are hindered by the lack of real-time detection and reporting, and piranha can be used to complement direct detection sequencing approaches.

Modulation of long-term potentiation following microdoses of LSD captured by thalamo-cortical modelling in a randomised, controlled trial.

BACKGROUND: Microdosing psychedelics is a phenomenon with claimed cognitive benefits that are relatively untested clinically. Pre-clinically, psychedelics have demonstrated enhancing effects on neuroplasticity, which cannot be measured directly in humans, but may be indexed by non-invasive electroencephalography (EEG) paradigms. This study used a visual long-term potentiation (LTP) EEG paradigm to test the effects of microdosed lysergic acid diethylamide (LSD) on neural plasticity, both acutely while on the drug and cumulatively after microdosing every third day for six weeks. Healthy adult males (n = 80) completed the visual LTP paradigm at baseline, 2.5 h following a dose of 10 µg of LSD or inactive placebo, and 6 weeks later after taking 14 repeated microdoses. Visually induced LTP was used as indirect index of neural plasticity. Surface level event-related potential (ERPs) based analyses are presented alongside dynamic causal modelling of the source localised data using a generative thalamocortical model (TCM) of visual cortex to elucidate underlying synaptic circuitry. RESULTS: Event-related potential (ERP) analyses of N1b and P2 components did not show evidence of changes in visually induced LTP by LSD either acutely or after 6 weeks of regular dosing. However modelling the complete timecourse of the ERP with the TCM demonstrated changes in laminar connectivity in primary visual cortex. This primarily included changes to self-gain and inhibitory input parameters acutely. Layer 2/3 to layer 5 excitatory connectivity was also different between LSD and placebo groups. After regular dosing only excitatory input from layer 2/3 into layer 5 and inhibitory input into layer 4 were different between groups. CONCLUSIONS: Without modulation of the ERPs it is difficult to relate the findings to other studies visually inducing LTP. It also indicates the classic peak analysis may not be sensitive enough to demonstrate evidence for changes in LTP plasticity in humans at such low doses. The TCM provides a more sensitive approach to assessing changes to plasticity as differences in plasticity mediated laminar connectivity were found between the LSD and placebo groups. TRIAL REGISTRATION:  ANZCTR registration number ACTRN12621000436875; Registered 16/04/2021 https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=381476 .

Neurophysiological evidence that frontoparietal connectivity and GABA-A receptor changes underpin the antidepressant response to ketamine.

Revealing the acute cortical pharmacodynamics of an antidepressant dose of ketamine in humans with depression is key to determining the specific mechanism(s) of action for alleviating symptoms. While the downstream effects are characterised by increases in plasticity and reductions in depressive symptoms-it is the acute response in the brain that triggers this cascade of events. Computational modelling of cortical interlaminar and cortico-cortical connectivity and receptor dynamics provide the opportunity to interrogate this question using human electroencephalography (EEG) data recorded during a ketamine infusion. Here, resting-state EEG was recorded in a group of 30 patients with major depressive disorder (MDD) at baseline and during a 0.44 mg/kg ketamine dose comprising a bolus and infusion. Fronto-parietal connectivity was assessed using dynamic causal modelling to fit a thalamocortical model to hierarchically connected nodes in the medial prefrontal cortex and superior parietal lobule. We found a significant increase in parietal-to-frontal AMPA-mediated connectivity and a significant decrease in the frontal GABA time constant. Both parameter changes were correlated across participants with the antidepressant response to ketamine. Changes to the NMDA receptor time constant and inhibitory intraneuronal input into superficial pyramidal cells did not survive correction for multiple comparisons and were not correlated with the antidepressant response. These results provide evidence that the antidepressant effects of ketamine may be mediated by acute fronto-parietal connectivity and GABA receptor dynamics. Furthermore, it supports the large body of literature suggesting the acute mechanism underlying ketamine's antidepressant properties is related to GABA-A and AMPA receptors rather than NMDA receptor antagonism.

Plasma-Enabled Selective Synthesis of Biobased Phenolics from Lignin-Derived Feedstock.

Converting abundant biomass-derived feedstocks into value-added platform chemicals has attracted increasing interest in biorefinery; however, the rigorous operating conditions that are required limit the commercialization of these processes. Nonthermal plasma-based electrification using intermittent renewable energy is an emerging alternative for sustainable next-generation chemical synthesis under mild conditions. Here, we report a hydrogen-free tunable plasma process for the selective conversion of lignin-derived anisole into phenolics with a high selectivity of 86.9% and an anisole conversion of 45.6% at 150 °C. The selectivity to alkylated chemicals can be tuned through control of the plasma alkylation process by changing specific energy input. The combined experimental and computational results reveal that the plasma generated H and CH3 radicals exhibit a "catalytic effect" that reduces the activation energy of the transalkylation reactions, enabling the selective anisole conversion at low temperatures. This work opens the way for the sustainable and selective production of phenolic chemicals from biomass-derived feedstocks under mild conditions.

Wastewater Surveillance in Europe for Non-Polio Enteroviruses and Beyond.

Wastewater surveillance (WWS) was developed in the early 1960s for the detection of poliovirus (PV) circulation in the population. It has been used to monitor several pathogens, including non-polio enteroviruses (NPEVs), which are increasingly recognised as causes of morbidity in children. However, when applying WWS to a new pathogen, it is important to consider the purpose of such a study as well as the suitability of the chosen methodology. With this purpose, the European Non-Polio Enterovirus Network (ENPEN) organised an expert webinar to discuss its history, methods, and applications; its evolution from a culture-based method to molecular detection; and future implementation of next generation sequencing (NGS). The first simulation experiments with PV calculated that a 400 mL sewage sample is sufficient for the detection of viral particles if 1:10,000 people excrete poliovirus in a population of 700,000 people. If the method is applied correctly, several NPEV types are detected. Despite culture-based methods remaining the gold standard for WWS, direct methods followed by molecular-based and sequence-based assays have been developed, not only for enterovirus but for several pathogens. Along with case-based sentinel and/or syndromic surveillance, WWS for NPEV and other pathogens represents an inexpensive, flexible, anonymised, reliable, population-based tool for monitoring outbreaks and the (re)emergence of these virus types/strains within the general population.

Sensitive poliovirus detection using nested PCR and nanopore sequencing: a prospective validation study.

Timely detection of outbreaks is needed for poliovirus eradication, but gold standard detection in the Democratic Republic of the Congo takes 30 days (median). Direct molecular detection and nanopore sequencing (DDNS) of poliovirus in stool samples is a promising fast method. Here we report prospective testing of stool samples from suspected polio cases, and their contacts, in the Democratic Republic of the Congo between 10 August 2021 and 4 February 2022. DDNS detected polioviruses in 62/2,339 (2.7%) of samples, while gold standard combination of cell culture, quantitative PCR and Sanger sequencing detected polioviruses in 51/2,339 (2.2%) of the same samples. DDNS provided case confirmation in 7 days (median) in routine surveillance conditions. DDNS enabled confirmation of three serotype 2 circulating vaccine-derived poliovirus outbreaks 23 days (mean) earlier (range 6-30 days) than the gold standard method. The mean sequence similarity between sequences obtained by the two methods was 99.98%. Our data confirm the feasibility of implementing DDNS in a national poliovirus laboratory.

Noninvasive Fecal Cytokine and Microbiota Profiles Predict Commencement of Necrotizing Enterocolitis in a Proof-of-Concept Study.

Background and Aims: Necrotizing enterocolitis (NEC) is a life-threatening disease and the most common gastrointestinal emergency in premature infants. Accurate early diagnosis is challenging. Modified Bell's staging is routinely used to guide diagnosis, but early diagnostic signs are nonspecific, potentially leading to unobserved disease progression, which is problematic given the often rapid deterioration observed. We investigated fecal cytokine levels, coupled with gut microbiota profiles, as a noninvasive method to discover specific NEC-associated signatures that can be applied as potential diagnostic markers. Methods: Premature babies born below 32 weeks of gestation were admitted to the 2-site neonatal intensive care unit (NICU) of Imperial College hospitals (St. Mary's or Queen Charlotte's & Chelsea) between January 2011 and December 2012. During the NICU stay, expert neonatologists grouped individuals by modified Bell's staging (healthy, NEC1, NEC2/3) and fecal samples from diapers were collected consecutively. Microbiota profiles were assessed by 16S rRNA gene amplicon sequencing and cytokine concentrations were measured by V-Plex multiplex assays. Results: Early evaluation of microbiota profiles revealed only minor differences. However, at later time points, significant changes in microbiota composition were observed for Bacillota (adj. P = .0396), with Enterococcus being the least abundant in Bell stage 2/3 NEC. Evaluation of fecal cytokine levels revealed significantly higher concentrations of IL-1α (P = .045), IL-5 (P = .0074), and IL-10 (P = .032) in Bell stage 1 NEC compared to healthy individuals. Conclusion: Differences in certain fecal cytokine profiles in patients with NEC indicate their potential use as diagnostic biomarkers to facilitate earlier diagnosis. Additionally, associations between microbial and cytokine profiles contribute to improving knowledge about NEC pathogenesis.

Particular genomic and virulence traits associated with preterm infant-derived toxigenic Clostridium perfringens strains.

Clostridium perfringens is an anaerobic toxin-producing bacterium associated with intestinal diseases, particularly in neonatal humans and animals. Infant gut microbiome studies have recently indicated a link between C. perfringens and the preterm infant disease necrotizing enterocolitis (NEC), with specific NEC cases associated with overabundant C. perfringens termed C. perfringens-associated NEC (CPA-NEC). In the present study, we carried out whole-genome sequencing of 272 C. perfringens isolates from 70 infants across 5 hospitals in the United Kingdom. In this retrospective analysis, we performed in-depth genomic analyses (virulence profiling, strain tracking and plasmid analysis) and experimentally characterized pathogenic traits of 31 strains, including 4 from CPA-NEC patients. We found that the gene encoding toxin perfringolysin O, pfoA, was largely deficient in a human-derived hypovirulent lineage, as well as certain colonization factors, in contrast to typical pfoA-encoding virulent lineages. We determined that infant-associated pfoA+ strains caused significantly more cellular damage than pfoA- strains in vitro, and further confirmed this virulence trait in vivo using an oral-challenge C57BL/6 murine model. These findings suggest both the importance of pfoA+ C. perfringens as a gut pathogen in preterm infants and areas for further investigation, including potential intervention and therapeutic strategies.

Changes in Visual Long-Term Potentiation Show Preserved Cyclicity in Human Females Taking Combined Oral Contraceptives.

INTRODUCTION: The combined oral contraceptive (COC) pill is often employed to address physical and neurological symptoms in menstrual cycle-related disorders by suppressing shifts in endogenous gonadal hormone fluctuations. Symptom persistence, especially in the lead up to the hormone-free interval (HFI), suggests an underlying neurobiological mechanism of preserved cycling. Our study utilised a non-invasive method of visually inducing long-term potentiation (LTP) to index changes in neural plasticity in the absence of hormonal fluctuations. METHODS: Visually induced LTP was recorded using electroencephalography in 24 healthy female COC users across three sessions: days 3 and 21 during active hormone pills, and day 24 during the HFI. The Daily Record of the Severity of Problems (DRSP) questionnaire tracked premenstrual symptoms. Dynamic causal modelling (DCM) was used to elucidate the neural connectivity and receptor activity changes associated with LTP across different days of COC. RESULTS: Visually induced LTP was greater on day 21 than day 3 (p = 0.011) and was localised to the P2 visually evoked potential. There was no effect of the HFI (day 24) on LTP. DCM of differences between days 3 and 21 showed changes to inhibitory interneuronal gating of LTP in cortical layer VI. The DRSP only showed a significant increase in symptoms in the HFI, meaning the LTP result appeared more sensitive to cyclicity. CONCLUSIONS: This study provides objective evidence of preserved cyclicity in COC users through enhanced LTP on day 21 compared to day 3 of a 28-day COC regimen, indicating that relatively higher excitation in the brain despite peripheral gonadal suppression may underlie and exacerbate menstrual cycle-related disorders.

Comparison of Eleven RNA Extraction Methods for Poliovirus Direct Molecular Detection in Stool Samples.

Direct detection by PCR of poliovirus RNA in stool samples provides a rapid diagnostic and surveillance tool that can replace virus isolation by cell culture in global polio surveillance. The sensitivity of direct detection methods is likely to depend on the choice of RNA extraction method and sample volume. We report a comparative analysis of 11 nucleic acid extraction methods (7 manual and 4 semiautomated) for poliovirus molecular detection using stool samples (n = 59) that had been previously identified as poliovirus positive by cell culture. To assess the effect of RNA recovery methods, extracted RNA using each of the 11 methods was tested with a poliovirus-specific reverse transcription-quantitative PCR (RT-qPCR), a pan-poliovirus RT-PCR (near-whole-genome amplification), a pan-enterovirus RT-PCR (entire capsid region), and a nested VP1 PCR that is the basis of a direct detection method based on nanopore sequencing. We also assessed extracted RNA integrity and quantity. The overall effect of extraction method on poliovirus PCR amplification assays tested in this study was found to be statistically significant (P < 0.001), thus indicating that the choice of RNA extraction method is an important component that needs to be carefully considered for any diagnostic based on nucleic acid amplification. Performance of the methods was generally consistent across the different assays used. Of the 11 extraction methods tested, the MagMAX viral RNA isolation kit used manually or automatically was found to be the preferable method for poliovirus molecular direct detection considering performance, cost, and processing time. IMPORTANCE Poliovirus, the causative agent of poliomyelitis, is a target of global eradication led by the World Health Organization since 1988. Direct molecular detection and genomic sequencing without virus propagation in cell culture is arguably a critical tool in the final stages of polio eradication. Efficient recovery of good-quality viral RNA from stool samples is a prerequisite for direct detection by nucleic acid amplification. We tested 11 nucleic acid extraction methods to identify those facilitating sensitive, fast, simple, and cost-effective extraction, with flexibility for manual and automated protocols considered. Several different PCR assays were used to compare the recovered viral RNA to test suitability for poliovirus direct molecular detection. Our findings highlight the importance of choosing a suitable RNA extraction protocol and provide useful information to diagnostic laboratories and researchers facing the choice of RNA extraction method for direct molecular virus detection from stool.

Development of the gut microbiota during early life in premature and term infants.

BACKGROUND: The gastrointestinal (GI) microbiota has been linked to health consequences throughout life, from early life illnesses (e.g. sepsis and necrotising enterocolitis) to lifelong chronic conditions such as obesity and inflammatory bowel disease. It has also been observed that events in early life can lead to shifts in the microbiota, with some of these changes having been documented to persist into adulthood. A particularly extreme example of a divergent early GI microbiota occurs in premature neonates, who display a very different GI community to term infants. Certain characteristic patterns have been associated with negative health outcomes during the neonatal period, and these patterns may prove to have continual damaging effects if not resolved. RESULTS: In this study we compared a set of premature infants with a paired set of term infants (n = 37 pairs) at 6 weeks of age and at 2 years of age. In the samples taken at 6 weeks of age we found microbial communities differing in both diversity and specific bacterial groups between the two infant cohorts. We identified clinical factors associated with over-abundance of potentially pathogenic organisms (e.g. Enterobacteriaceae) and reduced abundances of some beneficial organisms (e.g. Bifidobacterium). We contrasted these findings with samples taken at 2 years of age, which indicated that despite a very different initial gut microbiota, the two infant groups converged to a similar, more adult-like state. We identified clinical factors, including both prematurity and delivery method, which remain associated with components of the gut microbiota. Both clinical factors and microbial characteristics are compared to the occurrence of childhood wheeze and eczema, revealing associations between components of the GI microbiota and the development of these allergic conditions. CONCLUSIONS: The faecal microbiota differs greatly between infants born at term and those born prematurely during early life, yet it converges over time. Despite this, early clinical factors remain significantly associated with the abundance of some bacterial groups at 2 years of age. Given the associations made between health conditions and the microbiota, factors that alter the makeup of the gut microbiota, and potentially its trajectory through life, could have important lifelong consequences.

Neurophysiological consequences of synapse loss in progressive supranuclear palsy.

Synaptic loss occurs early in many neurodegenerative diseases and contributes to cognitive impairment even in the absence of gross atrophy. Currently, for human disease there are few formal models to explain how cortical networks underlying cognition are affected by synaptic loss. We advocate that biophysical models of neurophysiology offer both a bridge from preclinical to clinical models of pathology and quantitative assays for experimental medicine. Such biophysical models can also disclose hidden neuronal dynamics generating neurophysiological observations such as EEG and magnetoencephalography. Here, we augment a biophysically informed mesoscale model of human cortical function by inclusion of synaptic density estimates as captured by 11C-UCB-J PET, and provide insights into how regional synapse loss affects neurophysiology. We use the primary tauopathy of progressive supranuclear palsy (Richardson's syndrome) as an exemplar condition, with high clinicopathological correlations. Progressive supranuclear palsy causes a marked change in cortical neurophysiology in the presence of mild cortical atrophy and is associated with a decline in cognitive functions associated with the frontal lobe. Using parametric empirical Bayesian inversion of a conductance-based canonical microcircuit model of magnetoencephalography data, we show that the inclusion of regional synaptic density-as a subject-specific prior on laminar-specific neuronal populations-markedly increases model evidence. Specifically, model comparison suggests that a reduction in synaptic density in inferior frontal cortex affects superficial and granular layer glutamatergic excitation. This predicted individual differences in behaviour, demonstrating the link between synaptic loss, neurophysiology and cognitive deficits. The method we demonstrate is not restricted to progressive supranuclear palsy or the effects of synaptic loss: such pathology-enriched dynamic causal models can be used to assess the mechanisms of other neurological disorders, with diverse non-invasive measures of pathology, and is suitable to test the effects of experimental pharmacology.

Gastrointestinal, vaginal, nasopharyngeal, and breast milk microbiota profiles and breast milk metabolomic changes in Gambian infants over the first two months of lactation: A prospective cohort study.

Microbiota composition in breast milk affects intestinal and respiratory microbiota colonization and the mucosal immune system's development in infants. The metabolomic content of breast milk is thought to interact with the microbiota and may influence developing infant immunity. One hundred seven Gambian mothers and their healthy, vaginally delivered, exclusively breastfed infants were included in our study. We analyzed 32 breast milk samples, 51 maternal rectovaginal swabs and 30 infants' rectal swabs at birth. We also analyzed 9 breast milk samples and 18 infants' nasopharyngeal swabs 60 days post-delivery. We used 16S rRNA gene sequencing to determine the microbiota composition. Metabolomic profiling analysis was performed on colostrum and mature breast milk samples using a multiplatform approach combining 1-H Nuclear Magnetic Resonance Spectroscopy and Gas Chromatography-Mass Spectrometry. Bacterial communities were distinct in composition and diversity across different sample types. Breast milk composition changed over the first 60 days of lactation. α-1,4- and α-1,3-fucosylated human milk oligosaccharides, and other 33 key metabolites in breast milk (monosaccharides, sugar alcohols and fatty acids) increased between birth and day 60 of life. This study's results indicate that infant gut and respiratory microbiota are unique bacterial communities, distinct from maternal gut and breast milk, respectively. Breast milk microbiota composition and metabolomic profile change throughout lactation. These changes may contribute to the infant's immunological, metabolic, and neurological development and could consist the basis for future interventions to correct disrupted early life microbial colonization.

Sustained detection of type 2 poliovirus in London sewage between February and July, 2022, by enhanced environmental surveillance.

BACKGROUND: The international spread of poliovirus exposes all countries to the risk of outbreaks and is designated a Public Health Emergency of International Concern by WHO. This risk can be exacerbated in countries using inactivated polio vaccine, which offers excellent protection against paralysis but is less effective than oral vaccine against poliovirus shedding, potentially allowing circulation without detection of paralytic cases for long periods of time. Our study investigated the molecular properties of type 2 poliovirus isolates found in sewage with an aim to detect virus transmission in the community. METHODS: We performed environmental surveillance in London, UK, testing sewage samples using WHO recommended methods that include concentration, virus isolation in cell culture, and molecular characterisation. We additionally implemented direct molecular detection and determined whole-genome sequences of every isolate using novel nanopore protocols. FINDINGS: 118 genetically linked poliovirus isolates related to the serotype 2 Sabin vaccine strain were detected in 21 of 52 sequential sewage samples collected in London between Feb 8 and July 4, 2022. Expansion of environmental surveillance sites in London helped localise transmission to several boroughs in north and east London. All isolates have lost two key attenuating mutations, are recombinants with a species C enterovirus, and an increasing proportion (20 of 118) meet the criterion for a vaccine-derived poliovirus, having six to ten nucleotide changes in the gene coding for VP1 capsid protein. INTERPRETATION: Environmental surveillance allowed early detection of poliovirus importation and circulation in London, permitting a rapid public health response, including enhanced surveillance and an inactivated polio vaccine campaign among children aged 1-9 years. Whole-genome sequences generated through nanopore sequencing established linkage of isolates and confirmed transmission of a unique recombinant poliovirus lineage that has now been detected in Israel and the USA. FUNDING: Medicines and Healthcare products Regulatory Agency, UK Health Security Agency, Bill & Melinda Gates Foundation, and National Institute for Health Research Medical Research Council.

Time Taken to Detect and Respond to Polio Outbreaks in Africa and the Potential Impact of Direct Molecular Detection and Nanopore Sequencing.

BACKGROUND: Detection of poliovirus outbreaks relies on a complex laboratory algorithm of cell-culture, polymerase chain reaction (PCR), and sequencing to distinguish wild-type and vaccine-derived polioviruses (VDPV) from Sabin-like strains. We investigated the potential for direct molecular detection and nanopore sequencing (DDNS) to accelerate poliovirus detection. METHODS: We analyzed laboratory data for time required to analyze and sequence serotype-2 VDPV (VDPV2) in stool collected from children with acute flaccid paralysis in Africa (May 2016-February 2020). Impact of delayed detection on VDPV2 outbreak size was assessed through negative binomial regression. RESULTS: VDPV2 confirmation in 525 stools required a median of 49 days from paralysis onset (10th-90th percentile, 29-74), comprising collection and transport (median, 16 days), cell-culture (7 days), intratypic differentiation quantitative reverse transcription PCR (3 days), and sequencing, including shipping if required (15 days). New VDPV2 outbreaks were confirmed a median of 35 days (27-60) after paralysis onset, which we estimate could be reduced to 16 days by DDNS (9-37). Because longer delays in confirmation and response were positively associated with more cases (P < .001), we estimate that DDNS could reduce the number of VDPV2 cases before a response by 28% (95% credible interval, 12%-42%). CONCLUSIONS: DDNS could accelerate poliovirus outbreak response, reducing their size and the cost of eradication.

Hamiltonian Simulation with Random Inputs.

The algorithmic error of digital quantum simulations is usually explored in terms of the spectral norm distance between the actual and ideal evolution operators. In practice, this worst-case error analysis may be unnecessarily pessimistic. To address this, we develop a theory of average-case performance of Hamiltonian simulation with random initial states. We relate the average-case error to the Frobenius norm of the multiplicative error and give upper bounds for the product formula (PF) and truncated Taylor series methods. As applications, we estimate average-case error for the digital Hamiltonian simulation of general lattice Hamiltonians and k-local Hamiltonians. In particular, for the nearest-neighbor Heisenberg chain with n spins, the error is quadratically reduced from O(n) in the worst case to O(sqrt[n]) on average for both the PF method and the Taylor series method. Numerical evidence suggests that this theory accurately characterizes the average error for concrete models. We also apply our results to error analysis in the simulation of quantum scrambling.

A comparison of GABA-ergic (propofol) and non-GABA-ergic (dexmedetomidine) sedation on visual and motor cortical oscillations, using magnetoencephalography.

Studying changes in cortical oscillations can help elucidate the mechanistic link between receptor physiology and the clinical effects of anaesthetic drugs. Propofol, a GABA-ergic drug produces divergent effects on visual cortical activity: increasing induced gamma-band responses (GBR) while decreasing evoked responses. Dexmedetomidine, an α2- adrenergic agonist, differs from GABA-ergic sedatives both mechanistically and clinically as it allows easy arousability from deep sedation with less cognitive side-effects. Here we use magnetoencephalography (MEG) to characterize and compare the effects of GABA-ergic (propofol) and non-GABA-ergic (dexmedetomidine) sedation, on visual and motor cortical oscillations. Sixteen male participants received target-controlled infusions of propofol and dexmedetomidine, producing mild-sedation, in a placebo-controlled, cross-over study. MEG data was collected during a combined visuomotor task. The key findings were that propofol significantly enhanced visual stimulus induced GBR (44% increase in amplitude) while dexmedetomidine decreased it (40%). Propofol also decreased the amplitudes of the Mv100 (visual M100) (27%) and Mv150 (52%) visual evoked fields (VEF), whilst dexmedetomidine had no effect on these. During the motor task, neither drug had any significant effect on movement related gamma synchrony (MRGS), movement related beta de-synchronisation (MRBD) or Mm100 (movement-related M100) movement-related evoked fields (MEF), although dexmedetomidine slowed the Mm300. Dexmedetomidine increased (92%) post-movement beta synchronisation/rebound (PMBR) power while propofol reduced it (70%, statistically non- significant). Overall, dexmedetomidine and propofol, at equi-sedative doses, produce contrasting effects on visual induced GBR, VEF, PMBR and MEF. These findings provide a mechanistic link between the known receptor physiology of these sedative drugs with their known clinical effects and may be used to explore mechanisms of other anaesthetic drugs on human consciousness.

Improving Antioxidant Capacity in Children With Autism: A Randomized, Double-Blind Controlled Study With Cysteine-Rich Whey Protein.

Previous studies indicate that children with autism spectrum disorder (ASD) have lower levels of glutathione. Nutritional interventions aim to increase glutathione levels suggest a positive effect on ASD behaviors, but findings are mixed or non-significant. A commercially available nutritional supplement comprising a cysteine-rich whey protein isolate (CRWP), a potent precursor of glutathione, was previously found to be safe and effective at raising glutathione in several conditions associated with low antioxidant capacity. Therefore, we investigated the effectiveness of a 90-day CRWP intervention in children with ASD and examined whether intracellular reduced and oxidized glutathione improvements correlated with behavioral changes. We enrolled 46 (of 81 screened) 3-5-year-old preschool children with confirmed ASD. Using a double-blind, randomized, placebo-controlled design, we evaluated the effectiveness of daily CRWP (powder form: 0.5 g/kg for children <20 kg or a 10-g dose for those >20 kg), compared with placebo (rice protein mimicking the protein load in the intervention group), on glutathione levels and ASD behaviors assessed using different behavioral scales such as Childhood Autism Rated Scale, Preschool Language Scale, Social Communication Questionnaire, Childhood Behavioral Checklist and the parent-rated Vineland Adaptive Behavior Scale, 2nd edition (VABS-II). Forty children (CRWP, 21; placebo, 19) completed the 90-day treatment period. Improvements observed in some behavioral scales were comparable. However, the VABS-II behavioral assessment, demonstrated significant changes only in children receiving CRWP compared to those observed in the placebo group in the composite score (effect size 0.98; 95% confidence intervals 1.42-4.02; p = 0.03). Further, several VABS-II domain scores such as adaptive behavior (p = 0.03), socialization (p = 0.03), maladaptive behavior (p = 0.04) and internalizing behavior (p = 0.02) also indicated significant changes. Children assigned to the CRWP group showed significant increases in glutathione levels (p = 0.04) compared to those in the placebo group. A subanalysis of the VABS-II scale results comparing responders (>1 SD change from baseline to follow up) and non-responders in the CRWP group identified older age and higher levels of total and reduced glutathione as factors associated with a response. CRWP nutritional intervention in children with ASD significantly improved both glutathione levels and some behaviors associated with ASD. Further studies are needed to confirm these results. Clinical Trial Registration: https://clinicaltrials.gov/ct2/show/study/NCT01366859, identifier: NCT01366859.