High-magnification Faraday rotation imaging and analysis of X-pinch implosion dynamics.

An X-pinch load driven by an intense current pulse (>100 kA in ∼100 ns) can result in the formation of a small radius, runaway compressional micro-pinch. A micro-pinch is characterized by a hot (>1 keV), current-driven (>100 kA), high-density plasma column (near solid density) with a small neck diameter (1-10 µm), a short axial extent (<1 mm), and a short duration (≲1 ns). With material pressures often well into the multi-Mbar regime, a micro-pinch plasma often radiates an intense, sub-ns burst of sub-keV to multi-keV x rays. A low-density coronal plasma immediately surrounding the dense plasma neck could potentially shunt current away from the neck and thus reduce the magnetic drive pressure applied to the neck. To study the current distribution in the coronal plasma, a Faraday rotation imaging diagnostic (1064 nm) capable of producing simultaneous high-magnification polarimetric and interferometric images has been developed for the MAIZE facility at the University of Michigan. Designed with a variable magnification (1-10×), this diagnostic achieves a spatial resolution of ∼35 µm, which is useful for resolving the ∼100-µm-scale coronal plasma immediately surrounding the dense core. This system has now been used on a reduced-output MAIZE (100-200 kA, 150 ns) to assess the radial distribution of drive current immediately surrounding the dense micro-pinch neck. The total current enclosed was found to increase as a function of radius, r, from a value of ≈50±25 kA at r ≈ 140 µm (at the edge of the dense neck) to a maximal value of ≈150±75 kA for r ≥ 225 µm. This corresponds to a peak magnetic drive pressure of ≈75±50 kbar at r ≈ 225 µm. The limitations of these measurements are discussed in the paper.

Estimating the aquatic risk from exposure to up to twenty-two pesticide active ingredients in waterways discharging to the Great Barrier Reef.

Pesticides decrease the quality of water reaching the Great Barrier Reef (GBR), Australia. Up to 86 pesticide active ingredients (PAIs) were monitored between July 2015 to end of June 2018 at 28 sites in waterways that discharge to the GBR. Twenty-two frequently detected PAIs were selected to calculate their combined risk when they co-occur in water samples. Species sensitivity distributions (SSDs) for the 22 PAIs to fresh and marine species were developed. The SSDs, the multi-substance potentially affected fraction (msPAF) method, Independent Action model of joint toxicity and a Multiple Imputation method were combined to convert measured PAI concentration data to estimates of the Total Pesticide Risk for the 22 PAIs (TPR22) expressed as the average percentage of species affected during the wet season (i.e., 182 days). The TPR22 and percent contribution of active ingredients of Photosystem II inhibiting herbicides, Other Herbicides, and Insecticides to the TPR22 were estimated. The TPR22 ranged from <1 % to 42 % of aquatic species being affected. Approximately 85 % of the TPR22 estimates were >1 % - meaning they did not meet the Reef 2050 Water Quality Improvement Plan's pesticide target for waters entering the GBR. There were marked spatial differences in TPR22 estimates - regions dominated by grazing had lower estimates while those with sugar cane tended to have higher estimates. On average, active ingredients of PSII herbicides contributed 39 % of the TPR22, the active ingredients of Other Herbicides contributed ~36 % and of Insecticides contributed ~24 %. Nine PAIs (diuron, imidacloprid, metolachlor, atrazine, MCPA, imazapic, metsulfuron, triclopyr and ametryn) were responsible for >97 % of TPR22 across all the monitored waterways.

No life-history cost of tebufenozide resistance in the smaller tea tortrix moth.

BACKGROUND: Tebufenozide is widely used to control populations of the smaller tea tortrix, Adoxophyes honmai. However, A. honmai has evolved resistance such that straightforward pesticide application is an untenable long-term approach for population control. Evaluating the fitness cost of resistance is key to devising a management strategy that slows the evolution of resistance. RESULTS: We used three approaches to assess the life-history cost of tebufenozide resistance with two strains of A. honmai: a tebufenozide-resistant strain recently collected from the field in Japan and a susceptible strain that has been maintained in the laboratory for decades. First, we found that the resistant strain with standing genetic variation did not decline in resistance in the absence of insecticide over four generations. Second, we found that genetic lines that spanned a range of resistance profiles did not show a negative correlation between their LD50 , the dosage at which 50 % of individuals died, and life-history traits that are correlates of fitness. Third, we found that the resistant strain did not manifest life-history costs under food limitation. Our crossing experiments indicate that the allele at an ecdysone receptor locus known to confer resistance explained much of the variance in resistance profiles across genetic lines. CONCLUSION: Our results indicate that the point mutation in the ecdysone receptor, which is widespread in tea plantations in Japan, does not carry a fitness cost in the tested laboratory conditions. The absence of a cost of resistance and the mode of inheritance have implications for which strategies may be effective in future resistance management efforts. © 2023 The Authors. Pest Management Science published by John Wiley & Sons Ltd on behalf of Society of Chemical Industry.

Perpendicular Subcritical Shock Structure in a Collisional Plasma Experiment.

We present a study of perpendicular subcritical shocks in a collisional laboratory plasma. Shocks are produced by placing obstacles into the supermagnetosonic outflow from an inverse wire array z pinch. We demonstrate the existence of subcritical shocks in this regime and find that secondary shocks form in the downstream. Detailed measurements of the subcritical shock structure confirm the absence of a hydrodynamic jump. We calculate the classical (Spitzer) resistive diffusion length and show that it is approximately equal to the shock width. We measure little heating across the shock (<10% of the ion kinetic energy) which is consistent with an absence of viscous dissipation.

Investigation of Mitochondrial Related Variants in a Cerebral Small Vessel Disease Cohort.

Monogenic forms of cerebral small vessel disease (CSVD) can be caused by both variants in nuclear DNA and mitochondrial DNA (mtDNA). Mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) is known to have a phenotype similar to Cerebral Autosomal Dominant Arteriopathy with Sub-cortical Infarcts and Leukoencephalopathy (CADASIL), and can be caused by variants in the mitochondrial genome and in several nuclear-encoded mitochondrial protein (NEMP) genes. The aim of this study was to screen for variants in the mitochondrial genome and NEMP genes in a NOTCH3-negative CADASIL cohort, to identify a potential link between mitochondrial dysfunction and CSVD pathology. Whole exome sequencing was performed for 50 patients with CADASIL-like symptomology on the Ion Torrent system. Mitochondrial sequencing was performed using an in-house designed protocol with sequencing run on the Ion GeneStudio S5 Plus (S5 +). NEMP genes and mitochondrial sequencing data were examined for rare (MAF < 0.001), non-synonymous variants that were predicted to have a deleterious effect on the protein. We identified 29 candidate NEMP variants that had links to either MELAS-, encephalopathy-, or Alzheimer's disease-related phenotypes. Based on these changes, variants affecting POLG, MTO1, LONP1, NDUFAF6, NDUFB3, and TCIRG1 were thought to play a potential role in CSVD pathology in this cohort. Overall, the exploration of the mitochondrial genome identified a potential role for mitochondrial related proteins and mtDNA variants contributing to CSVD pathologies.

Resource Allocation in a National Dental Service Using Program Budgeting Marginal Analysis.

INTRODUCTION: In any health system, choices must be made about the allocation of resources (budget), which are often scarce. Economics has defined frameworks to aid resource allocation, and program budgeting marginal analysis (PBMA) is one such framework. In principle, patient and public values can be incorporated into these frameworks, using techniques such as willingness to pay (WTP). However, this has not been done before, and few formal resource allocation processes have been undertaken in dentistry. This study aimed to undertake a PBMA with embedded WTP values in a national dental setting. METHODS: The PBMA process was undertaken by a panel of participant-researchers representing commissioners, dentists, dental public health staff, and academics. The panel reviewed current allocations and generated a set of weighted criteria to evaluate services against. Services to be considered for removal and investment were determined by the panel and wider discussion and then scored against the criteria. Values from a nationally representative WTP survey of the public contributed to the scores for interventions. Final decisions on removal and investment were taken after panel discussion using individual anonymous electronic voting. RESULTS: The PBMA process resulted in recommendations to invest in new program components to improve access to general dentists, care home dentistry, and extra support for dental public health input into local government decisions. Disinvestments were recommended in orthodontics and to remove routine scaling and polishing of teeth. DISCUSSION: The PBMA process was successful in raising awareness of resource allocation issues. Implementation of findings will depend on the ability of decision makers to find ways of operationalizing the decisions. The process illustrates practical aspects of the process that future dental PBMAs could learn from. KNOWLEDGE TRANSFER STATEMENT: This study illustrates a framework for resource allocation in dental health services and will aid decision makers in implementing their own resource allocation systems.

An imaging refractometer for density fluctuation measurements in high energy density plasmas.

We report on a recently developed laser-probing diagnostic, which allows direct measurements of ray-deflection angles in one axis while retaining imaging capabilities in the other axis. This allows us to measure the spectrum of angular deflections from a laser beam, which passes through a turbulent high-energy-density plasma. This spectrum contains information about the density fluctuations within the plasma, which deflect the probing laser over a range of angles. We create synthetic diagnostics using ray-tracing to compare this new diagnostic with standard shadowgraphy and schlieren imaging approaches, which demonstrates the enhanced sensitivity of this new diagnostic over standard techniques. We present experimental data from turbulence behind a reverse shock in a plasma and demonstrate that this technique can measure angular deflections between 0.06 and 34 mrad, corresponding to a dynamic range of over 500.

Sources and space-time distribution of the electromagnetic pulses in experiments on inertial confinement fusion and laser-plasma acceleration.

When high-energy and high-power lasers interact with matter, a significant part of the incoming laser energy is transformed into transient electromagnetic pulses (EMPs) in the range of radiofrequencies and microwaves. These fields can reach high intensities and can potentially represent a significative danger for the electronic devices placed near the interaction point. Thus, the comprehension of the origin of these electromagnetic fields and of their distribution is of primary importance for the safe operation of high-power and high-energy laser facilities, but also for the possible use of these high fields in several promising applications. A recognized main source of EMPs is the target positive charging caused by the fast-electron emission due to laser-plasma interactions. The fast charging induces high neutralization currents from the conductive walls of the vacuum chamber through the target holder. However, other mechanisms related to the laser-target interaction are also capable of generating intense electromagnetic fields. Several possible sources of EMPs are discussed here and compared for high-energy and high-intensity laser-matter interactions, typical for inertial confinement fusion and laser-plasma acceleration. The possible effects on the electromagnetic field distribution within the experimental chamber, due to particle beams and plasma emitted from the target, are also described. This article is part of a discussion meeting issue 'Prospects for high gain inertial fusion energy (part 2)'.

Multiple deprivation and geographic distance to community physical activity events - achieving equitable access to parkrun in England.

OBJECTIVES: To evaluate geographic access to free weekly outdoor physical activity events ('parkrun') in England, with a particular focus on deprived communities, and to identify optimal locations for future events to further maximise access. STUDY DESIGN: This study is a cross-sectional ecological analysis of the socio-economic disparities in geographic access to parkrun events in England in late 2018. METHODS: We combined geolocation data on all English Lower Layer Super Output Areas and parkrun events to calculate geodesic distances to the nearest event for more than 32,000 communities in England. We use this measure of geographic access to summarise the relationship between access and socio-economic deprivation, measured using the index of multiple deprivation. We then used geographic coordinates of public green spaces in England to conduct a simple location-allocation analysis to identify 200 locations for future event locations that would maximise access. RESULTS: In England, 69% of the population live within 5 km of one of the 465 parkrun events. There is a small negative correlation between distance and deprivation, indicating that access is slightly better in more socio-economically deprived areas. Setting up an additional 200 events in optimal locations would improve access: the average distance to the nearest parkrun event would improve by 1.22 km, from 4.65 km to 3.43 km, and approximately 82% of the English population would live within 5 km of a parkrun event. CONCLUSION: Over two-thirds of the English population live within 5 km of a parkrun event, and contrary to our expectation, we find that geographic access is slightly better for those living in more deprived communities. Creating additional events may improve geographic access, but effective strategies will still be needed to increase engagement in new and existing events by those living in socio-economically deprived areas.

Analysis of pesticide mixtures discharged to the lagoon of the Great Barrier Reef, Australia.

Organisms and ecosystems are generally exposed to mixtures of chemicals rather than to individual chemicals, but there have been relatively few detailed analyses of the mixtures of pesticides that occur in surface waters. This study examined over 2600 water samples, analysed for between 21 and 47 pesticides, from 15 waterways that discharge to the lagoon of the Great Barrier Reef in Queensland, Australia between July 1, 2011 and June 30, 2015. Essentially all the samples (99.8%) contained detectable concentrations (>limit of detection) of pesticides and pesticide mixtures. Approximately, 10% of the samples contained no quantifiable (>limit of reporting) pesticides, 10% contained one quantifiable pesticide and 80% contained quantifiable mixtures of 2-20 pesticides. Approximately 82% of samples that contained quantifiable mixtures had more than two modes of action (MoAs), but only approximately 6% had five or more MoAs. The mode, average and median number of quantifiable pesticides in all the samples were 2, 5.1 and 4, respectively. The most commonly detected compounds both individually and in mixtures were the pesticides atrazine, diuron, imidacloprid, hexazinone, 2,4-D, and the degradation product desethylatrazine. The number of pesticides and modes of action of pesticides in mixtures differed spatially and were affected by land use. Waterways draining catchments where sugar cane was a major land use had mixtures with the most pesticides.

Investigating diagnostic sequencing techniques for CADASIL diagnosis.

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a cerebral small vessel disease caused by mutations in the NOTCH3 gene. Our laboratory has been undertaking genetic diagnostic testing for CADASIL since 1997. Work originally utilised Sanger sequencing methods targeting specific NOTCH3 exons. More recently, next-generation sequencing (NGS)-based technologies such as a targeted gene panel and whole exome sequencing (WES) have been used for improved genetic diagnostic testing. In this study, data from 680 patient samples was analysed for 764 tests utilising 3 different sequencing technologies. Sanger sequencing was performed for 407 tests, a targeted NGS gene panel which includes NOTCH3 exonic regions accounted for 354 tests, and WES with targeted analysis was performed for 3 tests. In total, 14.7% of patient samples (n = 100/680) were determined to have a mutation. Testing efficacy varied by method, with 10.8% (n = 44/407) of tests using Sanger sequencing able to identify mutations, with 15.8% (n = 56/354) of tests performed using the NGS custom panel successfully identifying mutations and a likely non-NOTCH3 pathogenic variant (n = 1/3) identified through WES. Further analysis was then performed through stratification of the number of mutations detected at our facility based on the number of exons, level of pathogenicity and the classification of mutations as known or novel. A systematic review of NOTCH3 mutation testing data from 1997 to 2017 determined the diagnostic rate of pathogenic findings and found the NGS-customised panel increases our ability to identify disease-causing mutations in NOTCH3.

Generation of intense quasi-electrostatic fields due to deposition of particles accelerated by petawatt-range laser-matter interactions.

We demonstrate here for the first time that charge emitted by laser-target interactions at petawatt peak-powers can be efficiently deposited on a capacitor-collector structure far away from the target and lead to the rapid (tens of nanoseconds) generation of large quasi-static electric fields over wide (tens-of-centimeters scale-length) regions, with intensities much higher than common ElectroMagnetic Pulses (EMPs) generated by the same experiment in the same position. A good agreement was obtained between measurements from a classical field-probe and calculations based on particle-flux measurements from a Thomson spectrometer. Proof-of-principle particle-in-cell simulations reproduced the measurements of field evolution in time, giving a useful insight into the charging process, generation and distribution of fields. The understanding of this charging phenomenon and of the related intense fields, which can reach the MV/m order and in specific configurations might also exceed it, is very important for present and future facilities studying laser-plasma-acceleration and inertial-confinement-fusion, but also for application to the conditioning of accelerated charged-particles, the generation of intense electric and magnetic fields and many other multidisciplinary high-power laser-driven processes.

Clinical and genetic spectrum of SCN2A-associated episodic ataxia.

BACKGROUND: Pathogenic variants in SCN2A are associated with various neurological disorders including epilepsy, autism spectrum disorder and intellectual disability. Few reports have recently described SCN2A-associated episodic ataxia (EA). Our study identifies its broader clinical and genetic spectrum, and describes pharmacological approaches. RESULTS: We report 21 patients with SCN2A-associated EA, of which 9 are unpublished cases. The large majority of patients present with epileptic seizures (18/21, 86%), often starting within the first three months of life (12/18, 67%). In contrast, onset of episodic ataxia ranged from 10 months to 14 years of age. The frequency of EA episodes ranged from brief, daily events up to 1-2 episodes per year each lasting several weeks. Potential triggers include minor head traumas and sleep deprivation. Cognitive outcome is favorable in most patients with normal or mildly impaired cognitive development in 17/21 patients (81%). No clear genotype-phenotype correlations were identified in this cohort. However, two mutational hotspots were identified, i.e. 7/21 patients (33%) harbor the identical pathogenic variant p.A263V, whereas 5/21 (24%) carry pathogenic variants that affect the S4 segment and its cytoplasmic loop within the domain IV. In addition, we identified six novel pathogenic variants in SCN2A. While acetazolamide was previously reported as beneficial in SCN2A-associated EA in one case, our data show a conflicting response in 8 additional patients treated with acetazolamide: three of them profited from acetazolamide treatment, while 5/8 did not. CONCLUSIONS: Our study describes the heterogeneous clinical spectrum of SCN2A-associated EA, identifies two mutational hotspots and shows positive effects of acetazolamide in about 50%.

Observation of a superconducting glass state in granular superconducting diamond.

The magnetic field dependence of the superconductivity in nanocrystalline boron doped diamond thin films is reported. Evidence of a superconducting glass state is presented, as demonstrated by the observation of a quasi de Almeida-Thouless line in the phase diagram and a logarithmic time dependence of the magnetism. The position of the phase boundary in the H-T plane is determined from electrical transport data by detailed fitting to quasi-zero-dimensional fluctuation conductivity theory. This allows determination of the boundary between resistive and non-resistive behaviour to be made with greater precision than the standard ad hoc onset/midpoint/offset criterion. We attribute the glassy superconductivity to the morphological granularity of the diamond films.

A pilot investigation of differential neuroendocrine associations with fronto-limbic activation during semantically-cued list learning in mood disorders.

BACKGROUND: Decreased volume and disrupted function in neural structures essential for memory formation (e.g. medial temporal lobe and prefrontal cortex) are common among individuals with depression. Hypothalamic-pituitary-axis function, as reflected by measurement of cortisol levels, is linked to neural activity during memory encoding in healthy people. However, it is not as well understood whether cortisol is associated with alterations in fronto-temporal recruitment during memory encoding in depression. METHODS: In this pilot study, we evaluated associations between cortisol and neural activation during memory encoding in 62 adults (18-65 years) with mood disorders (MD; n = 39, 66.7% female), including major depression (n = 28) and bipolar I disorder (n = 11), and healthy controls (HC; n = 23, 43.5% female). Participants provided salivary cortisol samples before and after completing a semantically-cued list-learning task during 3-Tesla fMRI. Links between pre-scan cortisol (and cortisol change) and activation during encoding were evaluated using block and event-related models. RESULTS: Overall, pre-scan cortisol level was positively associated with greater engagement of fronto-limbic activation during the encoding block. However, in MD, pre-scan cortisol was associated with attenuated activation during encoding in medial frontal, superior and middle temporal gyri, insula, lingual gyrus, and claustrum relative to HCs. Cortisol-related attenuation of activation in MD was also observed during encoding of words subsequently recalled in the ventral anterior cingulate, hypothalamus, and middle temporal gyrus. By and large, cortisol change (pre/post scan) predicted the same pattern of findings in both block and event-related contrasts. LIMITATIONS: Although analyses accounted for variations in scanner time of day, circadian alterations in cortisol may have introduced variability into the results. CONCLUSIONS: Pre-scan cortisol may selectively interfere with recruitment of important fronto-temporal memory circuitry in mood disorders. The inverted associations between cortisol and neural function in MD relative to HC also elucidate potentially unique pathophysiological markers of mood disorders.

Assessment of bulbar function in amyotrophic lateral sclerosis: validation of a self-report scale (Center for Neurologic Study Bulbar Function Scale).

BACKGROUND AND PURPOSE: Impaired bulbar functions of speech and swallowing are among the most serious consequences of amyotrophic lateral sclerosis (ALS). Despite this, clinical trials in ALS have rarely emphasized bulbar function as an endpoint. The rater-administered Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised (ALSFRS-R) or various quality-of-life measures are commonly used to measure symptomatic benefit. Accordingly, we sought to evaluate the utility of measures specific to bulbar function in ALS. METHODS: We assessed bulbar functions in 120 patients with ALS, with clinicians first making direct observations of the degree of speech, swallowing and salivation impairment in these subjects. Clinical diagnosis of bulbar impairment was then compared with ALSFRS-R scores, speech rate, time to swallow liquids and solids, and scores obtained when patients completed visual analog scales (VASs) and the newly-developed 21-question self-administered Center for Neurologic Study Bulbar Function Scale (CNS-BFS). RESULTS: The CNS-BFS, ALSFRS-R, VAS and timed speech and swallowing were all concordant with clinician diagnosis. The self-report CNS-BFS and ALSFRS-R bulbar subscale best predicted clinician diagnosis with misclassification rates of 8% and 14% at the optimal cut-offs, respectively. In addition, the CNS-BFS speech and swallowing subscales outperformed both the bulbar component of the ALSFRS-R and speech and swallowing VASs when correlations were made between these scales and objective measures of timed reading and swallowing. CONCLUSIONS: Based on these findings and its relative ease of administration, we conclude that the CNS-BFS is a useful metric for assessing bulbar function in patients with ALS.

Absolute calibration of optical streak cameras on picosecond time scales using supercontinuum generation.

We report a new method using high-stability, laser-driven supercontinuum generation in a liquid cell to calibrate the absolute photon response of fast optical streak cameras as a function of wavelength when operating at fastest sweep speeds. A stable, pulsed white light source based around the use of self-phase modulation in a salt solution was developed to provide the required brightness on picosecond time scales, enabling streak camera calibration in fully dynamic operation. The measured spectral brightness allowed for absolute photon response calibration over a broad spectral range (425-650 nm). Calibrations performed with two Axis Photonique streak cameras using the Photonis P820PSU streak tube demonstrated responses that qualitatively follow the photocathode response. Peak sensitivities were one photon/count above background. The absolute dynamic sensitivity is less than the static by up to an order of magnitude. We attribute this to the dynamic response of the phosphor being lower.

Staged reconstruction of diaphyseal fractures with segmental defects: Surgical and patient-reported outcomes.

INTRODUCTION: Two-stage limb reconstruction is an option for patients with critical size segmental bone defects following acute trauma or non-union. Reconstruction is technically demanding and associated with a high complication rate. Current protocols for limb reconstruction have well-documented challenges, and no study has reported on patient outcomes using a validated questionnaire. In this study, we aimed to examine the clinical and patient-centered outcomes following our surgical protocol for two-stage limb reconstruction following critical size segmental defects. PATIENTS AND METHODS: A single surgeon performed reconstruction of long bone defects using antibiotic impregnated cement spacers and intramedullary cancellous bone autograft. A retrospective chart review was performed. Three reviewers independently measured time to union based on radiographs. The Lower Extremity Functional Scale (LEFS) survey was administered to patients after most recent follow-up. RESULTS: Ten limbs representing nine patients were included. All patients sustained a lower extremity injury, and one patient had bilateral lower extremity injuries. Average clinical follow-up was 18.3 months (range 7-33) from final surgical intervention, and follow-up to questionnaire administration was 28 months (range 24-37). The mean time between stages was 3.1 months. Average time to unrestricted weight-bearing was 7.9 months from Stage 1 (range 3.4-15.9) and 4.5 months from Stage 2 (range 1.1-11.6). Average time to full union was 16.7 months from Stage 1 (range 6.4-28.6) and 13.5 months from Stage 2 (range 1.8-27). Eight patients (nine limbs) participated in the LEFS survey, the average score was 53.1 (range 30-67), equating to 66% of full functionality (range 38%-84%). Complications included 5 infections, 3 non-unions, and one amputation. There was a moderate positive correlation between infection at any time point and non-union (R=0.65, p=0.03). DISCUSSION AND CONCLUSIONS: Outcomes in this small patient cohort were good despite risks of complication. There is an association between infection and non-union. Further studies addressing clinical and functional outcomes will help to guide expectations for future surgeons and patients.

Monte Carlo profile confidence intervals for dynamic systems.

Monte Carlo methods to evaluate and maximize the likelihood function enable the construction of confidence intervals and hypothesis tests, facilitating scientific investigation using models for which the likelihood function is intractable. When Monte Carlo error can be made small, by sufficiently exhaustive computation, then the standard theory and practice of likelihood-based inference applies. As datasets become larger, and models more complex, situations arise where no reasonable amount of computation can render Monte Carlo error negligible. We develop profile likelihood methodology to provide frequentist inferences that take into account Monte Carlo uncertainty. We investigate the role of this methodology in facilitating inference for computationally challenging dynamic latent variable models. We present examples arising in the study of infectious disease transmission, demonstrating our methodology for inference on nonlinear dynamic models using genetic sequence data and panel time-series data. We also discuss applicability to nonlinear time-series and spatio-temporal data.

Low-noise time-resolved optical sensing of electromagnetic pulses from petawatt laser-matter interactions.

We report on the development and deployment of an optical diagnostic for single-shot measurement of the electric-field components of electromagnetic pulses from high-intensity laser-matter interactions in a high-noise environment. The electro-optic Pockels effect in KDP crystals was used to measure transient electric fields using a geometry easily modifiable for magnetic field detection via Faraday rotation. Using dielectric sensors and an optical fibre-based readout ensures minimal field perturbations compared to conductive probes and greatly limits unwanted electrical pickup between probe and recording system. The device was tested at the Vulcan Petawatt facility with 1020 W cm-2 peak intensities, the first time such a diagnostic has been used in this regime. The probe crystals were located ~1.25 m from target and did not require direct view of the source plasma. The measured signals compare favourably with previously reported studies from Vulcan, in terms of the maximum measured intra-crystal field of 10.9 kV/m, signal duration and detected frequency content which was found to match the interaction chamber's horizontal-plane fundamental harmonics of 76 and 101 MHz. Methods for improving the diagnostic for future use are also discussed in detail. Orthogonal optical probes offer a low-noise alternative for direct simultaneous measurement of each vector field component.