How can we address the uncertainties regarding the potential clinical utility of polygenic score-based tests?

As common low penetrance variants associated with diseases are uncovered, attempts continue to be made to harness this knowledge for improving healthcare. Polygenic scores have been developed as the mechanism by which knowledge of common variants can be used to investigate genetic contributions to disease risk. They serve as a biomarker to provide an estimate of the genetic liability for a particular disease. Discussion continues as to whether polygenic scores are a useful biomarker and their readiness for incorporation into clinical and public health practice. In this paper, we investigate the key challenges that need to be addressed, in the description and assessment of the clinical utility of polygenic score-based tests for use in clinical and public health practice.

The risk of developing many common diseases, such as heart disease is influenced by both genetic and lifestyle factors. Polygenic scores (PGS) are one way of assessing an individual's risk of developing certain diseases. There is still uncertainty as to whether and how to use PGS for individual care. Much of this is because it is unclear as to whether tests that give a PGS can provide useful information for the care of individuals and patients as part of prevention or healthcare pathways. In this paper, we describe some of the challenges that need to be addressed, so that we can move forward and better understand when and how to use these tests for population and individual benefit.

Optimising Exome Prenatal Sequencing Services (EXPRESS): a study protocol to evaluate rapid prenatal exome sequencing in the NHS Genomic Medicine Service.

Background: Prenatal exome sequencing (ES) for the diagnosis of fetal anomalies was implemented nationally in England in October 2020 by the NHS Genomic Medicine Service (GMS). is the GMS is based around seven regional Genomic Laboratory Hubs (GLHs). Prenatal ES has the potential to significantly improve NHS prenatal diagnostic services by increasing genetic diagnoses and informing prenatal decision-making. Prenatal ES has not previously been offered routinely in a national healthcare system and there are gaps in knowledge and guidance. Methods: Our mixed-methods evaluation commenced in October 2020, aligning with the start date of the NHS prenatal ES service . Study design draws on a framework developed in previous studies of major system innovation. There are five interrelated workstreams. Workstream-1 will use interviews and surveys with professionals, non-participant observations and documentary analysis to produce in-depth case studies across all GLHs. Data collection at multiple time points will track changes over time. In Workstream-2 qualitative interviews with parents offered prenatal ES will explore experiences and establish information and support needs. Workstream-3 will analyse data from all prenatal ES tests for nine-months to establish service outcomes (e.g. diagnostic yield, referral rates, referral sources). Comparisons between GLHs will identify factors (individual or service-related) associated with any variation in outcomes. Workstream-4 will identify and analyse practical ethical problems. Requirements for an effective ethics framework for an optimal and equitable service will be determined. Workstream-5 will assess costs and cost-effectiveness of prenatal ES versus standard tests and evaluate costs of implementing an optimal prenatal ES care pathway. Integration of findings will determine key features of an optimal care pathway from a service delivery, parent and professional perspective. Discussion: The proposed formative and summative evaluation will inform the evolving prenatal ES service to ensure equity of access, high standards of care and benefits for parents across England.

BACKGROUND: Prenatal exome sequencing is a new test that is offered through the NHS Genomic Medicine Service. Prenatal exome sequencing is offered to pregnant women when ultrasound scans suggest that their baby may have a genetic condition that cannot be diagnosed using standard tests. If a genetic condition is diagnosed this can give parents important information about the outlook for their baby. It can also help with their decisions about whether to continue or end the pregnancy, pregnancy management, post-birth care and future pregnancies. STUDY METHODS: The aim of this study is to evaluate the prenatal exome sequencing service. To do this we will; 1. Study how prenatal exome sequencing is delivered across England using surveys and interviews with professionals.2. Interview parents to ask what they think of prenatal exome sequencing and how support and information could be improved3. Look at how many parents have prenatal exome sequencing and the test results. We will look carefully at who has access to the test and whether any particular groups are less likely to be offered testing.4. Conduct workshops with health professionals and parents to identify any practical or ethical problems that arise when prenatal exome sequencing is offered.5. Look at the cost of prenatal exome sequencing and compare it to the cost of other tests that are offered to diagnose genetic conditions in pregnancy.6. Gather our findings together to make recommendations for best practice. Patient and Public Involvement: A patient and public Involvement, engagement and participation (PPIEP) advisory group will work closely with the research team to design the study and develop study materials. They will also help us understand our findings to make sure the information and recommendations that come out of our research will be helpful to parents and the NHS.

The effect of the electric trapping field on state-selective loading of molecules into rf ion traps.

Trapped molecular ions in pure rovibronic states are desirable in experiments ranging from cold chemistry to searches for physics beyond the Standard Model. Resonance-enhanced multiphoton ionisation (REMPI) can be used to prepare molecular ions in specific internal states with high fidelities. However, in the presence of electric fields, ionisation spectra exhibit frequency shifts and the ionisation thresholds are broadened. For this reason, REMPI studies are normally conducted in low and highly homogeneous electric fields, whereas the operating principle of rf ion traps requires electric fields that vary in space and time. In order to investigate the impact of this on the state-selectivity of REMPI in ion traps, we have simulated the expected broadening of the ionisation threshold under various operating conditions of a typical linear Paul trap. In many cases, the width of the ionisation threshold exceeds the separation between rotational energy levels, preventing state-selective ionisation. Careful choice of the trapping and laser parameters during loading can reduce this broadening, enabling state-selective ionisation in some instances. Where this strategy is not sufficient, the broadening can be reduced further by rapidly switching the trapping voltages off and on again during loading. This has been demonstrated experimentally for a Coulomb crystal of [Formula: see text] ions without descrystallising it.

Evaluation of linear and non-linear activation dynamics models for insect muscle.

In computational modelling of sensory-motor control, the dynamics of muscle contraction is an important determinant of movement timing and joint stiffness. This is particularly so in animals with many slow muscles, as is the case in insects-many of which are important models for sensory-motor control. A muscle model is generally used to transform motoneuronal input into muscle force. Although standard models exist for vertebrate muscle innervated by many motoneurons, there is no agreement on a parametric model for single motoneuron stimulation of invertebrate muscle. Although several different models have been proposed, they have never been evaluated using a common experimental data set. We evaluate five models for isometric force production of a well-studied model system: the locust hind leg tibial extensor muscle. The response of this muscle to motoneuron spikes is best modelled as a non-linear low-pass system. Linear first-order models can approximate isometric force time courses well at high spike rates, but they cannot account for appropriate force time courses at low spike rates. A linear third-order model performs better, but only non-linear models can account for frequency-dependent change of decay time and force potentiation at intermediate stimulus frequencies. Some of the differences among published models are due to differences among experimental data sets. We developed a comprehensive toolbox for modelling muscle activation dynamics, and optimised model parameters using one data set. The "Hatze-Zakotnik model" that emphasizes an accurate single-twitch time course and uses frequency-dependent modulation of the twitch for force potentiation performs best for the slow motoneuron. Frequency-dependent modulation of a single twitch works less well for the fast motoneuron. The non-linear "Wilson" model that optimises parameters to all data set parts simultaneously performs better here. Our open-access toolbox provides powerful tools for researchers to fit appropriate models to a range of insect muscles.

The effect of self efficacy and meaning in life on posttraumatic stress disorder and depression severity among veterans.

OBJECTIVE: The current study examined the relationships among combat exposure, presence of and search for meaning in life, general and social self-efficacy, and both posttraumatic stress disorder (PTSD) and depression symptom severity for a Veteran sample (N = 93). METHOD: Participants completed an online survey comprising the Combat Exposure Scale, Meaning in Life Questionnaire, Self-Efficacy Scale, Depression subscale of the Depression, Anxiety, Stress Scales-21, and PTSD Checklist-Specific Stressor version. The majority of participants were male and Caucasian. Participants served in various service eras RESULTS: To determine factors that predicted PTSD and depression severity, separate hierarchical linear regressions were performed. In the final PTSD model, rank, combat exposure, and general self-efficacy were significant predictors, with officer rank, lower combat exposure, and higher general self-efficacy associated with lower PTSD severity. The interaction between combat exposure and general self-efficacy was also significant, with self-efficacy moderating the relationship between combat exposure and PTSD severity. For depression, rank, presence of meaning in life, and general self-efficacy were significant predictors in the model, with officer rank, higher presence of meaning in life, and general self-efficacy associated with lower depression severity. CONCLUSION: A focus on strengthening self-efficacy may assist with lower levels of PTSD and depression symptomatology after combat trauma.

First-dose pharmacokinetics of aminoglycosides in critically ill haematological malignancy patients.

The primary objective of this study was to determine the volume of distribution (Vd) (L/kg) of intravenous aminoglycosides (AGs) in critically ill haematological malignancy patients. Secondary objectives were to determine the body weight (actual, ideal, adjusted or lean) that yields the most precise estimate of Vd when normalised in L/kg as well as the frequency that current first-dose strategies result in post-distributional peak concentrations (C(peak)) within the target range (tobramycin 16-24 mg/L; amikacin 32-48 mg/L). In total, 58 AG doses were included (tobramycin, n = 34; amikacin, n = 24). Median Vd was 0.38 L/kg normalised per the most precise dose weight, which was actual body weight (ABW). The median dose was 445 mg (5.8 mg/kg ABW) for tobramycin and 1200 mg (13.8 mg/kg ABW) for amikacin. Target C(peak) (tobramycin 20mg/L; amikacin 40 mg/L) was achieved in only 25% of all AG episodes, with 4% exceeding the target and 71% falling below the target. Twenty-four organisms were isolated in the study sample; target C(peak) achievement (tobramycin 20 mg/L; amikacin 40 mg/L) would yield a peak:minimum inhibitory concentration of 10 in 75% and 52% of organisms, respectively. In conclusion, an increased Vd of AGs was identified in this critically ill haematological malignancy patient sample, and current dosing yielded a suboptimal C(peak) in the majority of patients.

Differences in relationship conflict, attachment, and depression in treatment-seeking veterans with hazardous substance use, PTSD, or PTSD and hazardous substance use.

Veterans (N = 133) who were seeking treatment in either the Posttraumatic Stress Program or Substance Use Disorders Program at a Veterans Affairs Medical Center (VAMC) and, based on self-report of symptoms, met clinical norms for posttraumatic stress disorder (PTSD) or hazardous substance use (HSU) completed a survey related to relationship conflict behaviors, attachment styles, and depression severity. Participants were grouped into one of three categories on the basis of clinical norm criteria: PTSD only, HSU only, and PTSD + HSU. Participants completed the PTSD Checklist-Military, Experiences in Close Relationships Scale-Short Form, Center for Epidemiologic Studies-Depression scale, Alcohol Use Disorders Identification Test, Drug Use Disorders Identification Test, and Psychological Aggression and Physical Violence subscales of the Conflict Tactics Scale. Most participants were male and Caucasian. Significant differences were found between groups on depression, avoidant attachment, psychological aggression perpetration and victimization, and physical violence perpetration and victimization. Post hoc analyses revealed that the PTSD + HSU group had significantly higher levels of depression, avoidant attachment, and psychological aggression than the HSU only group. The PTSD + HSU group had significantly higher levels of physical violence than did the PTSD only group, but both groups had similar mean scores on all other variables. Potential treatment implications are discussed.

What does "local" firewood buy you? Managing the risk of invasive species introduction.

Firewood can serve as a vector in the transport of non-native species, including wood-boring insects that feed within the wood and thus can be transported accidentally. Governments have enacted limitations on the movement of firewood in an effort to limit the anthropogenic movement of non-native species through, for example, recreational camping. Although the movement of invasive species through firewood is a documented invasion pathway, it is not trivial for governments to determine a "safe" allowable distance for moving firewood. We were motivated by this challenge and developed a theoretical simulation to determine the campgrounds that could be potentially exposed to infested firewood based upon the hypothetical distribution of an invasive species and the allowable distance for moving firewood. We extend this concept to the known distributions of emerald ash borer, Agrilus planipennis Fairmaire (Coleoptera: Buprestidae) and Asian longhorned beetle, Anoplophora glabripennis (Motschulsky) Coleoptera: Cerambycidae). We illustrate, based upon theoretical and empirical observations, that as the distribution of an invasive species increases, more rigid constraints on the movement of firewood would be required relative to those species that are distributed over a smaller scale. Also, on the level of management within a state, smaller states have far less margin for error than larger ones, as even extremely rigid restrictions on the movement of firewood could have little management effect unless the infested area is spatially limited. These results collectively suggest the potential for a dynamic management strategy that adjusts allowable distances for firewood movement based upon the distribution of the non-native species.

Human visitation rates to the Apostle Islands National Lakeshore and the introduction of the non-native species Lymantria dispar (L.).

The introduction of non-native species has accelerated due to increasing levels of global trade and travel, threatening the composition and function of ecosystems. Upon arrival and successful establishment, biological invaders begin to spread and often do so with considerable assistance from humans. Recreational areas can be especially prone to the problem of accidental non-native species transport given the number of visitors that arrive from geographically diverse areas. In this paper, we examine camping permit data to the Apostle Islands National Lakeshore in northwestern Wisconsin, USA, from 1999 to 2007 relative to gypsy moth distribution, phenology and outbreak data. During this time, gypsy moth populations became established in this area ahead of the moving population front of the gypsy moth, suggesting anthropogenic introduction. The permit data revealed that the majority of visitors arrived from outside of the gypsy moth established area. However, there was a consistent yearly trend of visitors that arrived from areas of high gypsy moth populations and who arrived during the gypsy moth life stage (egg masses) most likely to be successfully introduced. Using available data on the gypsy moth and its relationship to camping permit data, we describe how recreational managers could optimize park strategies to mitigate unwanted introductions of the gypsy moth as well as develop analogous strategies for managing other biological invaders in recreational areas.

Motor neurone responses during a postural reflex in solitarious and gregarious desert locusts.

Desert locusts show extreme phenotypic plasticity and can change reversibly between two phases that differ radically in morphology, physiology and behaviour. Solitarious locusts are cryptic in appearance and behaviour, walking slowly with the body held close to the ground. Gregarious locusts are conspicuous in appearance and much more active, walking rapidly with the body held well above the ground. During walking, the excursion of the femoro-tibial (F-T) joint of the hind leg is smaller in solitarious locusts, and the joint is kept more flexed throughout an entire step. Under open loop conditions, the slow extensor tibiae (SETi) motor neurone of solitarious locusts shows strong tonic activity that increases at more extended F-T angles. SETi of gregarious locusts by contrast showed little tonic activity. Simulated flexion of the F-T joint elicits resistance reflexes in SETi in both phases, but regardless of the initial and final position of the leg, the spiking rate of SETi during these reflexes was twice as great in solitarious compared to gregarious locusts. This increased sensory-motor gain in the neuronal networks controlling postural reflexes in solitarious locusts may be linked to the occurrence of pronounced behavioural catalepsy in this phase similar to other cryptic insects such as stick insects.

Long-distance dispersal of the gypsy moth (Lepidoptera: Lymantriidae) facilitated its initial invasion of Wisconsin.

Gypsy moth (Lymantria dispar L.) spread is dominated by stratified dispersal, and, although spread rates are variable in space and time, the gypsy moth has invaded Wisconsin at a consistently higher rate than in other regions. Allee effects, which act on low-density populations ahead of the moving population that contribute to gypsy moth spread, have also been observed to be consistently weaker in Wisconsin. Because a major cause of an Allee effect in the gypsy moth is mate-finding failure at low densities, supplementing low-density populations with immigrants that arrive through dispersal may facilitate establishment and consequent spread. We used local indicator of spatial autocorrelation methods to examine space-time gypsy moth monitoring data from 1996 to 2006 and identify isolated, low-density colonies that arrived through dispersal. We measured the distance of these colonies from the moving population front to show that long-distance dispersal was markedly present in earlier years when Wisconsin was still mainly uninfested. Recently, however, immigrants arriving through long-distance dispersal may no longer be detected because instead of invading uninfested areas, they are now supplementing high-density colonies. In contrast, we observed no temporal pattern in the distance between low-density colonies and the population front in West Virginia and Virginia. We submit that long-distance dispersal, perhaps facilitated through meteorological mechanisms, played an important role in the spread dynamics of the initial Wisconsin gypsy moth invasion, but it currently plays a lesser role because the portion of Wisconsin most susceptible to long-distance immigrants from alternate sources is now heavily infested.