Applications of OPM-MEG for translational neuroscience: a perspective.

Magnetoencephalography (MEG) allows the non-invasive measurement of brain activity at millisecond precision combined with localization of the underlying generators. So far, MEG-systems consisted of superconducting quantum interference devices (SQUIDS), which suffer from several limitations. Recent technological advances, however, have enabled the development of novel MEG-systems based on optically pumped magnetometers (OPMs), offering several advantages over conventional SQUID-MEG systems. Considering potential improvements in the measurement of neuronal signals as well as reduced operating costs, the application of OPM-MEG systems for clinical neuroscience and diagnostic settings is highly promising. Here we provide an overview of the current state-of-the art of OPM-MEG and its unique potential for translational neuroscience. First, we discuss the technological features of OPMs and benchmark OPM-MEG against SQUID-MEG and electroencephalography (EEG), followed by a summary of pioneering studies of OPMs in healthy populations. Key applications of OPM-MEG for the investigation of psychiatric and neurological conditions are then reviewed. Specifically, we suggest novel applications of OPM-MEG for the identification of biomarkers and circuit deficits in schizophrenia, dementias, movement disorders, epilepsy, and neurodevelopmental syndromes (autism spectrum disorder and attention deficit hyperactivity disorder). Finally, we give an outlook of OPM-MEG for translational neuroscience with a focus on remaining methodological and technical challenges.

Superiority and cost-effectiveness of Individual Placement and Support versus standard employment support for people with alcohol and drug dependence: a pragmatic, parallel-group, open-label, multicentre, randomised, controlled, phase 3 trial.

Background: Individual Placement and Support (IPS) is a specialist intervention to help people attain employment in the open competitive labour market. IPS has been developed in severe mental illness and other disabilities, but it is of unknown effectiveness for people with alcohol and drug dependence. The Individual Placement and Support-Alcohol and Drug (IPS-AD) is the first superiority trial to evaluate effectiveness and cost-effectiveness. Methods: IPS-AD was a pragmatic, parallel-group, multi-centre, randomised, controlled, phase 3 trial of standard employment support (treatment-as-usual [TAU]) versus IPS. IPS was offered as a single episode for up to 13 months. The study was done at seven community treatment centres for alcohol and drug dependence in England. Study participants were adults (18-65 years), who had been enrolled for at least 14 days in treatment for alcohol use disorder (AUD), opioid use disorder (OUD), or another drug use disorder (DUD; mostly cannabis and stimulants); were unemployed or economically inactive for at least six months; and wished to attain employment in the open competitive labour market. After random allocation to study interventions, the primary outcome was employment during 18-months of follow-up, analysed by mixed-effects logistic regression, using multiple imputation for the management of missing outcome data. There were two cost-effectiveness outcomes: a health outcome expressed as a quality adjusted life year (QALY) using £30,000 and £70,000 willingness-to-pay [WTP] thresholds; and additional days of employment, with a WTP threshold of £200 per day worked. The study was registered with ISRCTN (ISRCTN24159790) and is completed. Findings: Between 8 May 2018 and 30 September 2019, 2781 potentially eligible patients were identified. 812 were excluded before screening, and 1720 participants were randomly allocated to TAU or IPS. In error, nine participants were randomised to study interventions on two occasions-so data for their first randomisation was analysed (modified intention-to-treat). A further 24 participants withdrew consent for all data to be used (full-analysis set therefore 1687 participants [70.1% male; mean age 40.8 years]; TAU, n = 844; IPS, n = 843 [AUD, n = 610; OUD, n = 837; DUD, n = 240]). Standard employment support was received by 559 [66.2%] of 844 participants in the TAU group. IPS was received by 804 [95.37%] of 843 participants in the IPS group. IPS was associated with an increase in attainment of employment compared with TAU (adjusted odds ratio [OR] 1.29; 95% CI 1.02-1.64; p-value 0.036). IPS was effective for the AUD and DUD groups (OR 1.48; 95% CI 1.14-1.92; p-value 0.004; OR 1.45, 95% CI 1.03-2.04, p-value 0.031, respectively), but not the OUD group. IPS returned an incremental QALY outcome gain of 0.01 (range 0.003-0.02) per participant with no evidence of cost-effectiveness at either WTP threshold-but QALY gains were cost-effective for the AUD and DUD groups at the £70,000 WTP threshold (probability 0.52 and 0.97, respectively). IPS was cost-effective for additional days of employment (probability 0.61), with effectiveness relating to the AUD group only (probability >0.99). Serious Adverse Events were reported by 39 participants (13 [1.5%] of 844 participants in the TAU group and 23 [2.7%] of 43 participants in the IPS group). There was a total of 25 deaths (1.5%; 9 in the TAU group and 16 in the IPS group)-none judged related to study interventions. Interpretation: In this first superiority randomised controlled trial of IPS in alcohol and drug dependence, IPS helped more people attain employment in the open competitive labour market than standard employment support. IPS was cost-effective for a QALY health outcome (£70,000 WTP threshold) for the AUD and DUD groups, and for additional days of employment for the AUD group (£200 per day worked WTP threshold). Funding: UK government Work and Health Unit.

Reference ranges for ambulatory heart rate measurements in a middle-aged population.

BACKGROUND: Elevated heart rate (HR) predicts cardiovascular disease and mortality, but there are no established normal limits for ambulatory HR. We used data from the Swedish CArdioPulmonary Imaging Study to determine reference ranges for ambulatory HR in a middle-aged population. We also studied clinical correlates of ambulatory HR. METHODS: A 24-hour ECG was registered in 5809 atrial fibrillation-free individuals, aged 50-65 years. A healthy subset (n=3942) was used to establish reference values (excluding persons with beta-blockers, cardiovascular disease, hypertension, heart failure, anaemia, diabetes, sleep apnoea or chronic obstructive pulmonary disease).Minimum HR was defined as the lowest 1-minute HR. Reference ranges are reported as means±SDs and 2.5th-97.5th percentiles. Clinical correlates of ambulatory HR were analysed with multivariable linear regression. RESULTS: The average mean and minimum HRs were 73±9 and 48±7 beats per minute (bpm) in men and 76±8 and 51±7 bpm in women; the reference range for mean ambulatory HR was 57-90 bpm in men and 61-92 bpm in women. Average daytime and night-time HRs are also reported. Clinical correlates, including age, sex, height, body mass index, physical activity, smoking, alcohol intake, diabetes, hypertension, haemoglobin level, use of beta-blockers, estimated glomerular filtration rate, per cent of predicted forced expiratory volume in 1 s and coronary artery calcium score, explained <15% of the interindividual differences in HR. CONCLUSION: Ambulatory HR varies widely in healthy middle-aged individuals, a finding with relevance for the management of patients with a perception of tachycardia. Differences in ambulatory HR between individuals are largely independent of common clinical correlates.

Genotyping single nucleotide polymorphisms and inferring ploidy by amplicon sequencing for polyploid, ploidy-variable organisms.

Whole genome duplication is hypothesized to have played a critical role in the evolution of several major taxa, including vertebrates, and while many lineages have rediploidized, some retain polyploid genomes. Additionally, variation in ploidy can occur naturally or be artificially induced within select plant and animal species. Modern genetic techniques have not been widely applied to polyploid or ploidy-variable species, in part due to the difficulty of obtaining genotype data from polyploids. In this study, we demonstrate a strategy for developing an amplicon sequencing panel of single nucleotide polymorphisms for high-throughput genotyping of polyploid organisms. We then develop a method to infer ploidy of individuals from amplicon sequencing data that is generalized to apply to any ploidy and does not require prior identification of heterozygous genotypes. Combining these two techniques will allow researchers to both infer ploidy and generate ploidy-aware genotypes with the same amplicon sequencing panel. We demonstrate this approach with white sturgeon Acipenser transmontanus, a ploidy-variable (octoploid, decaploid and dodecaploid) imperiled species under conservation management in the Pacific Northwest and obtained a panel of 325 loci. These loci were validated by examining inheritance in known-cross families, and the ploidy inference method was validated with known ploidy samples. We provide scripts that adapt existing pipelines to genotype polyploids and an R package for application of the ploidy inference method. We expect that these techniques will empower studies of genetic variation and inheritance in polyploid organisms that vary in ploidy level, either naturally or as a result of artificial propagation practices.

The effect evaluation of Individual Placement and Support (IPS) for patients with substance use disorders: study protocol for a randomized controlled trial of IPS versus enhanced self-help.

BACKGROUND: Employment is associated with better outcomes of substance use treatment and protects against relapse after treatment completion. Unemployment rates are high for people with substance use disorders (SUD) who undergo treatment, with Norwegian estimates ranging from 81 to 91%. Evidence-based vocational models are lacking for patients in SUD treatment but exist for patients with psychosis in terms of Individual Placement and Support (IPS). The aim of the IPS for substance use disorders (IPS-SUD) trial is to investigate the effect of IPS in a SUD population. METHODS/DESIGN: The IPS-SUD trial is a randomized controlled trial (RCT) comparing IPS to an enhanced control intervention. The study is a seven-site, two-arm, pragmatic, parallel-group, superiority RCT. Participants are randomly assigned (1:1) to receive either IPS plus treatment as usual (TAU) or to receive a self-help guide book and 12-h workshop plus 1-h individual vocational guidance plus TAU. Aiming to recruit 200 participants, we will be able to detect a 20% difference in the main outcome of employment with 90% power. We will make assessments at inclusion and at 6- and 12-month follow-ups and obtain outcome data on employment from national mandatory registries. The primary outcome will be at least 1 day of competitive employment during the 18-month follow-up period. Secondary employment outcomes will capture the pattern and extent of employment in terms of total time worked (days/hours), time to first employment, number of different jobs, duration of the longest employment, and sustained employment. Secondary non-employment outcomes will be substance use, mental distress, and quality of life measured by validated instruments at 6, 12, and 18 months follow-up assessments. To be eligible, participants must be between 18 and 65 years, currently unemployed and in treatment for SUD. DISCUSSION: The IPS-SUD trial will provide evidence for the use of IPS in a SUD population. Findings from the study will have implications for service delivery. TRIAL REGISTRATION: ClinicalTrials.gov NCT04289415 . Registered on February 28, 2020.

Protocol for a multi-centre, definitive randomised controlled trial of the effectiveness of Individual Placement and Support for employment support among people with alcohol and drug dependence.

BACKGROUND: Unemployment is highly prevalent in populations with alcohol and drug dependence and the employment support offered in addiction-treatment programmes is ineffective. Individual Placement and Support (IPS) is an evidence-based intervention for competitive employment. IPS has been extensively studied in severe mental illness and physical disabilities, but there have been no formal randomised controlled trials (RCTs) in alcohol and drug dependence. The Individual Placement and Support for Alcohol and Drug Dependence (IPS-AD) study should determine whether IPS for patients with alcohol use disorder (AUD), opioid use disorder (OUD) and other drug use disorder is effective. DESIGN/METHODS: The IPS-AD study is a seven-site, pragmatic, two-arm, parallel-group, superiority RCT. IPS-AD includes a realist process evaluation. Eligible patients (adult, unemployed or economically inactive for at least 6 months and wishing to obtain open job market employment and enrolled in ongoing community treatment-as-usual (TAU; the control condition) in England for AUD, OUD and other drug use disorders) will be randomised (1:1) to receive TAU and any standard employment support, or TAU plus IPS (the experimental condition) for 9 months with up to 4 months of in-work support. The primary outcome measure will be competitive employment status (at least 1 day (7 h)) during an 18-month follow-up, determined by patient-level, trial-data-linkage with national tax and state benefit databases. From meta-analysis, an 18% target difference on this measure of vocational effectiveness (for the experimental intervention) and a two-sided 5% level of statistical significance, will require a minimum target sample of 832 participants to achieve 90% power for a pre-registered, mixed-effects, multi-variable logistic regression model. A maximum-likelihood multiple-imputation approach will manage missing outcome data. IPS-AD has six vocational secondary outcome measures during the 18-month follow-up: (1) total time in competitive employment (and corresponding National Insurance contributions and tax paid); (2) time from randomisation to first competitive employment; (3) number of competitive job appointments; (4) job tenure (length of longest held competitive employment); (5) sustained employment (tenure in a single appointment for at least 13 weeks); and (6) job search self-efficacy. A primary cost-benefit analysis and a secondary cost-effectiveness analysis will be done using the primary outcome and secondary vocational outcomes, respectively and will include addiction treatment and social and health outcomes and their associated reference costs. The process evaluation will address IPS implementation and delivery. DISCUSSION: The IPS-AD study is the first large-scale, multi-site, definitive, superiority RCT of IPS for people with alcohol and drug dependence. Findings from the study will have substantial implications for service delivery. TRIAL REGISTRATION: ISRCTN Registry, ID: ISRCTN24159790. Registered on 1 February 2018.

Heart rate and premature atrial contractions at 24hECG independently predict atrial fibrillation in a population-based study.

BACKGROUND: Low resting heart rate and premature atrial contractions (PACs) predict incident atrial fibrillation (AF) and could be interdependent, since PACs occur in the gaps between normal beats. OBJECTIVE: To study the association between low heart rate at 24hECG, PACs and incident AF in a prospective population-based cohort. METHODS: In the Malmö Diet and Cancer study, 24hECGs were performed in 377 AF-free subjects. The endpoint was clinical AF retrieved from national hospital (mean follow-up 17 years). The interaction between increased supraventricular activity (SVA) top quartile of either PACs/hour or supraventricular tachycardias/hour) and mean heart rate (mHR) as regards AF risk was assessed in multivariable Cox regression analyses adjusted for age, sex, height, BMI, systolic blood pressure, antihypertensive medication, smoking and homeostasis model assessment of insulin resistance. RESULTS: There were 80 (21%) incident cases of AF. Below median mHR (80 bpm/75 bpm for women/men) was associated with increased AF incidence (HR: 1.89, 95% CI 1.18 to 3.02, p=0.008). There was no correlation between mHR and SVA (p=0.6) or evidence of a multiplicative interaction between these factors for AF risk (p for interaction=0.6) In the group with both increased SVA and below median mHR (17% of the population) the relative risk of AF was very high (HR 4.5, 95% CI 2.2 to 9.1, p=0.001). CONCLUSION: Low mHR at 24hECG independently predicts AF, but there is no association between mHR and SVA, and these factors are independent as regards AF risk. Subjects with both low mHR and increased SVA have high AF risk.

Development of a quantitative polymerase chain reaction assay and environmental DNA sampling methods for Giant Gartersnake (Thamnophis gigas).

The Giant Gartersnake (Thamnophis gigas) is a low density visually evasive species with a low detection probability based on standard field survey methods (e.g., traps, visual census). Habitat loss has resulted in extirpations or serious declines for T. gigas populations throughout the southern two thirds of its historic range. Uncertainty regarding its current distribution and occupancy present management challenges for the species. Enhancing survey sensitivity through development of environmental DNA sampling (eDNA) methods would improve compliance monitoring under the Endangered Species Act, recovery planning for T. gigas, and evaluation of California's Central Valley tule marsh habitat on which this species depends. To address these needs, we designed and validated diagnostic quantitative Polymerase Chain Reaction (qPCR) assays for identifying portions of the Cytochrome B (CytB) and the Nicotinamide adenine dinucleotide (NADH) dehydrogenase subunit 4 (ND4) genes of the T. gigas mitochondrial genome. The designed ND4 qPCR assay was not specific to T. gigas DNA and amplified DNA from a closely related and spatially co-occurring Thamnophis species (T.s. fitchi). The CytB T. gigas qPCR assay proved specific to a species level with a sensitivity that reliably detected T. gigas DNA at a concentration of 2.0x10-5 ng µL-1. To assess detection range, coordinated field sampling was conducted at aquatic sites with an observed and documented population of T. gigas. The T. gigas qPCR assay reliably detected DNA from samples taken 300m downstream from the known source. We then used environmental eDNA sampling and qPCR analysis to augment unsuccessful trap surveys in the southern range of T. gigas and detected DNA in 28 of the 52 locations sampled, confirming that T. gigas was still present at some sites where physical trapping failed to identify presence. QPCR-based DNA detection coupled with eDNA sampling methods provides an effective means to obtain critical population metrics from this otherwise cryptic, federally protected and hard to study organism, offering great promise for elucidating patterns of occupancy with greater efficiency and at far less cost than trapping methods, particularly where detection probabilities are low.