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PurposeThe increased adoption of genomic strategies in the clinic makes it imperative for diagnostic laboratories to improve the efficiency of variant interpretation. Clinical exome sequencing (CES) is becoming a valuable diagnostic tool, capable of meeting the diagnostic demand imposed by the vast array of different rare monogenic disorders. We have assessed a clinician-led and phenotype-based approach for virtual gene panel generation for analysis of targeted CES in patients with rare disease in a single institution.MethodsRetrospective survey of 400 consecutive cases presumed by clinicians to have rare monogenic disorders, referred on singleton basis for targeted CES. We evaluated diagnostic yield and variant workload to characterise the usefulness of a clinician-led approach for generation of virtual gene panels that can incorporate up to three different phenotype-driven gene selection methods.ResultsAbnormalities of the nervous system (54.5%), including intellectual disability, head and neck (19%), skeletal system (16%), ear (15%) and eye (15%) were the most common clinical features reported in referrals. Combined phenotype-driven strategies for virtual gene panel generation were used in 57% of cases. On average, 7.3 variants (median=5) per case were retained for clinical interpretation. The overall diagnostic rate of proband-only CES using personalised phenotype-driven virtual gene panels was 24%.ConclusionsOur results show that personalised virtual gene panels are a cost-effective approach for variant analysis of CES, maintaining diagnostic yield and optimising the use of resources for clinical genomic sequencing in the clinic.

This qualitative study investigated the leadership strategies superintendents implemented in response to changes in school district budget development that have taken place since the Chapter 97 (PART A) of the New York State Laws of 2011 became a general municipal and education law. The study explored the relationship between the Real Property Tax Cap legislation and budget development in school districts where the budget put to voters exceeded the maximum allowable tax levy limit. The lens for investigating the impact of Real Property Tax Cap legislation was perceptions of superintendents. Superintendents leading school districts that exceeded the maximum allowable tax levy limit in either or both May 2012 and May 2013 were interviewed about change, school communication, and collaboration with building administrators, faculty and staff, students, parents and community members during the budget development process. A qualitative study was selected to help develop deep understanding about the perceptions of superintendents. The research questions were used to guide the study and gather data to investigate the leadership strategies superintendents implemented in response to changes in school district budget development since the 2011 Real Property Tax Cap legislation. Conclusions drawn from research questions revealed that the superintendents at districts that exceeded the maximum allowable tax levy limit found they needed to alter communication and collaboration practices in response to the Real Property Tax Levy legislation. Communication changes reported by the superintendents were the uses of new communication tools such as automatic phone calling systems, videos and video streaming, additional district newsletters and local televised media coverage. Collaboration changes reported by the superintendents were the use of forums to gather members of the community together to discuss the budget, sharing information with faculty to strengthen understanding, and involving students in various aspects of budget development. The superintendents in this study reaffirmed the value of communication and collaborative leadership functions during budget development when presenting a budget exceeding the maximum allowable tax levy limit.

Objective Statistically model the likelihood of changes in the activities of daily living (ADLs) over time for three groups of older adults: those on a pension at all time periods, those never on a pension, and those who transition onto a public pension. Methods Our study used data from the Canadian Longitudinal Study on Aging (CLSA), a large national survey. We used data from baseline (2010–2015) and the first follow-up wave (2015–2018). We used logistic regression to model the likelihood of ADL changes in males and females by pension receipt status, controlling for several potential confounders and allowing for the impact of public pensions to be modified by baseline income. Results The magnitudes of the estimates indicated that those who transition to a public pension are less likely to report ADL degradation and more likely to report ADL improvement compared to those with no public pension. In the lowest baseline income group, those who transitioned onto a pension at follow-up had a 15% (male) or 11% (female) lower likelihood of reporting degraded ADL scores compared to those not receiving a pension at follow-up. Those who transitioned onto a pension in the lowest income group were more likely to report an improved ADL score at follow-up. Conclusion Our results could provide evidence for the potential health benefits of more comprehensive guaranteed annual income programs beyond the pension program. The penalty of being low-income was mitigated by the stability of the pension income in terms of ADL improvement or degradation.

Background The Tight Control of psoriatic arthritis (TICOPA) trial confirmed improved clinical outcomes with a treat to target (T2T) strategy in psoriatic arthritis (PsA). This consisted of 4-weekly review and escalation of ‘step up’ therapy (single disease modifying therapy (DMARD), combination DMARDs and then biologics) based on remission criteria. Based on this, a T2T approach is supported by European PsA treatment recommendations. However, it is not commonly implemented in routine care primarily due to feasibility and cost concerns. In the TICOPA trial, the same treatment regime was used for all participants regardless of their disease profile. Despite the recognition of PsA as a highly heterogeneous condition, no studies have tailored which drugs are used depending on disease severity. The cohort will establish real world outcomes for the T2T approach in PsA and also form the basis of a trials within cohorts (TWiCs) design to test alternative therapeutic approaches within embedded clinical trials providing an evidence base for treatment strategy in PsA. Methods The Multicentre Observational Initiative in Treat to target Outcomes in Psoriatic Arthritis (MONITOR-PsA) cohort will apply a T2T approach within routine care. It will recruit newly diagnosed adult patients with PsA starting systemic therapies. The cohort is observational allowing routine therapeutic care within NHS clinics but a T2T approach will be supported when monitoring treatment within the cohort. Eligible participants will be adults (≥18 years) with active PsA with ≥ 1 tender or swollen joints or enthesis who have not previously had treatment with DMARDs for articular disease. Discussion This study is the first TWiC designed to support a fully powered randomised drug trial. The results from the observational cohort will be compared with those observed in the TICOPA trial investigating the clinical effectiveness and health care costs of the pragmatic T2T approach. Nested trials will provide definitive RCT evidence establishing the optimal management of PsA within the T2T approach. The TWiCs design allows robust generalizability to routine healthcare, avoids disappointment bias, aids recruitment and in future will allow assessment of longer-term outcomes. Trial registration ClinicalTrials.gov NCT03531073 . Retrospectively registered on 21 May 2018.

Microbial interactions are expected to be major determinants of microbiome structure and function. Although fungi are found in diverse microbiomes, their interactions with bacteria remain largely uncharacterized. In this work, we characterize interactions in 16 different bacterial–fungal pairs, examining the impacts of 8 different fungi isolated from cheese rind microbiomes on 2 bacteria ( Escherichia coli and a cheese-isolated Pseudomonas psychrophila ). Using random barcode transposon-site sequencing with an analysis pipeline that allows statistical comparisons between different conditions, we observed that fungal partners caused widespread changes in the fitness of bacterial mutants compared to growth alone. We found that all fungal species modulated the availability of iron and biotin to bacterial species, which suggests that these may be conserved drivers of bacterial–fungal interactions. Species-specific interactions were also uncovered, a subset of which suggested fungal antibiotic production. Changes in both conserved and species-specific interactions resulted from the deletion of a global regulator of fungal specialized metabolite production. This work highlights the potential for broad impacts of fungi on bacterial species within microbiomes. Bacterial–fungal interactions are studied using a combination of random barcode transposon-site sequencing, RNA sequencing, bacterial cytological profiling and metabolomics. Fungi cause widespread changes in the fitness of bacterial mutants and have both conserved and species-specific impacts on bacteria.

Introduction: In psoriatic arthritis (PsA), treatment recommendations support first-line use of disease-modifying antirheumatic drugs (DMARDs). There are few treatment strategy trials, and no previous studies have investigated tailored treatment choice by disease severity. Studies in oligoarthritis (<5 inflamed joints) are limited but have suggested that some can be managed without DMARDs, preventing unnecessary side effects. This study aimed to assess the feasibility and acceptability of a study comparing standard DMARD treatment against symptomatic therapy in patients with mild psoriatic oligoarthritis. Methods: This trial was embedded within the MONITOR-PsA cohort, which uses a Trials Within Cohorts (TWiCs) design. Patients with newly diagnosed psoriatic oligoarthritis, with low disease activity (PASDAS ⩽ 3.2) and the absence of poor prognostic factors [C reactive protein (CRP) < 5 mg/dL, HAQ < 1, no radiographic erosions] were randomised open-label to either standard care with ‘step-up’ DMARD therapy or to symptomatic therapy with nonsteroidal anti-inflammatory drugs (NSAIDs) and local corticosteroid injections to inflamed joints. Key outcomes were the proportion of eligible cohort patients, consent and study completion rate. Results: Over the 15-month study period, only one eligible patient was randomised. Although oligoarthritis patients represented 45% of patients in this early PsA cohort, the majority did not have mild disease (24% raised CRP, 51% moderate disease activity, 13% radiographic damage and/or poor function). Of those meeting trial inclusion criteria, many patients refused treatment in the observational cohort prior to an invitation into the trial as they did not wish to be treated with DMARDs. Conclusion: The study was not feasible as designed. Oligoarthritis represents around half of initial PsA presentations, but the majority starting therapy have high-impact disease. A small proportion have mild oligoarticular disease but many are not keen on treatment with DMARDs, given the potential side effects of these medications. Further research is needed to support evidence-based treatment in this subgroup. Trial registration number – ClinicalTrials.gov (NCT03797872) and EudraCT (2018-001085-42).

UCATS (the UAS Chromatograph for Atmospheric Trace Species) was designed and built for observations of important atmospheric trace gases from unmanned aircraft systems (UAS) in the upper troposphere and lower stratosphere (UTLS). Initially it measured major chlorofluorocarbons (CFCs) and the stratospheric transport tracers nitrous oxide (N2O) and sulfur hexafluoride (SF6), using gas chromatography with electron capture detection. Compact commercial absorption spectrometers for ozone (O3) and water vapor (H2O) were added to enhance its capabilities on platforms with relatively small payloads. UCATS has since been reconfigured to measure methane (CH4), carbon monoxide (CO), and molecular hydrogen (H2) instead of CFCs and has undergone numerous upgrades to its subsystems. It has served as part of large payloads on stratospheric UAS missions to probe the tropical tropopause region and transport of air into the stratosphere; in piloted aircraft studies of greenhouse gases, transport, and chemistry in the troposphere; and in 2021 is scheduled to return to the study of stratospheric ozone and halogen compounds, one of its original goals. Each deployment brought different challenges, which were largely met or resolved. The design, capabilities, modifications, and some results from UCATS are shown and described here, including changes for future missions.

Climate, behavior, ecology, and oceanography shape patterns of biodiversity in marine faunas in the absence of obvious geographic barriers. Marine turtles are an example of highly migratory creatures with deep evolutionary lineages and complex life histories that span both terrestrial and marine environments. Previous studies have focused on the deep isolation of evolutionary lineages (>3 mya) through vicariance; however, little attention has been given to the pathways of colonization of the eastern Pacific and the processes that have shaped diversity within the most recent evolutionary time. We sequenced 770 bp of the mtDNA control region to examine the stock structure and phylogeography of 545 green turtles from eight different rookeries in the central and eastern Pacific. We found significant differentiation between the geographically separated nesting populations and identified five distinct stocks (FST = 0.08–0.44, P < 0.005). Central and eastern Pacific Chelonia mydas form a monophyletic group containing 3 subclades, with Hawaii more closely related to the eastern Pacific than western Pacific populations. The split between sampled central/eastern and western Pacific haplotypes was estimated at around 0.34 mya, suggesting that the Pacific region west of Hawaii has been a more formidable barrier to gene flow in C. mydas than the East Pacific Barrier. Our results suggest that the eastern Pacific was colonized from the western Pacific via the Central North Pacific and that the Revillagigedos Islands provided a stepping‐stone for radiation of green turtles from the Hawaiian Archipelago to the eastern Pacific. Our results fit with a broader paradigm that has been described for marine biodiversity, where oceanic islands, such as Hawaii and Revillagigedo, rather than being peripheral evolutionary “graveyards”, serve as sources and recipients of diversity and provide a mechanism for further radiation. We conducted genetic analysis using mtDNA sequences to examine the stock structure and phylogeography of green turtles in the central and eastern Pacific and examine potential pathways of colonization of this region within the most recent evolutionary time. We found significant differentiation between the geographically separated nesting populations and identified five distinct stocks that were part of a monophyletic group containing 3 sub‐clades, with Hawaii more closely related to the eastern Pacific than western Pacific populations. Our results suggest that the region west of Hawaii has been a more formidable barrier to gene flow in C. mydas than the well known East Pacific Barrier and that the Revillagigedo Islands provided a stepping‐stone for radiation of green turtles from the Hawaiian Archipelago to the eastern Pacific.

The peopling of Sahul (the combined continent of Australia and New Guinea) represents the earliest continental migration and settlement event of solely anatomically modern humans, but its patterns and ecological drivers remain largely conceptual in the current literature. We present an advanced stochastic-ecological model to test the relative support for scenarios describing where and when the first humans entered Sahul, and their most probable routes of early settlement. The model supports a dominant entry via the northwest Sahul Shelf first, potentially followed by a second entry through New Guinea, with initial entry most consistent with 50,000 or 75,000 years ago based on comparison with bias-corrected archaeological map layers. The model’s emergent properties predict that peopling of the entire continent occurred rapidly across all ecological environments within 156–208 human generations (4368–5599 years) and at a plausible rate of 0.71–0.92 km year −1 . More broadly, our methods and approaches can readily inform other global migration debates, with results supporting an exit of anatomically modern humans from Africa 63,000–90,000 years ago, and the peopling of Eurasia in as little as 12,000–15,000 years via inland routes.

Leatherback turtles migrate long distances between nesting beaches and distant foraging areas worldwide. This study analyzes the genetic diversity, life history stage, spatiotemporal distribution, and associated threats of a foraging aggregation in the Southwest Atlantic Ocean. A total of 242 leatherbacks stranded or bycaught by artisanal fisheries were recorded from 1997 to 2021 in Uruguay, with sizes ranging from 110.0 to 170.0 cm carapace lengths, indicating that the aggregation is composed of large juveniles and adults. Results of Bayesian mixed-stock analysis show that leatherbacks come primarily from the West African rookeries, based on mitochondrial DNA sequences obtained from 59 of the turtles representing seven haplotypes, including a novel one (Dc1.7). The main threat identified in the area is the fisheries bycatch but most of the carcasses observed were badly decomposed. There was significant seasonal and interannual variability in strandings that is likely associated with the availability of prey and the intensity of the fishing effort. Taken together, these findings reinforce the importance of these South American foraging areas for leatherbacks and the need to determine regional habitat use and migratory routes across the broader Atlantic region, in order to develop effective conservation measures to mitigate threats both at nesting beaches and foraging areas.