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People with neuropsychiatric symptoms often experience delay in accurate diagnosis. Although cerebrospinal fluid neurofilament light (CSF NfL) shows promise in distinguishing neurodegenerative disorders (ND) from psychiatric disorders (PSY), its accuracy in a diagnostically challenging cohort longitudinally is unknown.
We collected longitudinal diagnostic information (mean = 36 months) from patients assessed at a neuropsychiatry service, categorising diagnoses as ND/mild cognitive impairment/other neurological disorders (ND/MCI/other) and PSY. We pre-specified NfL > 582 pg/mL as indicative of ND/MCI/other.
Diagnostic category changed from initial to final diagnosis for 23% (49/212) of patients. NfL predicted the final diagnostic category for 92% (22/24) of these and predicted final diagnostic category overall (ND/MCI/other vs. PSY) in 88% (187/212), compared to 77% (163/212) with clinical assessment alone.
CSF NfL improved diagnostic accuracy, with potential to have led to earlier, accurate diagnosis in a real-world setting using a pre-specified cut-off, adding weight to translation of NfL into clinical practice.
Early in the COVID-19 pandemic, the World Health Organization stressed the importance of daily clinical assessments of infected patients, yet current approaches frequently consider cross-sectional timepoints, cumulative summary measures, or time-to-event analyses. Statistical methods are available that make use of the rich information content of longitudinal assessments. We demonstrate the use of a multistate transition model to assess the dynamic nature of COVID-19-associated critical illness using daily evaluations of COVID-19 patients from 9 academic hospitals. We describe the accessibility and utility of methods that consider the clinical trajectory of critically ill COVID-19 patients.
As clinical trials were rapidly initiated in response to the COVID-19 pandemic, Data and Safety Monitoring Boards (DSMBs) faced unique challenges overseeing trials of therapies never tested in a disease not yet characterized. Traditionally, individual DSMBs do not interact or have the benefit of seeing data from other accruing trials for an aggregated analysis to meaningfully interpret safety signals of similar therapeutics. In response, we developed a compliant DSMB Coordination (DSMBc) framework to allow the DSMB from one study investigating the use of SARS-CoV-2 convalescent plasma to treat COVID-19 to review data from similar ongoing studies for the purpose of safety monitoring.
The DSMBc process included engagement of DSMB chairs and board members, execution of contractual agreements, secure data acquisition, generation of harmonized reports utilizing statistical graphics, and secure report sharing with DSMB members. Detailed process maps, a secure portal for managing DSMB reports, and templates for data sharing and confidentiality agreements were developed.
Four trials participated. Data from one trial were successfully harmonized with that of an ongoing trial. Harmonized reports allowing for visualization and drill down into the data were presented to the ongoing trial’s DSMB. While DSMB deliberations are confidential, the Chair confirmed successful review of the harmonized report.
It is feasible to coordinate DSMB reviews of multiple independent studies of a similar therapeutic in similar patient cohorts. The materials presented mitigate challenges to DSMBc and will help expand these initiatives so DSMBs may make more informed decisions with all available information.
Despite extensive paleoenvironmental research on the postglacial history of the Kenai Peninsula, Alaska, uncertainties remain regarding the region's deglaciation, vegetation development, and past hydroclimate. To elucidate this complex environmental history, we present new proxy datasets from Hidden and Kelly lakes, located in the eastern Kenai lowlands at the foot of the Kenai Mountains, including sedimentological properties (magnetic susceptibility, organic matter, grain size, and biogenic silica), pollen and macrofossils, diatom assemblages, and diatom oxygen isotopes. We use a simple hydrologic and isotope mass balance model to constrain interpretations of the diatom oxygen isotope data. Results reveal that glacier ice retreated from Hidden Lake's headwaters by ca. 13.1 cal ka BP, and that groundwater was an important component of Kelly Lake's hydrologic budget in the Early Holocene. As the forest developed and the climate became wetter in the Middle to Late Holocene, Kelly Lake reached or exceeded its modern level. In the last ca. 75 years, rising temperature caused rapid changes in biogenic silica content and diatom oxygen isotope values. Our findings demonstrate the utility of mass balance modeling to constrain interpretations of paleolimnologic oxygen isotope data, and that groundwater can exert a strong influence on lake water isotopes, potentially confounding interpretations of regional climate.
The ancient city of Gabii—an Italian polity of the first millennium BC and a peer to early Rome—has often been presented as an example of urban decline, a counterpoint to Rome's rise from a collection of hilltop huts to a Mediterranean hegemon. Here the authors draw on the results from recent excavations at Gabii that challenge such simplistic models of urban history. Diachronic evidence documenting activity at the site over the course of 1400 years highlights shifting values and rhythms materialised in the maintenance, transformation and abandonment of different urban components. This complex picture of adaptation and resilience provides a model of ancient urbanism that calls into question outdated narratives of urban success and failure.
About 800 foodborne disease outbreaks are reported in the United States annually. Few are associated with food recalls. We compared 226 outbreaks associated with food recalls with those not associated with recalls during 2006–2016. Recall-associated outbreaks had, on average, more illnesses per outbreak and higher proportions of hospitalisations and deaths than non-recall-associated outbreaks. The top confirmed aetiology for recall-associated outbreaks was Salmonella. Pasteurised and unpasteurised dairy products, beef and molluscs were the most frequently implicated foods. The most common pathogen−food pairs for outbreaks with recalls were Escherichia coli-beef and norovirus-molluscs; the top pairs for non-recall-associated outbreaks were scombrotoxin-fish and ciguatoxin-fish. For outbreaks with recalls, 48% of the recalls occurred after the outbreak, 27% during the outbreak, 3% before the outbreak, and 22% were inconclusive or had unknown recall timing. Fifty per cent of recall-associated outbreaks were multistate, compared with 2% of non-recall-associated outbreaks. The differences between recall-associated outbreaks and non-recall-associated outbreaks help define the types of outbreaks and food vehicles that are likely to have a recall. Improved outbreak vehicle identification and traceability of rarely recalled foods could lead to more recalls of these products, resulting in fewer illnesses and deaths.
Optical tracking systems typically trade off between astrometric precision and field of view. In this work, we showcase a networked approach to optical tracking using very wide field-of-view imagers that have relatively low astrometric precision on the scheduled OSIRIS-REx slingshot manoeuvre around Earth on 22 Sep 2017. As part of a trajectory designed to get OSIRIS-REx to NEO 101955 Bennu, this flyby event was viewed from 13 remote sensors spread across Australia and New Zealand to promote triangulatable observations. Each observatory in this portable network was constructed to be as lightweight and portable as possible, with hardware based off the successful design of the Desert Fireball Network. Over a 4-h collection window, we gathered 15 439 images of the night sky in the predicted direction of the OSIRIS-REx spacecraft. Using a specially developed streak detection and orbit determination data pipeline, we detected 2 090 line-of-sight observations. Our fitted orbit was determined to be within about 10 km of orbital telemetry along the observed 109 262 km length of OSIRIS-REx trajectory, and thus demonstrating the impressive capability of a networked approach to Space Surveillance and Tracking.
Studies suggest that alcohol consumption and alcohol use disorders have distinct genetic backgrounds.
We examined whether polygenic risk scores (PRS) for consumption and problem subscales of the Alcohol Use Disorders Identification Test (AUDIT-C, AUDIT-P) in the UK Biobank (UKB; N = 121 630) correlate with alcohol outcomes in four independent samples: an ascertained cohort, the Collaborative Study on the Genetics of Alcoholism (COGA; N = 6850), and population-based cohorts: Avon Longitudinal Study of Parents and Children (ALSPAC; N = 5911), Generation Scotland (GS; N = 17 461), and an independent subset of UKB (N = 245 947). Regression models and survival analyses tested whether the PRS were associated with the alcohol-related outcomes.
In COGA, AUDIT-P PRS was associated with alcohol dependence, AUD symptom count, maximum drinks (R2 = 0.47–0.68%, p = 2.0 × 10−8–1.0 × 10−10), and increased likelihood of onset of alcohol dependence (hazard ratio = 1.15, p = 4.7 × 10−8); AUDIT-C PRS was not an independent predictor of any phenotype. In ALSPAC, the AUDIT-C PRS was associated with alcohol dependence (R2 = 0.96%, p = 4.8 × 10−6). In GS, AUDIT-C PRS was a better predictor of weekly alcohol use (R2 = 0.27%, p = 5.5 × 10−11), while AUDIT-P PRS was more associated with problem drinking (R2 = 0.40%, p = 9.0 × 10−7). Lastly, AUDIT-P PRS was associated with ICD-based alcohol-related disorders in the UKB subset (R2 = 0.18%, p < 2.0 × 10−16).
AUDIT-P PRS was associated with a range of alcohol-related phenotypes across population-based and ascertained cohorts, while AUDIT-C PRS showed less utility in the ascertained cohort. We show that AUDIT-P is genetically correlated with both use and misuse and demonstrate the influence of ascertainment schemes on PRS analyses.
This article examines concurrence of self-reported love, trust, and dyadic quality experiences between partners in 293 male couples. Significant yet poor concurrence was observed for all three self-reported relationship measures, but varied by relationship characteristics. Using an actor-partner interdependence model (APIM), actor and partner characteristics were shown to be associated with self-reported relationship concerns, such as satisfaction and intimate partner violence. This knowledge is important in the development and delivery of couples-based health interventions, such as couples HIV testing and counselling, for interventions that respect the unique relationship dynamics of each couple are needed to effectively address dyadic health.
Recent modelling estimates up to two-thirds of new HIV infections among men who have sex with men occur within partnerships, indicating the importance of dyadic HIV prevention efforts. Although new interventions are available to promote dyadic health-enhancing behaviours, minimal research has examined what factors influence partners’ mutual engagement in these behaviours, a critical component of intervention success. Actor-partner interdependence modelling was used to examine associations between relationship characteristics and several dyadic outcomes theorised as antecedents to health-enhancing behaviours: planning and decision making, communication, and joint effort. Among 270 male-male partnerships, relationship satisfaction was significantly associated with all three outcomes for actors (p = .02, .02, .06 respectively). Latino men reported poorer planning and decision making (actor p = .032) and communication (partner p = .044). Alcohol use was significantly and negatively associated with all outcomes except actors’ planning and decision making (actors: p = .11, .038, .004 respectively; partners: p = .03, .056, .02 respectively). Having a sexual agreement was significantly associated with actors’ planning and decision making (p = .007) and communication (p = .008). Focusing on interactions between partners produces a more comprehensive understanding of male couples’ ability to engage in health-enhancing behaviours. This knowledge further identifies new and important foci for the tailoring of dyadic HIV prevention and care interventions.
To test the rate at which a lifeless but habitable environment (uninhabited habitat) can be colonized, artificial endolithic habitats were constructed in the laboratory and exposed to the natural environment. They were composed of sterile stacked sintered glass discs (stacks) containing CHNOPS elements, liquid water, energy and a carbon source, making them habitable for aerobic respiring organisms and phototrophs. One set of stacks was exposed fully to atmospheric conditions and one set was covered from direct overhead atmospheric input and precipitation. The process of colonization was heterogeneous across the stacks. After 3 months, all uninhabited habitats were colonized at all depths in both fully exposed and covered stacks. However, uninhabited habitable conditions persisted in covered stacks after 1 month, demonstrating the importance of the hydrological cycle in the connection between inhabited habitats and uninhabited habitats. Low porosity rocks were found to retard the extent of colonization compared with higher porosity rocks. Examination of genomic DNA demonstrated that the habitats were colonized by a community dominated by Proteobacteria. Covered stacks had a higher abundance of fungal sequences among eukaryotic colonizers. These data demonstrate the tight coupling between the appearance of habitable conditions and life and the reasons for the rarity of uninhabited habitats on the present-day Earth. On other planetary bodies, such as Mars, with more inclement atmospheres and less vigorous hydrological cycles or a lack of life, uninhabited habitats could persist for longer with consequences for the interpretation of data sent back by planetary science missions.
The Taipan galaxy survey (hereafter simply ‘Taipan’) is a multi-object spectroscopic survey starting in 2017 that will cover 2π steradians over the southern sky (δ ≲ 10°, |b| ≳ 10°), and obtain optical spectra for about two million galaxies out to z < 0.4. Taipan will use the newly refurbished 1.2-m UK Schmidt Telescope at Siding Spring Observatory with the new TAIPAN instrument, which includes an innovative ‘Starbugs’ positioning system capable of rapidly and simultaneously deploying up to 150 spectroscopic fibres (and up to 300 with a proposed upgrade) over the 6° diameter focal plane, and a purpose-built spectrograph operating in the range from 370 to 870 nm with resolving power R ≳ 2000. The main scientific goals of Taipan are (i) to measure the distance scale of the Universe (primarily governed by the local expansion rate, H0) to 1% precision, and the growth rate of structure to 5%; (ii) to make the most extensive map yet constructed of the total mass distribution and motions in the local Universe, using peculiar velocities based on improved Fundamental Plane distances, which will enable sensitive tests of gravitational physics; and (iii) to deliver a legacy sample of low-redshift galaxies as a unique laboratory for studying galaxy evolution as a function of dark matter halo and stellar mass and environment. The final survey, which will be completed within 5 yrs, will consist of a complete magnitude-limited sample (i ⩽ 17) of about 1.2 × 106 galaxies supplemented by an extension to higher redshifts and fainter magnitudes (i ⩽ 18.1) of a luminous red galaxy sample of about 0.8 × 106 galaxies. Observations and data processing will be carried out remotely and in a fully automated way, using a purpose-built automated ‘virtual observer’ software and an automated data reduction pipeline. The Taipan survey is deliberately designed to maximise its legacy value by complementing and enhancing current and planned surveys of the southern sky at wavelengths from the optical to the radio; it will become the primary redshift and optical spectroscopic reference catalogue for the local extragalactic Universe in the southern sky for the coming decade.
Recent studies of eurypterid paleoecology suggest that formation of eurypterid Lagerstätten in the mid-Paleozoic of Laurentia was controlled by the presence of an ecological–taphonomic window that recurred predictably in nearshore, marginal environments during transgressions. We tested this hypothesis by performing a high-resolution taxonomic, environmental, and stratigraphic survey and quantitative analysis of all Silurian–Lower Devonian eurypterid-bearing intervals in the Appalachian basin, the most prolific region for eurypterid remains in the world. Canonical correspondence analysis of sedimentological and faunal associations revealed a strong lithologic gradient between groupings of eurypterid genera and associated taxa across the basin, and a significant association of eurypterids with microbialites (thrombolites, stromatolites) and evaporitic structures. Field observations confirmed that, stratigraphically, eurypterids in the basin frequently occur above the microbialite structures and beneath evaporites and other indicators of increased salinity or subaerial exposure. Following interpretation of these features within a sequence stratigraphic framework, we present a preservational model in which (1) eurypterids inhabited nearshore settings following freshening conditions concomitant with minor transgressions, (2) their remains were subsequently buried by storms or microbialite sediment baffling, and (3) subsequent long-term preservation of tissues was facilitated by regression and cyclical shallowing-up successions that promoted hypersalinity and anoxia. In the central and southern region of the basin, where microbial structures and evidence for hypersalinity are less common, a similar pattern of cyclical shallowing-upward deposition within eurypterid-bearing units holds. Thus, eurypterid preservation appears to reflect a combination of ecological preferences and abiotic conditions that promoted inhabitation and eventual preservation within the same setting. This study provides the first quantitative support for a sea level–based control on preservation of eurypterids and adds to the growing body of evidence that suggests that analysis of exceptional preservation in the fossil record benefits from interpretation within a sequence stratigraphic framework.
The subsurface exploration of other planetary bodies can be used to unravel their geological history and assess their habitability. On Mars in particular, present-day habitable conditions may be restricted to the subsurface. Using a deep subsurface mine, we carried out a program of extraterrestrial analog research – MINe Analog Research (MINAR). MINAR aims to carry out the scientific study of the deep subsurface and test instrumentation designed for planetary surface exploration by investigating deep subsurface geology, whilst establishing the potential this technology has to be transferred into the mining industry. An integrated multi-instrument suite was used to investigate samples of representative evaporite minerals from a subsurface Permian evaporite sequence, in particular to assess mineral and elemental variations which provide small-scale regions of enhanced habitability. The instruments used were the Panoramic Camera emulator, Close-Up Imager, Raman spectrometer, Small Planetary Linear Impulse Tool, Ultrasonic drill and handheld X-ray diffraction (XRD). We present science results from the analog research and show that these instruments can be used to investigate in situ the geological context and mineralogical variations of a deep subsurface environment, and thus habitability, from millimetre to metre scales. We also show that these instruments are complementary. For example, the identification of primary evaporite minerals such as NaCl and KCl, which are difficult to detect by portable Raman spectrometers, can be accomplished with XRD. By contrast, Raman is highly effective at locating and detecting mineral inclusions in primary evaporite minerals. MINAR demonstrates the effective use of a deep subsurface environment for planetary instrument development, understanding the habitability of extreme deep subsurface environments on Earth and other planetary bodies, and advancing the use of space technology in economic mining.