A homogeneous nucleus for comet 67P/Churyumov-Gerasimenko from its gravity field.

Cometary nuclei consist mostly of dust and water ice. Previous observations have found nuclei to be low-density and highly porous bodies, but have only moderately constrained the range of allowed densities because of the measurement uncertainties. Here we report the precise mass, bulk density, porosity and internal structure of the nucleus of comet 67P/Churyumov-Gerasimenko on the basis of its gravity field. The mass and gravity field are derived from measured spacecraft velocity perturbations at fly-by distances between 10 and 100 kilometres. The gravitational point mass is GM = 666.2 ± 0.2 cubic metres per second squared, giving a mass M = (9,982 ± 3) × 10(9) kilograms. Together with the current estimate of the volume of the nucleus, the average bulk density of the nucleus is 533 ± 6 kilograms per cubic metre. The nucleus appears to be a low-density, highly porous (72-74 per cent) dusty body, similar to that of comet 9P/Tempel 1. The most likely composition mix has approximately four times more dust than ice by mass and two times more dust than ice by volume. We conclude that the interior of the nucleus is homogeneous and constant in density on a global scale without large voids. The high porosity seems to be an inherent property of the nucleus material.

Stability of a Novel PEGylation Site on a Putative Haemoglobin-Based Oxygen Carrier.

PEGylation of protein sulfhydryl residues is a common method used to create a stable drug conjugate to enhance vascular retention times. We recently created a putative haemoglobin-based oxygen carrier using maleimide-PEG to selectively modify a single engineered cysteine residue in the α subunit (αAla19Cys). However, maleimide-PEG adducts are subject to deconjugation via retro-Michael reactions, with consequent cross-conjugation to endogenous plasma thiols such as those found on human serum albumin or glutathione. In previous studies mono-sulfone-PEG adducts have been shown to be less susceptible to deconjugation. We therefore compared the stability of our maleimide-PEG Hb adduct with one created using a mono-sulfone PEG. The corresponding mono-sulfone-PEG adduct was significantly more stable when incubated at 37 °C for 7 days in the presence of 1 mM reduced glutathione, 20 mg/mL human serum albumin, or human serum. In all cases haemoglobin treated with mono-sulfone-PEG retained >90% of its conjugation whereas maleimide-PEG showed significant deconjugation, especially in the presence of 1 mM reduced glutathione where <70% of the maleimide-PEG conjugate remained intact. Although maleimide-PEGylation of Hb seems adequate for an oxygen therapeutic intended for acute use, if longer vascular retention is required reagents such as mono-sulfone-PEG may be more appropriate.

A systematic review of the behaviours associated with depression in people with severe-profound intellectual disability.

The assessment of depression in people with severe to profound intellectual disability (severe-profound ID) is challenging, primarily due to inability to report internal states such as mood, feelings of worthlessness and suicidal ideation. This group also commonly presents with challenging behaviours (e.g. aggression and self-injury) with debate about whether these behaviours should be considered 'depressive equivalents' or are sensitive for, but not specific to, depression in severe-profound ID. We conducted a systematic review exploring behaviours associated with depression and low mood in individuals with severe-profound ID. The review was conducted in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses (2009) guidelines. Three electronic databases were searched (Embase, PsycINFO and Ovid MEDLINE), and 13 studies were included and rated for quality. Few studies were rated as having high methodological quality. Behaviours captured by standard diagnostic schemes for depression (e.g. Diagnostic and Statistical Manual of Mental Disorders and International Classification of Diseases) showed a relationship with depression in severe-profound ID, including the two core symptoms (depressed affect and anhedonia), as well as irritability, sleep disturbance, psychomotor agitation, reduced appetite and fatigue. Challenging behaviours such as aggression, self-injury, temper tantrums, screaming and disruptive behaviour were associated with depression. Challenging behaviours show a robust relationship with depression. Whilst these behaviours may suggest an underlying depression, study limitations warrant caution in labelling them as 'depressive equivalents'. These limitations include not controlling for potential confounds (autism, other affective disorders and pain) and bias associated with comparing depressed/non-depressed groups on the same behavioural criteria used to initially diagnose and separate these groups. Future studies that use depressive measures designed for ID populations, which control for confounds and which explore low mood irrespective of psychiatric diagnosis, are warranted to better delineate the behaviours associated with depression in this population (PROSPERO 2018: CRD42018103244).

Life Goals Over Time Among Homeless Adults in Permanent Supportive Housing.

Permanent supportive housing (PSH) is a widely-accepted solution to the challenge of chronic homelessness. While housing support and retention, physical health, and healthcare continue to be important for formerly homeless persons in PSH, "higher-order" and humanistic needs such as thriving have received less attention and as a result are less well understood in this population. One important indicator of thriving is the ability to establish and articulate life goals. This study utilizes longitudinal data from 421 formerly homeless adults prior to their move into PSH, and at 3-, 6- and 12-months after move-in (369 respondents completed all four interviews), to examine what life goals are articulated by this population and how those goals change over time. Prior to housing, most respondents articulated housing attainment as their primary life goal, whereas at follow-up interviews health goals, housing relocation, and financial goals became more prevalent. Aspirational goals (e.g., independence, self-improvement, artistic pursuits) were also common, but demonstrated a decrease over time in housing. Relationship goals remained common and consistent over time. Findings indicate that housing is a necessary, but perhaps not sufficient, step for improving thriving among formerly homeless adults. Implications for practice and future research are discussed.

Fabrication and Testing of a Bi-2223 Test Coil for High Field NMR Magnets.

In 2005 the Committee on Opportunities in High Magnetic Fields (COHMAG) issued a challenge to develop a 30 T high-resolution NMR magnet. In response, the National High Magnetic Field Laboratory (NHMFL) is investigating all three commercially available high-temperature superconductors (HTS) including REBCO, Bi-2212 and most recently, a reinforced Bi-2223 conductor supplied by Sumitomo Electric, designated Type HT-NX. Recent investigations of Type HT-NX conductor at the NHMFL and by others suggest that operation at hoop stress above 400 MPa, and total strain above 0.7% may be feasible. We have fabricated a test coil from a single 240 m length of HT-NX. The coil was successfully operated to 19.5 T in a 14 T background field, with a total applied strain of 0.8% and coil current density of 243 A/mm2. The coil was cycled 20 times from half the design current to full current without observed degradation.

Bi-2223 Test Coils for High Resolution NMR Magnets.

Recently, significant improvement in the strain tolerance of Bi-2223 conductor has been achieved by lamination with high strength nickel alloy. The conductor, supplied by Sumitomo Electric and designated Type HT-NX, is now commercially available in lengths sufficient for manufacture of high-homogeneity solenoids. A program to fully exploit the improved conductor properties is now underway at the National High Magnetic Field Laboratory (NHMFL). Five coils are being made, the last of which is to demonstrate an NMR measurement approaching 1 GHz and 1 ppm over 10 mm volume. In so doing, we expect to demonstrate critical current fraction, and strain similar to that expected in 30 T NMR magnets. The coils will be tested inside an existing 16 Tesla large-bore background magnet at the NHMFL. The design of the NMR demonstration coil is presented first, with expected values for field, homogeneity and strain given. A technology development program is then outlined, which includes fabrication of four test coils to test various design features, develop fabrication tooling and train personnel.

What caused extinction of the Pleistocene megafauna of Sahul?

During the Pleistocene, Australia and New Guinea supported a rich assemblage of large vertebrates. Why these animals disappeared has been debated for more than a century and remains controversial. Previous synthetic reviews of this problem have typically focused heavily on particular types of evidence, such as the dating of extinction and human arrival, and have frequently ignored uncertainties and biases that can lead to misinterpretation of this evidence. Here, we review diverse evidence bearing on this issue and conclude that, although many knowledge gaps remain, multiple independent lines of evidence point to direct human impact as the most likely cause of extinction.

Development and characterisation of novel fentanyl-delta opioid receptor antagonist based bivalent ligands.

BACKGROUND: Opioid tolerance is a limiting factor in chronic pain. Delta opioid peptide (DOP)(δ) receptor antagonism has been shown to reduce tolerance. Here, the common clinical mu opioid peptide (MOP)(µ) receptor agonist fentanyl has been linked to the DOP antagonist Dmt-Tic (2',6'-dimethyl-L-tyrosyl-1,2,3,4-tetrahydrisoquinoline-3-carboxylic acid) to create new bivalent compounds. METHODS: Binding affinities of bivalents(#9, #10, #11, #12 and #13) were measured in Chinese hamster ovary (CHO) cells expressing recombinant human MOP, DOP, Kappa opioid peptide (KOP)(κ) and nociceptin/orphanin FQ opioid peptide (NOP) receptors. Functional studies, measuring GTPγ[(35)S] or ß-arrestin recruitment, were performed in membranes or whole cells respectively expressing MOP and DOP. RESULTS: The new bivalents bound to MOP (pKi : #9:7.31; #10:7.58; #11:7.91; #12:7.94; #13:8.03) and DOP (#9:8.03; #10:8.16; #11:8.17; #12:9.67; #13:9.71). In GTPγ[(35)S] functional assays, compounds #9(pEC50:6.74; intrinsic activity:0.05) #10(7.13;0.34) and #11(7.52;0.27) showed weak partial agonist activity at MOP. Compounds #12 and #13, with longer linkers, showed no functional activity at MOP. In antagonist assays at MOP, compounds #9 (pKb:6.87), #10(7.55) #11(7.81) #12(6.91) and #13(7.05) all reversed the effects of fentanyl. At DOP, all compounds showed antagonist affinity (#9:6.85; #10:8.06; #11:8.11; #12:9.42; #13:9.00), reversing the effects of DPDPE ([D-Pen(2,5)]enkephalin). In ß-arrestin assays, compared with fentanyl (with response at maximum concentration (RMC):13.62), all compounds showed reduced ability to activate ß-arrestin (#9 RMC:1.58; #10:2.72; #11:2.40; #12:1.29; #13:1.58). Compared with fentanyl, the intrinsic activity was: #9:0.12; #10:0.20; #11:0.18; #12:0.09 and #13:0.12. CONCLUSIONS: The addition of a linker between fentanyl and Dmt-Tic did not alter the ability to bind to MOP and DOP, however a substantial loss in MOP functional activity was apparent. This highlights the difficulty in multifunctional opioid development.

WITHDRAWN: Evaluation of Fourier Transform Infrared spectroscopy (IR Biotyper) as a complement to Whole genome sequencing (WGS) to characterise Enterobacter cloacae , Citrobacter freundii and Klebsiella pneumoniae isolates recovered from hospital sinks.

The authors have withdrawn their manuscript due to becoming aware of methodology issues related to the curation of the training set used to determine cut-off values for Biotyper cluster assignation and lack of replicate measurements on different days for the isolates analysed. It is therefore unclear whether the conclusions of the manuscript are founded and no further work is possible to correct these issues as the instrument is no longer available to the authors. If you have any questions, please contact the corresponding author.

Non-pharmacological interventions to improve mental health outcomes among female carers of people living with a neurological condition: a systematic review.

PURPOSE: This systematic review aims to examine the effectiveness of non-pharmacological interventions for improving mental health outcomes among female carers of people living with a neurological condition. MATERIALS AND METHODS: A narrative synthesis of English-language randomized controlled trials was undertaken. RESULTS: 18 unique studies were included. Intervention components that were found to have improved mental health outcomes were: delivered in person, to groups, on an intermittent schedule with ≥10 sessions; had a duration between 3-6 months; and were facilitated by research staff or allied health professionals. As the review had few robust studies, results of mental health outcomes reported in studies assessed as low risk of bias were highlighted in the review. Psychoeducation interventions, cognitive behavioural interventions, and support group interventions were found to improve depression. Psychoeducation interventions were also found to improve burden. CONCLUSIONS: There is a clear need for adequately powered, high-quality randomised controlled trials to determine the effectiveness of non-pharmacological interventions for female carers of people living with a neurological condition.

Female carers experience worse mental health and well-being outcomes and are at a higher risk of developing chronic health issues compared to their male counterparts.This review identified only very few, generally small, randomised controlled trials of non-pharmacological interventions in female carers of patients with neurological conditions.Interventions that provide psychoeducation, are group-based, face-to-face, and have an intervention duration between >3 months and <6 months, may be successful in improving some mental health outcomes, such as depression and coping.

The structure of Venus' middle atmosphere and ionosphere.

The atmosphere and ionosphere of Venus have been studied in the past by spacecraft with remote sensing or in situ techniques. These early missions, however, have left us with questions about, for example, the atmospheric structure in the transition region from the upper troposphere to the lower mesosphere (50-90 km) and the remarkably variable structure of the ionosphere. Observations become increasingly difficult within and below the global cloud deck (<50 km altitude), where strong absorption greatly limits the available investigative spectrum to a few infrared windows and the radio range. Here we report radio-sounding results from the first Venus Express Radio Science (VeRa) occultation season. We determine the fine structure in temperatures at upper cloud-deck altitudes, detect a distinct day-night temperature difference in the southern middle atmosphere, and track day-to-day changes in Venus' ionosphere.

Carer-supported home-based exercises designed to target physical activity levels and functional mobility after stroke: a scoping review.

PURPOSE: To explore the literature on carer-supported home-based exercise programs for people after stroke, as a form of physical activity. The review focus was to examine the training carers receive, the content of programs, and investigate the physical activity levels and functional mobility of people after stroke. MATERIALS AND METHODS: A scoping review was undertaken, guided by Joanna Briggs Institute methodology. The concept of home-based carer-supported exercise, in people after stroke, was searched across five databases. Outcomes of interest were physical activity levels and functional mobility. RESULTS: We screened 2285 references and included 10 studies: one systematic review, five randomised controlled trials, one trial with non-equivalent control, and four uncontrolled studies. Carer training ranged from one to twelve sessions. Exercise interventions commonly including walking, other whole body functional exercises and balance activities. In eight studies interventions were in addition to standard care. Five studies reported significant between-group differences for functional mobility, favouring the intervention. One study reported physical activity levels. CONCLUSION: There was large variation in the volume and content of training provided to carers. Physical activity levels were infrequently objectively reported. Future studies should include greater details on their protocols to allow for replication and implementation into clinical practice.

Carer-supported home-based exercises may improve functional mobility once home after a stroke.The optimal length, content, and model of delivery of carer training, so carers can provide better targeted home-based exercise support to people after stroke, is not known.Better monitoring of participation in home-based exercise and reporting of short and long-term physical activity is needed.

Sex differences in musculoskeletal injury epidemiology and subsequent loss of tactical readiness during Marine Corps Officer Candidates School.

INTRODUCTION: The US Marine Corps (USMC) Officer Candidates School (OCS) is a 10-week training course for Marine Officer Candidates (MOCs). OCS training is rigorous and demanding, which results in a high risk of musculoskeletal injuries (MSIs). The objective of this analysis was to describe MSIs among women and men during the USMC OCS at Quantico, Virginia, from September 2020 to November 2021. METHODS: This prospective cohort study assessed MSIs that occurred among 736 MOCs (women: 17.8% of sample, men: 82.2%). Data for the study were derived from routinely collected injury data by athletic trainers and physical therapists embedded within the training units. Injury incidence, event at the time of injury occurrence, anatomic location, injury type and disposition following injury were described. Fisher's exact tests were used to compare proportions of injured women and men. RESULTS: The cumulative injury incidence was higher among women (39.7%) compared with men (23.1%, p<0.001). When specific events associated with injuries were reported, most frequent events were the obstacle course (women: 20.9% of injuries, men: 12.9%) and the conditioning hike (women: 11.6%, men: 6.9%). Most injures affected the lower body (women: 67.4%, men: 70.8%). The most frequent body part injured was the lower leg (18.6%) in women and the knee (23.3%) in men. The most frequent injury type was strain (women: 39.5%, men: 24.3%), followed by sprain (women: 16.3%, men: 14.9%). A greater percentage of female (92.3%) compared with male MOCs (69.3%; p<0.001) were assigned light duty status following MSIs. CONCLUSIONS: Mitigation of injuries during OCS events such as the obstacle course and the conditioning hike needs further investigation. The high risk of overuse lower leg injuries among women and the higher incidence of injuries among women compared with men underscore the need for further investigation of modifiable sex-specific injury risk factors.

A flexible neutron spectrometer concept with a new ultra-high field steady-state vertical-bore magnet.

The proposed facility explores materials under ultra-high magnetic fields. By combining the power of high fields to tune materials and of neutron scattering to probe the resulting changes down to the atomic scale, this facility will enable transformative progress in the study of quantum materials and is named for the "TITAN" subset of Greek gods to reflect this transformation. TITAN will offer DC magnetic fields up to at least 20 T. Exploiting the record brightness and bandwidth of the Second Target Station at the Spallation Neutron Source, TITAN will probe atomic-scale responses through high efficiency neutron spectroscopy up to 80 meV energy transfer, high resolution diffraction, and small angle neutron scattering. Focusing neutron optics will maximize flux on accurately positioned samples, while radial collimation and optimized shielding and detection strategies will minimize backgrounds.

A novel bioassay to detect Nociceptin/Orphanin FQ release from single human polymorphonuclear cells.

Nociceptin/Orphanin FQ (N/OFQ) is the endogenous opioid agonist for the N/OFQ receptor or NOP. This receptor system is involved in pain processing but also has a role in immune regulation. Indeed, polymorphonuclear cells (PMNs) express mRNA for N/OFQ precursor and are a potential source for circulating N/OFQ. Current measurements are based on ELISA and RIA techniques. In this study we have designed a bioassay to measure N/OFQ release from single PMNs. Chinese Hamster Ovary (CHO) cells transfected with the human (h) NOP receptor and Gαiq5 chimera force receptor coupling in biosensor cells to increase intracellular Ca2+; this can be measured with FLUO-4 dye. If isolated PMNs from healthy human volunteers are layered next to CHOhNOPGαiq5 biosensor cells then stimulated with the chemoattractant N-formyl-methionyl-leucyl-phenylalanine (fMLP) we hypothesise that released N/OFQ will activate the biosensor. PMNs also release ATP and CHO cells express purinergic receptors coupled to elevated Ca2+. In a system where these receptors (P2Y1, P2Y2 and P2X7) are blocked with high concentrations of PPADS and oATP, PMN stimulation with fMLP increases Ca2+ in PMNs then shortly afterwards the biosensor cells. Our data therfore reports detection of single cell N/OFQ release from immune cells. This was absent when cells were preincubated with the selective NOP antagonist; SB-612111. Collectively this is the first description of single cell N/OFQ release. We will deploy this assay with further purified individual cell types and use this to further study the role of the N/OFQ-NOP system in disease; in particular sepsis where there is strong evidence for increased levels of N/OFQ worsening outcome.

MOP and NOP receptor interaction: Studies with a dual expression system and bivalent peptide ligands.

Opioids targeting mu;µ (MOP) receptors produce analgesia in the peri-operative period and palliative care. They also produce side effects including respiratory depression, tolerance/dependence and addiction. The N/OFQ opioid receptor (NOP) also produces analgesia but is devoid of the major MOP side effects. Evidence exists for MOP-NOP interaction and mixed MOP-NOP ligands produce analgesia with reduced side effects. We have generated a HEKMOP/NOP human expression system and used bivalent MOP-NOP and fluorescent ligands to (i) probe for receptor interaction and (ii) consequences of that interaction. We used HEKMOP/NOP cells and two bivalent ligands; Dermorphin-N/OFQ (MOP agonist-NOP agonist; DeNO) and Dermorphin-UFP101 (MOP agonist-NOP antagonist; De101). We have determined receptor binding profiles, GTPγ[35S] binding, cAMP formation and ERK1/2 activation. We have also probed MOP and NOP receptor interactions in HEK cells and hippocampal neurones using the novel MOP fluorescent ligand, DermorphinATTO488 and the NOP fluorescent ligand N/OFQATTO594. In HEKMOP/NOP MOP ligands displaced NOP binding and NOP ligands displaced MOP binding. Using fluorescent probes in HEKMOP/NOP cells we demonstrated MOP-NOP probe overlap and a FRET signal indicating co-localisation. MOP-NOP were also co-localised in hippocampal tissue. In GTPγ[35S] and cAMP assays NOP stimulation shifted the response to MOP rightwards. At ERK1/2 the response to bivalent ligands generally peaked later. We provide evidence for MOP-NOP interaction in recombinant and native tissue. NOP activation reduces responsiveness of MOP activation; this was shown with conventional and bivalent ligands.

The vertical profile of winds on Titan.

One of Titan's most intriguing attributes is its copious but featureless atmosphere. The Voyager 1 fly-by and occultation in 1980 provided the first radial survey of Titan's atmospheric pressure and temperature and evidence for the presence of strong zonal winds. It was realized that the motion of an atmospheric probe could be used to study the winds, which led to the inclusion of the Doppler Wind Experiment on the Huygens probe. Here we report a high resolution vertical profile of Titan's winds, with an estimated accuracy of better than 1 m s(-1). The zonal winds were prograde during most of the atmospheric descent, providing in situ confirmation of superrotation on Titan. A layer with surprisingly slow wind, where the velocity decreased to near zero, was detected at altitudes between 60 and 100 km. Generally weak winds (approximately 1 m s(-1)) were seen in the lowest 5 km of descent.

A generative co-design framework for healthcare innovation: development and application of an end-user engagement framework.

Background Continual improvements to health systems, products, and services are necessary for improvements in health. However, many of these improvements are not incorporated into everyday practice. When designing new health systems, products, and services, involving members of the healthcare community and the public with personal healthcare experience can help to make sure that improvements will be useful and relevant to others like them. Methods Together with healthcare workers and family members with healthcare experience, we developed and applied a step-by-step guide to involving those with personal experience in the design of health system improvements. Results Our guide has three phases- 'Pre-Design', 'Co-Design', and 'Post-Design'. This paper describes each of these phases and illustrates how we applied them to our own project, which is to use virtual healthcare methods to improve care for children with chronic healthcare conditions and their families. In our own work, we found that healthcare workers and family members with personal healthcare experiences were able to use their knowledge and creativity to help us imagine how to improve care for children with chronic healthcare conditions and their families. We have created action items from these family member- and healthcare worker-identified needs, which we will use to shape our virtual healthcare system. Conclusions This paper may be useful for those seeking to involve members of the healthcare community and the public in the creation of better healthcare systems, products, and services. Background Challenges with the adoption, scale, and spread of health innovations represent significant gaps in the evidence-to-practice cycle. In the health innovation design process, a lack of attention paid to the needs of end-users, and subsequent tailoring of innovations to meet these needs, is a possible reason for this deficit. In the creative field of health innovation, which includes the design of healthcare products, systems (governance and organization mechanisms), and services (delivery mechanisms), a framework for both soliciting the needs of end-users and translating these needs into the design of health innovations is needed. Methods To address this gap, our team developed and applied a seven-step methodological framework, called A Generative Co-Design Framework for Healthcare Innovation. This framework was developed by an interdisciplinary team that included patient partners. Results This manuscript contributes a framework and applied exemplar for those seeking to engage end-users in the creative process of healthcare innovation. Through the stages of 'Pre-Design', 'Co-Design', and 'Post-Design', we were able to harness the creative insights of end-users, drawing on their experiences to shape a future state of care. Using an expository example of our own work, the DigiComp Kids project, we illustrate the application of each stage of the Framework. Conclusions A Generative Co-Design Framework for Healthcare Innovation provides healthcare innovators, applied health science researchers, clinicians, and quality improvement specialists with a guide to eliciting and incorporating the viewpoints of end-users while distilling practical considerations for healthcare innovation and design.