Cycle threshold values are inversely associated with poorer outcomes in hospitalised patients with Covid-19:a prospective, observational cohort study conducted at a UK tertiary hospital

ABSTRACT: This single-centre observational study demonstrated that lower cycle threshold (Ct) values (indicating higher viral loads) on admission to hospital were associated with poorer outcomes in unvaccinated, hospitalized patients with coronavirus disease 2019 (COVID-19). Demographic and outcome data were collected prospectively for all adult patients who tested positive for severe acute respiratory syndrome coronavirus-2 on admission to the University Hospitals North Midlands NHS Trust between 1 February and 1 July 2020. Nasopharyngeal swab samples were obtained, and a valid Ct value was determined for all patients using the Viasure reverse transcription polymerase chain reaction assay, validated by Public Health England, on admission to hospital. Multi-variable logistic regression results based on data from 618 individuals demonstrated a significant inverse relationship between the odds of death and Ct values (adjusted odds ratio 0.95, 95% confidence interval 0.92–0.98, P=0.001). The association remained highly significant after adjusting for known clinical risk factors for COVID-1

ZiFiT (Zinc Finger Targeter): an updated zinc finger engineering tool

ZiFiT (Zinc Finger Targeter) is a simple and intuitive web-based tool that provides an interface to identify potential binding sites for engineered zinc finger proteins (ZFPs) in user-supplied DNA sequences. In this updated version, ZiFiT identifies potential sites for ZFPs made by both the modular assembly and OPEN engineering methods. In addition, ZiFiT now integrates additional tools and resources including scoring schemes for modular assembly, an interface with the Zinc Finger Database (ZiFDB) of engineered ZFPs, and direct querying of NCBI BLAST servers for identifying potential off-target sites within a host genome. Taken together, these features facilitate design of ZFPs using reagents made available to the academic research community by the Zinc Finger Consortium. ZiFiT is freely available on the web without registration at http://bindr.gdcb.iastate.edu/ZiFiT/

The challenges of intersectionality: Researching difference in physical education

Researching the intersection of class, race, gender, sexuality and disability raises many issues for educational research. Indeed, Maynard (2002, 33) has recently argued that ‘difference is one of the most significant, yet unresolved, issues for feminist and social thinking at the beginning of the twentieth century’. This paper reviews some of the key imperatives of working with ‘intersectional theory’ and explores the extent to these debates are informing research around difference in education and Physical Education (PE). The first part of the paper highlights some key issues in theorising and researching intersectionality before moving on to consider how difference has been addressed within PE. The paper then considers three ongoing challenges of intersectionality – bodies and embodiment, politics and practice and empirical research. The paper argues for a continued focus on the specific context of PE within education for its contribution to these questions

The Business-Society Nexus for the 21st Century

Eurocentric academic and policy propositions on global sustainability tend to emphasize the transfer of knowledge, skills, technology, funds, or social values to lower and middle income countries. Yet, India and China increasingly influence geo-economic and geo-political shifts, accompanied by sociocultural and environmental consequences. Their increasing independence and global agenda setting capacity, as well as their capabilities to institutionally coordinate and execute programs toward economic and social development within and well beyond their national borders transcend the current imaginaries of most stakeholders from higher income countries. Although we are witnessing a transformation of the business-society nexus and its consequences on public, private, and civic spheres, research in particular and academia more generally have been slow to acknowledge and respond to these paradigm shifts. The importance to understand and to be understood by India and China, however, can no longer be ignored. Globally, businesses, societies, and governments must find new ways of interacting in the interest of mutual survival and prosperity. But what does this mean in practice? What could be a sustainable business-society nexus for the 21st century? In this paper, we examine the opportunities and challenges inherent in emerging trends and the positions stakeholders and contemporary academic disciplines take in relation to these. We outline the potential for a future research agenda on a sustainable business-society nexus that is business-relevant, solution-driven, future-oriented, culture-sensitive, and devoted to people, planet, prosperity, partnerships, and peace

A diagnosis of prostate cancer and pursuit of active surveillance is not followed by weight loss: potential for a teachable moment

BACKGROUND: Obesity is a risk factor for incident prostate cancer (PC) as well as risk of disease progression and mortality. We hypothesized that men diagnosed with lower-risk PC and who elected active surveillance (AS) for their cancer management would likely initiate lifestyle changes that lead to weight loss. METHODS: Patients were enrolled in the Prostate Active Surveillance Study (PASS), a multicenter prospective biomarker discovery and validation study of men who have chosen AS for their PC. Data from 442 men diagnosed with PC within 1 year of study entry who completed a standard of care 12-month follow-up visit were analyzed. We examined the change in weight and body mass index (BMI) over the first year of study participation. RESULTS: After 1 year on AS, 7.5% (33/442) of patients had lost 5% or more of their on-study weight. The proportion of men who lost 5% or more weight was similar across categories of baseline BMI: normal/underweight (8%), overweight (6%) and obese (10%, χ2 test P=0.44). The results were similar for patients enrolled in the study 1 year or 6 months after diagnosis. By contrast, after 1 year, 7.7% (34/442) of patients had gained >5% of their weight. CONCLUSIONS: Only 7.5% of men with low-risk PC enrolled in AS lost a modest (⩾5%) amount of weight after diagnosis. Given that obesity is related to PC progression and mortality, targeted lifestyle interventions may be effective at this 'teachable moment', as men begin AS for low-risk PC

Problem-solving therapy rather than treatment as usual for adults after self-harm: a pragmatic, feasibility, randomised controlled trial (the MIDSHIPS trial)

Background: Non-fatal self-harm is one of the commonest reasons for adults’ emergency hospital attendance. Although strongly associated with fatal and non-fatal repetition, there is weak evidence about effective interventions—and no clear NICE guidance or clinical consensus concerning aftercare. We examined the practicability of a definitive trial to evaluate problem-solving therapy (PST) to reduce repetition of self-harm; MIDSHIPS is a single-centre, parallel-group, individually randomised controlled feasibility trial comparing treatment-as-usual (TAU) alone to TAU plus up to six sessions of brief problem-solving therapy (PST) with adults who had recently attended hospital because of self-harm. Objectives were to adapt the intervention for a UK setting, train therapists, recruit and randomise patients, deliver PST under supervision, and establish comparative outcomes, assessed blindly. Methods: We adapted the problem-solving intervention from an earlier trial and trained a mental-health nurse to deliver it. Adult patients attending the general hospital for self-harm were recruited while undergoing psychosocial assessment by the mental health team, and 62 were randomly allocated (32 TAU, 30 PST). The primary outcome assessed repeat hospital attendance due to further self-harm 6 months post-randomisation. Secondary outcomes included participant-reported outcomes and service use at 3 and 6 months post-randomisation. Results: The recruitment period had to be extended and 710 patients screened in order to establish a trial sample of the planned size (N = 62). A quarter of participants allocated to PST did not undertake the therapy offered; those who received PST attended a median of three sessions. Secondary outcomes were established for 49 (79%) participants at 6 months; all participants’ hospital records were retrieved. Repetition of self-harm leading to hospital presentation occurred in 19 of the 62 participants (30.6%, 95% CI 19.2%, 42.1%) within 6 months of randomisation. Promising differential rates of self-harm were observed with an event rate of 23.3% (95% CI 8.2%, 38.5%) in the PST arm; and 37.5% (95% CI 20.7%, 54.3%) in TAU. Economic findings were also encouraging, with a small QALY gain (0.0203) in the PST arm together with less reported use of the NHS in the PST arm (average £2120) than with TAU-only (£2878). Conclusions: The feasibility trial achieved its objectives despite considerable difficulties with recruitment—adapting the PST, training a therapist, recruiting patients who had recently self-harmed, delivering the therapy, and establishing primary and secondary outcomes. These data provide a robust platform for a definitive multicentre randomised controlled trial of brief problem-solving therapy after hospital attendance due to self-harm. Trial registration: Identification number and URL: ISRCTN54036115 http://www.isrctn.com/search?q=midships. Registered: 13 January 201

Zinc finger protein-dependent and -independent contributions to the in vivo off-target activity of zinc finger nucleases

Zinc finger nucleases (ZFNs) facilitate tailor-made genomic modifications in vivo through the creation of targeted double-stranded breaks. They have been employed to modify the genomes of plants and animals, and cell-based therapies utilizing ZFNs are undergoing clinical trials. However, many ZFNs display dose-dependent toxicity presumably due to the generation of undesired double-stranded breaks at off-target sites. To evaluate the parameters influencing the functional specificity of ZFNs, we compared the in vivo activity of ZFN variants targeting the zebrafish kdrl locus, which display both high on-target activity and dose-dependent toxicity. We evaluated their functional specificity by assessing lesion frequency at 141 potential off-target sites using Illumina sequencing. Only a minority of these off-target sites accumulated lesions, where the thermodynamics of zinc finger–DNA recognition appear to be a defining feature of active sites. Surprisingly, we observed that both the specificity of the incorporated zinc fingers and the choice of the engineered nuclease domain could independently influence the fidelity of these ZFNs. The results of this study have implications for the assessment of likely off-target sites within a genome and point to both zinc finger-dependent and -independent characteristics that can be tailored to create ZFNs with greater precision

Mating patterns influence vulnerability to the extinction vortex

Earth's biodiversity is undergoing mass extinction due to anthropogenic compounding of environmental, demographic and genetic stresses. These different stresses can trap populations within a reinforcing feedback loop known as the extinction vortex, in which synergistic pressures build upon one another through time, driving down population viability. Sexual selection, the widespread evolutionary force arising from competition, choice and reproductive variance within animal mating patterns could have vital consequences for population viability and the extinction vortex: (a) if sexual selection reinforces natural selection to fix ‘good genes’ and purge ‘bad genes’, then mating patterns encouraging competition and choice may help protect populations from extinction; (b) by contrast, if mating patterns create load through evolutionary or ecological conflict, then population viability could be further reduced by sexual selection. We test between these opposing theories using replicate populations of the model insect Tribolium castaneum exposed to over 10 years of experimental evolution under monogamous versus polyandrous mating patterns. After a 95‐generation history of divergence in sexual selection, we compared fitness and extinction of monogamous versus polyandrous populations through an experimental extinction vortex comprising 15 generations of cycling environmental and genetic stresses. Results showed that lineages from monogamous evolutionary backgrounds, with limited opportunities for sexual selection, showed rapid declines in fitness and complete extinction through the vortex. By contrast, fitness of populations from the history of polyandry, with stronger opportunities for sexual selection, declined slowly, with 60% of populations surviving by the study end. The three vortex stresses of (a) nutritional deprivation, (b) thermal stress and (c) genetic bottlenecking had similar impacts on fitness declines and extinction risk, with an overall sigmoid decline in survival through time. We therefore reveal sexual selection as an important force behind lineages facing extinction threats, identifying the relevance of natural mating patterns for conservation management

Perturbation evolution in cosmologies with a decaying cosmological constant

Structure formation models with a cosmological constant are successful in explaining large-scale structure data, but are threatened by the magnitude-redshift relation for Type Ia supernovae. This has led to discussion of models where the cosmological `constant' decays with time, which might anyway be better motivated in a particle physics context. The simplest such models are based on scalar fields, and general covariance demands that a time-evolving scalar field also supports spatial perturbations. We consider the effect of such perturbations on the growth of adiabatic energy density perturbations in a cold dark matter component. We study two types of model, one based on an exponential potential for the scalar field and the other on a pseudo-Nambu Goldstone boson. For each potential, we study two different scenarios, one where the scalar field presently behaves as a decaying cosmological constant and one where it behaves as dust. The initial scalar field perturbations are fixed by the adiabatic condition, as expected from the inflationary cosmology, though in fact we show that the choice of initial condition is of little importance. Calculations are carried out in both the zero-shear (conformal newtonian) and uniform-curvature gauges. We find that both potentials allow models which can provide a successful alternative to cosmological constant models.Comment: 14 pages RevTeX file with three figures incorporated (uses RevTeX and epsf). Also available by e-mailing ARL, or by WWW at http://star-www.maps.susx.ac.uk/papers/lsstru_papers.html Revised version corrects an error in Eq10; results unchange