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This realist enquiry applying behavioural theory aimed to identify behavioural mechanisms and contexts that facilitate prescribers tapering opioids. We identified relevant opioid tapering interventions and services from a 2018 international systematic review and a 2019 England-wide survey, respectively. Interventions and services were eligible if they provided information about contexts and/or behavioural mechanisms influencing opioid tapering success. A stakeholder group (n=23) generated draft programme theories based around the 14 domains of the theoretical domains framework. We refined these using the trial and service data. From 71 articles and 21 survey responses, 56 and 16 respectively were included, representing primary care, hospital, specialist pain facilities and prison services. We identified six programme theories that included five behavioural mechanisms: prescribers’ knowledge about how to taper; build prescribers’ beliefs about capabilities to initiate tapering discussions and manage psychological consequences of tapering; perceived professional role in tapering; the environmental context enabling referral to specialists; and facilitating positive social influence by aligning patient: prescriber expectations of tapering. No interventions are addressing all six mechanisms supportive of tapering. Work is required to operationalise programme theories according to organisational structures and resources. An example operationalisation is combining tapering guidelines with information about local excess opioid problems and endorsing these with organisational branding. Prescribers being given the skills and confidence to initiate tapering discussions by training them in cognitive-based interventions and incorporating access to psychological and physical support in the patient pathway. Patients being provided with leaflets about the tapering process and informed about the patient pathway.

Yimin Yao

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Background/Purpose: Systemic sclerosis (SSc) is characterised by progressive multiple-organ fibrosis leading to morbidity and mortality. Lysyl oxidases play a vital role in the cross-linking of collagens and subsequent build-up of fibrosis in the extracellular matrix. As such, their inhibition provides a novel treatment paradigm for SSc. Experimental Approach: Lysyl oxidases are upregulated in preclinical models of fibrosis in skin, lung, heart, kidney and liver. A novel small molecule pan-lysyl oxidase inhibitor, PXS-5505, currently in clinical development for bone fibrosis treatment was evaluated in in vivo rodent models resembling the fibrotic conditions in SSc. Key Results: Both lysyl oxidase and lysyl oxidase-like 2 (LOXL2) expression was elevated in the skin and lung of SSc patients. Once-a-day oral application of PXS-5505 inhibited lysyl oxidase activity in the skin and LOXL2 activity in the lung. PXS-5505 exhibited anti-fibrotic effects in the SSc skin mouse model, reducing dermal thickness and α-smooth muscle actin compared to the disease controls. Similarly, in the bleomycin-induced mouse lung model, PXS-5505 reduced tissue fibrosis toward normal levels. The anti-fibrotic efficacy of PXS-5505 in the bleomycin exposed lungs was mediated by its ability to normalise collagen/elastin crosslink formation, a direct consequence of lysyl oxidase inhibition. PXS-5505 also reduced area of fibrosis in rodent models of the ischaemia-reperfusion heart, the unilateral ureteral obstruction kidney and the CCl4-induced fibrotic liver. Conclusion/Implication: PXS-5505 consistently demonstrates potent anti-fibrotic efficacy in multiple models of organ fibrosis relevant to the pathogenesis of SSc, suggesting that it may be efficacious as a novel approach for treating SSc.

Robert Desharnais

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1. Competition from invasive species is an increasing threat to biodiversity. In Southern California, the western gray squirrel (Sciurus griseus, WGS) is facing increasing competition from the fox squirrel (Sciurus niger, FS), an invasive congener. 2. We used spectral methods to analyze 140 consecutive monthly censuses of WGS and FS within a 11.3 ha section of the California Botanic Garden. Variation in the numbers for both species and their synchrony was distributed across long timescales (> 15 months). 3. After filtering out annual changes, concurrent mean monthly temperatures from nearby Ontario Airport (ONT) yielded a spectrum with a large semiannual peak and significant spectral power at long timescales (> 30 months). Squirrel-temperature cospectra showed significant negative covariation at long timescales (> 35 months) for WGS and smaller significant negative peaks at 6 months for both species. 4. Simulations from a Lotka-Volterra model of two competing species indicates that the risk of extinction for the weaker competitor increases quickly as environmental noise shifts from short to long timescales. 5. We analyzed the timescales of fluctuations in detrended mean annual temperatures for the time period 1915-2014 from 1218 locations across the continental USA. In the last two decades, significant shifts from short timescales to long timescales have occurred, changing from less than 3 years to 4-6 years. 6. Our results indicate that (i) population fluctuations in co-occurring native and invasive tree squirrels are synchronous, occur over long timescales, and may be driven by fluctuations in environmental conditions; (ii) long timescale population fluctuations increase the risk of extinction in competing species, especially for the inferior competitor; and (iii) the timescales of interannual environmental fluctuations may be increasing from recent historical values. These results have broad implications for the impact of climate change on the maintenance of biodiversity.

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