IntroductionLow back pain (LBP) is the leading global cause of disability. Patients with moderate to severe LBP who respond positively to a diagnostic medial nerve branch block can be offered ...radiofrequency denervation (RFD). However, high-quality evidence on the effectiveness of RFD is lacking.Methods and analysisRADICAL (RADIofrequenCy denervAtion for Low back pain) is a double-blind, parallel-group, superiority randomised controlled trial. A total of 250 adults listed for RFD will be recruited from approximately 20 National Health Service (NHS) pain and spinal clinics. Recruitment processes will be optimised through qualitative research during a 12-month internal pilot phase. Participants will be randomised in theatre using a 1:1 allocation ratio to RFD or placebo. RFD technique will follow best practice guidelines developed for the trial. Placebo RFD will follow the same protocol, but the electrode tip temperature will not be raised. Participants who do not experience a clinically meaningful improvement in pain 3 months after randomisation will be offered the alternative intervention to the one provided at the outset without disclosing the original allocation. The primary clinical outcome will be pain severity, measured using a pain Numeric Rating Scale, at 3 months after randomisation. Secondary outcomes will be assessed up to 2 years after randomisation and include disability, health-related quality of life, psychological distress, time to pain recovery, satisfaction, adverse events, work outcomes and healthcare utilisation. The primary statistical analyses will be by intention to treat and will follow a prespecified analysis plan. The primary economic evaluation will take an NHS and social services perspective and estimate the discounted cost per quality-adjusted life-year and incremental net benefit of RFD over the 2-year follow-up period.Ethics and disseminationEthics approval was obtained from the London—Fulham Research Ethics Committee (21/LO/0471). Results will be disseminated in open-access publications and plain language summaries.Trial registration number ISRCTN16473239.
The bald eagle (Haliaeetus leucocephalus) is a culturally and ecologically vital species in North America that embodies conservation success but continues to face threats that include emerging ...pathogens. The introduction of A/goose/Guangdong/1/1996 lineage highly pathogenic (HP) clade 2.3.4.4b H5N1 influenza A virus (IAV) in North America in late 2021 resulted in high rates of mortality among bald eagles. Here we show an alarming rate of bald eagle nest failure and mortality attributed to HP IAV. We documented fatal, systemic HP IAV infection in breeding adult and nestling bald eagles along the southeastern U.S. coast. Concurrently, annual bald eagle nest surveys in Georgia and Florida revealed a precipitous drop in success in coastal counties compared with previous years, portending negative impacts on population recruitment. As an apex predator and efficient scavenger, it is likely that bald eagles become infected through consumption of infected waterfowl. These results and similar reports of raptor mortality in Europe, Asia, and Africa, indicate a clear threat to raptor health. The possible long-term persistence of HP H5N1 IAV in North America poses an impending threat to bald eagle populations not only related to direct mortality but also decreased recruitment and warrants continued efforts to understand these potential impacts.
The worlds’ coral reefs are declining due to the combined effects of natural disturbances and anthropogenic pressures including thermal coral bleaching associated with global climate change. ...Nearshore corals are receiving increased anthropogenic stress from coastal development and nutrient run-off. Considering forecast increases in global temperatures, greater understanding of drivers of recovery on nearshore coral reefs following widespread bleaching events is required to inform management of local stressors. The west Pilbara coral reefs, with cross-shelf turbidity gradients coupled with a large nearby dredging program and recent history of repeated coral bleaching due to heat stress, represent an opportune location to study recovery from multiple disturbances. Mean coral cover at west Pilbara reefs was monitored from 2009 to 2018 and declined from 45% in 2009 to 5% in 2014 following three heat waves. Recruitment and juvenile abundance of corals were monitored from 2014 to 2018 and were combined with biological and physical data to identify which variables enhanced or hindered early-stage coral recovery of all hard corals and separately for the acroporids, the genera principally responsible for recovery in the short-term (<7 years). From 2014 to 2018, coral cover increased from 5 to 10% but recovery varied widely among sites (0–13%). Hard coral cover typically recovered most at shallower sites that had higher abundance of herbivorous fish, less macroalgae, and lower turbidity. Similarly, acroporid corals recovered most at sites with lower turbidity and macroalgal cover. Juvenile acroporid densities were a good indicator of recovery at least two years after they were recorded. However, recruitment to settlement tiles was not a good predictor of total coral or acroporid recovery. This study shows that coral recovery can be slower in areas of high turbidity and the rate may be reduced by local pressures, such as dredging. Management should focus on improving or maintaining local water quality to increase the likelihood of coral recovery under climate stress. Further, in turbid environments, juvenile coral density predicts early coral recovery better than recruits on tiles and may be a more cost-effective technique for monitoring recovery potential.
•Three thermal anomalies over four years bleached corals and reduced cover by ~90%.•Coral recovery varied spatially, limited driven mostly by turbidity.•Better water quality increases the likelihood of coral recovery under climate stress.•Juvenile coral density predicted early coral recovery better than recruits on tiles.
To assess the effectiveness of lunchbox interventions aiming to improve the foods and beverages packed and consumed by children at centre-based care or school; and subsequent impact on children's ...adiposity.
Systematic search of nine databases for controlled trials published in English between 1995-January 2017. Where appropriate, data were pooled in a random effects meta-analysis.
Of the 1601 articles identified, ten studies (centre-based care n = 4, school n = 6) were included of which eight were RCTs. The impact of interventions on the packing of discretionary foods, sugar-sweetened drinks and other core foods was inconsistent. Meta-analysis of four RCTs trials found a moderate increase in provision of vegetables (SMD = 0.40 95% CI 0.16 to 0.64, p = 0.001, I
= 82%; equivalent to a mean difference of 0.28 serves) but not fruit. Four studies reported impact on children's dietary intake, one reported no significant effect on consumption of discretionary foods, one reported improvements in the consumption of sugar-sweetened drinks and water, and two reported improvements in consumption of vegetables and fruit. Two studies, that were broader obesity prevention interventions, reported no significant impact on adiposity.
There is some evidence that lunchbox interventions are effective in improving the packing of vegetables in children's lunchboxes, however more robust research is required to determine the impact on children's dietary intake and adiposity.
PROSPERO 2016: CRD42016035646 .
Trait stacking via targeted genome editing Ainley, William M.; Sastry‐Dent, Lakshmi; Welter, Mary E. ...
Plant biotechnology journal,
December 2013, Letnik:
11, Številka:
9
Journal Article
Recenzirano
Summary
Modern agriculture demands crops carrying multiple traits. The current paradigm of randomly integrating and sorting independently segregating transgenes creates severe downstream breeding ...challenges. A versatile, generally applicable solution is hereby provided: the combination of high‐efficiency targeted genome editing driven by engineered zinc finger nucleases (ZFNs) with modular ‘trait landing pads’ (TLPs) that allow ‘mix‐and‐match’, on‐demand transgene integration and trait stacking in crop plants. We illustrate the utility of nuclease‐driven TLP technology by applying it to the stacking of herbicide resistance traits. We first integrated into the maize genome an herbicide resistance gene, pat, flanked with a TLP (ZFN target sites and sequences homologous to incoming DNA) using WHISKERS™‐mediated transformation of embryogenic suspension cultures. We established a method for targeted transgene integration based on microparticle bombardment of immature embryos and used it to deliver a second trait precisely into the TLP via cotransformation with a donor DNA containing a second herbicide resistance gene, aad1, flanked by sequences homologous to the integrated TLP along with a corresponding ZFN expression construct. Remarkably, up to 5% of the embryo‐derived transgenic events integrated the aad1 transgene precisely at the TLP, that is, directly adjacent to the pat transgene. Importantly and consistent with the juxtaposition achieved via nuclease‐driven TLP technology, both herbicide resistance traits cosegregated in subsequent generations, thereby demonstrating linkage of the two independently transformed transgenes. Because ZFN‐mediated targeted transgene integration is becoming applicable across an increasing number of crop species, this work exemplifies a simple, facile and rapid approach to trait stacking.
Western Australia’s coral reefs have largely escaped the chronic pressures affecting other reefs around the world, but are regularly affected by seasonal storms and cyclones, and increasingly by heat ...stress and coral bleaching. Reef systems north of 18°S have been impacted by heat stress and coral bleaching during strong El Niño phases and those further south during strong La Niña phases. Cumulative heat stress and the extent of bleaching throughout the northern reefs in 2016 were higher than at any other time on record. To assess the changing regime of disturbance to reef systems across Western Australia (WA), we linked their site-specific exposure to damaging waves and heat stress since 1990 with mean changes in coral cover. Since 2010, there has been a noticeable increase in heat stress and coral bleaching across WA. Over half the reef systems have been severely impacted by coral bleaching since 2010, which was further compounded by cyclones at some reefs. For most (75%) reef systems with long-term data (5–26 yrs), mean coral cover is currently at (or near) the lowest on record and a full recovery is unlikely if disturbances continue to intensify with climate change. However, some reefs have not yet experienced severe bleaching and their coral cover has remained relatively stable or increased in recent years. Additionally, within all reef systems the condition of communities and their exposure to disturbances varied spatially. Identifying the communities least susceptible to future disturbances and linking them through networks of protected areas, based on patterns of larval connectivity, are important research and management priorities in coming years while the causes of climate change are addressed.
Mendelian randomization (MR), the use of genetic variants as instrumental variables (IVs) to test causal effects, is increasingly used in aetiological epidemiology. Few of the methodological ...developments in MR have considered the specific situation of using genetic IVs to test the causal effect of exposures in pregnant women on postnatal offspring outcomes. In this paper, we describe specific ways in which the IV assumptions might be violated when MR is used to test such intrauterine effects. We highlight the importance of considering the extent to which there is overlap between genetic variants in offspring that influence their outcome with genetic variants used as IVs in their mothers. Where there is overlap, and particularly if it generates a strong association of maternal genetic IVs with offspring outcome via the offspring genotype, the exclusion restriction assumption of IV analyses will be violated. We recommend a set of analyses that ought to be considered when MR is used to address research questions concerned with intrauterine effects on post-natal offspring outcomes, and provide details of how these can be undertaken and interpreted. These additional analyses include the use of genetic data from offspring and fathers, examining associations using maternal non-transmitted alleles, and using simulated data in sensitivity analyses (for which we provide code). We explore the extent to which new methods that have been developed for exploring violation of the exclusion restriction assumption in the two-sample setting (MR-Egger and median based methods) might be used when exploring intrauterine effects in one-sample MR. We provide a list of recommendations that researchers should use when applying MR to test the effects of intrauterine exposures on postnatal offspring outcomes and use an illustrative example with real data to demonstrate how our recommendations can be applied and subsequent results appropriately interpreted.
Osteoporosis is a common disease diagnosed primarily by measurement of bone mineral density (BMD). We undertook a genome-wide association study (GWAS) in 142,487 individuals from the UK Biobank to ...identify loci associated with BMD as estimated by quantitative ultrasound of the heel. We identified 307 conditionally independent single-nucleotide polymorphisms (SNPs) that attained genome-wide significance at 203 loci, explaining approximately 12% of the phenotypic variance. These included 153 previously unreported loci, and several rare variants with large effect sizes. To investigate the underlying mechanisms, we undertook (1) bioinformatic, functional genomic annotation and human osteoblast expression studies; (2) gene-function prediction; (3) skeletal phenotyping of 120 knockout mice with deletions of genes adjacent to lead independent SNPs; and (4) analysis of gene expression in mouse osteoblasts, osteocytes and osteoclasts. The results implicate GPC6 as a novel determinant of BMD, and also identify abnormal skeletal phenotypes in knockout mice associated with a further 100 prioritized genes.
Breast cancer is the most commonly diagnosed cancer in Australian women. Given the diverse geography and populations within Australia, the ability to offer a telemedicine-supported breast screening ...and assessment service may increase access. The aim of this study was to assess clinical outcomes of a telemedicine-based remote radiology assessment service delivery model for detecting breast cancer in regional Australian women compared to the traditional radiologist onsite model.
This study was a pre-post intervention study using de-identified administrative data. Data were collected from seven sites across three health jurisdictions within Australia. There were a total of 21,117 assessment visits, with 10,508 (49.8%) pre- and 10,609 (50.2%) post-remote model implementation. Of the 10,609 post-remote model visits, 3,904 (36.8%) were under the remote model. The main outcome was cancer detection, split into any cancer, any invasive cancer or any small invasive cancer. Timeliness of assessment was also examined.
After adjusting for multiple factors, there were no statistically significant differences in cancer detection rates between the remote and onsite models (adjusted odds ratio (AOR) = 1.02, 95% CI 0.86-1.19, n.s.). Implementing the remote assessment model had statistically significant positive effects on the timeliness of assessment (AOR = 0.68, 95% CI 0.59-0.77, p < 0.001).
This study found the remote model delivers safe and high-quality assessment services, with equivalent rates of cancer detection and improved timeliness of assessment when compared to the traditional onsite model. Careful monitoring and ongoing evaluation of any health-service model is important for ongoing safety, efficiency and acceptability.
Paranoia is a common, distressing, and persistent experience that can negatively impact on health, wellbeing, and functioning. This study examined the immediate and short term (2-weeks) effects of ...two values-based interventions, versus a non-values control, on paranoia, as well as the moderating effect of self-esteem.
171 non-clinical adults were randomised to a value-affirmation and goals task (VAG: clarifying and reflecting on core values and setting value-based goals) (n = 57), a value-affirmation task (VA: clarifying and reflecting on core values without setting value-based goals) (n = 57), or a non-affirmation control task (NAC) (n = 57). Paranoia was assessed at baseline (T1), post-intervention (T2), and two weeks post-intervention (T3). Self-esteem was measured at baseline.
VAG participants had significantly lower state paranoia scores at T3 than VA (d = .34) and NAC (d = .31) participants. This effect was moderated by trait self-esteem: At follow-up, the differential effect of condition on state paranoia was greatest amongst those with low self-esteem, with the VAG condition being most beneficial for participants with low self-esteem and the VA condition being least beneficial.
Without a goals only control group it is possible that the benefits of VAG over VA were attributable to setting and achieving goals. Use of a nonclinical sample limits generalisability to clinical groups.
The findings suggest that focusing on a deeply held value and setting goals in line with that value reduced paranoia. This intervention may be most beneficial for individuals with low self-esteem.
•Focusing on values and setting value-based goals significantly reduced paranoia.•Focusing on values, without setting goals, did not.•Self-esteem moderated the effect of condition on paranoia.•People with low self-esteem benefitted most from the VAG intervention.
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