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Design Investigator-led, prospective, open-labelled marker-based strategy (hybrid) randomised trial. Background Allografts in 3% of kidney transplant patients fail annually. Development of antibodies against human leucocyte antigens is a validated predictive biomarker of allograft failure. Under immunosuppression is recognised to contribute, but whether increasing immunosuppression can prevent allograft failure in human leucocyte antigen Ab+ patients is unclear. Participants Renal transplant recipients > 1 year post-transplantation attending 13 United Kingdom transplant clinics, without specific exclusion criteria. Interventions Regular screening for human leucocyte antigen antibodies followed, in positive patients by interview and tailored optimisation of immunosuppression to tacrolimus, mycophenolate mofetil and prednisolone. Objective To determine if optimisation of immunosuppression in human leucocyte antigen Ab+ patients can cost-effectively prevent kidney allograft failure. Outcome Time to graft failure after 43 months follow-up in patients receiving the intervention, compared to controls, managed by standard of care. Costs and quality-adjusted life-years were used in the cost-effectiveness analysis. Randomisation and blinding Random allocation (1 : 1) to unblinded biomarker-led care or double-blinded standard of care stratified by human leucocyte antigen antibodies status (positive/negative) and in positives, presence of donor-specific antibodies (human leucocyte antigen antibodies against donor human leucocyte antigen) or not (human leucocyte antigen antibodies against non-donor human leucocyte antigen), baseline immunosuppression and transplant centre. Biomaker-led care human leucocyte antigen Ab+ patients received intervention. Human leucocyte antigen Ab-negative patients were screened every 8 months. Recruitment Began September 2013 and for 37 months. The primary endpoint, scheduled for June 2020, was moved to March 2020 because of COVID-19. Numbers randomised From 5519 screened, 2037 were randomised (1028 biomaker-led care, 1009 to standard of care) including 198 with human leucocyte antigen antibodies against donor human leucocyte antigen (106 biomaker-led care, 92 standard of care) and 818 with human leucocyte antigens antibodies against non-donor human leucocyte antigen (427 biomaker-led care, 391 standard of care). Numbers analysed Two patients were randomised in error so 2035 were included in the intention-to-treat analysis. Outcome The trial had 80% power to detect a hazard ratio of 0.49 in biomarker-led care DSA+ group, > 90% power to detect hazard ratio of 0.35 in biomarker-led care non-DSA+ group (with 5% type 1 error). Actual hazard ratios for graft failure in these biomarker-led care groups were 1.54 (95% CI: 0.72 to 3.30) and 0.97 (0.54 to 1.74), respectively. There was 90% power to demonstrate non-inferiority of overall biomarker-led care group with assumed hazard ratio of 1.4: This was not demonstrated as the upper confidence limit for graft failure exceeded 1.4: (1.02, 95% CI 0.72 to 1.44). The hazard ratio for biopsy-proven rejection in the overall biomarker-led care group was 0.5 [95% CI: 0.27 to 0.94: p = 0.03]. The screening approach was not cost-effective in terms of cost per quality-adjusted life-year. Harms No significant differences in other secondary endpoints or adverse events. Limitations Tailored interventions meant optimisation was not possible in some patients. We did not study pathology on protocol transplant biopsies in DSA+ patients. Conclusions No evidence that optimised immunosuppression in human leucocyte antigen Ab+ patients delays renal transplant failure. Informing patients of their human leucocyte antigen antibodies status appears to reduce graft rejection. Future work We need a better understanding of the pathophysiology of transplant failure to allow rational development of effective therapies. Trial registration This trial is registered as EudraCT (2012-004308-36) and ISRCTN (46157828). Funding This project was funded by the National Institute for Health and Care Research (NIHR) Efficacy and Mechanism Evaluation programme (11/100/34) and will be published in full in Efficacy and Mechanism Evaluation; Vol. 10, No. 5. See the NIHR Journals Library website for further project information. Plain language summary Although kidney transplantation is the gold-standard treatment for kidney failure, thousands of transplants fail each year due to damage by the immune system. Finding circulating antibodies against the transplant can identify patients at high risk of failure. Under-treatment with immunosuppressive drugs plays a part in promoting the damage and increasing immunosuppression can slow progression in some but not all patients. In the Optimized TacrolimuS and MMF for HLA Antibodies after Renal Transplantation OuTSMART trial, we screened kidney transplant patients for circulating antibodies then, in the intervention arm, counselled everyone on the importance of taking immunosuppression, before optimising treatments to ‘best available’. We recruited > 2000 patients and split them into two groups randomly; in the first we revealed antibody results, encouraged adherence and tailored treatment to a combination of three drugs called tacrolimus, mycophenolate, and prednisolone, in a regimen that was judged optimal for each. In the second group, we did not release the antibody test results to patients or their doctors, and all treatment decision were based on local standard of care. At the end, we compared the numbers of transplant failures in each group. We confirmed that patients with antibodies were at higher risk of transplant failure, but found no differences in failures between those in whom we had intervened compared to those treated by standard of care. Although more developed rejection after standard care, there were no differences in the other things we measured, including the numbers who died, developed diabetes, infections or cancer and no differences in the number who developed new side effects. We therefore conclude that there is no basis for optimising drug treatment in those with antibodies at risk of transplant failure. Instead, novel treatments are needed. This trial will influence current practice around the world and hopefully incentivise research into new strategies to prevent transplant failure. Scientific summary Background Kidney transplants do not last for the natural lifespan of most recipients, and many patients eventually suffer progressive decline in transplant function leading to graft failure and need to return to dialysis. Around the world, this problem is significant, as 3% of kidney transplant patients return to dialysis each year. The single biggest cause of allograft dysfunction leading to transplant failure is immune-mediated damage and a prevalent hypothesis in the field is that inappropriately low levels of immunosuppression, either physician-led or due to patient non-adherence, is an important contributor to the initiation and progression of this immune-mediated damage. There are still no effective treatments for allograft dysfunction that is proven to be due to immune-mediated damage. Enhancing baseline immunosuppression appears to stabilise graft function in some patients. Two recent randomised trials of the anti-CD20 monoclonal antibody rituximab showed no impact, although both were stopped prematurely as they were underpowered. More recent reports indicate that anti-IL-6 monoclonals show promise at stabilising estimated Glomerular Filtration Rate (eGFR), but these have yet to be tested in large randomised trials. Since the development of circulating antibodies (Ab) against human leucocyte antigens (HLA) has been validated as a strong prognostic biomarker of kidney transplant failure, and there is genuine equipoise about whether increasing or optimising immunosuppression can benefit patients at risk of transplant failure, in the OuTSMART trial we tested the hypothesis that screening for these Ab followed by optimising oral immunosuppression treatment, could prevent allograft failure. Objectives Primary Determine the time to graft failure in patients testing positive for HLA Ab at baseline or within 32 months of randomisation who receive an optimised anti-rejection medication intervention with prednisolone, tacrolimus (Tac) and mycophenolate mofetil (MMF) (‘treatment’), compared to a control group who test positive for HLA Ab at baseline or within 32 months post-randomisation who remain on their established immunotherapy and whose clinicians are not aware of their Ab status. The primary endpoint was to be assessed remotely when 43 months post-randomisation was achieved by all. Secondary Determine the time to graft failure in patients randomised to ‘unblinded’ HLA Ab screening, compared to a control group randomised to ‘blinded’ HLA Ab screening. Determine whether treatment influences patient survival. Determine whether ‘treatment’ influences the development of graft dysfunction as assessed by presence of proteinuria (protein:creatinine ratio > 50 or albumin:creatinine ratio > 35) and change in eGFR. Determine whether ‘treatment’ influences the rates of acute rejection in these groups. Determine the adverse effect profiles of ‘treatment’ in this group, in particular whether they are associated with increased risk of infection, malignancy or diabetes mellitus. Determine the cost-effectiveness of routine screening for HLA Ab and prolonging transplant survival using this screening/treatment protocol. Determine the impact of biomarker screening and ‘treatment’ on the patients’ adherence to drug therapy and their perceptions of risk to the health of the transplant. Methods OuTSMART was an investigator-led, prospective, open-labelled marker-based strategy (hybrid) randomised trial. Eligible patients were recipients of cross-match negative transplants aged 18–75, more than 1 year post-transplant with an eGFR ≥30 ml/min willing to consent to the screening/treatment process. Patients were excluded if they were recipients of cross-match positive transplant requiring HLA desensitisation to remove Ab, recipients of additional solid organ transplants (e.g. pancreas, heart, etc.), had a history of malignancy (except non-melanomatous lesions restricted to the skin), had recent acute rejection, had a history of hepatitis B, C or human immunodeficiency virus (HIV), were known to have HLA Ab and received specific treatment for that Ab, had known hypersensitivity to any of the investigational medicinal products (IMPs), had known hereditary disorders of carbohydrate metabolism, were pregnant at the time of consent, or were females who refused to consent to using suitable contraception through the trial. Additionally, patients enrolled in any other studies involving administration of another IMP at time of recruitment were excluded. Stratified randomisation was 1 : 1 to two arms, blinded standard care (SC) or unblinded biomarker-led care (BLC). Randomisation was stratified first by the result from blood test screening for HLA Ab. The HLA Ab+ patients were further screened with single antigen beads to determine whether donor-specific Ab (DSA) were present or whether the only Ab detected was non-DSA. Thus, biomarker stratification led to three groups within each arm (DSA+, non-DSA+ and HLA Ab-neg). The second stratification was based on current immunosuppression, to ensure balanced numbers already on Tac or MMF in each group. The final stratification was by site. Patients in the SC arm were blinded to their biomarker status, as were their physicians, and remained on baseline immunotherapy, whereas patients in the BLC arm were told their HLA Ab status and were offered intervention. HLA Ab-negative patients in either arm remained on their existing immunotherapy and were rescreened for new HLA Abs every 8 months. Those patients who become positive during subsequent screening rounds were moved to the appropriate HLA Ab positive groups (DSA+ or non-DSA+) for final data analysis. All patients in the unblinded arm found to be positive on second or subsequent rounds were offered the same intervention as those patients who were positive in the first screening round, and these were intensively followed up for an additional 32 months from the time they become positive. Thus the maximum amount of time any single patient remained in intensive follow-up was 64 months. New patients were recruited to the study at each successive screening round. Intervention in the unblinded HLA Ab + patients consisted of informing patients of their HLA Ab status, followed by, in those with DSA or non-DSA, an interview to encourage medication adherence followed by medication changes to optimised doses of Tac, MMF and Prednisolone. Medication changes were tailored to each individual and failure to change, or to tolerate changes was not regarded as treatment failure, so some patients stayed on the same drug regimen. Patients with DSA and non-DSA were offered the same intervention. The primary outcome was originally transplant failure rates over 3 years, but this was changed to time to graft failure after an audit revealed that the prevalence and incidence rates of HLA Ab + patients were less than expected when planning the trial. With a planned minimum follow-up period of 43 months, the trial had 80% power to detect a hazard ratio (HR) of 0.49 in donor-specific antibody+ patients. Secondary endpoints were collected at 32 months and included patient death/survival, rates of biopsy-proven acute rejection, diabetes, infection and cancer, a health economic analysis and formal assessment of adherence. Results Recruitment started in September 2013. Over 37 months, 5519 patients were screened for eligibility and 2037 were randomised (1028 to unblinded BLC and 1009 to double-blinded SC). We identified 198 with DSA and 818 with non-DSA, and at the end of screening, there were 1021 in the Ab-neg groups. Baseline variables were well-matched between groups at the end of Ab-screening. Forty-five per cent of the DSA detected were directed against HLA-DQB antigens. Although the majority of patients were taking Tac (73%), MMF (67%) or prednisolone (55%), only 22% with DSA and 27% with non-DSA were taking all three drugs. Baseline immunosuppression use was balanced across arms and did not change during the trial in the SC arm. Ninety-seven per cent of HLA Ab+ recruits in the BLC arm had the formal interview, and the proportion taking all three drugs in the BLC arm increased to 54% (DSA) and 44% (non-DSA). There were 34 graft failures in HLA Ab+ recruits in the SC arm over the course of the study compared to 42 in the BLC arm. The HRs for graft failure in BLC DSA+ and non-DSA+ groups were 1.54 [95% confidence interval (CI) 0.72 to 3.30] and 0.97 (0.54 to 1.74), respectively, providing no evidence of a difference. The data for DSA+ groups confirmed that the presence of DSA was associated with an increased risk of graft failure, but non-DSA were not associated with graft failure compared to patients without Ab. Non-inferiority for the overall unblinded versus blinded comparison was not demonstrated as the upper confidence limit of the HR for graft failure exceeded 1.4 : (1.02, 95% CI 0.72 to 1.44). The HR for the secondary endpoint biopsy-proven rejection in the overall unblinded BLC group was 0.5 (95% CI 0.27 to 0.94; p = 0.03), but there were no significant differences in patient survival, biopsy-proven rejection, proven infections, malignancies, diabetes, development of proteinuria or mean eGFRs at the end of the trial. After adjusting for baseline quality of life, there was no significant gain of quality-adjusted life-year (QALY) in the BLC arm, but an incremental cost-effectiveness ratio per QALY that was significantly higher than the threshold set by the National Institute for Health and Care Excellence. Our analysis of adherence revealed significantly improved adherences for all three drugs in the BLC DSA+ group. Conclusions Thus, we conclude that the development of DSA (but not non-DSA) is associated with an increased risk of graft failure, but there is no evidence to support the primary hypothesis, that optimisation of immunosuppression in DSA+ patients can prevent this from happening. Trial registration This trial is registered as EudraCT (2012-004308-36) and ISRCTN (46157828). Funding This project was funded by the National Institute for Health and Care Research (NIHR) Efficacy and Mechanism Evaluation programme (11/100/34) and will be published in full in Efficacy and Mechanism Evaluation; Vol. 10, No. 5. See the NIHR Journals Library website for further project information.

Background Eyes sustaining open globe trauma are at high risk of severe visual impairment. Proliferative vitreoretinopathy is the most common cause of retinal detachment and visual loss in eyes with open globe trauma. There is evidence from experimental studies and pilot clinical trials that the use of adjunctive steroid medication triamcinolone acetonide can reduce the incidence of proliferative vitreoretinopathy and improve outcomes of surgery for open globe trauma. Objective The Adjunctive Steroid Combination in Ocular Trauma or ASCOT study aimed to investigate the clinical effectiveness of adjunctive triamcinolone acetonide given at the time of vitreoretinal surgery for open globe trauma. Design A phase 3 multicentre double-masked randomised controlled trial randomising patients undergoing vitrectomy following open globe trauma to either adjunctive triamcinolone acetonide or standard care. Setting Hospital vitreoretinal surgical services dealing with open globe trauma. Participants Patients undergoing vitrectomy surgery who had sustained open globe trauma. Interventions Triamcinolone acetonide 4 mg/0.1 ml into the vitreous cavity and 40 mg/1 ml sub-Tenon’s or standard vitreoretinal surgery and postoperative care. Main outcome measures The primary outcome was the proportion of patients with at least 10 letters of improvement in corrected visual acuity at six months. Secondary outcomes included retinal detachment secondary to proliferative vitreoretinopathy, retinal reattachment, macula reattachment, tractional retinal detachment, number of operations, hypotony, elevated intraocular pressure and quality of life. Health-related quality of life was assessed using the EuroQol Five Domain and Visual Function Questionnaire 25 questionnaires. Results A total of 280 patients were randomised; 129 were analysed from the control group and 130 from the treatment group. The treatment group appeared, by chance, to have more severe pathology on presentation. The primary outcome (improvement in visual acuity) and principal secondary outcome (change in visual acuity) did not demonstrate any treatment benefit for triamcinolone acetonide. The proportion of patients with improvement in visual acuity was 47% for triamcinolone acetonide and 43% for standard care (odds ratio 1.03, 95% confidence interval 0.61 to 1.75, p = 0.908); the baseline adjusted mean difference in the six-month change in visual acuity was –2.65 (95% confidence interval –9.22 to 3.92, p = 0.430) for triamcinolone acetonide relative to control. Similarly, the secondary outcome measures failed to show any treatment benefit. For two of the secondary outcome measures, stable complete retinal reattachment and stable macular retinal reattachment, outcomes for the treatment group were significantly worse for triamcinolone acetonide at the 5% level (respectively, odds ratio 0.59, 95% confidence interval 0.36 to 0.99, p = 0.044 and odds ratio 0.59, 95% confidence interval 0.35 to 0.98, p = 0.041) compared with control in favour of control. The cost of the intervention was £132 per patient. Health economics outcome measures (Early Treatment Diabetic Retinopathy Study, Visual Function Questionnaire 25 and EuroQol Five Dimensions) did not demonstrate any significant difference in quality-adjusted life-years. Conclusions The use of combined intraocular and sub-Tenon’s capsule triamcinolone acetonide is not recommended as an adjunct to vitrectomy surgery for intraocular trauma. Secondary outcome measures are suggestive of a negative effect of the adjunct, although the treatment group appeared to have more severe pathology on presentation. Future work The use of alternative adjunctive medications in cases undergoing surgery for open globe trauma should be investigated. Refinement of clinical grading and case selection will enable better trail design for future studies. Trial registration This trial is registered as ISRCTN 30012492, EudraCT number 2014-002193-37, REC 14/LNO/1428, IRAS 156358, Local R&D registration CHAD 1031. Funding This project was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme (12/35/64) and will be published in full in Health Technology Assessment; Vol. 27, No. 12. See the NIHR Journals Library website for further project information. Plain language summary Despite advances in surgical techniques, eye trauma remains a leading cause of blindness and visual impairment. The main cause of trauma is a scarring process within the eye – proliferative vitreoretinopathy. There is good evidence from laboratory work and small-scale clinical studies that the addition of a steroid medication, triamcinolone acetonide, given in and around the eye at the time of surgery for eye trauma, can reduce the incidence of proliferative vitreoretinopathy scarring and improve the outcomes of surgery. The Adjunctive Steroid Combination in Ocular Trauma or ASCOT study was a multicentre clinical trial designed to test the use of triamcinolone acetonide as an addition to surgery to improve outcomes in eyes with ‘open globe’ penetrating injuries. A total of 280 patients were recruited and randomised to receive standard surgery or surgery with the additional steroid (triamcinolone acetonide). No benefit was found from the addition of the steroid medication. The addition of steroid medication was not good value for money. Secondary outcome measures suggested that triamcinolone acetonide may have had a negative effect on outcomes, although this may have been due to the presence of more severe cases amongst the patients allocated to receive the additional steroid (triamcinolone acetonide). The use of adjunctive triamcinolone acetonide in eye trauma cases undergoing surgery is therefore not recommended. Future studies with different additional medications and/or more targeted case selection are indicated to improve outcomes for eyes experiencing penetrating trauma. Scientific summary Background Eyes sustaining penetrating or open globe trauma (OGT) are a group at high risk of severe visual impairment. Retinal detachment (RD) is common in these eyes and multiple surgical interventions are often necessary. Proliferative vitreoretinopathy (PVR) is the most common cause of recurrent RD and visual loss in eyes, with OGT occurring in 10–45% of cases. There is good evidence from experimental, preclinical studies and pilot clinical trials that the use of adjunctive steroid medication, in particular triamcinolone acetonide (TA), can reduce the incidence of PVR and improve outcomes of surgery for OGT. Objective The Adjunctive Steroid Combination in Ocular Trauma (ASCOT) study aimed to investigate the clinical effectiveness of adjunctive TA given at the time of vitreoretinal surgery for OGT. This included analysis of the economic and quality of life benefits of the adjunctive treatment. From an NHS perspective, to explore the incremental cost-effectiveness of TA and to explore the cost per quality-adjusted life-year (QALY) of adjunctive TA in vitreoretinal surgery for OGT to determine whether this falls below the National Institute of Health and Care Excellence threshold of £20,000–30,000 per QALY. Methods A phase 3 multicentre double-masked randomised controlled clinical trial randomising patients undergoing vitrectomy following OGT to either adjunctive TA (4 mg/0.1 ml into the vitreous cavity and 40 mg/1 ml sub-Tenon’s) or standard care. Inclusion criteria were as follows: 1.adult subjects (aged 18 years or over at the time of enrolment) 2.full thickness, open globe ocular trauma undergoing vitrectomy 3.ability to give written informed consent 4.willingness to accept randomisation and attend follow-up for six months. Patients were recruited prior to vitrectomy surgery and randomised at the completion of surgery. The primary outcome was to determine whether adjunctive intraocular and periocular steroid (TA) improves visual acuity (VA) at six months compared with standard treatment in eyes undergoing vitreoretinal surgery for OGT. This was defined as the proportion of patients with at least 10 letters of improvement in corrected VA on the Early Treatment Diabetic Retinopathy Study (ETDRS) chart at six months. Secondary outcomes were to determine whether adjunctive intraocular and periocular steroid (TA) influences the development of scarring (PVR), RD (stable complete retinal and macular reattachment), intraocular pressure abnormalities and other complications in eyes undergoing surgery for OGT. In addition, to assess the effects of treatment on quality of life measured using the EuroQol Five Dimensions (EQ-5D) questionnaire and the Visual Function Questionnaire-25 (VFQ-25) tools. The study sample size was calculated from previously published work and two non-randomised trials carried out by the investigators. Based on previous studies, to detect a 19% increase in the proportion of patients with clinically meaningful improvement in VA [from 55% to 74%, corresponding to an odds ratio (OR) of 2.33], with an allowance for an estimated 7% dropout rate, the target sample size was 300 patients (150 per study arm). The main analysis followed the intention-to-treat principle and was conducted subgroup blind (i.e. as group A vs. group B) in accordance with the prespecified ASCOT statistical analysis plan. The primary analysis model consisted of a mixed logistic model with change in VA (

This column describes findings and best-practice recommendations from CARE (Communicating and Relating Effectively), a prospective randomized study in which 5,169 mothers were screened for postpartum depression. The prevalence rate was 13%. Results support use of the Edinburgh Postnatal Depression Screening Scale and a diagnostic assessment for those who screen positive. Of the 674 mothers with positive screens, 26% were not asked about their emotional state by clinicians. Screening must be linked to treatment options via referral and follow-up. Best-practice strategies for implementing screening include educating clinicians and postpartum women. [ABSTRACT FROM AUTHOR]

Abstract Background Biofuels produced from biomass are considered to be promising sustainable alternatives to fossil fuels. The conversion of lignocellulose into fermentable sugars for biofuels production requires the use of enzyme cocktails that can efficiently and economically hydrolyze lignocellulosic biomass. As many fungi naturally break down lignocellulose, the identification and characterization of the enzymes involved is a key challenge in the research and development of biomass-derived products and fuels. One approach to meeting this challenge is to mine the rapidly-expanding repertoire of microbial genomes for enzymes with the appropriate catalytic properties. Results Semantic technologies, including natural language processing, ontologies, semantic Web services and Web-based collaboration tools, promise to support users in handling complex data, thereby facilitating knowledge-intensive tasks. An ongoing challenge is to select the appropriate technologies and combine them in a coherent system that brings measurable improvements to the users. We present our ongoing development of a semantic infrastructure in support of genomics-based lignocellulose research. Part of this effort is the automated curation of knowledge from information on fungal enzymes that is available in the literature and genome resources. Conclusions Working closely with fungal biology researchers who manually curate the existing literature, we developed ontological natural language processing pipelines integrated in a Web-based interface to assist them in two main tasks: mining the literature for relevant knowledge, and at the same time providing rich and semantically linked information.

Abstract Background Breathlessness is a common and distressing symptom affecting many patients with advanced disease both from malignant and non-malignant origin. A combination of pharmacological and non-pharmacological measures is necessary to treat this symptom successfully. Breathlessness services in various compositions aim to provide comprehensive care for patients and their carers by a multiprofessional team but their effectiveness and cost-effectiveness have not yet been proven. The Breathlessness Support Service (BSS) is a newly created multiprofessional and interdisciplinary outpatient service at a large university hospital in South East London. The aim of this study is to develop and evaluate the effectiveness and cost effectiveness of this multidisciplinary out–patient BSS for the palliation of breathlessness, in advanced malignant and non-malignant disease. Methods The BSS was modelled based on the results of qualitative and quantitative studies, and systematic literature reviews. A randomised controlled fast track trial (RCT) comprising two groups: 1) intervention (immediate access to BSS in addition to standard care); 2) control group (standard best practice and access to BSS after a waiting time of six weeks). Patients are included if suffering from breathlessness on exertion or at rest due to advanced disease such as cancer, chronic obstructive pulmonary disease (COPD), chronic heart failure (CHF), interstitial lung disease (ILD) or motor neurone disease (MND) that is refractory to maximal optimised medical management. Both quantitative and qualitative outcomes are assessed in face to-face interviews at baseline, after 6 and 12 weeks. The primary outcome is patients' improvement of mastery of breathlessness after six weeks assessed on the Chronic Respiratory Disease Questionnaire (CRQ). Secondary outcomes for patients include breathlessness severity, symptom burden, palliative care needs, service use, and respiratory measures (spirometry). For analyses, the primary outcome, mastery of breathlessness after six weeks, will be analysed using ANCOVA. Selection of covariates will depend on baseline differences between the groups. Analyses of secondary outcomes will include patients’ symptom burden other than breathlessness, physiological measures (lung function, six minute walk distance), and caregiver burden. Discussion Breathlessness services aim to meet the needs of patients suffering from this complex and burdensome symptom and their carers. The newly created BSS is different to other current services as it is run in close collaboration of palliative medicine and respiratory medicine to optimise medical care of patients. It also involves professionals from various medical, nursing, physiotherapy, occupational therapy and social work background. Trial registration ClinicalTrials.gov (NCT01165034)

Abstract Background The UK Equality Act 2010 makes it unlawful for employers to ask health questions before making an offer of employment except in certain circumstances. While the majority of employers would prefer applicants to disclose a mental illness at the application stage, many people either wait until they have accepted the job and then disclose to an occupational health professional, or do not do so at all due to the anticipation of discrimination or a wish for privacy. However, non disclosure precludes the ability to request reasonable adjustments in the workplace or to make a claim of direct discrimination. Disclosure to employers is therefore a difficult decision. A recent pilot study by our group of the CORAL decision aid showed that it helped mental health service users clarify their needs and values regarding disclosure and led to reduction in decisional conflict. The present proof of concept trial aims to determine whether a full scale randomised controlled trial (RCT) is justifiable and feasible, and to optimise its design. Methods In this single blind exploratory RCT in London, a total of 80 participants (inclusion criteria: age ≥18 years, on the caseload of a specialist employment adviser working with people with mental illness; referred to the adviser either from primary care via Improving Access to Psychological Therapies or secondary mental health service; currently seeking or interested in either paid or voluntary employment, and a Decisional Conflict Scale score of 37.5 or greater and stage of decision score 1–5) will be recruited from vocational advice services. After completing a baseline assessment, participants will be randomly assigned to one of two conditions (1) Use of the CORAL Decision Aid (DA) in addition to treatment as usual or (2) Treatment as usual. Those allocated to the DA condition will be given it to read and complete, and the researcher will be present to record the time taken and any content that causes confusion. Intervention participants may keep the decision aid but are discouraged from showing it to other service users to avoid contamination. Follow up interviews will be conducted at 3 months. Primary outcomes are: (i) stage of decision making score; (ii) decisional conflict scores and (iii) employment related outcomes. Secondary analyses will identify predictors of disclosure and qualitative analysis will explore the impact of the intervention. Discussion A reduction in decisional conflict regarding disclosure leading to more effective job seeking activity could have significant economic consequences for people with mental illness in terms of employment rates and productivity. Trial registration number NCT01379014 (ClinicalTrials.gov Identifier)

Abstract Background Increased consumption of plant-based diets has been linked to the presence of certain phytochemicals, including polyphenols such as flavonoids. Several of these compounds exert their protective effect via inhibition of tumor angiogenesis. Identification of additional phytochemicals with potential antiangiogenic activity is important not only for understanding the mechanism of the preventive effect, but also for developing novel therapeutic interventions. Results In an attempt to identify phytochemicals contributing to the well-documented preventive effect of plant-based diets on cancer incidence and mortality, we have screened a set of hitherto untested phytoestrogen metabolites concerning their anti-angiogenic effect, using endothelial cell proliferation as an end point. Here, we show that a novel phytoestrogen, 6-methoxyequol (6-ME), inhibited VEGF-induced proliferation of human umbilical vein endothelial cells (HUVE) cells, whereas VEGF-induced migration and survival of HUVE cells remained unaffected. In addition, 6-ME inhibited FGF-2-induced proliferation of bovine brain capillary endothelial (BBCE) cells. In line with its role in cell proliferation, 6-ME inhibited VEGF-induced phosphorylation of ERK1/2 MAPK, the key cascade responsible for VEGF-induced proliferation of endothelial cells. In this context, 6-ME inhibited in a dose dependent manner the phosphorylation of MEK1/2, the only known upstream activator of ERK1/2. 6-ME did not alter VEGF-induced phosphorylation of p38 MAPK or AKT, compatible with the lack of effect on VEGF-induced migration and survival of endothelial cells. Peri-tumor injection of 6-ME in A-431 xenograft tumors resulted in reduced tumor growth with suppressed neovasularization compared to vehicle controls (P Conclusions 6-ME inhibits VEGF- and FGF2-induced proliferation of ECs by targeting the phosphorylation of MEK1/2 and it downstream substrate ERK1/2, both key components of the mitogenic MAPK pathway. Injection of 6-ME in mouse A-431 xenograft tumors results to tumors with decreased neovascularization and reduced tumor volume suggesting that 6-ME may be developed to a novel anti-angiogenic agent in cancer treatment.

Abstract Background Amyotrophic lateral sclerosis is a rapidly progressive neurodegenerative disorder characterised by loss of motor neurons leading to severe weakness and death from respiratory failure within 3-5 years. Riluzole prolongs survival in ALS. A published report has suggested a dramatic effect of lithium carbonate on survival. 44 patients were studied, with 16 randomly selected to take LiCO3 and riluzole and 28 allocated to take riluzole alone. In the group treated with lithium, no patients had died (i.e., 100% survival) at the end of the study (15 months from entry), compared to 71% surviving in the riluzole-only group. Although the trial can be criticised on several grounds, there is a substantial rationale from other laboratory studies that lithium is worth investigating therapeutically in amyotrophic lateral sclerosis. Methods/Design LiCALS is a multi-centre double-blind randomised parallel group controlled trial of the efficacy, safety, and tolerability of lithium carbonate (LiCO3) at doses to achieve stable 'therapeutic' plasma levels (0.4-0.8 mmol/L), plus standard treatment, versus matched placebo plus standard treatment, in patients with amyotrophic lateral sclerosis. The study will be based in the UK, in partnership with the MND Association and DeNDRoN (the Dementias and Neurodegnerative Diseases Clinical Research Network). 220 patients will be recruited. All patients will be on the standard treatment for ALS of riluzole 100 mg daily. The primary outcome measure will be death from any cause at 18 months defined from the date of randomisation. Secondary outcome measures will be changes in three functional rating scales, the ALS Functional Rating Scale-Revised, The EuroQOL (EQ-5D), and the Hospital Anxiety and Depression Scale. Eligible patients will have El Escorial Possible, Laboratory-supported Probable, Probable or Definite amyotrophic lateral sclerosis with disease duration between 6 months and 36 months (inclusive), vital capacity ≥ 60% of predicted within 1 month prior to randomisation and age at least18 years. Discussion Patient recruitment began in June 2009 and the last patient is expected to complete the trial protocol in November 2011. Trial registration Current controlled trials ISRCTN83178718

Abstract Background The Arabidopsis bypass1 (bps1) mutant root produces a biologically active mobile compound that induces shoot growth arrest. However it is unknown whether the root retains the capacity to synthesize the mobile compound, or if only shoots of young seedlings are sensitive. It is also unknown how this compound induces arrest of shoot growth. This study investigated both of these questions using genetic, inhibitor, reporter gene, and morphological approaches. Results Production of the bps1 root-synthesized mobile compound was found to require active root growth. Inhibition of postembryonic root growth, by depleting glutathione either genetically or chemically, allowed seedlings to escape shoot arrest. However, the treatments were not completely effective, as the first leaf pair remained radialized, but elongated. This result indicated that the embryonic root transiently synthesized a small amount of the mobile substance. In addition, providing glutathione later in vegetative development caused shoot growth arrest to be reinstated, revealing that these late-arising roots were still capable of producing the mobile substance, and that the older vegetative leaves were still responsive. To gain insight into how leaf development responds to the mobile signal, leaf development was followed morphologically and using the CYCB1,1::GUS marker for G2/M phase cells. We found that arrest of leaf growth is a fully penetrant phenotype, and a dramatic decrease in G2/M phase cells was coincident with arrest. Analyses of stress phenotypes found that late in development, bps1 cotyledons produced necrotic lesions, however neither hydrogen peroxide nor superoxide were abundant as leaves underwent arrest. Conclusions bps1 roots appear to require active growth in order to produce the mobile bps1 signal, but the potential for this compound's synthesis is present both early and late during vegetative development. This prolonged capacity to synthesize and respond to the mobile compound is consistent with a possible role for the mobile compound in linking shoot growth to subterranean conditions. The specific growth-related responses in the shoot indicated that the mobile substance prevents full activation of cell division in leaves, although whether cell division is a direct response remains to be determined.

Abstract As The World health report 2006 emphasized, there is increasing consensus that training programmes should focus on "know-how" instead of "know-all." Health workers need to know how to do the job they will be expected to do. IntraHealth International's Learning for performance: a guide and toolkit for health worker training and education programs offers a step-by-step, customizable approach designed to develop the right skills linked to job responsibilities. Using Learning for performance (LFP) yields more efficient training that focuses on what is essential for health workers to do their jobs and on effective learning methods, while addressing the factors that ensure application of new skills on the job. This brief communication describes the Learning for performance approach and initial findings from its application for pre-service education and in-service training in three countries: India, Mali and Bangladesh. Based on IntraHealth's experiences, the author provides thoughts on how LFP's performance-based learning approach can be a useful tool in training scale-up to strengthen human resources for health.

Background: Non-professional involvement in delivering health and social care support in areas of socio-economic deprivation is considered important in attempting to reduce health inequalities. However, trials of peer mentoring programmes have yielded inconsistent evidence of benefit: difficulties in implementation have contributed to uncertainty regarding their efficacy. We aimed to explore difficulties encountered in conducting a randomised controlled trial of a peer-mentoring programme for first-time mothers in socially disadvantaged areas, in order to provide information relevant to future research and practice. This paper describes the experiences of lay-workers, women and health professionals involved in the trial.Methods: Thematic analysis of semi-structured interviews with women (n = 11) who were offered peer mentor support, lay-workers (n = 11) who provided mentoring and midwives (n = 2) who supervised the programme, which provided support, from first hospital antenatal visit to one year postnatal. Planned frequency of contact was two-weekly (telephone or home visit) but was tailored to individuals' needs.Results: Despite lay-workers living in the same locality, they experienced difficulty initiating contact with women and this affected their morale adversely. Despite researchers' attempts to ensure that the role of the mentor was understood clearly it appeared that this was not achieved for all participants. Mentors attempted to develop peer-mentor relationships by offering friendship and sharing personal experiences, which was appreciated by women. Mentors reported difficulties developing relationships with those who lacked interest in the programme. External influences, including family and friends, could prevent or facilitate mentoring. Time constraints in reconciling flexible mentoring arrangements with demands of other commitments posed major personal difficulties for lay-workers.Conclusion: Difficulties in initiating contact, developing peer-mentor relationships and time constraints pose challenges to delivering lay-worker peer support. In developing such programmes, awareness of potential difficulties and of how professional support may help resolve these should improve uptake and optimise evaluation of their effectiveness.Trial Registration Number: ISRCTN55055030. [ABSTRACT FROM AUTHOR]

Introduction: Studies directly comparing the effectiveness of different biologics over long observation periods are lacking. As many treatment guidelines are formulated based on drug class, there is a particular need to compare drug classes rather than specific biologic agents., Methods: This post hoc analysis compares the effectiveness and durability of biologics that target the interleukin (IL)-17 A ligands or the IL-17 receptor A (IL-17RA) relative to other approved drug classes in patients with moderate-to-severe plaque psoriasis, through 12 months in a real-world setting., Results: In the Psoriasis Study of Health Outcomes (PSoHO) (N = 1981), patients treated with anti-IL-17A/RA resulted in a higher proportion of patients who achieved the primary outcome [proportion of patients who had at least a 90% improvement in Psoriasis Area and Severity Index score (PASI90) and/or a score of 0 or 1 in static Physician Global Assessment (sPGA)] compared to anti-IL-23-, anti-IL-12/23-, and tumor necrosis factor (TNF)-α-treated patients at week 12, month 6, and month 12, except versus anti-IL-23 at month 12. Similar trends were observed for a 100% improvement in PASI score (PASI100), PASI90, and Dermatology Life Quality Index score of 0 or 1 [DLQI (0,1)]. At month 12, the unadjusted response rates across the drug classes were 53.5-69.1% for the primary outcome, 27.6-40.8% for PASI100, 41.7-55.9% for PASI90, and 31.8-33.0% for DLQI (0,1). Regarding the durability of effectiveness, anti-IL-17A/RA patients had the highest response rate, and for the adjusted analysis, using Frequentist Model Averaging (FMA), patients had 1.4-2.6 times higher odds of achieving the primary durability outcome compared to patients treated with any other drug class., Conclusion: Overall, anti-IL-17A/RA had the highest effectiveness of achieving early response to treatment and maintaining that response through 12 months compared to other drug classes., Trial Registration: The study was registered at the European Network of Centers for Pharmacoepidemiology and Pharmacovigilance (ENCEPP24207)., (© 2024. The Author(s).)

Background: Phonological difficulties are prevalent in children with speech and/or language disorders and may hamper their later language outcomes and academic achievements. These children often form a significant proportion of speech and language therapists' caseloads. There is a shortage of information on evidence-based interventions for improving phonological skills in children and adolescents with speech and language disorder., Aims: The aim of this systematic literature review and meta-analysis was to systematically examine the effects of different intervention approaches on speech production accuracy and phonological representation skills in children with speech and language disorders., Methods: A preregistered systematic review (International Prospective Register of Systematic Reviews ID: CRD42017076075) adhering to Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines was completed. Seven electronic databases (PubMed, Web of Science, ERIC, PsychINFO, Cochrane Library, SCOPUS and Linguistics & Language Behavior Abstracts) were searched for studies related to oral language interventions with children with developmental speech and/or language disorder (mean age ranging from 3-18 years) published between January 2006 and August 2022. The included articles reported intervention studies with a group design in which speech production accuracy was the outcome measure. Studies were appraised using the Cochrane risk of bias tool, and individual effect sizes were calculated using standardised means differences when enough data was available. A meta-analysis was conducted obtaining the average standardised mean difference d. Heterogeneity, influence of possible moderator variables and publication bias were explored., Results: The 23 studies that met the inclusion criteria presented low-medium risk of bias. Nine effect sizes were obtained from seven of these studies that presented a pre-post-test with a control group design. Medium-high average effect sizes were found in phonological accuracy. Heterogeneity was found between individual effect sizes. Significant moderator variables and publication bias were not detected., Conclusions: The results of this meta-analysis indicate positive effects on speech production accuracy. Based on this review, further improvements in the quality of reporting for intervention research are required in developing the evidence base for practice., What This Paper Adds: What is already known on the subject An increasing number of interventions is available for children and adolescents with developmental speech and/or language disorders. Previous reviews suggest relatively low levels of evidence of interventions having phonology as an outcome measure. What this paper adds to the existing knowledge This review and meta-analysis summarise the intervention evidence from a substantial body of group design studies, indicating positive results from a range of interventions with phonological outcomes. It highlights the need to systematically implement and replicate different intervention procedures to understand factors that will maximise positive outcomes and to grow the evidence base for best practice. What are the potential or actual clinical implications of this study? Tentative evidence is emerging for the effectiveness of various approaches in enhancing speech production accuracy skills of children and adolescents with developmental speech and/or language disorder., (© 2024 The Author(s). International Journal of Language & Communication Disorders published by John Wiley & Sons Ltd on behalf of Royal College of Speech and Language Therapists.)

Less invasive surfactant administration (LISA) is an increasingly popular technique to deliver surfactant to spontaneously breathing preterm infants with respiratory distress syndrome. The optimal method of alleviating the pain and discomfort associated with LISA, either pharmacological or non-pharmacological, while maintaining spontaneous respiration remains unclear. There is limited evidence to guide clinicians, resulting in wide variations in practice. The aim of this article is to summarise the current knowledge and evidence gaps regarding the use of premedication prior to LISA., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

Molecular, cellular, and organismal alterations are important descriptors of toxic effects, but our ability to extrapolate and predict ecological risks is limited by the availability of studies that link measurable end points to adverse population relevant outcomes such as cohort survival and growth. In this study, we used laboratory gene expression and behavior data from two populations of Atlantic killifish Fundulus heteroclitus [one reference site (SCOKF) and one PCB-contaminated site (NBHKF)] to inform individual-based models simulating cohort growth and survival from embryonic exposures to environmentally relevant concentrations of neurotoxicants. Methylmercury exposed SCOKF exhibited brain gene expression changes in the si:ch211-186j3.6, si:dkey-21c1.4, scamp1, and klhl6 genes, which coincided with changes in feeding and swimming behaviors, but our models simulated no growth or survival effects of exposures. PCB126-exposed SCOKF had lower physical activity levels coinciding with a general upregulation in nucleic and cellular brain gene sets (BGS) and downregulation in signaling, nucleic, and cellular BGS. The NBHKF, known to be tolerant to PCBs, had altered swimming behaviors that coincided with 98% fewer altered BGS. Our models simulated PCB126 decreased growth in SCOKF and survival in SCOKF and NBHKF. Overall, our study provides a unique demonstration linking molecular and behavioral data to develop quantitative, testable predictions of ecological risk.

Understanding how sublethal impacts of toxicants affect population-relevant outcomes for organisms is challenging. We tested the hypotheses that the well-known sublethal impacts of methylmercury (MeHg) and a polychlorinated biphenyl (PCB126) would have meaningful impacts on cohort growth and survival in yellow perch (Perca flavescens) and Atlantic killifish (Fundulus heteroclitus) populations, that inclusion of model uncertainty is important for understanding the sublethal impacts of toxicants, and that a model organism (zebrafish Danio rerio) is an appropriate substitute for ecologically relevant species (yellow perch, killifish). Our simulations showed that MeHg did not have meaningful impacts on growth or survival in a simulated environment except to increase survival and growth in low mercury exposures in yellow perch and killifish. For PCB126, the high level of exposure resulted in lower survival for killifish only. Uncertainty analyses increased the variability and lowered average survival estimates across all species and toxicants, providing a more conservative estimate of risk. We demonstrate that using a model organism instead of the species of interest does not necessarily give the same results, suggesting that using zebrafish as a surrogate for yellow perch and killifish may not be appropriate for predicting contaminant impacts on larval cohort growth and survival in ecologically relevant species. Our analysis also reinforces the notion that uncertainty analyses are necessary in any modeling assessment of the impacts of toxicants on a population because it provides a more conservative, and arguably realistic, estimate of impact. Environ Toxicol Chem 2024;43:2122-2133. © 2024 SETAC., (© 2024 SETAC.)

Exposure to artificial light during the night is known to promote disruption to the biological clock, which can lead to impaired mood and metabolism. Metabolic hormone secretion is modulated by the circadian pacemaker and recent research has shown that hormones such as insulin and leptin can also directly affect behavioral outcomes and the circadian clock. In turn, obesity itself is known to modulate the circadian rhythm and alter emotionality. This study investigated the behavioral and metabolic effects of constant light exposure in two models of obesity - a leptin null mutant (OB) and diet-induced obesity via high-fat diet. For both experiments, mice were placed into either a standard Light:Dark cycle (LD) or constant light (LL) and their circadian locomotor rhythms were continuously monitored. After 10 weeks of exposure to their respective lighting conditions, all mice were subjected to an open field assay to assess their explorative behaviors. Their metabolic hormone levels and inflammation levels were also measured. Behaviorally, exposure to constant light led to increased period lengthening and open field activity in the lean mice compared to both obesity models. Metabolically, LL led to increased cytokine levels and poorer metabolic outcomes in both lean and obese mice, sometimes exacerbating the metabolic issues in the obese mice, independent of weight gain. This study illustrates that LL can produce altered behavioral and physiological outcomes, even in lean mice. These results also indicate that obesity induced by different reasons can lead to shortened circadian rhythmicity and exploratory activity when exposed to chronic light., Competing Interests: Declaration of competing interest The authors declare no competing financial interests., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Light-at-night is known to produce a wide variety of behavioral outcomes including promoting anxiety, depression, hyperactivity, abnormal sociability, and learning and memory deficits. Unfortunately, we all live in a 24-h society where people are exposed to light-at-night or light pollution through night-shift work - the need for all-hours emergency services - as well as building and street-lights, making light-at-night exposure practically unavoidable. Additionally, the increase in screentime (tvs and smart devices) during the night also contributes to poorer sleep and behavioral impairments. Compounding these factors is the fact that adolescents tend to be "night owls" and prefer an evening chronotype compared to younger children and adults, so these teenagers will have a higher likelihood of being exposed to light-at-night. Making matters worse is the prevalence of high-school start times of 8 am or earlier - a combination of too early school start times, light exposure during the night, and preference for evening chronotypes is a recipe for reduced and poorer sleep, which can contribute to increased susceptibility for behavioral issues for this population. As such, this mini-review will show, using both human and rodent model studies, how light-at-night affects behavioral outcomes and stress responses, connecting photic signaling and the circadian timing system to the hypothalamic-pituitary adrenal axis. Additionally, this review will also demonstrate that adolescents are more likely to exhibit abnormal behavior in response to light-at-night due to changes in development and hormone regulation during this time period, as well as discuss potential interventions that can help mitigate these negative effects., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Guindon, Murphy, Milano and Seggio.)

The development of biomaterials tailored for various tissue engineering applications has been increasingly researched in recent years; however, stimulating cells to synthesise the extracellular matrix (ECM) is still a significant challenge. In this study, we investigate the use of ECM-like hydrogel materials composed of Gelatin methacryloyl (GelMA) and glycosaminoglycans (GAG), such as hyaluronic acid (HA) and chondroitin sulphate (CS), to provide a biomimetic environment for tissue repair. These hydrogels are fully characterised in terms of physico-chemical properties, including compression, swelling behaviour, rheological behaviour and via 3D printing trials. Furthermore, porous scaffolds were developed through freeze drying, producing a scaffold morphology that better promotes cell proliferation, as shown by in vitro analysis with fibroblast cells. We show that after cell seeding, freeze-dried hydrogels resulted in significantly greater amounts of DNA by day 7 compared to the GelMA hydrogel. Furthermore, freeze-dried constructs containing HA or HA/CS were found to have a significantly higher metabolic activity than GelMA alone.

Background: States in the United States (US) have passed and enacted legislation for the purpose of preventing child sexual abuse (CSA) since 2000, but it is unknown whether these legislative policies reduce adult-perpetrated CSA., Objective: Review the literature from 2000 to 2023 to understand which US CSA prevention policies have been evaluated, the effectiveness of these policies, study populations, and barriers and facilitators associated with the implementation of CSA prevention policies., Methods: The study protocol was published prior to undertaking the review: PMC10603531. The review follows Joanna Briggs Institute methodology and is reported according to the PRISMA-ScR Checklist. We searched 27 databases, hand searched reference lists of included studies, and sent notice via listserv to other researchers in the field. Articles were included if the content focused on CSA prevention policies and the effects. No limits to methodology were applied. Methodological rigor was assessed., Results: 2209 potentially relevant articles were identified; 20 articles advanced to full-text review, three satisfied the inclusion criteria. Three eligible studies focused on CSA prevention education policies, while the other focused on mandated reporting policies. Effects of these policies were mixed in relation to CSA reporting and substantiation rates. No study considered child demographics., Conclusions: Despite decades of legislative action for CSA prevention across the US, only a few studies have assessed the effects of these policies. These findings highlight the need for additional research to ensure that CSA prevention policies such as CSA prevention education in schools and mandated reporting practices are working as intended., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Peer mediated intervention (PMI) is an evidence-based approach to supporting social and communication development for children on the autism spectrum. For PMI to be integrated into everyday practice, it needs to be acceptable to stakeholders. This article engaged with autistic individuals, early childhood educators, parents, and speech and language pathologists on the prospective acceptability of implementing PMI with minimally speaking preschoolers in inclusive preschool settings. Focus groups and semi-structured interviews were conducted. The transcriptions were analyzed qualitatively using reflexive thematic analysis. Stakeholders described PMI as an acceptable intervention approach for this population and provided valuable insights to inform the development and implementation of PMIs. Attention needs to be paid to how to support preschools to adopt a PMI-friendly philosophy., (© 2023. The Author(s).)

Problem formulation (PF) is a critical initial step in planning risk assessments for chemical exposures to wildlife, used either explicitly or implicitly in various jurisdictions to include registration of new pesticides, evaluation of new and existing chemicals released to the environment, and characterization of impact when chemical releases have occurred. Despite improvements in our understanding of the environment, ecology, and biological sciences, few risk assessments have used this information to enhance their value and predictive capabilities. In addition to advances in organism-level mechanisms and methods, there have been substantive developments that focus on population- and systems-level processes. Although most of the advances have been recognized as being state-of-the-science for two decades or more, there is scant evidence that they have been incorporated into wildlife risk assessment or risk assessment in general. In this article, we identify opportunities to consider elevating the relevance of wildlife risk assessments by focusing on elements of the PF stage of risk assessment, especially in the construction of conceptual models and selection of assessment endpoints that target population- and system-level endpoints. Doing so will remain consistent with four established steps of existing guidance: (1) establish clear protection goals early in the process; (2) consider how data collection using new methods will affect decisions, given all possibilities, and develop a decision plan a priori; (3) engage all relevant stakeholders in creating a robust, holistic conceptual model that incorporates plausible stressors that could affect the targets defined in the protection goals; and (4) embrace the need for iteration throughout the PF steps (recognizing that multiple passes may be required before agreeing on a feasible plan for the rest of the risk assessment). Integr Environ Assess Manag 2024;20:658-673. © 2022 The Authors. Integrated Environmental Assessment and Management published by Wiley Periodicals LLC on behalf of Society of Environmental Toxicology & Chemistry (SETAC). This article has been contributed to by U.S. Government employees and their work is in the public domain in the USA., (© 2022 The Authors. Integrated Environmental Assessment and Management published by Wiley Periodicals LLC on behalf of Society of Environmental Toxicology & Chemistry (SETAC). This article has been contributed to by U.S. Government employees and their work is in the public domain in the USA.)

Purpose: Qualitative engagement with stakeholders in the development of interventions can provide insight into strategies to maximize feasibility in real-life settings. We engaged stakeholders (autistic adults, early childhood educators, early childhood sector leaders and policy influencers, parents of autistic children, and speech-language pathologists) to inform the development of an educator-led peer-mediated intervention (PMI) for autistic preschoolers who use minimal speech that is feasible to implement in inclusive early childhood education and care (ECEC) settings., Method: A qualitative iterative intervention design process was utilized. Stakeholders ( N = 15) attended an online workshop and completed a document review exploring the acceptability and feasibility of the proposed embedded PMI. A two-step analysis procedure using the Theoretical Domains Framework and template analysis was conducted to identify the barriers, enablers, and supports to the implementation of embedded PMI in early childhood settings., Results: While embedded PMI was unanimously acceptable to stakeholders, several participants expressed concerns regarding feasibility. Barriers to the successful integration and implementation of PMI in inclusive preschool contexts included access to skills, knowledge, and resources. Participants identified strategies to overcome modifiable barriers and to enhance the existing enablers. These strategies are reflected in the following themes: build on the familiar, build capacity in augmentative and alternative communication, adopt a whole center approach, adapt to meet the needs of the ECEC setting, and engage in proactive implementation., Conclusion: To address barriers to the implementation of embedded PMI, action is needed at various levels: macro (national/policy), meso (organization/setting), and micro (individual)., Supplemental Material: https://doi.org/10.23641/asha.25155770.

Introduction: The Accreditation Council for Graduate Medical Education (ACGME) approved the first pain medicine fellowship programs over three decades ago, designed around a pharmacological philosophy. Following that, there has been a rise in the transition of pain medicine education toward a multidisciplinary interventional model based on a tremendous surge of contemporaneous literature in these areas. This trend has created variability in clinical experience and education amongst accredited pain medicine programs with minimal literature evaluating the differences and commonalities in education and experience of different pain medicine fellowships through Program Director (PD) experiences. This study aims to gather insight from pain medicine fellowship program directors across the country to assess clinical and interventional training, providing valuable perspectives on the future of pain medicine education., Methods: This study involved 56 PDs of ACGME-accredited pain fellowship programs in the United States. The recruitment process included three phases: advanced notification, invitation, and follow-up to maximize response rate. Participants completed a standard online questionnaire, covering various topics such as subcategory fields, online platforms for supplemental education, clinical experience, postgraduate practice success, and training adequacy., Results: Surveys were completed by 39/56 (69%) standing members of the Association of Pain Program Directors (APPD). All PDs allowed fellows to participate in industry-related and professional society-related procedural workshops, with 59% encouraging these workshops. PDs emphasized the importance of integrity, professionalism, and diligence for long-term success. Fifty-four percent of PDs expressed the need for extension of fellowship training to avoid supplemental education by industry or pain/spine societies., Conclusion: This study highlights the challenge of providing adequate training in all Pain Medicine subtopics within a 12-month pain medicine fellowship. PDs suggest the need for additional training for fellows and discuss the importance of curriculum standardization., (© 2024 World Institute of Pain.)

Ecosystems that are coupled by reciprocal flows of energy and nutrient subsidies can be viewed as a single "meta-ecosystem." Despite these connections, the reciprocal flow of subsidies is greatly asymmetrical and seasonally pulsed. Here, we synthesize existing literature on stream-riparian meta-ecosystems to quantify global patterns of the amount of subsidy consumption by organisms, known as "allochthony." These resource flows are important since they can comprise a large portion of consumer diets, but can be disrupted by human modification of streams and riparian zones. Despite asymmetrical subsidy flows, we found stream and riparian consumer allochthony to be equivalent. Although both fish and stream invertebrates rely on seasonally pulsed allochthonous resources, we find allochthony varies seasonally only for fish, being nearly three times greater during the summer and fall than during the winter and spring. We also find that consumer allochthony varies with feeding traits for aquatic invertebrates, fish, and terrestrial arthropods, but not for terrestrial vertebrates. Finally, we find that allochthony varies by climate for aquatic invertebrates, being nearly twice as great in arid climates than in tropical climates, but not for fish. These findings are critical to understanding the consequences of global change, as ecosystem connections are being increasingly disrupted., (© 2024 The Authors. Ecology Letters published by John Wiley & Sons Ltd.)

Background: Newborns are at high risk of sepsis. At present there is no definitive "rule in" blood test for sepsis at the point of clinical concern. A positive blood culture remains the gold standard test for neonatal sepsis, however laboratory markers that correlate prospectively with culture positive sepsis could aid clinicians in making decisions regarding administration of empiric antibiotic therapies., Methods: This multi-site, prospective observational study will take place in two neonatal intensive care units (National Maternity Hospital and Rotunda Hospital, Dublin). Neonates born at less than 34 weeks will be enroled and informed consent obtained prior to late onset sepsis work up. If at any point subsequently during their neonatal intensive care stay they develop signs and symptoms of possible sepsis requiring blood culture, an additional sodium citrate sample will be obtained. Infants will be categorised into three groups as follows: (i) culture positive sepsis, (ii) culture negative sepsis where an infant receives 5 days of antibiotics (iii) non sepsis. Our primary outcome is to establish if differential platelet/endothelial activation can prospectively identify neonatal culture positive late onset sepsis., Trial Registration Number: NCT05530330 IMPACT: Preterm infants are a high risk group for the development of sepsis which is a major cause of mortality in this population. Platelets have been associated with host response to invasive bacterial infections both in animal models and translational work. A positive blood culture is the gold standard test for neonatal sepsis but can be unreliable due to limited blood sampling in the very low birth weight population. This study hopes to establish if platelet/endothelial associated plasma proteins can prospectively identify late onset neonatal sepsis., (© 2023. The Author(s), under exclusive licence to the International Pediatric Research Foundation, Inc.)

Child sexual abuse (CSA) is a significant threat to the health and well-being of children in the United States (US). Public policies are a key public health strategy for the primary prevention of violence, including CSA. In 2021, the Enough Abuse Campaign and Prevent Child Abuse America published a comprehensive report entitled A Call to Action for Policymakers and Advocates: Child Sexual Abuse Prevention Legislation in the States to encourage state leaders to create a comprehensive strategy to prevent CSA in the US. Findings from the report show that the nation has made some effort to address CSA, but more focus needs to be given to primary prevention strategies that stop it from occurring in the first place. The report also illustrates the variability of CSA prevention policies across the US and highlights critical gaps in current approaches that must be addressed. In the spirit of the special issue, the authors reflect on key policy issues in the field, including the lack of a federal policy framework for CSA prevention, dedicated funding for the prevention of CSA, and research on the effectiveness of policies intended to prevent CSA. Suggestions for future directions in relation to policy development provided in this commentary will be useful to a variety of stakeholders interested in the topic of CSA prevention policy.

Objective: We explore apparent infection of Salmincola californiensis arising during investigations involving this lernaeopodid copepod parasitic on Pacific salmon and trout Oncorhynchus spp., Methods: We noted occasional unusual coloration of adult female copepods collected from the wild. These females were bright blue and pink in contrast to the cream white coloration characteristic of the copepod. We also observed that similar color patterns developed under laboratory settings when copepod eggs were held for hatching. In paired egg cases, we found consistent hatching failure of blue and pink eggs and patterns in apparent disease development that would be consistent with both vertical and horizontal transmission., Result: Attempts to identify the cause of the apparent infection using genetic methods and transmission electron microscopy were inconclusive., Conclusion: Iridovirus infection was initially suspected, but bacterial infection is also plausible. This apparent reduced hatching success of S. californiensis warrants further exploration as it could reduce local abundances. Given the potential importance of a disease impacting this copepod, a parasite that itself affects endangered and commercially important Pacific salmon and trout, future research would benefit from clarification of the apparent infection through additional sequencing, primer development, visualization, and exploration into specificity and transmission., (© 2023 American Fisheries Society.)

Introduction: Child sexual abuse (CSA) poses a significant threat to the health and well-being of children in the USA and globally. Many states have introduced or implemented policies to address and prevent CSA, but little research has linked the effects of this legislation on the reduction of adult-perpetrated CSA. The objective of this scoping review is to identify US policies which aim to prevent CSA, explain the components of these types of legislation, review evidence of effectiveness, describe the populations included in the literature, and identify barriers and facilitators to the implementation of said policies., Methods and Analysis: This scoping review will follow Joanna Briggs Institute methodology for scoping reviews and will use the Preferred Reporting Items for Systematic reviews and Meta-Analyses extension for Scoping Reviews Checklist. Sources of peer-reviewed evidence from January 2000 to July 2023 will be included. Relevant publications will first be searched in PubMed/MEDLINE database, then 25 other databases. The reference lists of included studies and high-yield journals will be hand searched. Articles which focus on the types of CSA prevention policies and their effects will be included. Studies must clearly demonstrate a connection between policies and CSA outcomes. Title, abstract, full-text screening and extraction will be completed by a team of three researchers. Critical appraisal of the included studies will be performed. Extracted data will be displayed in tabular form and a narrative summary will describe the results of the review., Ethics and Dissemination: This scoping review will provide an extensive overview of legislative policies which aim to prevent CSA in the USA. Results of this review will inform future CSA prevention policies in the USA, particularly regarding policy development, evaluation and implementation. Results will be disseminated through a peer-reviewed publication., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Purpose: The aim of this study was to map the use of implementation science frameworks, models, and theories in intervention research targeting learning needs in the classroom., Method: A scoping review was conducted. Electronic database and manual searches were conducted. Two reviewers independently completed screening, data extraction, and quality appraisal. Qualitative content analysis was undertaken using Nilsen's taxonomy and the domains of the Consolidated Framework for Implementation Research (CFIR). The data were further analyzed using the CFIR valence and strength rating scales., Results: Included papers ( n = 22) used a diverse sample of implementation science frameworks and models. Most studies used determinant frameworks to guide data collection and analysis. Few studies used implementation science theory. Most studies were mixed methods ( n = 11), published since 2019 ( n = 20), and conducted in North America ( n = 15). Over half of the interventions targeted social, emotional, and mental health ( n = 13). A complex interplay of inner setting factors was identified as having a strong influence on implementation. Teachers' knowledge and beliefs, adaptability, and complexity of interventions were also identified as important considerations when conducting research in this context., Conclusions: Early engagement with stakeholders in education is recommended when designing universal level speech, language, and communication interventions for use in the ordinary classroom. Adaptive, hybrid designs that test both implementation strategies and effectiveness of interventions may be warranted given the influence of inner setting factors on implementation outcomes.

Background: Ten percent of the school-aged population have speech, language, and communication needs (SLCN) that impact access to the curriculum. Successful implementation of classroom-based SLCN interventions can reduce barriers to learning, thereby improving educational outcomes for this vulnerable population. The challenges of implementing innovations in educational settings are well-documented, yet limited studies have addressed such considerations when developing, and piloting universal level SLCN interventions for use in Irish schools., Methods: A qualitative exploratory study was undertaken to establish the acceptability, feasibility, and appropriateness of a universal level SLCN intervention. An advisory panel of teachers (n = 8) and children with SLCN (n = 2) were engaged as co-researchers in the study. The Communication Supporting Classrooms Observation Tool, developed as part of the Better Communication Project in the UK, was trialled across a diverse sample of school settings (n = 5). Semi-structured interviews were conducted with school practitioners and school leaders, and a deductive content analysis was undertaken using the domains of the Consolidation Framework for Implementation Research., Discussion: The observation tool was viewed as acceptable with suggested additions. Integrating use of the tool within existing data-informed, school self-evaluation processes aimed at supporting school improvement was noted as a potential means of supporting implementation. A knowledge gap in relation to school-based models of support for SLCN was identified which may negatively impact implementation. An implementation strategy targeting coherence, cognitive engagement and contextual integration is indicated if the tool is to be normalised into routine practice in Irish classrooms. Implementation needs appeared to vary at the school level., Conclusions: The importance of early-stage exploration to guide implementation planning with regards to developing and testing universal level interventions for SLCN in schools is highlighted. Engaging an advisory panel provides important insights to guide implementation decisions. Findings suggest an adaptive design is required when planning implementation studies targeting classroom setting., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Gallagher et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background: Obesity is a chronic relapsing disorder that is caused by an excess of caloric intake relative to energy expenditure. There is growing recognition that food motivation is altered in people with obesity. However, it remains unclear how brain circuits that control food motivation are altered in obese animals., Methods: Using a novel behavioral assay that quantifies work during food seeking, in vivo and ex vivo cell-specific recordings, and a synaptic blocking technique, we tested the hypothesis that activity of circuits promoting appetitive behavior in the core of the nucleus accumbens (NAc) is enhanced in the obese state, particularly during food seeking., Results: We first confirmed that mice made obese with ad libitum exposure to a high fat diet work harder than lean mice to obtain food, consistent with an increase in food motivation in obese mice. We observed greater activation of D 1 receptor-expressing NAc spiny projection neurons (NAc D1 SPNs ) during food seeking in obese mice relative to lean mice. This enhanced activity was not observed in D 2 receptor-expressing neurons (D2 SPNs ). Consistent with these in vivo findings, both intrinsic excitability and excitatory drive onto D1 SPNs were enhanced in obese mice relative to lean mice, and these measures were selective for D1 SPNs . Finally, blocking synaptic transmission from D1 SPNs , but not D2 SPNs , in the NAc core decreased physical work during food seeking and, critically, attenuated high fat diet-induced weight gain., Conclusions: These experiments demonstrate the necessity of NAc core D1 SPNs in food motivation and the development of diet-induced obesity, establishing these neurons as a potential therapeutic target for preventing obesity., (Copyright © 2022 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

Parasitism is an energetically costly event for host species. Dynamic energy budget (DEB) theory describes the metabolic dynamics of an individual organism through its lifetime. Models derived from DEB theory specify how an organism converts food to reserves (maintenance-free energy available for metabolism) and allocates mobilized reserves to maintenance, growth (increase of structural body mass) and maturation or reproduction. DEB models thus provide a useful approach to describe the consequences of parasitism for host species. We developed a DEB model for siscowet lake trout and modeled the impact of sea lamprey parasitism on growth and reproduction using data collected from studies documenting the long-term effects following a non-lethal sea lamprey attack. The model was parameterized to reflect the changes in allocation of energy towards growth and reproduction observed in lake trout following sea lamprey parasitism and includes an estradiol module that describes the conversion of reproductive reserves to ovarian mass based on estradiol concentration. In our DEB model, parasitism increased somatic and maturity maintenance costs, reduced estradiol and decreased the estradiol-mediated conversion efficiency of reproductive reserves to ovarian mass. Muscle lipid composition of lake trout influenced energy mobilization from the reserve (efficiency of converting reserves allocated to reproduction into eggs) and reproductive efficiency. These model changes accurately reflect observed empirical changes to ovarian mass and growth. This model provides a plausible explanation of the energetic mechanisms that lead to skipped spawning following sea lamprey parasitism and could be used in population models to explore sublethal impacts of sea lamprey parasitism and other stressors on population dynamics., (© The Author(s) 2023. Published by Oxford University Press and the Society for Experimental Biology.)

The hard-to-heal (chronic) wound condition, now believed to be inextricably linked to the presence of microbial biofilm, has posed challenges in translating scientific understanding to clinical practice in recent decades. During this time, multiple descriptive terms of the wound pathology have been described, including critical colonisation, biofilm infection and inflammatory stasis. However, the absence of naming this disease state as a specifically identified condition that is tangible to treat has led to some confusion and delay in possible therapeutic approaches. When there is clinical uncertainty of wound status, antibiotics are too often inappropriately administered as a precaution. We therefore propose that introducing the term 'granulitis' (inflamed, unhealthy granulation tissue) could be used to identify the biofilm-induced, persistent inflammatory wound condition. This will help to raise clinician and public awareness of the condition, guide appropriate and prompt local wound hygiene, and encourage allocation of adequate resources to improve wound healing outcomes globally.

In the United States, childcare subsidies are available to low-income working parents to assist with the cost of childcare. The subsidies are provided as block grants to states, which allows for a great deal of flexibility in the specific policies guiding their distribution. Prior research has found a protective link between childcare subsidies and child maltreatment, but the variations in policies have been much less explored. The current study used longitudinal administrative child welfare data from 10 years (2009-2019) linked with state policies regarding the income eligibility requirements of states to examine the impact of these policies on child abuse and neglect among young children (0-5); early school-age children (6-12), and older children (13-17). Using multiple regression and controlling for state demographic characteristics, the study found that more generous policies surrounding income eligibility were related to lower rates of child abuse and neglect investigations at the state level.

Inborn errors of metabolism are an individually rare but collectively significant cause of mortality and morbidity in the neonatal period. They are identified by either newborn screening programmes or clinician-initiated targeted biochemical screening. This study examines the relative contribution of these two methods to the identification of inborn errors of metabolism and describes the incidence of these conditions in a large, tertiary, neonatal unit. We also examined which factors could impact the reliability of metabolic testing in this cohort. This is a retrospective, single-site study examining infants in whom a targeted metabolic investigation was performed from January 2018 to December 2020 inclusive. Data was also provided by the national newborn screening laboratory regarding newborn screening diagnoses. Two hundred and four newborns received a clinician-initiated metabolic screen during the time period examined with 5 newborns being diagnosed with an inborn error of metabolism (IEM) (2.4%). Of the 25,240 infants born in the hospital during the period examined, a further 11 newborns had an inborn error of metabolism diagnosed on newborn screening. This produced an incidence in our unit over the time described of 6.34 per 10,000 births. This number reflects a minimum estimate, given that the conditions diagnosed refer to early-onset disorders and distinctive categories of IEM only. Efficiency of the clinician-initiated metabolic screening process was also examined. The only statistically significant variable in requiring repeat metabolic screening was early day of life (z-score = - 2.58, p = 0.0098). A total of 28.4% was missing one of three key metabolic investigation parameters of blood glucose, ammonia or lactate concentration with ammonia the most common investigation missing. While hypoglycemia was the most common clinical rationale for a clinician-initiated metabolic test, it was a poor predictor of inborn error of metabolism with no newborns of 25 screened were diagnosed with a metabolic disorder., Conclusion: Clinician-targeted metabolic screening had a high diagnostic yield given the relatively low prevalence of inborn errors of metabolism in the general population. Thoughts should be given to the rationale behind each targeted metabolic test and what specific metabolic disease or category of inborn error of metabolism they are concerned along with commencing targeted testing., What Is Known: • Inborn errors of metabolism are a rare but potentially treatable cause of newborn mortality and morbidity. • A previous study conducted in a tertiary unit in an area with limited newborn screening demonstrated a diagnostic yield of 5.4%., What Is New: • Clinician-initiated targeted metabolic screening has a good diagnostic performance even with a more expanded newborn screening programme. • Further optimisation could be achieved by examining the best timing and also the rationale of metabolic testing in the newborn period., (© 2022. The Author(s).)