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Surgery for colorectal liver metastases results in an overall survival of about 40% at 5 years. Progression-free survival is increased with the addition of oxaliplatin and fluorouracil chemotherapy. The addition of cetuximab to these chemotherapy regimens results in an overall survival advantage in patients with advanced disease who have the KRAS exon 2 wild-type tumour genotype. We aimed to assess the benefit of addition of cetuximab to standard chemotherapy in patients with resectable colorectal liver metastasis. Patients with KRAS exon 2 wild-type resectable or suboptimally resectable colorectal liver metastases were randomised in a 1:1 ratio to receive chemotherapy with or without cetuximab before and after liver resection. Randomisation was done using minimisation with factors of surgical centre, poor prognostic tumour (one or more of: ≥4 metastases, N2 disease, or poor differentiation of primary tumour), and previous adjuvant treatment with oxaliplatin. Chemotherapy consisted of oxaliplatin 85 mg/m2 intravenously over 2 h and fluorouracil bolus 400 mg/m2 intravenously over 5 min, followed by a 46 h infusion of fluorouracil 2400 mg/m2 repeated every 2 weeks (regimen one) or oxaliplatin 130 mg/m2 intravenously over 2 h and oral capecitabine 1000 mg/m2 twice daily on days 1–14 repeated every 3 weeks (regimen two). Patients who had received adjuvant oxaliplatin could receive irinotecan 180 mg/m2 intravenously over 30 min with fluorouracil instead of oxaliplatin (regimen three). Cetuximab was given as an intravenous dose of 500 mg/m2 every 2 weeks with regimen one and three or a loading dose of 400 mg/m2 followed by a weekly infusion of 250 mg/m2 with regimen two. The primary endpoint was progression-free survival. This is an interim analysis, up to Nov 1, 2012, when the trial was closed, having met protocol-defined futility criteria. This trial is registered, ISRCTN22944367. 128 KRAS exon 2 wild-type patients were randomised to chemotherapy alone and 129 to chemotherapy with cetuximab between Feb 26, 2007, and Nov 1, 2012. 117 patients in the chemotherapy alone group and 119 in the chemotherapy plus cetuximab group were included in the primary analysis. The median follow-up was 21·1 months (95% CI 12·6–33·8) in the chemotherapy alone group and 19·8 months (12·2–28·7) in the chemotherapy plus cetuximab group. With an overall median follow-up of 20·7 months (95% CI 17·9–25·6) and 123 (58%) of 212 required events observed, progression-free survival was significantly shorter in the chemotherapy plus cetuximab group than in the chemotherapy alone group (14·1 months [95% CI 11·8–15·9] vs 20·5 months [95% CI 16·8–26·7], hazard ratio 1·48, 95% CI 1·04–2·12, p=0·030). The most common grade 3 or 4 adverse events were low neutrophil count (15 [11%] preoperatively in the chemotherapy alone group vs six [4%] in the chemotherapy plus cetuximab group; four [4%] vs eight [8%] postoperatively), embolic events (six [4%] vs eight [6%] preoperatively; two [2%] vs three [3%] postoperatively), peripheral neuropathy (six [4%] vs one [1%] preoperatively; two [2%] vs four [4%] postoperatively), nausea or vomiting (four [3%] vs six [4%] preoperatively; four [4%] vs two [2%] postoperatively), and skin rash (two [1%] vs 21 [15%] preoperatively; 0 vs eight [8%] postoperatively). There were three deaths in the chemotherapy plus cetuximab group (one interstitial lung disease and pulmonary embolism, one bronchopneumonia, and one pulmonary embolism) and one in the chemotherapy alone group (heart failure) that might have been treatment related. Addition of cetuximab to chemotherapy and surgery for operable colorectal liver metastases in KRAS exon 2 wild-type patients results in shorter progression-free survival. Translational investigations to explore the molecular basis for this unexpected interaction are needed but at present the use of cetuximab in this setting cannot be recommended. Cancer Research UK.

ABSTRACT BACKGROUND Depression contributes to disability and there are ethnic/racial disparities in access and outcomes of care. Quality improvement (QI) programs for depression in primary care improve outcomes relative to usual care, but health, social and other community-based service sectors also support clients in under-resourced communities. Little is known about effects on client outcomes of strategies to implement depression QI across diverse sectors. OBJECTIVE To compare the effectiveness of Community Engagement and Planning (CEP) and Resources for Services (RS) to implement depression QI on clients’ mental health-related quality of life (HRQL) and services use. DESIGN Matched programs from health, social and other service sectors were randomized to community engagement and planning (promoting inter-agency collaboration) or resources for services (individual program technical assistance plus outreach) to implement depression QI toolkits in Hollywood-Metro and South Los Angeles. PARTICIPANTS From 93 randomized programs, 4,440 clients were screened and of 1,322 depressed by the 8-item Patient Health Questionnaire (PHQ-8) and providing contact information, 1,246 enrolled and 1,018 in 90 programs completed baseline or 6-month follow-up. MEASURES Self-reported mental HRQL and probable depression (primary), physical activity, employment, homelessness risk factors (secondary) and services use. RESULTS CEP was more effective than RS at improving mental HRQL, increasing physical activity and reducing homelessness risk factors, rate of behavioral health hospitalization and medication visits among specialty care users (i.e. psychiatrists, mental health providers) while increasing depression visits among users of primary care/public health for depression and users of faith-based and park programs (each p  < 0.05). Employment, use of antidepressants, and total contacts were not significantly affected (each p  > 0.05). CONCLUSION Community engagement to build a collaborative approach to implementing depression QI across diverse programs was more effective than resources for services for individual programs in improving mental HRQL, physical activity and homelessness risk factors, and shifted utilization away from hospitalizations and specialty medication visits toward primary care and other sectors, offering an expanded health-home model to address multiple disparities for depressed safety-net clients.

Agronomical and environmental benefits are associated with replacing winter fallow by cover crops (CCs). Yet, the effect of this practice on nitrous oxide (N2O) emissions remains poorly understood. In this context, a field experiment was carried out under Mediterranean conditions to evaluate the effect of replacing the traditional winter fallow (F) by vetch (Vicia sativa L.; V) or barley (Hordeum vulgare L.; B) on greenhouse gas (GHG) emissions during the intercrop and the maize (Zea mays L.) cropping period. The maize was fertilized following integrated soil fertility management (ISFM) criteria. Maize nitrogen (N) uptake, soil mineral N concentrations, soil temperature and moisture, dissolved organic carbon (DOC) and GHG fluxes were measured during the experiment. Our management (adjusted N synthetic rates due to ISFM) and pedo-climatic conditions resulted in low cumulative N2O emissions (0.57 to 0.75 kg N2O-N ha−1 yr−1), yield-scaled N2O emissions (3–6 g N2O-N kg aboveground N uptake−1) and N surplus (31 to 56 kg N ha−1) for all treatments. Although CCs increased N2O emissions during the intercrop period compared to F (1.6 and 2.6 times in B and V, respectively), the ISFM resulted in similar cumulative emissions for the CCs and F at the end of the maize cropping period. The higher C : N ratio of the B residue led to a greater proportion of N2O losses from the synthetic fertilizer in these plots when compared to V. No significant differences were observed in CH4 and CO2 fluxes at the end of the experiment. This study shows that the use of both legume and nonlegume CCs combined with ISFM could provide, in addition to the advantages reported in previous studies, an opportunity to maximize agronomic efficiency (lowering synthetic N requirements for the subsequent cash crop) without increasing cumulative or yield-scaled N2O losses.

Factors influencing production of greenhouse gases nitrous oxide (N 2 O) and nitrogen (N 2 ) in arable soils include high nitrate, moisture and plants; we investigate how differences in the soil microbiome due to antecedent soil treatment additionally influence denitrification. Microbial communities, denitrification gene abundance and gas production in soils from tilled arable plots with contrasting fertilizer inputs (no N, mineral N, FYM) and regenerated woodland in the long-term Broadbalk field experiment were investigated. Soil was transferred to pots, kept bare or planted with wheat and after 6 weeks, transferred to sealed chambers with or without K 15 NO 3 fertilizer for 4 days; N 2 O and N 2 were measured daily. Concentrations of N 2 O were higher when fertilizer was added, lower in the presence of plants, whilst N 2 increased over time and with plants. Prior soil treatment but not exposure to N-fertiliser or plants during the experiment influenced denitrification gene ( nirK, nirS, nosZ I , nosZ II) relative abundance. Under our experimental conditions, denitrification generated mostly N 2 ; N 2 O was around 2% of total gaseous N 2  + N 2 O. Prior long-term soil management influenced the soil microbiome and abundance of denitrification genes. The production of N 2 O was driven by nitrate availability and N 2 generation increased in the presence of plants.

Background Currently, the most frequently used treatment for acute appendicitis in children in the United Kingdom (UK) is an appendicectomy. However, there is increasing scientific and patient interest and research into non-operative treatment of appendicitis. Despite a number of non-randomised studies in children and randomised studies in adults, comparative outcomes of non-operative treatment and appendicectomy in comparable groups of children remain unknown. Following the successful completion of a feasibility study, we now aim to perform a UK-based multi-centre open-label randomised controlled trial (RCT) to investigate the clinical and cost-effectiveness of non-operative treatment pathway of acute uncomplicated appendicitis in children compared with appendicectomy. Methods Non-inferiority RCT with internal pilot, health economic evaluation and qualitative communication sub-study. The study is conducted in England, Northern Ireland, Scotland and Wales at both specialist children’s hospitals and district general hospitals. Children (aged 4–15 years inclusive) diagnosed with acute uncomplicated appendicitis that would normally be treated with an appendicectomy are eligible for the RCT. Exclusion criteria include clinical/radiological suspicion of perforated appendicitis, appendix mass or previous non-operative treatment of appendicitis. Sample size is 376 participants, recruited by surgeons and supported by research staff and randomised with a 1:1 allocation ratio to either non-operative treatment pathway (intervention) or appendicectomy (control). Participants in the intervention arm are treated with antibiotics, analgesia and regular clinical assessment to ensure clinical improvement. Participants in the control arm receive appendicectomy. Randomisation is minimised by age, sex, duration of symptoms and centre. The primary end-point is a composite outcome of treatment success at 1 year following randomisation. Secondary outcomes include: duration of hospital stay, measures of recovery from acute appendicitis, complications, need for further treatment, persistent symptoms, health care resource use, quality of life and costs. Adverse events, serious adverse events and suspected unexpected serious adverse events are collected directly on the database and by paper form up to 12-month visit. Primary outcome will be analysed on a non-inferiority basis using a 20% non-inferiority margin to test the hypothesis that non-operative treatment pathway is non-inferior to appendicectomy. Children and families who are approached for the RCT will be invited to participate in the embedded qualitative sub-study. This will include recording of recruitment consultations, which will inform future interventions to optimise recruitment. We have involved children, young people and parents in study design and delivery. Discussion This RCT will allow determination of the comparative clinical and cost-effectiveness of non-operative treatment pathway compared to appendicectomy for children with uncomplicated acute appendicitis in the UK. Trial status First planned enrolment—December 2022, first actual recruit—March 2022, current status of trial—open to recruitment. Trial registration ISRCTN16720026 . Registered on July 28, 2021.

Background Despite rehabilitation being increasingly advocated for people living with incurable cancer, there is limited evidence supporting efficacy or component parts. The progressive decline in function and nutritional in this population would support an approach that targets these factors. This trial aimed to assess the feasibility of an exercise and nutrition based rehabilitation programme in people with incurable cancer. Methods We randomized community dwelling adults with incurable cancer to either a personalized exercise and nutrition based programme (experimental arm) or standard care (control arm) for 8 weeks. Endpoints included feasibility, quality of life, physical activity (step count), and body weight. Qualitative and health economic analyses were also included. Results Forty‐five patients were recruited (23 experimental arm, 22 control arm). There were 26 men (58%), and the median age was 78 years (IQR 69–84). At baseline, the median BMI was 26 kg/m2 (IQR: 22–29), and median weight loss in the previous 6 months was 5% (IQR: −12% to 0%). Adherence to the experimental arm was >80% in 16/21 (76%) patients. There was no statistically significant difference in the following between trial arms: step count − median % change from baseline to endpoint, per trial arm (experimental −18.5% [IQR: −61 to 65], control 5% [IQR: −32 to 50], P = 0.548); weight − median % change from baseline to endpoint, per trial arm (experimental 1%[IQR: −3 to 3], control −0.5% [IQR: −3 to 1], P = 0.184); overall quality of life − median % change from baseline to endpoint, per trial arm (experimental 0% [IQR: −20 to 19], control 0% [IQR: −23 to 33], P = 0.846). Qualitative findings observed themes of capability, opportunity, and motivation amongst patients in the experimental arm. The mean incremental cost of the experimental arm versus control was £‐319.51 [CI −7593.53 to 6581.91], suggesting the experimental arm was less costly. Conclusions An exercise and nutritional rehabilitation intervention is feasible and has potential benefits for people with incurable cancer. A larger trial is now warranted to test the efficacy of this approach.

Background Deaths from alcohol-related liver disease (ARLD) are rising in the UK, representing a significant public health crisis. Effective interventions are urgently needed to reduce alcohol consumption and improve outcomes for individuals with ARLD. While behaviour change interventions (BCIs) are effective, their scalability is limited. Digital therapeutics offer a promising avenue for delivering BCIs remotely and at scale. AlcoChange, a novel digital therapeutic combining a smartphone app and digital breathalyser, delivers personalised BCIs based on patient triggers. Preliminary data suggest its potential efficacy in reducing alcohol use. Methods This is a multi-centre, two-arm, parallel-group, individually randomised controlled trial comparing usual care (review by a hospital Alcohol Care Team and brief intervention) with usual care plus AlcoChange in patients with ARLD. Population Adults aged 18 years or older with a diagnosis of ARLD (including cirrhosis, fibrosis, steatohepatitis, or recent alcoholic hepatitis) who have been advised to abstain from alcohol and intend to do so, and who have access to a smartphone. Intervention Usual care plus AlcoChange, comprising a smartphone app and digital breathalyser delivering personalised behaviour change techniques. Comparison Usual care alone. Outcome The primary outcome is the proportion of patients abstinent or reporting low-risk alcohol consumption (< 14 units/week) at 180 days post-randomisation, assessed using the Timeline Follow-Back (TLFB) method. Secondary outcomes include self-reported alcohol use at various time points, liver disease severity, health-related quality of life, healthcare resource utilisation, and cost-effectiveness. Four hundred participants will be recruited from up to 18 NHS hospitals in England and randomised 1:1. A mixed-methods approach was used to develop the trial protocol, including a theory of change framework and bespoke training materials for the TLFB assessment. Discussion This trial will evaluate the real-world efficacy and cost-effectiveness of AlcoChange in reducing alcohol consumption and alcohol-related harm in individuals with ARLD. The study addresses the urgent need for scalable interventions to combat the rising burden of ARLD in the UK. The pragmatic design and mixed methods approach to implementation aim to enhance the generalizability and impact of the findings. The trial will provide valuable evidence to inform clinical practice and policy regarding the use of digital therapeutics for alcohol use disorder and liver disease.

This paper explores the effects of a group-randomized controlled trial, Community Partners in Care (CPIC), on the development of interagency networks for collaborative depression care improvement between a community engagement and planning (CEP) intervention and a resources for services (RS) intervention that provided the same content solely via technical assistance to individual programs. Both interventions consisted of a diverse set of service agencies, including health, mental health, substance abuse treatment, social services, and community-trusted organizations such as churches and parks and recreation centers. Participants in the community councils for the CEP intervention reflected a range of agency leaders, staff, and other stakeholders. Network analysis of partnerships among agencies in the CEP versus RS condition, and qualitative analysis of perspectives on interagency network changes from multiple sources, suggested that agencies in the CEP intervention exhibited greater growth in partnership capacity among themselves than did RS agencies. CEP participants also viewed the coalition development intervention both as promoting collaboration in depression services and as a meaningful community capacity building activity. These descriptive results help to identify plausible mechanisms of action for the CPIC interventions and can be used to guide development of future community engagement interventions and evaluations in under-resourced communities.

Quality improvement (QI) for depression in primary care can reduce disparities in outcomes. We describe how community-partnered participatory research was used to design Community Partners in Care, a randomized trial of community engagement to activate a multiple-agency network versus support for individual agencies to implement depression QI in underserved communities.