ESMO Recommendations on clinical reporting of genomic test results for solid cancers.

BACKGROUND: Genomic tumour profiling has a crucial role in the management of patients with solid cancers, as it helps selecting and prioritising therapeutic interventions based on prognostic and predictive biomarkers, as well as identifying markers of hereditary cancers. Harmonised approaches to interpret the results of genomic testing are needed to support physicians in their decision making, prevent inequalities in precision medicine and maximise patient benefit from available cancer management options. METHODS: The European Society for Medical Oncology (ESMO) Translational Research and Precision Medicine Working Group assembled a group of international experts to propose recommendations for preparing clinical genomic reports for solid cancers. These recommendations aim to foster best practices in integrating genomic testing within clinical settings. After review of available evidence, several rounds of surveys and focused discussions were conducted to reach consensus on the recommendation statements. Only consensus recommendations were reported. Recommendation statements were graded in two tiers based on their clinical importance: level A (required to maintain common standards in reporting) and level B (optional but necessary to achieve ideal practice). RESULTS: Genomics reports should present key information in a front page(s) followed by supplementary information in one or more appendices. Reports should be structured into sections: (i) patient and sample details; (ii) assay and data analysis characteristics; (iii) sample-specific assay performance and quality control; (iv) genomic alterations and their functional annotation; (v) clinical actionability assessment and matching to potential therapy indications; and (vi) summary of the main findings. Specific recommendations to prepare each of these sections are made. CONCLUSIONS: We present a set of recommendations aimed at structuring genomics reports to enhance physician comprehension of genomic profiling results for solid cancers. Communication between ordering physicians and professionals reporting genomic data is key to minimise uncertainties and to optimise the impact of genomic tests in patient care.

The clinical landscape of cell-free DNA alterations in 1671 patients with advanced biliary tract cancer.

BACKGROUND: Targeted therapies have transformed clinical management of advanced biliary tract cancer (BTC). Cell-free DNA (cfDNA) analysis is an attractive approach for cancer genomic profiling that overcomes many limitations of traditional tissue-based analysis. We examined cfDNA as a tool to inform clinical management of patients with advanced BTC and generate novel insights into BTC tumor biology. PATIENTS AND METHODS: We analyzed next-generation sequencing data of 2068 cfDNA samples from 1671 patients with advanced BTC generated with Guardant360. We carried out clinical annotation on a multi-institutional subset (n = 225) to assess intra-patient cfDNA-tumor concordance and the association of cfDNA variant allele fraction (VAF) with clinical outcomes. RESULTS: Genetic alterations were detected in cfDNA in 84% of patients, with targetable alterations detected in 44% of patients. Fibroblast growth factor receptor 2 (FGFR2) fusions, isocitrate dehydrogenase 1 (IDH1) mutations, and BRAF V600E were clonal in the majority of cases, affirming these targetable alterations as early driver events in BTC. Concordance between cfDNA and tissue for mutation detection was high for IDH1 mutations (87%) and BRAF V600E (100%), and low for FGFR2 fusions (18%). cfDNA analysis uncovered novel putative mechanisms of resistance to targeted therapies, including mutation of the cysteine residue (FGFR2 C492F) to which covalent FGFR inhibitors bind. High pre-treatment cfDNA VAF was associated with poor prognosis and shorter response to chemotherapy and targeted therapy. Finally, we report the frequency of promising targets in advanced BTC currently under investigation in other advanced solid tumors, including KRAS G12C (1.0%), KRAS G12D (5.1%), PIK3CA mutations (6.8%), and ERBB2 amplifications (4.9%). CONCLUSIONS: These findings from the largest and most comprehensive study to date of cfDNA from patients with advanced BTC highlight the utility of cfDNA analysis in current management of this disease. Characterization of oncogenic drivers and mechanisms of therapeutic resistance in this study will inform drug development efforts to reduce mortality for patients with BTC.

Comparing the accuracy of lay diagnosis of childhood malaria and pneumonia with that of the revised IMCI guidelines in Nigeria.

BACKGROUND: Improving caregivers' recognition of childhood malaria and pneumonia is crucial to early treatment and improving outcomes. The objective of this study was to assess the accuracy and reliability of caregivers' recognition of malaria and pneumonia (lay diagnosis) as compared to the revised IMCI guidelines. METHODS: A cross-sectional study design was used to recruit 903 children aged 2-59 months who were assessed for malaria and pneumonia by health workers at five primary healthcare centres in Benin City, Nigeria. Accuracy of lay diagnosis as compared to the revised IMCI guidelines was assessed using sensitivity, specificity, positive and negative predictive values and area under the receiver operating characteristic curve (AUROC) values. RESULTS: The accuracy of caregivers' ability to recognise malaria (AUROC: 0.60; 95% CI: 0.57-0.64) and pneumonia (AUROC: 0.54; 95% CI: 0.50-0.58) was, respectively, moderate and poor as compared to the IMCI guidelines. Caregivers were better able to identify children without than those with malaria and pneumonia. Agreement between caregivers and the IMCI guidelines for malaria and pneumonia diagnosis was poor (k = 0.14, 95% CI: 0.09-0.19; P = 0.0001). CONCLUSION: Caregivers' ability to recognise these childhood diseases as compared to the IMCI guidelines was poor overall, which was partly due to the approach used to ascertain lay diagnosis.

International comparison of civilian violent deaths: a public health approach to reduce gun-related deaths in US youth.

OBJECTIVES: The political controversy surrounding firearm fatalities in US youths (aged 15-24 years) continues. This study examines whether a public health approach could reduce gun-related deaths in the US. METHODS: Based on the latest World Health Organization (WHO) data, current (2015) numbers and rates per million of US civilian violent deaths (CVDs) (including transport deaths, suicides and homicides) for both the general population and youths (aged 15-24 years) are examined. US CVD results are considered in a wider context by comparing the results with those of seven other major Western countries (MWCs). To demonstrate the effectiveness of a public health policy, transport deaths between 1979 and 2015 are analysed, which corresponds to a time period when government interventions based on technical improvements and behaviour change were implemented to improve road safety. The statistical significance of the comparison between road fatalities and suicide rates between 1979 and 2015 is determined by the chi-squared test. RESULTS: In 2015, the total number of US CVDs was 101,456, consisting of 44,193 suicides and 17,588 homicides (of which 30,891 were likely to be gun-related deaths). Youth deaths totalled 17,432; 5491 suicides and 4732 homicides, including approximately 5112 gun-related deaths. US CVDs are substantially higher than the other MWCs for both the general population and youths. In 1979, US transport deaths were 57,577, which decreased to 39,675 in 2015. Every country's public health approach to reduce road deaths, when compared with suicides, was highly statistically significant. CONCLUSIONS: Government interventions have reduced transport deaths; thus, new policies may also reduce gun-related violence. The evidence points towards a public health approach, such as that used to reduce road deaths, which could help reduce US firearm-related deaths to levels comparable with other MWCs.

Controlled population-based comparative study of USA and international adult [55-74] neurological deaths 1989-2014.

OBJECTIVES: A population-based controlled study to determine whether adult (55-74 years) neurological disease deaths are continuing to rise and are there significant differences between America and the twenty developed countries 1989-91 and 2012-14. METHOD: Total Neurological Deaths (TND) rates contrasted against control Cancer and Circulatory Disease Deaths (CDD) extrapolated from WHO data. Confidence intervals compare USA and the other countries over the period. The Over-75's TND and population increases are examined as a context for the 55-74 outcomes. RESULTS: Male neurological deaths rose >10% in eleven countries, the other countries average rose 20% the USA 43% over the period. Female neurological deaths rose >10% in ten counties, averaging 14%, the USA up 68%. USA male and female neurological deaths increased significantly more than twelve and seventeen countries, respectively. USA over-75s population increased by 49%, other countries 56%. Other countries TND up 187% the USA rose fourfold. Male and female cancer and CDD fell in every country averaging 26% and 21%, respectively, and 64% and 67% for CDD. Male neurological rates rose significantly more than Cancer and CCD in every country; Female neurological deaths rose significantly more than cancer in 17 countries and every country for CDD. There was no significant correlation between increases in neurological deaths and decreases in control mortalities. CONCLUSIONS: There are substantial increases in neurological deaths in most countries, significantly so in America. Rises in the 55-74 and over-75's rates are not primarily due to demographic changes and are a matter of concern warranting further investigation.

The portrayal of infant feeding in British women's magazines: a qualitative and quantitative content analysis.

Background: Exclusive breastfeeding is the best start an infant can receive. However, in many high-income countries breastfeeding rates are low and this may be a reflection of social norms which in turn may be influenced by the media. This study therefore explored the portrayal of infant feeding in women's general interest magazines. Methods: The five top selling women's weekly magazines in Britain and Ireland for 2013 over a 4-month period were included. A quantitative and qualitative content analysis was conducted for both written and visual content. Results: In 58 magazines, there were 90 references to infant feeding with an average of 1.5 (range: 0-5) per magazine. Breastfeeding and formula feeding references were present in equal number and both were predominantly portrayed positively. There was only 1 visual representation of breast feeding compared with 11 of bottle feeding. Potential drivers for breastfeeding included its role in post-pregnancy weight loss and celebrity endorsement while family routine, the role of males in the house and concerns about adverse health effects were identified as barriers to breastfeeding. Conclusion: An improvement in visual representations of breast feeding and factual information in women's weekly magazines may be helpful in re-defining social norms regarding infant feeding. Keywords: food and nutrition, health promotion, public health.

The cost-effectiveness of patient-controlled analgesia vs. standard care in patients presenting to the Emergency Department in pain, who are subsequently admitted to hospital.

The clinical effectiveness of patient-controlled analgesia has been demonstrated in a variety of settings. However, patient-controlled analgesia is rarely utilised in the Emergency Department. The aim of this study was to compare the cost-effectiveness of patient-controlled analgesia vs. standard care in participants admitted to hospital from the Emergency Department with pain due to traumatic injury or non-traumatic abdominal pain. Pain scores were measured hourly for 12 h using a visual analogue scale. Cost-effectiveness was measured as the additional cost per hour in moderate to severe pain avoided by using patient-controlled analgesia rather than standard care (the incremental cost-effectiveness ratio). Sampling variation was estimated using bootstrap methods and the effects of parameter uncertainty explored in a sensitivity analysis. The cost per hour in moderate or severe pain averted was estimated as £24.77 (€29.05, US$30.80) (bootstrap estimated 95%CI £8.72 to £89.17) for participants suffering pain from traumatic injuries and £15.17 (€17.79, US$18.86) (bootstrap estimate 95%CI £9.03 to £46.00) for participants with non-traumatic abdominal pain. Overall costs were higher with patient-controlled analgesia than standard care in both groups: pain from traumatic injuries incurred an additional £18.58 (€21.79 US$23.10) (95%CI £15.81 to £21.35) per 12 h; and non-traumatic abdominal pain an additional £20.18 (€23.67 US$25.09) (95%CI £19.45 to £20.84) per 12 h.

Investigation of induced recirculation during planned ventilation system maintenance.

The Office of Mine Safety and Health Research (OMSHR) investigated ways to increase mine airflow to underground metal/nonmetal (M/NM) mine working areas to improve miners' health and safety. One of those areas is controlled recirculation. Because the quantity of mine air often cannot be increased, reusing part of the ventilating air can be an effective alternative, if implemented properly, until the capacity of the present system is improved. The additional airflow can be used to provide effective dilution of contaminants and higher flow velocities in the underground mine environment. Most applications of controlled recirculation involve taking a portion of the return air and passing it back into the intake to increase the air volume delivered to the desired work areas. OMSHR investigated a Nevada gold mine where shaft rehabilitation was in progress and one of the two main fans was shut down to allow reduced air velocity for safe shaft work. Underground booster fan operating pressures were kept constant to maintain airflow to work areas, inducing controlled recirculation in one work zone. Investigation into system behavior and the effects of recirculation on the working area during times of reduced primary ventilation system airflow would provide additional information on implementation of controlled recirculation into the system and how these events affect M/NM ventilation systems. The National Institute for Occupational Safety and Health monitored the ventilation district when both main fans were operating and another scenario with one of the units turned off for maintenance. Airflow and contaminants were measured to determine the exposure effects of induced recirculation on miner health. Surveys showed that 19% controlled recirculation created no change in the overall district airflow distribution and a small reduction in district fresh air intake. Total dust levels increased only modestly and respirable dust levels were also low. Diesel particulate matter (DPM) levels showed a high increase in district intake mass flow, but minor increases in exposure levels related to the recirculation percentage. Utilization of DPM mass flow rates allows input into ventilation modeling programs to better understand and plan for ventilation changes and district recirculation effects on miners' health.

Durable benefit from poly(ADP-ribose) polymerase inhibitors in metastatic prostate cancer in routine practice: biomarker associations and implications for optimal clinical next-generation sequencing testing.

BACKGROUND: Controlled trials have consistently demonstrated the efficacy of poly(ADP-ribose) polymerase inhibitors (PARPis) in patients with metastatic castration-resistant prostate cancer (mCRPC) and BRCA1 or BRCA2 alterations (BRCAalt). However, the reported efficacy of PARPi for alterations in other homologous recombination repair (HRR) genes is less consistent. We sought to evaluate the routine practice effectiveness of PARPi between and within these groups. DESIGN: Patient-level data from a deidentified nationwide (USA-based) cancer clinico-genomic database between January 2011 and September 2023 were extracted. Patients with mCRPC and comprehensive genomic profiling by liquid biopsy [circulating tumor DNA (ctDNA)] or tissue (tumor) biopsy and who received single-agent PARPi were included and grouped by BRCAalt, ATMalt, other HRR, or no HRR. We further subcategorized BRCAalt into homozygous loss (BRCAloss) and all other deleterious BRCAalt (otherBRCAalt). RESULTS: A total of 445 patients met inclusion criteria: 214 with tumor and 231 with ctDNA. BRCAalt had more favorable outcomes to PARPi compared with ATM, other HRR, and no HRR groups. Within the BRCAalt subgroup, compared with other BRCAalt, BRCAloss had a more favorable time to next treatment (median 9 versus 19.4 months, P = 0.005), time to treatment discontinuation (median 8 versus 14 months, P = 0.006), and routine practice overall survival (median 14.7 versus 19.4 months, P = 0.016). Tumor BRCAloss prevalence (3.1%) was similar to ctDNA prevalence in liquid biopsy specimens with high tumor fraction (>20%). BRCAloss was not detected in orthogonal germline testing. CONCLUSIONS: PARPi routine practice effectiveness between groups mirrors prospective trials. Within the BRCAalt group, BRCAloss had the best outcomes. Unless the ctDNA tumor fraction is very high, somatic tissue testing (archival or metastatic) should be prioritized to identify patients who may benefit most from PARPi. When tissue testing is not clinically feasible, sufficient ctDNA tumor fraction levels for detection are enriched at clinical timepoints associated with tumor progression.

Changing patterns of neurological mortality in the 10 major developed countries--1979-2010.

OBJECTIVES: To examine whether there is a continued increase in neurological deaths in the major developed countries over the period 1979-2010. STUDY DESIGN: Analyzes changing patterns of neurological deaths and Total Mortality of people aged 55-74 years by sex. METHODS: Baseline WHO 3-year average mortality for 1979-81 were compared with changes in 2008-10, for Total Mortality and the neurological categories Nervous Disease, and Alzheimer & other Dementias deaths in rates per million. To control for different diagnostic practice, the focus is upon Total Neurological Deaths in relation to Total Mortality and Odds ratios are calculated. UK Motor Neuron Disease, Parkinson's disease and variant CJD are explored as possible constituent categories of Nervous Disease for other countries. RESULTS: Total Mortality fell substantially in every country, conversely, Nervous Disease and Alzheimer's rose in seven and six countries respectively. Total Neurological Deaths for males and females increased significantly in Australia, Canada, England & Wales, Italy, the Netherlands and especially the USA. Unlike motor neurone disease, variant CJD' deaths in England and Wales did not contribute substantially to the overall neurological increases found. Odds ratios indicated that neurological deaths differentially increased significantly in every country compared to Total Mortality. CONCLUSIONS: These results pose a major public health problem, as the epigenetic contribution to these changes, rather than longevity, have serious implications indicating earlier onset of neurological morbidity pressurizing families, health and social care services, with resource implications especially for Australia, Canada, Italy, Netherlands, Spain, the UK and the USA.

A novel founder MSH2 deletion in Ethiopian Jews is mainly associated with early-onset colorectal cancer.

Lynch syndrome is an inherited cancer predisposition syndrome caused by germline defects in any of the mismatch repair (MMR) genes. Diagnosis of carriers makes precision prevention, early detection, and tailored treatment possible. Herein we report a novel founder deletion of 18,758 bp, mediated by Alu repeats on both sides, detected in Ethiopian Jews. The deletion, which encompasses exon 9-10 of the MSH2 coding sequence, is associated mainly with early-onset MSH2/MSH6-deficient colorectal cancer (CRC) and liposarcoma. Testing of 35 members of 5 seemingly unrelated families of Ethiopian origin yielded 10/21 (48%) carriers, of whom 9 had CRC. Age at first tumor diagnosis ranged from 16 to 89 years. Carriers from the oldest generations were diagnosed after age 45 years (mean 57), and carriers from the younger generation were diagnosed before age 45 years (mean 30). Awareness of this founder deletion is important to improve patient diagnosis, institute surveillance from an early age, and refer patients for genetic counseling addressing the risk of bi-allelic constitutional MMR deficiency syndrome.

Comparing cancer mortality and GDP health expenditure in England and Wales with other major developed countries from 1979 to 2006.

BACKGROUND: Cancer and gross-domestic-product on health expenditure (GDPHE) are critical issues for major developed countries (MDC). Each country's economic input, GDPHE 1980-2005 is contrasted with clinical outputs, cancer mortality rates (CMRs), to compare their efficiency and effectiveness in reducing CMR. METHODS: World Health Organization's CMR data for baseline years (1979-1981) are compared with 2004-2006 by sex and age. The χ(2)-tests are used to determine differences between MDC. Efficiency is analysed by calculating a ratio of average GDPHE to reduced CMR over the period. RESULTS: Inputs: All the countries GDPHE grew substantially. For the United Kingdom this reached 9.3%, which is below the MDC average (10%). Outputs: CMR fell substantially (>20%) in six of the ten countries. The male average (15-74 years) CMR in England and Wales had been third highest but by 2004-2006 was sixth, a 31% reduction, which was significantly greater than seven other countries. Initially England and Wales female average CMR was the highest of all countries and is now the second highest. There were significantly greater reductions for the 55-64 and 65-74 years old than in seven and four countries, respectively. GDPHE reduced CMR ratios--the average GDPHE:reduced CMR ratio of England and Wales was 1:120, greater than all MDC and double that in four countries. CONCLUSION: Comparing GDPHE input with CMR output showed that relatively the NHS achieved more with proportionately less than other MDC.

Spatial behaviour of sheep during the neonatal period: Preliminary study on the influence of shelter.

Effective shelter has been demonstrated to reduce neonatal lamb mortality rates during periods of inclement weather. Periods of high wind speed and rainfall have been shown to influence shelter usage; however, it is not yet known how ewe factors such as breed, age and body condition score influence shelter-seeking behaviour. This study, conducted on a working upland farm in the UK, examined impact of artificial shelter on the biological and climatic factors that influence peri-parturient ewe behaviour. Pregnant ewes (n = 147) were randomly allocated between two adjacent fields which were selected for their similarity in size, topography, pasture management, orientation to the prevailing wind and available natural shelter. In one field, three additional artificial shelters were installed to increase the available shelter for ewes, this field was designated the Test field; no additional artificial shelter was provided in the second field which was used as the Control field. Individual ewes were observed every 2 h between 0800 and 1600 for 14 continuous days to monitor their location relative to shelter. Ewe breed (Aberfield and Highlander), age (2-8 years) and body condition score were considered as explanatory variables to explain flock and individual variance in shelter-seeking behaviour and the prevalence of issues which required the intervention of the shepherd, termed 'shepherding problems'. Any ewe observed with dystocia, a dead or poor vigour lamb or who exhibited mismothering behaviour was recorded as a shepherding problem. The prevalence of these shepherding problems which necessitate human intervention represents arguably the most critical limiting factor for the successful management of commercial sheep flocks in outdoor lambing systems. Overall, ewes in the Test field with access to additional artificial shelter experienced fewer shepherding problems than those in the Control field (P < 0.05). A significant breed effect was also observed, with Highlander ewes more likely to seek shelter than Aberfield ewes (P < 0.001), and experiencing significantly fewer shepherding interventions (P < 0.05). These findings demonstrate the substantial and significant benefits to animal welfare and productivity that can be achieved through the provision of shelter in commercial, upland, outdoor lambing systems in the UK.

National mortality rates from chronic liver disease and consumption of alcohol and pig meat.

A correlation between national pig-meat consumption and mortality rates from chronic liver disease (CLD) across developed countries was reported in 1985. One possible mechanism explaining this may be hepatitis E infection spread via pig meat. We aimed to re-examine the original association in more recent international data. Regression models were used to estimate associations between national pig-meat consumption and CLD mortality, adjusting for confounders. Data on CLD mortality, alcohol consumption, hepatitis B virus (HBV) and hepatitis C virus (HCV) seroprevalence for 18 developed countries (1990-2000) were obtained from WHO databases. Data on national pig-meat and beef consumption were obtained from the UN database. Univariate regression showed that alcohol and pig-meat consumption were associated with mortality from CLD, but beef consumption, HBV and HCV seroprevalence were not. A 1 litre per capita increase in alcohol consumption was associated with an increase in mortality from CLD in excess of 1.6 deaths/100,000 population. A 10 kg higher national annual average per capita consumption of pork meat was associated with an increase in mortality from CLD of between 4 and 5 deaths/100,000 population. Multivariate regression showed that alcohol, pig-meat consumption and HBV seroprevalence were independently associated with mortality from CLD, but HCV seroprevalence was not. Pig-meat consumption remained independently associated with mortality from CLD in developed countries in the 1990-2000 period. Further work is needed to establish the mechanism.

Accessibility of chewing tobacco products in England.

BACKGROUND: The carcinogenicity of chewing tobacco is well established. It is predominantly used by the South Asian community in England. Little is known about the accessibility of the products available for use in England. METHODS: Wards with high proportions or numbers of residents from the South Asian community were identified using 2001 Census data. Within each ward product purchasers identified retail outlets and purchased chewing tobacco products from them. RESULTS: Chewing tobacco products were found in a broad variety of premises in all but one ward, and were easily accessible. Ninety-eight products were identified and purchased with a mean price of pound1.82. Of the ninety four pre-packaged products purchased only 15% (95% CI: 8%, 22%) complied with legal health warning requirements. CONCLUSION: The study indicates the need to improve compliance with legal controls and enforcement to protect the South Asian community from health risks associated with chewing tobacco products.

Learning to implement Smart Healthy Age-Friendly Environments.

To develop trainings on the implementation of smart healthy age-friendly environments for people who aim to support, for example, their parents, their neighbours or local community, there are precautionary measures that have to be taken into account: the role of the facilitator (volunteer or self-employed), the level of skills, the needs of the end-users, training content and methodologies together with the sustainability of the learning. This article examines these aspects, based on desk research and expert interviews in the Smart Healthy Age-Friendly Environments (SHAFE) fields.

The 6-month safety and efficacy of abatacept in patients with rheumatoid arthritis who underwent a washout after anti-tumour necrosis factor therapy or were directly switched to abatacept: the ARRIVE trial.

OBJECTIVE: To assess the safety, tolerability and efficacy of abatacept in patients with rheumatoid arthritis (RA) who had failed anti-tumour necrosis factor (TNF) therapy and were switched to abatacept directly or after completing washout. METHODS: In this international, 6-month, open-label trial, patients had active RA, an inadequate response to anti-TNF therapy for 3 months or longer and a disease activity score in 28 joints (DAS28 (C-reactive protein; CRP) of 5.1 or greater. "Washout" patients discontinued anti-TNF therapy 2 months or longer pre-screening; "direct-switch" patients began abatacept ( approximately 10 mg/kg) at their next scheduled anti-TNF therapy dose. RESULTS: 1046 patients were treated (449 washout, 597 direct-switch; baseline characteristics were similar between groups). At 6 months, adverse events (AE; 78.0% vs 79.2%), serious AE (11.1% vs 9.9%) and discontinuations due to AE (3.8% vs 4.0%) and serious AE (2.0% vs 1.3%) were comparable in washout versus direct-switch patients. There were no opportunistic infections. At 6 months, in washout versus direct-switch patients, similar clinically meaningful improvements were seen in DAS28 (CRP) (> or =1.2 unit improvement, 59.5% vs 53.6%, respectively; low disease activity state, 22.5% vs 22.3%; DAS28-defined remission, 12.0% vs 13.7%), physical function (health assessment questionnaire disability index > or =0.22 improvement; 46.3% vs 47.1%) and health-related quality of life (mean change in short-form 36 scores: physical component summary, 5.5 vs 6.1; mental component summary, 4.8 vs 5.4). CONCLUSION: Abatacept demonstrated acceptable safety and tolerability and clinically meaningful efficacy over 6 months in patients with inadequate response to anti-TNF therapy. Results were comparable with or without a washout, supporting direct switching from anti-TNF therapy to abatacept as an option in clinical practice. TRIAL REGISTRATION NUMBER: NCT00124982.

RAE1 is a shuttling mRNA export factor that binds to a GLEBS-like NUP98 motif at the nuclear pore complex through multiple domains.

Gle2p is implicated in nuclear export of poly(A)+ RNA and nuclear pore complex (NPC) structure and distribution in Saccharomyces cerevisiae. Gle2p is anchored at the nuclear envelope (NE) via a short Gle2p-binding motif within Nup116p called GLEBS. The molecular mechanism by which Gle2p and the Gle2p-Nup116p interaction function in mRNA export is unknown. Here we show that RAE1, the mammalian homologue of Gle2p, binds to a GLEBS-like NUP98 motif at the NPC through multiple domains that include WD-repeats and a COOH-terminal non-WD-repeat extension. This interaction is direct, as evidenced by in vitro binding studies and chemical cross-linking. Microinjection experiments performed in Xenopus laevis oocytes demonstrate that RAE1 shuttles between the nucleus and the cytoplasm and is exported from the nucleus in a temperature-dependent and RanGTP-independent manner. Docking of RAE1 to the NE is highly dependent on new mRNA synthesis. Overexpression of the GLEBS-like motif also inhibits NE binding of RAE1 and induces nuclear accumulation of poly(A)+ RNA. Both effects are abrogated either by the introduction of point mutations in the GLEBS-like motif or by overexpression of RAE1, indicating a direct role for RAE1 and the NUP98-RAE1 interaction in mRNA export. Together, our data suggest that RAE1 is a shuttling transport factor that directly contributes to nuclear export of mRNAs through its ability to anchor to a specific NUP98 motif at the NPC.

Chemotherapy in the community: what do patients want?

The aim of this study was to compare the outcomes of chemotherapy delivered at a cancer centre with chemotherapy given at a community hospital. The services were compared in terms of safety, preference for location, satisfaction and resource use. Patients were randomly allocated to two groups. One group received their first two cycles of chemotherapy at a community hospital; the other group received theirs at the cancer centre. The patients then crossed over to receive their next two cycles of chemotherapy at outreach or the cancer centre and then chose where they wanted to receive the remaining two cycles of their chemotherapy. Data were collected about patient preference, anxiety and depression, satisfaction and chemotherapy-related toxicity. Forty-two patients were randomized to the study: 38, 31 and 28 patients completed cycles two, four and final chemotherapies respectively. Thirty-one patients reached the end of the crossover period, of which 30 chose the outreach location for the remainder of their chemotherapy treatments. There was strong evidence that patients were more satisfied with outreach location for ease of access and also the environment. Recommendation from this study was that a permanent outreach chemotherapy service to community hospitals be established.