An Integrated TCGA Pan-Cancer Clinical Data Resource to Drive High-Quality Survival Outcome Analytics

For a decade, The Cancer Genome Atlas (TCGA) program collected clinicopathologic annotation data along with multi-platform molecular profiles of more than 11,000 human tumors across 33 different cancer types. TCGA clinical data contain key features representing the democratized nature of the data collection process. To ensure proper use of this large clinical dataset associated with genomic features, we developed a standardized dataset named the TCGA Pan-Cancer Clinical Data Resource (TCGA-CDR), which includes four major clinical outcome endpoints. In addition to detailing major challenges and statistical limitations encountered during the effort of integrating the acquired clinical data, we present a summary that includes endpoint usage recommendations for each cancer type. These TCGA-CDR findings appear to be consistent with cancer genomics studies independent of the TCGA effort and provide opportunities for investigating cancer biology using clinical correlates at an unprecedented scale. Analysis of clinicopathologic annotations for over 11,000 cancer patients in the TCGA program leads to the generation of TCGA Clinical Data Resource, which provides recommendations of clinical outcome endpoint usage for 33 cancer types

Sealant Effectiveness for Children Receiving a Combination of Preventive Methods in a Fluoridated Community: Two-Year Results

A series of preventive methods in combination have been used to reduce dental caries in children including dental health education, prophylaxes, pit and fissure sealants, topical application of fluoride and restorative care. Prophylaxes, sealant, and fluoride procedures are repeated every six months. Two-year results show reductions of occlusal caries increments of 74.3% for first graders and 77.1% for sixth graders. Sealant loss, as defined in this study, varied from 33% to 90% with the highest loss occurring in the newly erupted permanent molars during the first six months of the project. These high sealant loss rates are thought to be related to the age of the population which was designed to include children at the ages of peak eruption of permanent molar teeth (ages six and twelve). These teeth were often only minimally erupted and maintaining the dry field required for sealant retention was extremely difficult. However, in spite of these high rates of sealant loss, caries reduction on occlusal surfaces was highly significant in comparison to that of children who did not receive sealants.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/68154/2/10.1177_00220345770560121801.pd

Anticoagulant rodenticides in red kites (Milvus milvus) in Britain in 2017 and 2018

Second generation anticoagulant rodenticides (SGARs) can be toxic to all mammals and birds. Various studies have shown that, in Britain, there is widespread exposure to SGARs in a diverse range of predatory mammals and birds, including red kites (Milvus milvus) which scavenge dead rats, a target species for rodent control. The Wildlife Incident Monitoring Scheme (WIIS) and the Predatory Bird Monitoring Scheme (PBMS) have shown that some mortalities result from this secondary exposure. In the present study, we analysed liver SGAR residues in 77 red kites that had been found dead in Britain in either 2017 or 2018. The carcasses were submitted to and necropsied by the Disease Risk Analysis and Health Surveillance (DRAHS) programme, the PBMS, the WIIS for England & Wales, the WIIS for Scotland and the Raptor Health Scotland study; the livers from the kites were subsequently analysed for SGAR residues. All the organisations are partners in the WILDCOMS network that promotes collaboration among surveillance schemes that monitor disease and contaminants in vertebrate wildlife. All of the 66 kites from England & Wales and 10 of the 11 red kites from Scotland had detectable liver residues of at least one SGAR. When considering the sample of kites as a whole, brodifacoum, difenacoum and bromadiolone were each detected in 73, 71 and 60 kites, respectively. Difethialone was found in 11 individuals while flocoumafen was detected in only one bird. Sum liver SGAR concentrations ranged between non-detected and 1218 ng/g wet wt. (arithmetic mean: 246 ng/g, median 154 ng/g). Post-mortem examinations indicated that 13 (16.8%) of red kites examined had internal haemorrhaging that was not associated with detectable trauma and had detectable liver SGAR concentrations. These birds had sum SGAR liver concentrations that ranged from 135 ng/g wet weight to 1218 ng/g wet weight. SGARs were considered a contributory cause of death in these cases. The stewardship scheme for anticoagulant rodenticides came fully into force in mid-2016 as re-registration of products for use in the UK was completed. A key aim is to reduce exposure of non-target wildlife to anticoagulant rodenticides but stewardship also aims to maintain efficacious rat control and so the number and density of AR-contaminated rats may remain unchanged. However, diligent searching, removal and safe disposal of poisoned rats, as promoted by stewardship, might be expected to reduce the availability of poisoned dead rats to red kites [and other scavengers] and thereby reduce the proportion of birds that are exposed and/or the magnitude of exposure. Concomitant with stewardship was a relaxation of the indoor use only restriction previously applied to brodifacoum, flocoumafen and difethialone, the three most acutely toxic SGARs. Any consequent increase in outdoor use of these three SGARs could increase the risk of secondary exposure in red kites. We therefore compared the data in the current report with that collected in 2015 and 2016 to determine if there was any evidence of a change in pattern or magnitude of exposure in red kites that might be connected to stewardship and/or change in usage restriction. The proportion of red kites exposed to SGARs in 2015 (90.6%), 2016 (89.6%) 2017 (96,4%) and 2018 (100%) was always 90% or more; the higher percentages in 2017 and 2018 were principally due to a greater proportion of birds from Scotland containing residues. Brodifacoum and difenacoum were the most prevalent compounds (89% of red kites across the four years for each compound) along with bromadiolone (75%). On average, there were residues of three different SGARs in each kite liver. There was no significant difference between years in liver sum (Σ) SGAR concentrations. We investigated if there was a change between years in the exposure of red kites to brodifacoum, flocoumafen and difethialone, the compounds for which indoor only usage restrictions were relaxed in 2016. To enable statistical analysis of data on residue prevalence, it was necessary to pool the data into two-year blocks. Data on presence/absence of detectable brodifacoum, flocoumafen or difethialone residues were therefore compared for 2015/16 (pre and year of implementation of change in usage restriction) and 2017/18 (post-change in usage restriction). The proportion of red kites with detectable residues was 82% (50 out of 61 red kites) in 2015/16 but significantly higher (95%; 73 out of 77 red kites) in 2017/18. However, there was also an increase [albeit not statistically significant] in the proportion of red kites with detectable liver difenacoum or bromadiolone residues (90% in 2015/16 vs. 97% in 2017/18). Therefore, these data may simply reflect an increase in the prevalence of exposure to SGARs generally rather than any effect of change in usage restriction. There was no difference between the four years in the summed magnitude of liver brodifacoum, difethialone and flocoumafen concentrations. The percentage of red kites examined that were diagnosed as birds in which SGARs were implicated as a contributory cause of death did not differ significantly between individual years nor show a significant trend across the years; the overall average across the four years was 22%. However, if data were pooled by pairs of years (2017/8 vs 2015/16), the proportion of red kites for which SGARs were implicated as a contributory cause of death was lower (18%) in 2017/18 than in 2015/16 (33%) for red kites from England & Wales. Our findings do not indicate that there has been any reduction in exposure in red kites to SGARs following implementation of stewardship, in terms of either the proportion of individuals exposed or the magnitude of residues detected. There is some evidence (depending upon the statistical approach used) that the proportion of red kites in which SGARs were implicated as a contributory mortality factor has decreased in more recent years. There was no clear evidence that relaxation of usage restrictions on brodifacoum, difethialone and flocoumafen has altered the pattern of residue accumulation in red kites to date

Second generation anticoagulant rodenticide residues in red kites 2022

•Second-generation anticoagulant rodenticides (SGARs) can be toxic to all mammals and birds if consumed. Various studies have shown that, in Britain, there is widespread exposure to SGARs in a diverse range of predatory mammals and birds, including red kites (Milvus milvus) which scavenge dead rats, a target species for rodent control. The Wildlife Incident Investigation Scheme (WIIS) and the Predatory Bird Monitoring Scheme (PBMS) have shown that some mortalities result from this secondary exposure. •In the present study, we analysed liver SGAR residues in 14 red kites that had been found dead in Britain in 2022. One bird collected in 2021 was also chemically analysed and added to the time trend analysis of this report. The carcasses were submitted to and necropsied by the Disease Risk Analysis and Health Surveillance (DRAHS) programme, the PBMS, and the WIIS for England & Wales. In 2022, there were no birds received from Scotland (i.e., no bird from the WIIS for Scotland and the Raptor Health Scotland study). All these organisations are partners in the WILDCOMS (Wildlife Disease & Contaminant Monitoring & Surveillance Network) network that promotes collaboration among surveillance schemes that monitor disease and contaminants in vertebrate wildlife in the UK. •The UK Rodenticide Stewardship Regime (hereafter referred to as the stewardship scheme) began to come into force in mid-2016 as re-registration of products for use in the UK was approved by the HSE; full implementation of the scheme was in early 2018. The key aim of this stewardship initiative is to support competence among all users of professional SGAR products. A potential benefit of this may be the reduced exposure of non-target wildlife to anticoagulant rodenticides. However, the number and density of SGAR-contaminated rats may remain unchanged although diligent searching, removal, and safe disposal of poisoned rats, as promoted by the stewardship regime, might be expected to reduce the availability of poisoned dead rats to red kites (and other scavengers) and thereby reduce the proportion of birds that are exposed and/or the magnitude of exposure. Concomitant with the stewardship scheme was a relaxation of the indoor-use-only-restriction applied to brodifacoum, flocoumafen, and difethialone, the three most acutely toxic SGARs to use indoor and outdoor around buildings. Any consequent increase in outdoor use of these three SGARs could increase the risk of secondary exposure in red kites. We therefore compared the data in the current report with that collected in 2015 and 2016 to determine if there was any evidence of a change in pattern or magnitude of exposure in red kites that might be connected to stewardship and/or change in usage restriction. •All of the 14 red kites from England & Wales in 2022 had detectable liver residues of at least one type of SGAR. Brodifacoum, difenacoum, and bromadiolone were each detected in 13, 13 and 6 red kites, respectively. Difethialone was found in two individuals while flocoumafen was detected in no bird. •The proportion of analysed red kites exposed to SGARs in 2015 (91%), 2016 (90%), 2017 (96%), 2018 (100%), 2019 (91%), 2020 (88%), 2021 (98%), and 2022 (100%) was similar at circa 90% or more; the higher percentages in 2017 and 2018 were principally due to a greater proportion of birds from Scotland containing residues than observed in other years. However, all red kites from England and Wales were exposed to SGARs in 2022. Difenacoum, brodifacoum, and bromadiolone were the most prevalent compounds (detected in 87%, 87%, and 75% of red kites across the eight years for each compound, respectively). On average, there were detectable residues of two different SGARs in each red kite liver likely demonstrating multiple exposures. •Sum liver SGAR concentrations in birds from 2022 ranged between 30 and 988 ng/g wet weight (arithmetic mean: 380 ng/g wet weight, median 257.9 ng/g wet weight). Necropsy examinations indicated that two red kites showed signs of being poisoned by SGARs (i.e., showing internal haemorrhaging that is not associated with detectable trauma and also having detectable liver SGAR concentrations). These samples accounted for 17% of the red kites of the year excluding uncertain poisoning cases. These two birds had sum SGAR liver concentrations of 544.2 and 661.6 ng/g wet weight. SGARs were considered a contributory cause of death resulting from unspecified use in these cases. SGARs were a contributory cause of death in 16% of the red kite cases examined across all eight years. Over the period 2015 to 2022, a reduction has been observed in the percentage of red kites examined that were diagnosed as birds in which SGARs were implicated as a contributory cause of death. However, given that the WIIS scheme specifically examines suspected poisoning incidents, it is likely that poisoned birds are over represented in this sample compared to the population as a whole in all eight years. Due to these reasons, caution should be used when interpreting evident changes in poisoned bird rates due to the opportunistic sampling methods used in this study that may lead to over reporting of poisoned birds. Those rates being subject to variations in relative contribution of the WIIS and PBMS to each year’s sample. It should be noted that sub-lethal poisoning due to SGAR exposure is not considered in this report. •There were statistically significant differences between years in median summed SGAR residues for non-poisoned birds and in all red kites combined with poisoned and non-poisoned birds. The magnitude of accumulated summed SGAR residues, particularly sum of brodifacoum, flocoumafen, and difethialone concentrations, was significantly higher in 2022 than in 2019. Given low occurrence and low concentrations of flocoumafen and difethialone residues, it is demonstrated that the magnitude of brodifacoum residues has increased over recent years. •Data on presence/absence of detectable brodifacoum, flocoumafen or difethialone residues were compared for 2015/2016 and 2017/18/19/20/21/22. The proportion of red kites with detectable residues of these three SGARs was not significantly different between 2015/2016 (82%) and 2017/18/19/20/21/22 (89%). Similarly, there was no significant difference in the proportion of red kites with detectable liver difenacoum or bromadiolone residues (90% in 2015/2016 vs. 94% in 2017/18/19/20/21/22). Since the implementation of the stewardship regime, no difference in exposure pattern relating to active ingredients has been detected with the exception of an increase in the concentrations of brodifacoum. •Spatial analysis by county/region indicated that across the monitoring period highest exposure to SGARs in red kites appeared to be around the Berkshire/Hampshire and, to a lesser extent, North Yorkshire. •Our findings do not indicate that there has been a consistent broad scale change in exposure in red kites to SGARs following implementation of stewardship in terms of either the proportion of the sample exposed or the magnitude of sum SGARs residues detected. However, there is evidence that the proportion of red kites in which SGARs were implicated as a contributory mortality factor has decreased in more recent years. Alternative approaches to monitoring SGARs in red kites could be considered that analyse a random but representative sample, and as part of such a programme there may also be value in monitoring SGARs in the blood of tracked individuals. Brodifacoum exposure has increased in recent years, but whether this change in exposure has been caused by the relaxation of usage restrictions on brodifacoum, difethialone and flocoumafen is still a question to be addressed

Anticoagulant rodenticides in red kites (Milvus milvus) in Britain 2015

Second generation anticoagulant rodenticides (SGARs) can be toxic to all mammals and birds. Various studies have shown that, in Britain, there is widespread exposure to SGARs in a diverse range of predatory mammals and birds, including red kites (Milvus milvus) which scavenge dead rats, a target species for rodent control. The Wildlife Incident Monitoring Scheme (WIIS) and the Predatory Bird Monitoring Scheme (PBMS) have shown that some mortalities result from this secondary exposure. The aim of the current study was to assess the scale and severity of exposure to SGARs (as assessed from the presence of liver SGAR residues) in red kites found dead in Britain in 2015. Carcasses, typically found by members of the public, were submitted for examination and analysis either to the Institute of Zoology’s Disease Risk Analysis and Health Surveillance programme (DRAHS) or to the Centre for Ecology & Hydrology’s Predatory Bird Monitoring Scheme, partners in the WILDCOMS network. We also report the results of SGAR analysis of red kites from England, Wales and Scotland that died in 2015 and analysed by the WIIS, who are also partners of the WILDCOMS network. Eighteen red kites from England & Wales were necropsied by either the DRAHS or the PBMS and the livers of the birds were analysed for SGARs by the PBMS. All had detectable liver residues of difenacoum and brodifacoum, and most also contained detectable liver bromadiolone residues. Difethialone was less frequently detected and flocoumafen was not detected in any birds. The presence of detectable brodifacoum residues in all birds may partly reflect the predominance of adult birds in the 2015 sample but may also indicate a growing prevalence of exposure to this compound. The percentage of red kites found by the PBMS to contain brodifacoum has increased since 2010 although any influence of age on this trend has not yet been examined. Sum liver SGAR concentrations in the 18 kites ranged between 50 and 1266 ng/g wet wt. (arithmetic mean: 463 ng/g). Post-mortems indicated that 7 of the kites had internal hemorrhaging that was not associated with detectable trauma; these birds typically had elevated sum SGAR liver concentrations. On the basis of these two factors, it is considered probable that SGARs were a contributory cause of death in these birds. The exposure pattern observed in 8 red kites from England & Wales analysed by the WIIS was very similar to that observed in birds analysed by the PBMS, with detectable liver residues of difenacoum and brodifacoum in all birds and bromadiolone in most. SGARs were assessed to be a contributory cause of death in two birds. Thus, of the 26 red kites from England & Wales analysed overall, SGARs were considered to be implicated in the deaths of 9 (35%). Residue data were available through the WIIS for 6 red kites from Scotland that died in 2015. Three kites (50%) had liver residues of at least two SGARs (bromadiolone and difenacoum); brodifacoum was also detected in one of these kites. SGARs were assessed to be a contributory cause of death in the bird that had residues of three SGARs. The data, although sample size is small, suggest that exposure of kites to SGARs may have been less marked in Scotland than in England & Wales in 2015, as has been found for other species

Second generation anticoagulant rodenticide residues in red kites 2020

Second generation anticoagulant rodenticides (SGARs) can be toxic to all mammals and birds if consumed. Various studies have shown that, in Britain, there is widespread exposure to SGARs in a diverse range of predatory mammals and birds, including red kites (Milvus milvus) which scavenge dead rats, a target species for rodent control. The Wildlife Incident Investigation Scheme1 (WIIS) and the Predatory Bird Monitoring Scheme (PBMS) have shown that some mortalities result from this secondary exposure. In the present study, we analysed liver SGAR residues in 25 red kites that had been found dead in Britain in 2020. The carcasses were submitted to and necropsied by the Disease Risk Analysis and Health Surveillance (DRAHS) programme, the PBMS, the WIIS for England & Wales, the WIIS for Scotland and the Raptor Health Scotland study. All the organisations are partners in the WILDCOMS (Wildlife Disease & Contaminant Monitoring & Surveillance Network) network that promotes collaboration among surveillance schemes that monitor disease and contaminants in vertebrate wildlife in the UK. The UK Rodenticide Stewardship Regime began to come into force in mid-2016 as reregistration of products for use in the UK was approved by the HSE; full implementation of the scheme was in early 2018. The key aim of this stewardship initiative is to support competence among all SGAR users, a potential benefit of this may be the reduced exposure of non-target wildlife to anticoagulant rodenticides. However, the number and density of SGAR-contaminated rats may remain unchanged although diligent searching, removal and safe disposal of poisoned rats, as promoted by the stewardship regime, might be expected to reduce the availability of poisoned dead rats to red kites (and other scavengers) and thereby reduce the proportion of birds that are exposed and/or the magnitude of exposure. Concomitant with the stewardship scheme was a relaxation of the indoor-use-only-restriction previously applied to brodifacoum, flocoumafen and difethialone, the three most acutely toxic SGARs. Any consequent increase in outdoor use of these three SGARs could increase the risk of secondary exposure in red kites. We therefore compared the data in the current report with that collected in 2015 and 2016 to determine if there was any evidence of a change in pattern or magnitude of exposure in red kites that might be connected to stewardship and/or change in usage restriction. All but one of the 21 red kites from England & Wales and two of the four red kites from Scotland had detectable liver residues of at least one type of SGAR. When considering the sample of red kites as a whole, brodifacoum, difenacoum and bromadiolone were each detected in 21, 19 and 17 red kites, respectively. Difethialone was found in four individuals while flocoumafen was detected in one bird. The proportion of analysed red kites exposed to SGARs in 2015 (91%), 2016 (90%) 2017 (96%), 2018 (100%) 2019 (91%) and 2020 (88%) was similar at circa 88% or more; the higher percentages in 2017 and 2018 were principally due to a greater proportion of birds from Scotland containing residues than observe in other years. Difenacoum, brodifacoum, and bromodialone were the most prevalent compounds (detected in 86%, 85%, and 76% of red kites across the six years for each compound, respectively). On average, there were detectable residues of three different SGARs in each red kite liver likely demonstrating multiple exposures. Sum liver SGAR concentrations in birds from 2020 ranged between non-detectable and 1086 ng/g wet weight (arithmetic mean: 371 ng/g wet weight, median 307 ng/g wet weight). Necropsy examinations indicated that three (13%) of red kites examined had internal haemorrhaging that was not associated with detectable trauma and also had detectable liver SGAR concentrations. These birds had sum SGAR liver concentrations of 663, 905 and 1086 ng/g wet weight. SGARs were considered a contributory cause of death resulting from unspecified use in these cases. SGARs were a contributory cause of death in 17% of the red kite cases examined across all six years. Over the period 2015 to 2020, a reduction has been observed in the percentage of red kites examined that were diagnosed as birds in which SGARs were implicated as a contributory cause of death. However, given that the WIIS scheme specifically examines suspected poisoning incidents, it is likely that poisoned birds are over represented in this sample compared to the population as a whole in all six years. Due to these reasons, caution should be used when interpreting evident changes in mortality rates due to the sampling protocols used in this study that may lead to over reporting of mortality rates, and those rates being subject to variations in relative contribution of the WIIS and PBMS to each year’s sample. There was no statistically significant difference between years, irrespective of cause of death, in median summed SGAR residues, and no evidence that the magnitude of accumulated summed SGAR residues has changed consistently over time. Sum bromadiolone and difenacoum concentrations were lower in 2016 than 2015, however, there was no difference for sum brodifacoum, flocoumafen, and difethialone concentrations. Data on presence/absence of detectable brodifacoum, flocoumafen or difethialone residues were compared for 2015/16 and 2017/18/19/20. The proportion of red kites with detectable residues of these three SGARs was 82% in 2015/16 and similar proportions were observed in 2017/18/19/20 (86%). Similarly, there was no significant difference in the proportion of red kites with detectable liver difenacoum or bromadiolone residues (90% in 2015/16 vs. 93% in 2017/18/19/20). Since the implementation of the stewardship regime no difference in exposure pattern relating to active ingredient has been detected. Our findings do not indicate that there has been a broad scale change in exposure in red kites to SGARs following implementation of stewardship in terms of either the proportion of the sample exposed or the magnitude of sum SGARs residues detected. There is some evidence (depending upon the statistical approach used) that the proportion of red kites in which SGARs were implicated as a contributory mortality factor has decreased in more recent years. Alternative approaches to monitoring SGARs in red kites could be considered that analyses a random but representative sample, and as part of such a programme there may also be value in monitoring SGARs in the blood of tracked individuals. There was no clear evidence that relaxation of usage restrictions on brodifacoum, difethialone and flocoumafen has altered the pattern of residues for these compounds in red kites to date. However, data following full implementation of the rodenticide stewardship scheme is currently limited to four years

Second generation anticoagulant rodenticide residues in red kites 2021

Second-generation anticoagulant rodenticides (SGARs) can be toxic to all mammals and birds if consumed. Various studies have shown that, in Britain, there is widespread exposure to SGARs in a diverse range of predatory mammals and birds, including red kites (Milvus milvus) which scavenge dead rats, a target species for rodent control. The Wildlife Incident Investigation Scheme (WIIS) and the Predatory Bird Monitoring Scheme (PBMS) have shown that some mortalities result from this secondary exposure. In the present study, we analysed liver SGAR residues in 42 red kites that had been found dead in Britain in 2021. The carcasses were submitted to and necropsied by the Disease Risk Analysis and Health Surveillance (DRAHS) programme, the PBMS, the WIIS for England & Wales, the WIIS for Scotland and the Raptor Health Scotland study. All the organisations are partners in the WILDCOMS (Wildlife Disease & Contaminant Monitoring & Surveillance Network) network that promotes collaboration among surveillance schemes that monitor disease and contaminants in vertebrate wildlife in the UK. The UK Rodenticide Stewardship Regime (hereafter referred to as the stewardship scheme) began to come into force in mid-2016 as re-registration of products for use in the UK was approved by the HSE; full implementation of the scheme was in early 2018. The key aim of this stewardship initiative is to support competence among all users of professional SGAR products. A potential benefit of this may be the reduced exposure of non-target wildlife to anticoagulant rodenticides. However, the number and density of SGAR-contaminated rats may remain unchanged although diligent searching, removal, and safe disposal of poisoned rats, as promoted by the stewardship regime, might be expected to reduce the availability of poisoned dead rats to red kites (and other scavengers) and thereby reduce the proportion of birds that are exposed and/or the magnitude of exposure. Concomitant with the stewardship scheme was a relaxation of the indoor-use-only-restriction applied to brodifacoum, flocoumafen, and difethialone, the three most acutely toxic SGARs to use indoor and outdoor around buildings. Any consequent increase in outdoor use of these three SGARs could increase the risk of secondary exposure in red kites. We therefore compared the data in the current report with that collected in 2015 and 2016 to determine if there was any evidence of a change in pattern or magnitude of exposure in red kites that might be connected to stewardship and/or change in usage restriction. All of the 39 red kites from England & Wales and two of the three red kites from Scotland had detectable liver residues of at least one type of SGAR. When considering the sample of red kites as a whole, brodifacoum, difenacoum, and bromadiolone were each detected in 41, 39, and 32 red kites, respectively. Difethialone was found in four individuals, while flocoumafen was detected in no bird. The proportion of analysed red kites exposed to SGARs in 2015 (91%), 2016 (90%), 2017 (96%), 2018 (100%), 2019 (91%), 2020 (88%), and 2021 (98%) was similar at circa 88% or more. Difenacoum, brodifacoum, and bromadiolone were the most prevalent compounds (detected in 87%, 87%, and 76% of red kites across the seven years for each compound, respectively). On average, there were detectable residues of three different SGARs in each red kite liver likely demonstrating multiple exposures. Sum liver SGAR concentrations in birds from 2021 ranged between non-detectable and 3223.7 ng/g wet weight (arithmetic mean: 482 ng/g wet weight, median 334.4 ng/g wet weight). Necropsy examinations indicated that five red kites showed signs of being poisoned by SGARs (i.e., showing internal haemorrhaging that is not associated with detectable trauma and also having detectable liver SGAR concentrations). These samples accounted for 14% of the red kites of this year excluding uncertain poisoning cases. These five birds had sum SGAR liver concentrations of 463.5, 684, 990, 1405.9, and 3223.7 ng/g wet weight. SGARs were considered a contributory cause of death resulting from unspecified use in these cases. SGARs were a contributory cause of death in 16% of the red kite cases examined across all seven years. Over the period 2015 to 2021, a reduction has been observed in the percentage of red kites examined that were diagnosed as birds in which SGARs were implicated as a contributory cause of death. However, given that the WIIS scheme specifically examines suspected poisoning incidents, it is likely that poisoned birds are over represented in this sample compared to the population as a whole in all seven years. Due to these reasons, caution should be used when interpreting evident changes in mortality rates due to the sampling protocols used in this study that may lead to over reporting of mortality rates, and those rates being subject to variations in relative contribution of the WIIS and PBMS to each year’s sample. There were statistically significant differences between years in median summed SGAR residues, irrespective of cause of death. The magnitude of accumulated summed SGAR residues, particularly sum of brodifacoum, flocoumafen, and difethialone concentrations, was significantly higher in 2021 than in many of the previous years. Given low occurrence and low concentrations of flocoumafen and difethialone residues, it is likely that the magnitude of brodifacoum residues has increased over recent years. Data on presence/absence of detectable brodifacoum, flocoumafen or difethialone residues were compared for 2015/2016 and 2017/18/19/20/21. The proportion of red kites with detectable residues of these three SGARs was not significantly different between in 2015/2016 (82%) and in 2017/18/19/20/21 (88%). Similarly, there was no significant difference in the proportion of red kites with detectable liver difenacoum or bromadiolone residues (90% in 2015/2016 vs. 94% in 2017/18/19/20/21). Since the implementation of the stewardship regime, no difference in exposure pattern relating to active ingredient has been detected with the exception of an increase in the concentrations of brodifacoum. Spatial analysis, by county/region indicated that across the monitoring period highest exposure to SGARs in red kites appeared to be around the Berkshire/Hampshire and, to a lesser extent, North Yorkshire. Our findings do not indicate that there has been a broad scale change in exposure in red kites to SGARs following implementation of stewardship in terms of either the proportion of the sample exposed or the magnitude of sum SGARs residues detected. However, there is evidence that the proportion of red kites in which SGARs were implicated as a contributory mortality factor has decreased in more recent years. Alternative approaches to monitoring SGARs in red kites could be considered that analyses a random but representative sample, and as part of such a programme there may also be value in monitoring SGARs in the blood of tracked individuals. There was no clear evidence that relaxation of usage restrictions on brodifacoum, difethialone and flocoumafen has altered the pattern of residues for these compounds in red kites to date, when considered collectively but brodifacoum exposure has increased in recent year

The XMM-Newton serendipitous survey. IV. Optical identification of the XMM-Newton medium sensitivity survey (XMS)

Aims.X-ray sources at intermediate fluxes (a few 10-14 erg cm-2 s-1) with a sky density of ~100 deg-2 are responsible for a significant fraction of the cosmic X-ray background at various energies below 10 keV. The aim of this paper is to provide an unbiased and quantitative description of the X-ray source population at these fluxes and in various X-ray energy bands. Methods.We present the XMM-Newton Medium sensitivity Survey (XMS), including a total of 318 X-ray sources found among the serendipitous content of 25 XMM-Newton target fields. The XMS comprises four largely overlapping source samples selected at soft (0.5-2 keV), intermediate (0.5-4.5 keV), hard (2-10 keV) and ultra-hard (4.5-7.5 keV) bands, the first three of them being flux-limited. Results.We report on the optical identification of the XMS samples, complete to 85-95%. At the flux levels sampled by the XMS we find that the X-ray sky is largely dominated by Active Galactic Nuclei. The fraction of stars in soft X-ray selected samples is below 10%, and only a few per cent for hard selected samples. We find that the fraction of optically obscured objects in the AGN population stays constant at around 15-20% for soft and intermediate band selected X-ray sources, over 2 decades of flux. The fraction of obscured objects amongst the AGN population is larger (~35-45%) in the hard or ultra-hard selected samples, and constant across a similarly wide flux range. The distribution in X-ray-to-optical flux ratio is a strong function of the selection band, with a larger fraction of sources with high values in hard selected samples. Sources with X-ray-to-optical flux ratios in excess of 10 are dominated by obscured AGN, but with a significant contribution from unobscured AGN

Meat consumption and incident type 2 diabetes: an individual-participant federated meta-analysis of 1·97 million adults with 100 000 incident cases from 31 cohorts in 20 countries.

Meat consumption could increase the risk of type 2 diabetes. However, evidence is largely based on studies of European and North American populations, with heterogeneous analysis strategies and a greater focus on red meat than on poultry. We aimed to investigate the associations of unprocessed red meat, processed meat, and poultry consumption with type 2 diabetes using data from worldwide cohorts and harmonised analytical approaches. This individual-participant federated meta-analysis involved data from 31 cohorts participating in the InterConnect project. Cohorts were from the region of the Americas (n=12) and the Eastern Mediterranean (n=2), European (n=9), South-East Asia (n=1), and Western Pacific (n=7) regions. Access to individual-participant data was provided by each cohort; participants were eligible for inclusion if they were aged 18 years or older and had available data on dietary consumption and incident type 2 diabetes and were excluded if they had a diagnosis of any type of diabetes at baseline or missing data. Cohort-specific hazard ratios (HRs) and 95% CIs were estimated for each meat type, adjusted for potential confounders (including BMI), and pooled using a random-effects meta-analysis, with meta-regression to investigate potential sources of heterogeneity. Among 1 966 444 adults eligible for participation, 107 271 incident cases of type 2 diabetes were identified during a median follow-up of 10 (IQR 7-15) years. Median meat consumption across cohorts was 0-110 g/day for unprocessed red meat, 0-49 g/day for processed meat, and 0-72 g/day for poultry. Greater consumption of each of the three types of meat was associated with increased incidence of type 2 diabetes, with HRs of 1·10 (95% CI 1·06-1·15) per 100 g/day of unprocessed red meat (I <sup>2</sup> =61%), 1·15 (1·11-1·20) per 50 g/day of processed meat (I <sup>2</sup> =59%), and 1·08 (1·02-1·14) per 100 g/day of poultry (I <sup>2</sup> =68%). Positive associations between meat consumption and type 2 diabetes were observed in North America and in the European and Western Pacific regions; the CIs were wide in other regions. We found no evidence that the heterogeneity was explained by age, sex, or BMI. The findings for poultry consumption were weaker under alternative modelling assumptions. Replacing processed meat with unprocessed red meat or poultry was associated with a lower incidence of type 2 diabetes. The consumption of meat, particularly processed meat and unprocessed red meat, is a risk factor for developing type 2 diabetes across populations. These findings highlight the importance of reducing meat consumption for public health and should inform dietary guidelines. The EU, the Medical Research Council, and the National Institute of Health Research Cambridge Biomedical Research Centre