Time trends in service provision and survival outcomes for patients with renal cancer treated by nephrectomy in England 2000-2010.

OBJECTIVE: To describe the temporal trends in nephrectomy practice and outcomes for English patients with renal cell carcinoma (RCC). PATIENTS AND METHODS: Adult RCC nephrectomy patients treated between 2000 and 2010 were identified in the National Cancer Data Repository and Hospital Episode Statistics, and followed-up until date of death or 31 December 2015 (n = 30 763). We estimated the annual frequency for each nephrectomy type, the hospital and surgeon numbers and their case volumes. We analysed short-term surgical outcomes, as well as 1- and 5-year relative survivals. RESULTS: Annual RCC nephrectomy number increased by 66% during the study period. Hospital number decreased by 24%, whilst the median annual hospital volume increased from 10 to 23 (P < 0.01). Surgeon number increased by 27% (P < 0.01), doubling the median consultant number per hospital. The proportion of minimally invasive surgery (MIS) nephrectomies rose from 1% to 46%, whilst the proportion of nephron-sparing surgeries (NSS) increased from 5% to 16%, with 29% of all T1 disease treated with partial nephrectomy in 2010 (P < 0.01). The 30-day mortality rate halved from 2.4% to 1.1% and 90-day mortality decreased from 4.9% to 2.6% (P < 0.01). The 1-year relative survival rate increased from 86.9% to 93.4%, whilst the 5-year relative survival rate rose from 68.2% to 81.2% (P < 0.01). Improvements were most notable in patients aged ≥65 years and those with T3 and T4 disease. CONCLUSIONS: Surgical RCC management has changed considerably with nephrectomy centralisation and increased NSS and MIS. In parallel, we observed significant improvements in short- and long-term survival particularly for elderly patients and those with locally advanced disease

The impact of lidocaine plaster prescribing reduction strategies: A comparison of two national health services in Europe

AIMS: In 2017, two distinct interventions were implemented in Ireland and England to reduce prescribing of lidocaine medicated plasters. In Ireland, restrictions on reimbursement were introduced through implementation of an application system for reimbursement. In England, updated guidance on items which should not be routinely prescribed in primary care, including lidocaine plasters, was published. This study aims to compare how the interventions impacted prescribing of lidocaine plasters in these countries. METHODS: We conducted an interrupted time-series study using general practice data. For Ireland, monthly dispensing data (2015-2019) from the means-tested General Medical Services (GMS) scheme was used. For England, data covered all patients. Outcomes were the rate of dispensings, quantity and costs of lidocaine plasters, and we modelled level and trend changes from the first full month of the policy/guidance change. RESULTS: Ireland had higher rates of lidocaine dispensings compared to England throughout the study period; this was 15.22/1000 population immediately pre-intervention, and there was equivalent to a 97.2% immediate reduction following the intervention. In England, the immediate pre-intervention dispensing rate was 0.36/1000, with an immediate reduction of 0.0251/1000 (a 5.8% decrease), followed by a small but significant decrease in the monthly trend relative to the pre-intervention trend of 0.0057 per month. CONCLUSIONS: Among two different interventions aiming to decrease low-value lidocaine plaster prescribing, there was a substantially larger impact in Ireland of reimbursement restriction compared to issuing guidance in England. However, this is in the context of much higher baseline rates of use in Ireland compared to England

Intra- and Inter-Tumor Heterogeneity of BRAFV600EMutations in Primary and Metastatic Melanoma

The rationale for using small molecule inhibitors of oncogenic proteins as cancer therapies depends, at least in part, on the assumption that metastatic tumors are primarily clonal with respect to mutant oncogene. With the emergence of BRAFV600E as a therapeutic target, we investigated intra- and inter-tumor heterogeneity in melanoma using detection of the BRAFV600E mutation as a marker of clonality. BRAF mutant-specific PCR (MS-PCR) and conventional sequencing were performed on 112 tumors from 73 patients, including patients with matched primary and metastatic specimens (n = 18). Nineteen patients had tissues available from multiple metastatic sites. Mutations were detected in 36/112 (32%) melanomas using conventional sequencing, and 85/112 (76%) using MS-PCR. The better sensitivity of the MS-PCR to detect the mutant BRAFV600E allele was not due to the presence of contaminating normal tissue, suggesting that the tumor was comprised of subclones of differing BRAF genotypes. To determine if tumor subclones were present in individual primary melanomas, we performed laser microdissection and mutation detection via sequencing and BRAFV600E-specific SNaPshot analysis in 9 cases. Six of these cases demonstrated differing proportions of BRAFV600Eand BRAFwild-type cells in distinct microdissected regions within individual tumors. Additional analyses of multiple metastatic samples from individual patients using the highly sensitive MS-PCR without microdissection revealed that 5/19 (26%) patients had metastases that were discordant for the BRAFV600E mutation. In conclusion, we used highly sensitive BRAF mutation detection methods and observed substantial evidence for heterogeneity of the BRAFV600E mutation within individual melanoma tumor specimens, and among multiple specimens from individual patients. Given the varied clinical responses of patients to BRAF inhibitor therapy, these data suggest that additional studies to determine possible associations between clinical outcomes and intra- and inter-tumor heterogeneity could prove fruitful

Dispersal Routes and Habitat Utilization of Juvenile Atlantic Bluefin Tuna, Thunnus thynnus, Tracked with Mini PSAT and Archival Tags

Between 2005 and 2009, we deployed 58 miniature pop-up satellite archival tags (PSAT) and 132 implanted archival tags on juvenile Atlantic bluefin tuna (age 2–5) in the northwest Atlantic Ocean. Data returned from these efforts (n = 26 PSATs, 1 archival tag) revealed their dispersal routes, horizontal and vertical movements and habitat utilization. All of the tagged bluefin tuna remained in the northwest Atlantic for the duration observed, and in summer months exhibited core-use of coastal seas extending from Maryland to Cape Cod, MA, (USA) out to the shelf break. Their winter distributions were more spatially disaggregated, ranging south to the South Atlantic Bight, northern Bahamas and Gulf Stream. Vertical habitat patterns showed that juvenile bluefin tuna mainly occupied shallow depths (mean  = 5–12 m, sd  = 15–23.7 m) and relatively warm water masses in summer (mean  = 17.9–20.9°C, sd  = 4.2–2.6°C) and had deeper and more variable depth patterns in winter (mean  = 41–58 m, sd  = 48.9–62.2 m). Our tagging results reveal annual dispersal patterns, behavior and oceanographic associations of juvenile Atlantic bluefin tuna that were only surmised in earlier studies. Fishery independent profiling from electronic tagging also provide spatially and temporally explicit information for evaluating dispersals rates, population structure and fisheries catch patterns

A High Density SNP Array for the Domestic Horse and Extant Perissodactyla: Utility for Association Mapping, Genetic Diversity, and Phylogeny Studies

An equine SNP genotyping array was developed and evaluated on a panel of samples representing 14 domestic horse breeds and 18 evolutionarily related species. More than 54,000 polymorphic SNPs provided an average inter-SNP spacing of ∼43 kb. The mean minor allele frequency across domestic horse breeds was 0.23, and the number of polymorphic SNPs within breeds ranged from 43,287 to 52,085. Genome-wide linkage disequilibrium (LD) in most breeds declined rapidly over the first 50–100 kb and reached background levels within 1–2 Mb. The extent of LD and the level of inbreeding were highest in the Thoroughbred and lowest in the Mongolian and Quarter Horse. Multidimensional scaling (MDS) analyses demonstrated the tight grouping of individuals within most breeds, close proximity of related breeds, and less tight grouping in admixed breeds. The close relationship between the Przewalski's Horse and the domestic horse was demonstrated by pair-wise genetic distance and MDS. Genotyping of other Perissodactyla (zebras, asses, tapirs, and rhinoceros) was variably successful, with call rates and the number of polymorphic loci varying across taxa. Parsimony analysis placed the modern horse as sister taxa to Equus przewalski. The utility of the SNP array in genome-wide association was confirmed by mapping the known recessive chestnut coat color locus (MC1R) and defining a conserved haplotype of ∼750 kb across all breeds. These results demonstrate the high quality of this SNP genotyping resource, its usefulness in diverse genome analyses of the horse, and potential use in related species

Late-Stage Metastatic Melanoma Emerges through a Diversity of Evolutionary Pathways

UNLABELLED: Understanding the evolutionary pathways to metastasis and resistance to immune-checkpoint inhibitors (ICI) in melanoma is critical for improving outcomes. Here, we present the most comprehensive intrapatient metastatic melanoma dataset assembled to date as part of the Posthumous Evaluation of Advanced Cancer Environment (PEACE) research autopsy program, including 222 exome sequencing, 493 panel-sequenced, 161 RNA sequencing, and 22 single-cell whole-genome sequencing samples from 14 ICI-treated patients. We observed frequent whole-genome doubling and widespread loss of heterozygosity, often involving antigen-presentation machinery. We found KIT extrachromosomal DNA may have contributed to the lack of response to KIT inhibitors of a KIT-driven melanoma. At the lesion-level, MYC amplifications were enriched in ICI nonresponders. Single-cell sequencing revealed polyclonal seeding of metastases originating from clones with different ploidy in one patient. Finally, we observed that brain metastases that diverged early in molecular evolution emerge late in disease. Overall, our study illustrates the diverse evolutionary landscape of advanced melanoma. SIGNIFICANCE: Despite treatment advances, melanoma remains a deadly disease at stage IV. Through research autopsy and dense sampling of metastases combined with extensive multiomic profiling, our study elucidates the many mechanisms that melanomas use to evade treatment and the immune system, whether through mutations, widespread copy-number alterations, or extrachromosomal DNA. See related commentary by Shain, p. 1294. This article is highlighted in the In This Issue feature, p. 1275

The Pediatric Obsessive-Compulsive Disorder Treatment Study II: rationale, design and methods

This paper presents the rationale, design, and methods of the Pediatric Obsessive-Compulsive Disorder Treatment Study II (POTS II), which investigates two different cognitive-behavior therapy (CBT) augmentation approaches in children and adolescents who have experienced a partial response to pharmacotherapy with a serotonin reuptake inhibitor for OCD. The two CBT approaches test a "single doctor" versus "dual doctor" model of service delivery. A specific goal was to develop and test an easily disseminated protocol whereby child psychiatrists would provide instructions in core CBT procedures recommended for pediatric OCD (e.g., hierarchy development, in vivo exposure homework) during routine medical management of OCD (I-CBT). The conventional "dual doctor" CBT protocol consists of 14 visits over 12 weeks involving: (1) psychoeducation, (2), cognitive training, (3) mapping OCD, and (4) exposure with response prevention (EX/RP). I-CBT is a 7-session version of CBT that does not include imaginal exposure or therapist-assisted EX/RP. In this study, we compared 12 weeks of medication management (MM) provided by a study psychiatrist (MM only) with two types of CBT augmentation: (1) the dual doctor model (MM+CBT); and (2) the single doctor model (MM+I-CBT). The design balanced elements of an efficacy study (e.g., random assignment, independent ratings) with effectiveness research aims (e.g., differences in specific SRI medications, dosages, treatment providers). The study is wrapping up recruitment of 140 youth ages 7–17 with a primary diagnosis of OCD. Independent evaluators (IEs) rated participants at weeks 0,4,8, and 12 during acute treatment and at 3,6, and 12 month follow-up visits

Human and Non-Human Primate Genomes Share Hotspots of Positive Selection

Among primates, genome-wide analysis of recent positive selection is currently limited to the human species because it requires extensive sampling of genotypic data from many individuals. The extent to which genes positively selected in human also present adaptive changes in other primates therefore remains unknown. This question is important because a gene that has been positively selected independently in the human and in other primate lineages may be less likely to be involved in human specific phenotypic changes such as dietary habits or cognitive abilities. To answer this question, we analysed heterozygous Single Nucleotide Polymorphisms (SNPs) in the genomes of single human, chimpanzee, orangutan, and macaque individuals using a new method aiming to identify selective sweeps genome-wide. We found an unexpectedly high number of orthologous genes exhibiting signatures of a selective sweep simultaneously in several primate species, suggesting the presence of hotspots of positive selection. A similar significant excess is evident when comparing genes positively selected during recent human evolution with genes subjected to positive selection in their coding sequence in other primate lineages and identified using a different test. These findings are further supported by comparing several published human genome scans for positive selection with our findings in non-human primate genomes. We thus provide extensive evidence that the co-occurrence of positive selection in humans and in other primates at the same genetic loci can be measured with only four species, an indication that it may be a widespread phenomenon. The identification of positive selection in humans alongside other primates is a powerful tool to outline those genes that were selected uniquely during recent human evolution

Recombinational Landscape and Population Genomics of Caenorhabditis elegans

Recombination rate and linkage disequilibrium, the latter a function of population genomic processes, are the critical parameters for mapping by linkage and association, and their patterns in Caenorhabditis elegans are poorly understood. We performed high-density SNP genotyping on a large panel of recombinant inbred advanced intercross lines (RIAILs) of C. elegans to characterize the landscape of recombination and, on a panel of wild strains, to characterize population genomic patterns. We confirmed that C. elegans autosomes exhibit discrete domains of nearly constant recombination rate, and we show, for the first time, that the pattern holds for the X chromosome as well. The terminal domains of each chromosome, spanning about 7% of the genome, exhibit effectively no recombination. The RIAILs exhibit a 5.3-fold expansion of the genetic map. With median marker spacing of 61 kb, they are a powerful resource for mapping quantitative trait loci in C. elegans. Among 125 wild isolates, we identified only 41 distinct haplotypes. The patterns of genotypic similarity suggest that some presumed wild strains are laboratory contaminants. The Hawaiian strain, CB4856, exhibits genetic isolation from the remainder of the global population, whose members exhibit ample evidence of intercrossing and recombining. The population effective recombination rate, estimated from the pattern of linkage disequilibrium, is correlated with the estimated meiotic recombination rate, but its magnitude implies that the effective rate of outcrossing is extremely low, corroborating reports of selection against recombinant genotypes. Despite the low population, effective recombination rate and extensive linkage disequilibrium among chromosomes, which are techniques that account for background levels of genomic similarity, permit association mapping in wild C. elegans strains

Changes of the human gut microbiome induced by a fermented milk product

The gut microbiota (GM) consists of resident commensals and transient microbes conveyed by the diet but little is known about the role of the latter on GM homeostasis. Here we show, by a conjunction of quantitative metagenomics, in silico genome reconstruction and metabolic modeling, that consumption of a fermented milk product containing dairy starters and Bifidobacterium animalis potentiates colonic short chain fatty acids production and decreases abundance of a pathobiont Bilophila wadsworthia compared to a milk product in subjects with irritable bowel syndrome (IBS, n = 28). The GM changes parallel improvement of IBS state, suggesting a role of the fermented milk bacteria in gut homeostasis. Our data challenge the view that microbes ingested with food have little impact on the human GM functioning and rather provide support for beneficial health effects