Timing the Landmark Events in the Evolution of Clear Cell Renal Cell Cancer: TRACERx Renal.

Clear cell renal cell carcinoma (ccRCC) is characterized by near-universal loss of the short arm of chromosome 3, deleting several tumor suppressor genes. We analyzed whole genomes from 95 biopsies across 33 patients with clear cell renal cell carcinoma. We find hotspots of point mutations in the 5' UTR of TERT, targeting a MYC-MAX-MAD1 repressor associated with telomere lengthening. The most common structural abnormality generates simultaneous 3p loss and 5q gain (36% patients), typically through chromothripsis. This event occurs in childhood or adolescence, generally as the initiating event that precedes emergence of the tumor's most recent common ancestor by years to decades. Similar genomic changes drive inherited ccRCC. Modeling differences in age incidence between inherited and sporadic cancers suggests that the number of cells with 3p loss capable of initiating sporadic tumors is no more than a few hundred. Early development of ccRCC follows well-defined evolutionary trajectories, offering opportunity for early intervention.

Deterministic Evolutionary Trajectories Influence Primary Tumor Growth: TRACERx Renal.

The evolutionary features of clear-cell renal cell carcinoma (ccRCC) have not been systematically studied to date. We analyzed 1,206 primary tumor regions from 101 patients recruited into the multi-center prospective study, TRACERx Renal. We observe up to 30 driver events per tumor and show that subclonal diversification is associated with known prognostic parameters. By resolving the patterns of driver event ordering, co-occurrence, and mutual exclusivity at clone level, we show the deterministic nature of clonal evolution. ccRCC can be grouped into seven evolutionary subtypes, ranging from tumors characterized by early fixation of multiple mutational and copy number drivers and rapid metastases to highly branched tumors with >10 subclonal drivers and extensive parallel evolution associated with attenuated progression. We identify genetic diversity and chromosomal complexity as determinants of patient outcome. Our insights reconcile the variable clinical behavior of ccRCC and suggest evolutionary potential as a biomarker for both intervention and surveillance.

Fumarate induces vesicular release of mtDNA to drive innate immunity.

Mutations in fumarate hydratase (FH) cause hereditary leiomyomatosis and renal cell carcinoma1. Loss of FH in the kidney elicits several oncogenic signalling cascades through the accumulation of the oncometabolite fumarate2. However, although the long-term consequences of FH loss have been described, the acute response has not so far been investigated. Here we generated an inducible mouse model to study the chronology of FH loss in the kidney. We show that loss of FH leads to early alterations of mitochondrial morphology and the release of mitochondrial DNA (mtDNA) into the cytosol, where it triggers the activation of the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING)-TANK-binding kinase 1 (TBK1) pathway and stimulates an inflammatory response that is also partially dependent on retinoic-acid-inducible gene I (RIG-I). Mechanistically, we show that this phenotype is mediated by fumarate and occurs selectively through mitochondrial-derived vesicles in a manner that depends on sorting nexin 9 (SNX9). These results reveal that increased levels of intracellular fumarate induce a remodelling of the mitochondrial network and the generation of mitochondrial-derived vesicles, which allows the release of mtDNAin the cytosol and subsequent activation of the innate immune response.

Clonal dynamics of haematopoiesis across the human lifespan.

Age-related change in human haematopoiesis causes reduced regenerative capacity1, cytopenias2, immune dysfunction3 and increased risk of blood cancer4-6, but the reason for such abrupt functional decline after 70 years of age remains unclear. Here we sequenced 3,579 genomes from single cell-derived colonies of haematopoietic cells across 10 human subjects from 0 to 81 years of age. Haematopoietic stem cells or multipotent progenitors (HSC/MPPs) accumulated a mean of 17 mutations per year after birth and lost 30 base pairs per year of telomere length. Haematopoiesis in adults less than 65 years of age was massively polyclonal, with high clonal diversity and a stable population of 20,000-200,000 HSC/MPPs contributing evenly to blood production. By contrast, haematopoiesis in individuals aged over 75 showed profoundly decreased clonal diversity. In each of the older subjects, 30-60% of haematopoiesis was accounted for by 12-18 independent clones, each contributing 1-34% of blood production. Most clones had begun their expansion before the subject was 40 years old, but only 22% had known driver mutations. Genome-wide selection analysis estimated that between 1 in 34 and 1 in 12 non-synonymous mutations were drivers, accruing at constant rates throughout life, affecting more genes than identified in blood cancers. Loss of the Y chromosome conferred selective benefits in males. Simulations of haematopoiesis, with constant stem cell population size and constant acquisition of driver mutations conferring moderate fitness benefits, entirely explained the abrupt change in clonal structure in the elderly. Rapidly decreasing clonal diversity is a universal feature of haematopoiesis in aged humans, underpinned by pervasive positive selection acting on many more genes than currently identified.

Extensive phylogenies of human development inferred from somatic mutations.

Starting from the zygote, all cells in the human body continuously acquire mutations. Mutations shared between different cells imply a common progenitor and are thus naturally occurring markers for lineage tracing1,2. Here we reconstruct extensive phylogenies of normal tissues from three adult individuals using whole-genome sequencing of 511 laser capture microdissections. Reconstructed embryonic progenitors in the same generation of a phylogeny often contribute to different extents to the adult body. The degree of this asymmetry varies between individuals, with ratios between the two reconstructed daughter cells of the zygote ranging from 60:40 to 93:7. Asymmetries pervade subsequent generations and can differ between tissues in the same individual. The phylogenies resolve the spatial embryonic patterning of tissues, revealing contiguous patches of, on average, 301 crypts in the adult colonic epithelium derived from a most recent embryonic cell and also a spatial effect in brain development. Using data from ten additional men, we investigated the developmental split between soma and germline, with results suggesting an extraembryonic contribution to primordial germ cells. This research demonstrates that, despite reaching the same ultimate tissue patterns, early bottlenecks and lineage commitments lead to substantial variation in embryonic patterns both within and between individuals.

The mutational landscape of human somatic and germline cells.

Over the course of an individual's lifetime, normal human cells accumulate mutations1. Here we compare the mutational landscape in 29 cell types from the soma and germline using multiple samples from the same individuals. Two ubiquitous mutational signatures, SBS1 and SBS5/40, accounted for the majority of acquired mutations in most cell types, but their absolute and relative contributions varied substantially. SBS18, which potentially reflects oxidative damage2, and several additional signatures attributed to exogenous and endogenous exposures contributed mutations to subsets of cell types. The rate of mutation was lowest in spermatogonia, the stem cells from which sperm are generated and from which most genetic variation in the human population is thought to originate. This was due to low rates of ubiquitous mutational processes and may be partially attributable to a low rate of cell division in basal spermatogonia. These results highlight similarities and differences in the maintenance of the germline and soma.

The mutational landscape of normal human endometrial epithelium.

All normal somatic cells are thought to acquire mutations, but understanding of the rates, patterns, causes and consequences of somatic mutations in normal cells is limited. The uterine endometrium adopts multiple physiological states over a lifetime and is lined by a gland-forming epithelium1,2. Here, using whole-genome sequencing, we show that normal human endometrial glands are clonal cell populations with total mutation burdens that increase at about 29 base substitutions per year and that are many-fold lower than those of endometrial cancers. Normal endometrial glands frequently carry 'driver' mutations in cancer genes, the burden of which increases with age and decreases with parity. Cell clones with drivers often originate during the first decades of life and subsequently progressively colonize the epithelial lining of the endometrium. Our results show that mutational landscapes differ markedly between normal tissues-perhaps shaped by differences in their structure and physiology-and indicate that the procession of neoplastic change that leads to endometrial cancer is initiated early in life.

The evolutionary history of 2,658 cancers.

Cancer develops through a process of somatic evolution1,2. Sequencing data from a single biopsy represent a snapshot of this process that can reveal the timing of specific genomic aberrations and the changing influence of mutational processes3. Here, by whole-genome sequencing analysis of 2,658 cancers as part of the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium of the International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA)4, we reconstruct the life history and evolution of mutational processes and driver mutation sequences of 38 types of cancer. Early oncogenesis is characterized by mutations in a constrained set of driver genes, and specific copy number gains, such as trisomy 7 in glioblastoma and isochromosome 17q in medulloblastoma. The mutational spectrum changes significantly throughout tumour evolution in 40% of samples. A nearly fourfold diversification of driver genes and increased genomic instability are features of later stages. Copy number alterations often occur in mitotic crises, and lead to simultaneous gains of chromosomal segments. Timing analyses suggest that driver mutations often precede diagnosis by many years, if not decades. Together, these results determine the evolutionary trajectories of cancer, and highlight opportunities for early cancer detection.

FLAIRR-Seq: A Method for Single-Molecule Resolution of Near Full-Length Antibody H Chain Repertoires.

Current Adaptive Immune Receptor Repertoire sequencing (AIRR-seq) using short-read sequencing strategies resolve expressed Ab transcripts with limited resolution of the C region. In this article, we present the near-full-length AIRR-seq (FLAIRR-seq) method that uses targeted amplification by 5' RACE, combined with single-molecule, real-time sequencing to generate highly accurate (99.99%) human Ab H chain transcripts. FLAIRR-seq was benchmarked by comparing H chain V (IGHV), D (IGHD), and J (IGHJ) gene usage, complementarity-determining region 3 length, and somatic hypermutation to matched datasets generated with standard 5' RACE AIRR-seq using short-read sequencing and full-length isoform sequencing. Together, these data demonstrate robust FLAIRR-seq performance using RNA samples derived from PBMCs, purified B cells, and whole blood, which recapitulated results generated by commonly used methods, while additionally resolving H chain gene features not documented in IMGT at the time of submission. FLAIRR-seq data provide, for the first time, to our knowledge, simultaneous single-molecule characterization of IGHV, IGHD, IGHJ, and IGHC region genes and alleles, allele-resolved subisotype definition, and high-resolution identification of class switch recombination within a clonal lineage. In conjunction with genomic sequencing and genotyping of IGHC genes, FLAIRR-seq of the IgM and IgG repertoires from 10 individuals resulted in the identification of 32 unique IGHC alleles, 28 (87%) of which were previously uncharacterized. Together, these data demonstrate the capabilities of FLAIRR-seq to characterize IGHV, IGHD, IGHJ, and IGHC gene diversity for the most comprehensive view of bulk-expressed Ab repertoires to date.

Intra-tumour diversification in colorectal cancer at the single-cell level.

Every cancer originates from a single cell. During expansion of the neoplastic cell population, individual cells acquire genetic and phenotypic differences from each other. Here, to investigate the nature and extent of intra-tumour diversification, we characterized organoids derived from multiple single cells from three colorectal cancers as well as from adjacent normal intestinal crypts. Colorectal cancer cells showed extensive mutational diversification and carried several times more somatic mutations than normal colorectal cells. Most mutations were acquired during the final dominant clonal expansion of the cancer and resulted from mutational processes that are absent from normal colorectal cells. Intra-tumour diversification of DNA methylation and transcriptome states also occurred; these alterations were cell-autonomous, stable, and followed the phylogenetic tree of each cancer. There were marked differences in responses to anticancer drugs between even closely related cells of the same tumour. The results indicate that colorectal cancer cells experience substantial increases in somatic mutation rate compared to normal colorectal cells, and that genetic diversification of each cancer is accompanied by pervasive, stable and inherited differences in the biological states of individual cancer cells.

Lineage-Independent Tumors in Bilateral Neuroblastoma.

Childhood tumors that occur synchronously in different anatomical sites usually represent metastatic disease. However, such tumors can be independent neoplasms. We investigated whether cases of bilateral neuroblastoma represented independent tumors in two children with pathogenic germline mutations by genotyping somatic mutations shared between tumors and blood. Our results suggested that in both children, the lineages that had given rise to the tumors had segregated within the first cell divisions of the zygote, without being preceded by a common premalignant clone. In one patient, the tumors had parallel evolution, including distinct second hits in SMARCA4, a putative predisposition gene for neuroblastoma. These findings portray cases of bilateral neuroblastoma as having independent lesions mediated by a germline predisposition. (Funded by Children with Cancer UK and Wellcome.).

Complication Rates in Patients With Classic and Radiographic Variants of Seymour Fractures.

BACKGROUND: At a tertiary-care, level 1 pediatric trauma center, we have observed fractures of the distal phalanx involving the physis, with associated nail bed injuries, that are distinct from the classic description of the Seymour fracture. We investigated the time to definitive management and the associated morbidity of these Seymour fracture variants compared with classically described Seymour fractures. We hypothesize that these Seymour variants are similarly problematic in terms of complications and delays to the definitive treatment and thus warrant increased awareness. METHODS: A retrospective chart review was performed of all patients with distal phalanx fractures involving the physis and associated nail bed injuries that were treated with operative intervention at a single pediatric specialty institution over a 9-year period. Radiographs and clinical photographs were reviewed to determine if the patient presented with a classic Seymour fracture or variant. Primary outcomes included time from injury to definitive treatment and complication rate. RESULTS: Of the 66 Seymour fractures identified in the chart review, 36 (55%) were identified as classic Seymour fractures and 30 (45%) were identified as variants. The mean time to operative intervention in the classic and variant groups was 7.3 versus 12.7 days (P=0.216). The complication rates in the classic and variant groups were 11.1% versus 23.3% (P=0.185), with infections accounting for nearly all complications identified. Overall infection rates for the classic and variant cohorts were 8.3% and 20.0% (P=0.169), respectively, with the majority presenting preoperatively (5.6% vs. 13.3%, P=0.274). CONCLUSIONS: We found that patients with classic Seymour fractures or radiographic variants had statistically similar incidence rates, complication rates, and delays in treatment, with a trend towards higher complication rates and delayed time to treatment in patients with variant-type injuries. We propose a minor expansion of the definition of Seymour fractures to include common variants to increase awareness of these problematic injuries, minimize delays in treatment, and decrease complications. LEVEL OF EVIDENCE: Level III; Retrospective Comparative Study.

Pediatric Hand and Wrist Fractures in Osteogenesis Imperfecta: An Analysis of Incidence, Patient-specific Risk Factors, and Fracture-specific Characteristics.

BACKGROUND: Children with osteogenesis imperfecta (OI) frequently present with fractures; however, hand and wrist fractures (HWFs), those distal to the radial and ulnar diaphysis, are seldom observed. Yet, HWFs remain among the most common fractures in children with non-OI. The objective of this study was to identify the incidence of OI HWFs. Secondary objectives aimed at identifying patient-specific risk factors for HWFs in OI and comparing clinical courses to non-OI HWFs. METHODS: A retrospective cohort study was conducted. Database query by ICD-10 codes identified 18 patients with OI HWF, 451 patients with OI without HWFs, and 26,183 patients with non-OI HWF. Power analysis estimated appropriate sample sizes and random sampling was utilized to collect patients. Patient demographics, OI-specific variables, fracture morphology, and fracture clinical courses were recorded. Data were analyzed for patient-specific and fracture-specific factors affecting OI HWF incidence. RESULTS: Of patients with OI, 3.8% (18/469) sustained HWFs. Patients with OI HWF were significantly older than patients with OI without HWFs ( P = 0.002) with no differences in height, weight, ethnicity, sex, or ambulatory status. Compared with non-OI HWFs, patients with OI HWF were significantly shorter ( P < 0.001), weighed less ( P = 0.002), and were less likely to be ambulatory ( P < 0.001). OI HWFs were more commonly on the side of hand dominance ( P < 0.001) with transverse patterns ( P = 0.001). OI HWFs were less frequent in the thumb ( P = 0.048) and trended towards significance in the metacarpals ( P = 0.054). All OI HWFs were treated nonoperatively with similar union rates and refracture rates to non-OI HWFs. Multivariate regression showed that older patient age (odds ratio: 1.079, 95% CI: 1.005,1.159, P = 0.037) and OI type I (odds ratio: 5.535, 95% CI: 1.069, 26.795, P = 0.041) were significant prognosticators for HWFs in patients with OI. CONCLUSION: OI HWFs are uncommon (3.8%, 18/469) but specific HWF morphologies and locations are more common in patients with OI; however, these are not pathognomonic. Older patients with mild penetrance of type I OI are at the highest risk for HWFs. OI HWFs do well when managed nonoperatively with noninferior clinical courses compared with non-OI HWFs. LEVEL OF EVIDENCE: Level III.

A Phase II study of neoadjuvant axitinib for reducing the extent of venous tumour thrombus in clear cell renal cell cancer with venous invasion (NAXIVA).

BACKGROUND: Surgery for renal cell carcinoma (RCC) with venous tumour thrombus (VTT) extension into the renal vein (RV) and/or inferior vena cava (IVC) has high peri-surgical morbidity/mortality. NAXIVA assessed the response of VTT to axitinib, a potent tyrosine kinase inhibitor. METHODS: NAXIVA was a single-arm, multi-centre, Phase 2 study. In total, 20 patients with resectable clear cell RCC and VTT received upto 8 weeks of pre-surgical axitinib. The primary endpoint was percentage of evaluable patients with VTT improvement by Mayo level on MRI. Secondary endpoints were percentage change in surgical approach and VTT length, response rate (RECISTv1.1) and surgical morbidity. RESULTS: In all, 35% (7/20) patients with VTT had a reduction in Mayo level with axitinib: 37.5% (6/16) with IVC VTT and 25% (1/4) with RV-only VTT. No patients had an increase in Mayo level. In total, 75% (15/20) of patients had a reduction in VTT length. Overall, 41.2% (7/17) of patients who underwent surgery had less invasive surgery than originally planned. Non-responders exhibited lower baseline microvessel density (CD31), higher Ki67 and exhausted or regulatory T-cell phenotype. CONCLUSIONS: NAXIVA provides the first Level II evidence that axitinib downstages VTT in a significant proportion of patients leading to reduction in the extent of surgery. CLINICAL TRIAL REGISTRATION: NCT03494816.

Sequential fungal pretreatment of unsterilized Miscanthus: changes in composition, cellulose digestibility and microbial communities.

A sequential fungal pretreatment of Miscanthus × giganteus was conducted by mixing unsterilized Miscanthus with material previously colonized with the white-rot fungus Ceriporiopsis subvermispora. For three generations, each generation started with inoculation by mixing unsterilized fresh Miscanthus with end material from the previous generation and ended after 28 days of incubation at 28 °C. After the first generation, the cellulose digestibility of the material doubled, compared to that of the unsterilized Miscanthus, but the second and third generations showed no enhancements in cellulose digestibility. Furthermore, high degradation of Miscanthus structural carbohydrates occurred during the first generation. A microbial community study showed that, even though the fungal community of the material previously colonized by C. subvermispora was composed mainly of this fungus (> 99%), by the first generation its relative abundance was down to only 9%, and other microbes had prevailed. Additionally, changes in the bacterial community occurred that might be associated with unwanted cellulose degradation in the system. This reiterates the necessity of feedstock microbial load reduction for the stability and reproducibility of fungal pretreatment of lignocellulosic biomass. KEY POINTS: • Sequential fungal pretreatment of unsterilized Miscanthus was unsuccessful. • Feedstock changes with white-rot fungi favored the growth of other microorganisms. • Feedstock microbial reduction is necessary for pretreatment with C. subvermispora.

Examining European Talent Development Environments: Athlete, Parent and Coach Perceptions.

Talent Development Environments (TDEs) aim to provide the appropriate conditions for youth athletes to realise their full sporting potential. How TDEs are designed and operated is therefore of great importance for the development of elite athletes. Stakeholders are vital in this process, yet their perspectives are poorly understood. This study assessed the quality of TDEs across 5 European countries, comparing athlete, parent and coach perceptions. A total of 571 athletes (Mean age = 15.2 ± 1.5 years), 759 parents and 134 coaches were recruited from TDEs across 27 sports. Participants completed the Talent Development Environment Questionnaire-5 or adapted versions. Overall, perceptions of European TDEs were positive. Coaches reported higher perceptions of TDE quality compared to athletes and parents, athletes reported marginally higher perceptions compared to parents. Across stakeholders, Long-Term Development was highest rated, followed by Communication. Support Network was lowest rated. Stakeholder perceptions varied most for the Holistic Quality Preparation subscale, highlighting perceived differences in TDE support for rounded athlete development. From an organisational perspective, identified strengths and weaknesses provide direction to coach and parent education. Practically, TDE leaders should consider how they can refine stakeholder coordination through integrating stakeholder perceptions as valuable feedback into their environment, especially for intangible factors.

The WIRE study a phase II, multi-arm, multi-centre, non-randomised window-of-opportunity clinical trial platform using a Bayesian adaptive design for proof-of-mechanism of novel treatment strategies in operable renal cell cancer - a study protocol.

BACKGROUND: Window-of-opportunity trials, evaluating the engagement of drugs with their biological target in the time period between diagnosis and standard-of-care treatment, can help prioritise promising new systemic treatments for later-phase clinical trials. Renal cell carcinoma (RCC), the 7th commonest solid cancer in the UK, exhibits targets for multiple new systemic anti-cancer agents including DNA damage response inhibitors, agents targeting vascular pathways and immune checkpoint inhibitors. Here we present the trial protocol for the WIndow-of-opportunity clinical trial platform for evaluation of novel treatment strategies in REnal cell cancer (WIRE). METHODS: WIRE is a Phase II, multi-arm, multi-centre, non-randomised, proof-of-mechanism (single and combination investigational medicinal product [IMP]), platform trial using a Bayesian adaptive design. The Bayesian adaptive design leverages outcome information from initial participants during pre-specified interim analyses to determine and minimise the number of participants required to demonstrate efficacy or futility. Patients with biopsy-proven, surgically resectable, cT1b+, cN0-1, cM0-1 clear cell RCC and no contraindications to the IMPs are eligible to participate. Participants undergo diagnostic staging CT and renal mass biopsy followed by treatment in one of the treatment arms for at least 14 days. Initially, the trial includes five treatment arms with cediranib, cediranib + olaparib, olaparib, durvalumab and durvalumab + olaparib. Participants undergo a multiparametric MRI before and after treatment. Vascularised and de-vascularised tissue is collected at surgery. A ≥ 30% increase in CD8+ T-cells on immunohistochemistry between the screening and nephrectomy is the primary endpoint for durvalumab-containing arms. Meanwhile, a reduction in tumour vascular permeability measured by Ktrans on dynamic contrast-enhanced MRI by ≥30% is the primary endpoint for other arms. Secondary outcomes include adverse events and tumour size change. Exploratory outcomes include biomarkers of drug mechanism and treatment effects in blood, urine, tissue and imaging. DISCUSSION: WIRE is the first trial using a window-of-opportunity design to demonstrate pharmacological activity of novel single and combination treatments in RCC in the pre-surgical space. It will provide rationale for prioritising promising treatments for later phase trials and support the development of new biomarkers of treatment effect with its extensive translational agenda. TRIAL REGISTRATION: ClinicalTrials.gov: NCT03741426 / EudraCT: 2018-003056-21 .

Prospective Randomized Trial of Standard Left Anterolateral Thoracotomy Versus Modified Bilateral Clamshell Thoracotomy Performed by Emergency Physicians.

STUDY OBJECTIVE: Resuscitative thoracotomy is a time-sensitive, lifesaving procedure that may be performed by emergency physicians. The left anterolateral thoracotomy (LAT) is the standard technique commonly used in the United States to gain rapid access to critical intrathoracic structures. However, the smaller incision and subsequent limited exposure may not be optimal for the nonsurgical specialist to complete time-sensitive interventions. The modified bilateral anterior clamshell thoracotomy (MCT) developed by Barts Health NHS Trust clinicians at London's Air Ambulance overcomes these inherent difficulties, maximizes thoracic cavity visualization, and may be the ideal technique for the nonsurgical specialist. The aim of this study is to identify the optimal technique for the nonsurgical-specialist-performed resuscitative thoracotomy. Secondary aims of the study are to identify technical difficulties, procedural concerns, and physician preferences. METHODS: Emergency medicine staff and senior resident physicians were recruited from an academic Level I trauma center. Subjects underwent novel standardized didactic and skills-specific training on both the MCT and LAT techniques. Later, subjects were randomized to the order of intervention and performed both techniques on separate fresh, nonfrozen human cadaver specimens. Success was determined by a board-certified surgeon and defined as complete delivery of the heart from the pericardial sac and subsequent 100% occlusion of the descending thoracic aorta with a vascular clamp. The primary outcome was time to successful completion of the resuscitative thoracotomy technique. Secondary outcomes included successful exposure of the heart, successful descending thoracic aortic cross clamping, successful procedural completion, time to exposure of the heart, time to descending thoracic aortic cross-clamp placement, number and type of iatrogenic injuries, correct anatomic structure identification, and poststudy participant questionnaire. RESULTS: Sixteen emergency physicians were recruited; 15 met inclusion criteria. All participants were either emergency medicine resident (47%) or emergency medicine staff (53%). The median number of previously performed training LATs was 12 (interquartile range 6 to 15) and the median number of previously performed MCTs was 1 (interquartile range 1 to 1). The success rates of our study population for the MCT and LAT techniques were not statistically different (67% versus 40%; difference 27%; 95% confidence interval -61% to 8%). However, staff emergency physicians were significantly more successful with the MCT compared with the LAT (88% versus 25%; difference 63%; 95% CI 9% to 92%). Overall, the MCT also had a significantly higher proportion of injury-free trials compared with the LAT technique (33% versus 0%; difference 33%; 95% CI 57% to 9%). Physician procedure preference favored the MCT over the LAT (87% versus 13%; difference 74%; 95% CI 23% to 97%). CONCLUSION: Resuscitative thoracotomy success rates were lower than expected in this capable subject population. Success rates and procedural time for the MCT and LAT were similar. However, the MCT had a higher success rate when performed by staff emergency physicians, resulted in less periprocedural iatrogenic injuries, and was the preferred technique by most subjects. The MCT is a potentially feasible alternative resuscitative thoracotomy technique that requires further investigation.

Structural Evolution of a Crustal-Scale Seismogenic Fault in a Magmatic Arc: The Bolfin Fault Zone (Atacama Fault System).

How major crustal-scale seismogenic faults nucleate and evolve in crystalline basements represents a long-standing, but poorly understood, issue in structural geology and fault mechanics. Here, we address the spatio-temporal evolution of the Bolfin Fault Zone (BFZ), a >40-km-long exhumed seismogenic splay fault of the 1000-km-long strike-slip Atacama Fault System. The BFZ has a sinuous fault trace across the Mesozoic magmatic arc of the Coastal Cordillera (Northern Chile) and formed during the oblique subduction of the Aluk plate beneath the South American plate. Seismic faulting occurred at 5-7 km depth and ≤ 300°C in a fluid-rich environment as recorded by extensive propylitic alteration and epidote-chlorite veining. Ancient (125-118 Ma) seismicity is attested by the widespread occurrence of pseudotachylytes. Field geologic surveys indicate nucleation of the BFZ on precursory geometrical anisotropies represented by magmatic foliation of plutons (northern and central segments) and andesitic dyke swarms (southern segment) within the heterogeneous crystalline basement. Seismic faulting exploited the segments of precursory anisotropies that were optimal to favorably oriented with respect to the long-term far-stress field associated with the oblique ancient subduction. The large-scale sinuous geometry of the BFZ resulted from the hard linkage of these anisotropy-pinned segments during fault growth.