RUNX1-mutated families show phenotype heterogeneity and a somatic mutation profile unique to germline predisposed AML.

First reported in 1999, germline runt-related transcription factor 1 (RUNX1) mutations are a well-established cause of familial platelet disorder with predisposition to myeloid malignancy (FPD-MM). We present the clinical phenotypes and genetic mutations detected in 10 novel RUNX1-mutated FPD-MM families. Genomic analyses on these families detected 2 partial gene deletions, 3 novel mutations, and 5 recurrent mutations as the germline RUNX1 alterations leading to FPD-MM. Combining genomic data from the families reported herein with aggregated published data sets resulted in 130 germline RUNX1 families, which allowed us to investigate whether specific germline mutation characteristics (type, location) could explain the large phenotypic heterogeneity between patients with familial platelet disorder and different HMs. Comparing the somatic mutational signatures between the available familial (n = 35) and published sporadic (n = 137) RUNX1-mutated AML patients showed enrichment for somatic mutations affecting the second RUNX1 allele and GATA2. Conversely, we observed a decreased number of somatic mutations affecting NRAS, SRSF2, and DNMT3A and the collective genes associated with CHIP and epigenetic regulation. This is the largest aggregation and analysis of germline RUNX1 mutations performed to date, providing a unique opportunity to examine the factors underlying phenotypic differences and disease progression from FPD to MM.

Novel germ line DDX41 mutations define families with a lower age of MDS/AML onset and lymphoid malignancies.

Recently our group and others have identified DDX41 mutations both as germ line and acquired somatic mutations in families with multiple cases of late onset myelodysplastic syndrome (MDS) and/or acute myeloid leukemia (AML), suggesting that DDX41 acts as a tumor suppressor. To determine whether novel DDX41 mutations could be identified in families with additional types of hematologic malignancies, our group screened two cohorts of families with a diverse range of hematologic malignancy subtypes. Among 289 families, we identified nine (3%) with DDX41 mutations. As previously observed, MDS and AML were the most common malignancies, often of the erythroblastic subtype, and 1 family displayed early-onset follicular lymphoma. Five novel mutations were identified, including missense mutations within important functional domains and start-loss and splicing mutations predicted to result in truncated proteins. We also show that most asymptomatic mutation carriers have normal blood counts until malignancy develops. This study expands both the mutation and phenotypic spectra observed in families with germ line DDX41 mutations. With an increasing number of both inherited and acquired mutations in this gene being identified, further study of how DDX41 disruption leads to hematologic malignancies is critical.

What are the demographic predictors in laparoscopic simulator performance?

BACKGROUND: Simulation is playing an increasingly important role in surgical education. There are a number of laparoscopic simulators of which the design and tasks vary considerably. It is unknown if any particular type may result in better outcomes for a specific population. This study assesses the predictors of acquisition of basic surgical skills on two different laparoscopic simulators. METHODS: Participants (n = 370) were randomized to be trained and assessed using either a fundamentals of laparoscopic surgery (FLS) or a LapSim (Surgical Science, Goteborg, Sweden) simulator. The number of attempts required to reach proficiency on individual tasks and on each simulator was recorded and compared with demographic data and surgical experience. RESULT: Skills acquisition on both simulators was positively affected by surgical experience. Gender was an influential factor on the LapSim with men reaching proficiency sooner than women. The effect of gaming had no clear influence on the participants' scores; however, for those who reported more than 1 h/week gaming, it had a positive influence on skills acquisition on the FLS and a negative influence on the LapSim. Playing a musical instrument had no impact. Practising non-surgical tasks requiring manual dexterity and handedness were not an influential factor in total proficient scores, but had a significant impact on individual task scores on the FLS simulator. CONCLUSIONS: The rate of skills acquisition on each simulator and individual tasks are influenced by different demographic characteristics of the participants. This has implications for surgical education as it may inform the selection of the most suitable laparoscopic simulators for specific populations of trainees.

Mobile Simulation Unit: taking simulation to the surgical trainee.

BACKGROUND: Simulation-based training has become an increasingly accepted part of surgical training. However, simulators are still not widely available to surgical trainees. Some factors that hinder the widespread implementation of simulation-based training are the lack of standardized methods and equipment, costs and time constraints. We have developed a Mobile Simulation Unit (MSU) that enables trainees to access modern simulation equipment tailored to the needs of the learner at the trainee's workplace. METHODS: From July 2012 to December 2012, the MSU visited six hospitals in South Australia, four in metropolitan and two in rural areas. Resident Medical Officers, surgical trainees, Fellows and International Medical Graduates were invited to voluntarily utilize a variety of surgical simulators on offer. Participants were asked to complete a survey about the accessibility of simulation equipment at their workplace, environment of the MSU, equipment available and instruction received. Utilization data were collected. RESULTS: The MSU was available for a total of 303 h over 52 days. Fifty-five participants were enrolled in the project and each spent on average 118 min utilizing the simulators. The utilization of the total available time was 36%. Participants reported having a poor access to simulation at their workplace and overwhelmingly gave positive feedback regarding their experience in the MSU. CONCLUSION: The use of the MSU to provide simulation-based education in surgery is feasible and practical. The MSU provides consistent simulation training at the surgical trainee's workplace, regardless of geographic location, and it has the potential to increase participation in simulation programmes.

Nontechnical skills training for the operating room: A prospective study using simulation and didactic workshop.

BACKGROUND: The best surgeons demonstrate skills beyond those required for the performance of technically competent surgery. These skills are described under the term nontechnical skills. Failure in these domains has been associated with adverse events inside the operating room. These nontechnical skills are not learned commonly in a structured manner during surgery training. The main purpose of this study was to explore the effects of participation in simulation-based training, either as a sole strategy or as part of a combined approach on surgeons and surgical trainees nontechnical skills performance in simulation environment. METHODS: The study consisted of a single-blinded, prospective comparative trial. Forty participants were enrolled, all participating in 2 simulation sessions challenging nontechnical skills comprising 3 surgical scenarios. Seventeen participants attended a 1-day, nontechnical skills workshop between simulation sessions. Scenarios were video-recorded for assessment and debriefing purposes. Assessment was made by 2 observers using the Non-Technical Skills for Surgeons (NOTSS) scoring system. RESULTS: There was a significant improvement in nontechnical skills performance of both groups from the first to the second simulation session, for 2 of the 3 scenarios. No difference in performance between the simulation and the simulation plus workshop groups was noted. CONCLUSION: This study provides evidence that formal training in nontechnical skills is feasible and can impact positively participants' nontechnical performance in a simulated environment. The addition of a 1-day didactic workshop does not seem to provide additional benefit over simulation-based training as a sole strategy for nontechnical skills training.

Laparoscopic skills maintenance: a randomized trial of virtual reality and box trainer simulators.

OBJECTIVE: A number of simulators have been developed to teach surgical trainees the basic skills required to effectively perform laparoscopic surgery; however, consideration needs to be given to how well the skills taught by these simulators are maintained over time. This study compared the maintenance of laparoscopic skills learned using box trainer and virtual reality simulators. DESIGN: Participants were randomly allocated to be trained and assessed using either the Society of American Gastrointestinal Endoscopic Surgeons Fundamentals of Laparoscopic Surgery (FLS) simulator or the Surgical Science virtual reality simulator. Once participants achieved a predetermined level of proficiency, they were assessed 1, 3, and 6 months later. At each assessment, participants were given 2 practice attempts and assessed on their third attempt. SETTING: The study was conducted through the Simulated Surgical Skills Program that was held at the Royal Australasian College of Surgeons, Adelaide, Australia. RESULTS: Overall, 26 participants (13 per group) completed the training and all follow-up assessments. There were no significant differences between simulation-trained cohorts for age, gender, training level, and the number of surgeries previously performed, observed, or assisted. Scores for the FLS-trained participants did not significantly change over the follow-up period. Scores for LapSim-trained participants significantly deteriorated at the first 2 follow-up points (1 and 3 months) (p < 0.050), but returned to be near initial levels by the final follow-up (6 months). CONCLUSIONS: This research showed that basic laparoscopic skills learned using the FLS simulator were maintained more consistently than those learned on the LapSim simulator. However, by the final follow-up, both simulator-trained cohorts had skill levels that were not significantly different to those at proficiency after the initial training period.

Effect of fatigue on laparoscopic skills: a comparative historical cohort study.

BACKGROUND: Fatigue has been shown to have a negative impact on surgical performance. However, there is a lack of research investigating its effect on laparoscopy, particularly in Australia. This study investigated whether fatigue associated with a surgeon's usual workday led to a measurable drop off in laparoscopic surgical skills as assessed on a laparoscopic simulator. METHODS: A comparative study involving two cohorts was undertaken: a study group whose data were collected prospectively was compared to a historical control group. Participants were required to reach a predetermined level of proficiency in each laparoscopic task on either a FLS or LapSim simulator. The participants in the study cohort were re-tested approximately 1 month after completing 10 h of work. The participants in the historical non-fatigued group were re-tested approximately 1 month after reaching proficiency. Comparisons between cohorts were made using a 'decrease in score per day elapsed' value to account for the natural attrition in skills over time and the variability in testing times within and between the two cohorts. RESULTS: The decrease in overall score per day elapsed for fatigued participants was significantly greater than for historical non-fatigued participants, irrespective of the simulator type. Fatigue had a greater impact on certain laparoscopic skills, including peg transfer and knot tying. Participants who self-reported higher level of fatigue demonstrated significantly better skills than those who self-reported lower levels. CONCLUSION: Overall laparoscopic skill proficiency was reduced in the fatigued participants compared to the historical non-fatigued participants, with certain laparoscopic skills more affected than others.

Laparoscopic skills acquisition: a study of simulation and traditional training.

BACKGROUND: Training in basic laparoscopic skills can be undertaken using traditional methods, where trainees are educated by experienced surgeons through a process of graduated responsibility or by simulation-based training. This study aimed to assess whether simulation trained individuals reach the same level of proficiency in basic laparoscopic skills as traditional trained participants when assessed in a simulated environment. METHODS: A prospective study was undertaken. Participants were allocated to one of two cohorts according to surgical experience. Participants from the inexperienced cohort were randomized to receive training in basic laparoscopic skills on either a box trainer or a virtual reality simulator. They were then assessed on the simulator on which they did not receive training. Participants from the experienced cohort, considered to have received traditional training in basic laparoscopic skills, did not receive simulation training and were randomized to either the box trainer or virtual reality simulator for skills assessment. The assessment scores from different cohorts on either simulator were then compared. RESULTS: A total of 138 participants completed the assessment session, 101 in the inexperienced simulation-trained cohort and 37 on the experienced traditionally trained cohort. There was no statistically significant difference between the training outcomes of simulation and traditionally trained participants, irrespective of the simulator type used. CONCLUSIONS: The results demonstrated that participants trained on either a box trainer or virtual reality simulator achieved a level of basic laparoscopic skills assessed in a simulated environment that was not significantly different from participants who had been traditionally trained in basic laparoscopic skills.

Multidisciplinary team simulation for the operating theatre: a review of the literature.

INTRODUCTION: Analyses of adverse events inside the operating theatre has demonstrated that many errors are caused by failure in non-technical skills and teamwork. While simulation has been used successfully for teaching and improving technical skills, more recently, multidisciplinary simulation has been used for training team skills. We hypothesized that this type of training is feasible and improves team skills in the operating theatre. METHODS: A systematic search of the literature for studies describing true multidisciplinary operating theatre team simulation was conducted in November and December 2012. We looked at the characteristics and outcomes of the team simulation programmes. RESULTS: 1636 articles were initially retrieved. Utilizing a stepwise evaluation process, 26 articles were included in the review. The studies reveal that multidisciplinary operating theatre simulation has been used to provide training in technical and non-technical skills, to help implement new techniques and technologies, and to identify latent weaknesses within a health system. Most of the studies included are descriptions of training programmes with a low level of evidence. No randomized control trial was identified. Participants' reactions to the training programme were positive in all studies; however, none of them could objectively demonstrate that skills acquired from simulation are transferred to the operating theatre or show a demonstrable benefit in patient outcomes. CONCLUSION: Multidisciplinary operating room team simulation is feasible and widely accepted by participants. More studies are required to assess the impact of this type of training on operative performance and patient safety.

The efficacy of laparoscopic skills training in a Mobile Simulation Unit compared with a fixed site: a comparative study.

BACKGROUND: Laparoscopic skills development via simulation-based medical education programs has gained support in recent years. However, the impact of training site type on skills acquisition has not been examined. The objective of this research was to determine whether laparoscopic skills training outcomes differ as a result of training in a Mobile Simulation Unit (MSU) compared with fixed simulation laboratories. METHODS: An MSU was developed to provide delivery of training. Fixed-site and MSU laparoscopic skills training outcomes data were compared. Fixed-site participants from three Australian states were pooled to create a cohort of 144 participants, which was compared with a cohort derived from pooled MSU participants in one Australian state. Data were sourced from training periods held from October 2009 to December 2010. LapSim and Fundamentals of laparoscopic surgery (FLS) simulators were used at the MSU and fixed sites. Participants self-reported on demographic and experience variables. They trained to a level of competence on one simulator and were assessed on the other simulator, thus producing crossover scores. No participants trained at both site types. RESULTS: When FLS-trained participants were assessed on LapSim, those who received MSU training achieved a significantly higher crossover score than their fixed-site counterparts (p < 0.001). Compared with baseline data, MSU LapSim-trained participants assessed on FLS displayed a performance increase of 23.1 %, whereas MSU FLS-trained participants assessed on LapSim demonstrated a 12.4 % increase in performance skills. Participants at fixed sites displayed performance increases of 5.2 and 10.9 %, respectively. CONCLUSIONS: Mobile Simulation Unit-delivered laparoscopic simulation training is not inferior to fixed-site training.

A randomized crossover trial examining low- versus high-fidelity simulation in basic laparoscopic skills training.

BACKGROUND: Previous randomized studies have compared high- versus low-fidelity laparoscopic simulators; however, no proficiency criteria were defined and results have been mixed. The purpose of this research was to determine whether there were any differences in the learning outcomes of participants who had trained to proficiency on low- or high-fidelity laparoscopic surgical simulators. METHODS: We conducted a randomized, prospective crossover trial with participants recruited from New South Wales, Western Australia, and South Australia. Participants were randomized to high-fidelity (LapSim, Surgical Science) or low-fidelity (FLS, SAGES) laparoscopic simulators and trained to proficiency in a defined number of tasks. They then crossed over to the other fidelity simulator and were tested. The outcomes of interest were the crossover mean scores, the proportion of tasks passed, and percentage passes for the crossover simulator tasks. RESULTS: Of the 228 participants recruited, 100 were randomized to LapSim and 128 to FLS. Mean crossover score increased from baseline for both simulators, but there was no significant difference between them (11.0 % vs. 11.9 %). FLS-trained participants passed a significantly higher proportion of crossover tasks compared with LapSim-trained participants (0.26 vs. 0.20, p = 0.016). A significantly higher percentage of FLS-trained participants passed intracorporeal knot tying than LapSim-trained participants (35 % vs. 8 %, p < 0.001). CONCLUSION: Similar increases in participant score from baseline illustrate that training on either simulator type is beneficial. However, FLS-trained participants demonstrated a greater ability to translate their skills to successfully complete LapSim tasks. The ability of FLS-trained participants to transfer their skills to new settings suggests the benefit of this simulator type compared with the LapSim.

Heritable GATA2 mutations associated with familial myelodysplastic syndrome and acute myeloid leukemia.

We report the discovery of GATA2 as a new myelodysplastic syndrome (MDS)-acute myeloid leukemia (AML) predisposition gene. We found the same, previously unidentified heterozygous c.1061C>T (p.Thr354Met) missense mutation in the GATA2 transcription factor gene segregating with the multigenerational transmission of MDS-AML in three families and a GATA2 c.1063_1065delACA (p.Thr355del) mutation at an adjacent codon in a fourth MDS family. The resulting alterations reside within the second zinc finger of GATA2, which mediates DNA-binding and protein-protein interactions. We show differential effects of the mutations on the transactivation of target genes, cellular differentiation, apoptosis and global gene expression. Identification of such predisposing genes to familial forms of MDS and AML is critical for more effective diagnosis and prognosis, counseling, selection of related bone marrow transplant donors and development of therapies.

Methionine-dependence phenotype in the de novo pathway in BRCA1 and BRCA2 mutation carriers with and without breast cancer.

Methionine-dependence phenotype (MDP) refers to the reduced ability of cells to proliferate when methionine is restricted and/or replaced by its immediate precursor homocysteine. MDP is a characteristic of human tumors in vivo, human tumor cell lines, and normal somatic tissue in some individuals. It was hypothesized that MDP is a risk factor for developing breast cancer in BRCA (BRCA1 and BRCA2) germline mutation carriers. To test the hypothesis, human peripheral blood lymphocytes of BRCA carriers with and without breast cancer and healthy non-carrier relatives (controls) were cultured for 9 days in medium containing either 0.1 mmol/L L-methionine or 0.2 mmol/L D,L-homocysteine, with the ratio of viable cell growth in both types of medium after 9 days used to calculate the methionine-dependence index (MDI), a measure of MDP. We also tested whether MDP was associated with common polymorphisms in methionine metabolism. Viable cell growth, MDI, and polymorphism frequency in MTRR (A66G and C524T) and MTHFR (A1298C and A1793G) did not differ among the study groups; however, MDI tended to be higher in BRCA carriers with breast cancer than those without and was significantly increased in MTHFR 677T allele carriers relative to wild-type carriers (P=0.017). The presence of MTR A2756G mutant allele and MTHFR C677T mutant allele in carriers was associated with increased breast cancer risk [odds ration, 3.2 (P=0.16; 95% confidence interval, 0.76-13.9) and 3.9 (P=0.09; 95% confidence interval, 0.93-16.3), respectively]. The results of this study support the hypothesis that defects in methionine metabolism may be associated with breast cancer risk in BRCA carriers.

Lymphocytes of BRCA1 and BRCA2 germ-line mutation carriers, with or without breast cancer, are not abnormally sensitive to the chromosome damaging effect of moderate folate deficiency.

Mutations in BRCA1 and BRCA2 genes may cause defective DNA repair and increase the risk for breast cancer. Folate deficiency is associated with increased breast cancer risk and induces chromosome abnormalities. We hypothesized that BRCA1 and BRCA2 germline mutation carriers are more sensitive to the genome damaging effect of folate deficiency compared with healthy non-carrier controls and that this sensitivity is further increased in those carriers who develop breast cancer. We tested these hypotheses in lymphocytes cultured in a medium containing 12 or 120 nM folic acid (FA) for 9 days and measured proliferative capacity and chromosomal instability using the cytokinesis-block micronucleus assay. BRCA1 and BRCA2 mutation carriers with or without breast cancer were not abnormally sensitive to FA deficiency-induced chromosome instability; however, BRCA2 mutation carriers had significantly reduced cell proliferation. FA deficiency reduced cell proliferation and increased micronucleus formation significantly, accounting for 45-59% and 70-75% of the variance in these parameters compared with 0.3-8.5% and 0.2-0.3% contributed by BRCA1 or BRCA2 mutation carrier status, respectively. The results of this study suggest that moderate folate deficiency has a stronger effect on chromosomal instability than BRCA1 or BRCA2 mutations found in breast cancer families.

Study of 250 children with idiopathic mental retardation reveals nine cryptic and diverse subtelomeric chromosome anomalies.

Cryptic subtelomeric chromosome anomalies have been recognized as a significant cause of dysmorphology and mental retardation. To determine whether the clinical cytogenetics laboratory should screen routinely for these aberrations, we have tested 250 patients with idiopathic mental retardation/developmental delay, either isolated (53) or associated with dysmorphic features and/or malformations in the absence of a recognizable syndrome (197). All had normal karyotypes at the 550-850 band level. Subtelomeric anomalies were found in 1/53 of the first group (1.9%) and 8/197 of the second group (4.1%). In one patient, two separate anomalies were present: a deletion (not inherited) and a duplication (inherited). It is possible that one of these 10 observed aberrations might represent a rare and previously unreported polymorphism and one a rare cross-hybridization. Our study supports the proposition that cryptic subtelomeric rearrangements are a significant cause of idiopathic mental retardation/developmental delay, but both the diversity of the phenotypes of the positive cases and the wide diversity of their associated chromosome abnormalities emphasize the central problem for the clinical cytogenetics laboratory-that of choosing the most productive patient base for this useful diagnostic test.