An initial exploration of factors that may impact radiographer performance in reporting mammograms.

OBJECTIVES: In the United Kingdom, radiographers with a qualification in image interpretation have interpreted mammograms since 1995. These radiographers work under the title of radiography advanced practitioners (RAP) or Consultant Radiographer. This study extends upon what has been very recently published by exploring further clinical, non-clinical and experiential factors that may impact the reporting performance of RAPs. METHODS: Fifteen RAPs interpreted an image test set of 60 2D mammograms of known truth using the Detected-X software platform. Unknown to the reader, twenty cases contained a malignancy. Sensitivity, specificity, lesion sensitivity, receiver operating characteristic (ROC) and jack-knife free response operating characteristic (AFROC) values were established for each RAP. Specific features that had significant impact on accuracy were identified using Student's-T and Mann Whitney tests. RESULTS: RAPs with more than 10 years' experience in image interpretation, compared to those with less than 10 years' experience, demonstrated lower specificity (51.3% vs 84.8%, p = 0.0264), ROC (0.83 vs 0.91, p = 0.0264) and AFROC (0.75 vs 0.87, p = 0.0037) values. Further, higher sensitivity values of 90.7% were seen in those RAPs who had an eye test in the last year compared to those who had not, 82% (p = 0.021). Other changes are presented in the paper. CONCLUSION: These data reveal previously unidentified factors that impact the diagnostic efficacy of RAPs when interpreting mammographic images. Highlighting such findings will empower screening authorities to better examine ways of standardising performance and offer a baseline for performance benchmarks. IMPLICATIONS FOR PRACTICE: This study for the first time performs an initial exploration of the factors that may be associated with RAP performance when interpreting screening mammograms.

Investigation of inherited noncoding genetic variation impacting the pharmacogenomics of childhood acute lymphoblastic leukemia treatment.

Defining genetic factors impacting chemotherapy failure can help to better predict response and identify drug resistance mechanisms. However, there is limited understanding of the contribution of inherited noncoding genetic variation on inter-individual differences in chemotherapy response in childhood acute lymphoblastic leukemia (ALL). Here we map inherited noncoding variants associated with treatment outcome and/or chemotherapeutic drug resistance to ALL cis-regulatory elements and investigate their gene regulatory potential and target gene connectivity using massively parallel reporter assays and three-dimensional chromatin looping assays, respectively. We identify 54 variants with transcriptional effects and high-confidence gene connectivity. Additionally, functional interrogation of the top variant, rs1247117, reveals changes in chromatin accessibility, PU.1 binding affinity and gene expression, and deletion of the genomic interval containing rs1247117 sensitizes cells to vincristine. Together, these data demonstrate that noncoding regulatory variants associated with diverse pharmacological traits harbor significant effects on allele-specific transcriptional activity and impact sensitivity to antileukemic agents.

Associations of seven measures of biological age acceleration with frailty and all-cause mortality among adult survivors of childhood cancer in the St. Jude Lifetime Cohort.

Survivors of childhood cancer may experience accelerated biological aging, resulting in premature frailty and death. We used seven measures of biological age in the St. Jude Lifetime (SJLIFE) Cohort to compare biological age acceleration between the SJLIFE Cohort and the third United States National Health and Nutrition Examination Survey controls, explore trajectories of biological age according to cancer treatment and type, and test associations of biological age acceleration with frailty and death (mean follow-up of 26.5 years) among survivors. Survivors of cancer aged 5% faster per year and measured, on average, 0.6-6.44 years biologically older compared to controls and 5-16 years biologically older compared to age-matched individuals at the population level. Survivors treated with hematopoietic cell transplant and vinca alkaloid chemotherapy evidenced the fastest trajectories of biological aging. Biologically, older and faster-aging survivors consistently and robustly had a higher risk of frailty and died earlier than those with slower biological aging, suggesting a potential opportunity to intervene on excess aging.

Briefings in surgical teams: a pilot study of experiences and attitudes.

While healthcare should not be compared to other high reliability organisations (HROs), many lessons, attitudes, and transferable practices can be applied and adapted from them to improve patient safety and team morale. Despite briefings improving both patient safety and effective team working, some in healthcare have not valued or actively engaged with them, deeming them to be irrelevant. In this pilot study we explored the experiences of, and attitudes to, briefings using a 10-question Survey Monkey. This was promoted during a human factors session at the 2023 Association of Surgeons in Training Conference (ASiT) and at a large NHS trust. Questions were asked about the number of briefings per day, attitudes, engagement, and respondents' attitudes to them. In total, 109 responses were received. A total of 85% reported at least one briefing on a normal operating day, 65% felt them to be interactive, 67% reported that briefings were led by the most senior surgical team member, and 58% lasted four minutes or more. Eighteen per cent of respondents felt they were of little benefit, and 56% did not routinely de-brief at the end of the day. This study has highlighted variable attitudes to team briefings, with some colleagues still seeing them as a 'tick box' exercise. While culture has changed following the introduction of the WHO checklist, the importance of active engagement and education to improve the delivery and value of effective briefings cannot be overestimated. It is also an opportunity to create a 'safe space' for team members and to confirm zero tolerance for any inappropriate behaviour, including sexual misconduct.

Epigenomic mapping reveals distinct B cell acute lymphoblastic leukemia chromatin architectures and regulators.

B cell lineage acute lymphoblastic leukemia (B-ALL) is composed of diverse molecular subtypes, and while transcriptional and DNA methylation profiling has been extensively examined, the chromatin landscape is not well characterized for many subtypes. We therefore mapped chromatin accessibility using ATAC-seq in primary B-ALL cells from 156 patients spanning ten molecular subtypes and present this dataset as a resource. Differential chromatin accessibility and transcription factor (TF) footprint profiling were employed and identified B-ALL cell of origin, TF-target gene interactions enriched in B-ALL, and key TFs associated with accessible chromatin sites preferentially active in B-ALL. We further identified over 20% of accessible chromatin sites exhibiting strong subtype enrichment and candidate TFs that maintain subtype-specific chromatin architectures. Over 9,000 genetic variants were uncovered, contributing to variability in chromatin accessibility among patient samples. Our data suggest that distinct chromatin architectures are driven by diverse TFs and inherited genetic variants that promote unique gene-regulatory networks.

Abbreviation use decreases effective clinical communication and can compromise patient safety.

Clear communication is paramount for achieving the safest and best patient outcomes, for maximising time efficiency, and lowering clinician workload. Multiple factors contribute to communication efficacy, including knowledge of topics between those communicating, interpersonal familiarity, and available time. Information exchange is growing faster and more frequent due to evolving communication technology, and communication is expanding as a response to increasing workloads. The number of referrals between specialties and the general practitioner (GP) is rising. The use of abbreviations has expanded in clinical communications and is likely to lead to misunderstanding, increased workload, and worse patient outcomes. In this article, we explore the use of abbreviations in the clinical setting.

Caffeine: benefits and drawbacks for technical performance.

Surgical and minimally-invasive procedures, including cardiac and radiological, have high-stake patient outcomes. Working pressures, altering shift rotas, and ever-increasing demands have led to worsening sleep patterns for surgeons and allied professionals. Sleep deprivation alone has harmful consequences in relation to clinical outcomes and the physical and mental health of the surgeon, and to offset fatigue, some surgeons use legal stimulants such as caffeine and energy drinks. This stimulant use, however, may come at the cost of negative effects on cognitive and physical function. We aimed to explore evidence behind the use of caffeine, and its consequences on technical performance and clinical outcomes.

Epigenomic mapping in B-cell acute lymphoblastic leukemia identifies transcriptional regulators and noncoding variants promoting distinct chromatin architectures.

B-cell lineage acute lymphoblastic leukemia (B-ALL) is comprised of diverse molecular subtypes and while transcriptional and DNA methylation profiling of B-ALL subtypes has been extensively examined, the accompanying chromatin landscape is not well characterized for many subtypes. We therefore mapped chromatin accessibility using ATAC-seq for 10 B-ALL molecular subtypes in primary ALL cells from 154 patients. Comparisons with B-cell progenitors identified candidate B-ALL cell-of-origin and AP-1-associated cis-regulatory rewiring in B-ALL. Cis-regulatory rewiring promoted B-ALL-specific gene regulatory networks impacting oncogenic signaling pathways that perturb normal B-cell development. We also identified that over 20% of B-ALL accessible chromatin sites exhibit strong subtype enrichment, with transcription factor (TF) footprint profiling identifying candidate TFs that maintain subtype-specific chromatin architectures. Over 9000 inherited genetic variants were further uncovered that contribute to variability in chromatin accessibility among individual patient samples. Overall, our data suggest that distinct chromatin architectures are driven by diverse TFs and inherited genetic variants which promote unique gene regulatory networks that contribute to transcriptional differences among B-ALL subtypes.

Identification of factors associated with diagnostic performance variation in reporting of mammograms: A review.

OBJECTIVES: This narrative review aims to identify what factors are linked to diagnostic performance variation for those who interpret mammograms. Identification of influential factors has potential to contribute to the optimisation of breast cancer diagnosis. PubMed, ScienceDirect and Google Scholar databases were searched using the following terms: 'Radiology', 'Radiologist', 'Radiographer', 'Radiography', 'Mammography', 'Interpret', 'read', 'observe' 'report', 'screen', 'image', 'performance' and 'characteristics.' Exclusion criteria included articles published prior to 2000 as digital mammography was introduced at this time. Non-English articles language were also excluded. 38 of 2542 studies identified were analysed. KEY FINDINGS: Influencing factors included, new technology, volume of reads, experience and training, availability of prior images, social networking, fatigue and time-of-day of interpretation. Advancements in breast imaging such as digital breast tomosynthesis and volume of mammograms are primary factors that affect performance as well as tiredness, time-of-day when images are interpreted, stages of training and years of experience. Recent studies emphasised the importance of social networking and knowledge sharing if breast cancer diagnosis is to be optimised. CONCLUSION: It was demonstrated that data on radiologist performance variability is widely available but there is a paucity of data on radiographers who interpret mammographic images. IMPLICATIONS FOR PRACTICE: This scarcity of research needs to be addressed in order to optimise radiography-led reporting and set baseline values for diagnostic efficacy.

Dietary fatty acids and endometrial cancer risk within the European Prospective Investigation into Cancer and Nutrition.

BACKGROUND: Diet may impact important risk factors for endometrial cancer such as obesity and inflammation. However, evidence on the role of specific dietary factors is limited. We investigated associations between dietary fatty acids and endometrial cancer risk in the European Prospective Investigation into Cancer and Nutrition (EPIC). METHODS: This analysis includes 1,886 incident endometrial cancer cases and 297,432 non-cases. All participants were followed up for a mean of 8.8 years. Multivariable Cox proportional hazard models were used to estimate hazard ratios (HR) and 95% confidence intervals (CI) of endometrial cancer across quintiles of individual fatty acids estimated from various food sources quantified through food frequency questionnaires in the entire EPIC cohort. The false discovery rate (q-values) was computed to control for multiple comparisons. RESULTS: Consumption of n-6 γ-linolenic acid was inversely associated with endometrial cancer risk (HR comparing 5th with 1st quintileQ5-Q1=0.77, 95% CI = 0.64; 0.92, ptrend=0.01, q-value = 0.15). This association was mainly driven by γ-linolenic acid derived from plant sources (HRper unit increment=0.94, 95%CI= (0.90;0.98), p = 0.01) but not from animal sources (HRper unit increment= 1.00, 95%CI = (0.92; 1.07), p = 0.92). In addition, an inverse association was found between consumption of n-3 α-linolenic acid from vegetable sources and endometrial cancer risk (HRper unit increment= 0.93, 95%CI = (0.87; 0.99), p = 0.04). No significant association was found between any other fatty acids (individual or grouped) and endometrial cancer risk. CONCLUSION: Our results suggest that higher consumption of γ-linolenic acid and α-linoleic acid from plant sources may be associated with lower risk of endometrial cancer.

Functional investigation of inherited noncoding genetic variation impacting the pharmacogenomics of childhood acute lymphoblastic leukemia treatment.

Although acute lymphoblastic leukemia (ALL) is the most common childhood cancer, there is limited understanding of the contribution of inherited genetic variation on inter-individual differences in chemotherapy response. Defining genetic factors impacting therapy failure can help better predict response and identify drug resistance mechanisms. We therefore mapped inherited noncoding variants associated with chemotherapeutic drug resistance and/or treatment outcome to ALL cis-regulatory elements and investigated their gene regulatory potential and genomic connectivity using massively parallel reporter assays and promoter capture Hi-C, respectively. We identified 53 variants with reproducible allele-specific effects on transcription and high-confidence gene targets. Subsequent functional interrogation of the top variant (rs1247117) determined that it disrupted a PU.1 consensus motif and PU.1 binding affinity. Importantly, deletion of the genomic interval containing rs1247117 sensitized ALL cells to vincristine. Together, these data demonstrate that noncoding regulatory variation associated with diverse pharmacological traits harbor significant effects on allele-specific transcriptional activity and impact sensitivity to chemotherapeutic agents in ALL.

Test-set training improves the detection rates of invasive cancer in screening mammography.

AIM: To investigate if mammographic test-set participation affects routine breast cancer screening performance. MATERIALS AND METHODS: Clinical audit data between 2008 and 2018 were collected for 35 breast screen readers who participated in the BreastScreen Reader Assessment Strategy (BREAST) and 22 readers with no history of test-set participation. For BREAST readers, the annual audit data were divided according to the year they completed their first test set, and the same years were used randomly to align and divide the data of non-BREAST readers into pre- and post-test set periods. Multiple audit parameters were inspected retrospectively for the two cohorts to identify how their reading performance has evolved in screening mammography. RESULTS: Investigating 2 calendar years before and after test-set participation, BREAST and non-BREAST readers recalled lower rates of women in the latter period (p=0.03 and p=0.02, respectively). They also improved their positive predictive value (PPV; p=0.01 and p=0.02, respectively). BREAST readers additionally improved their detection rates of invasive cancer (p=0.02) and all cancers (p=0.01). In an extended 3-year comparison, similar improvements occurred in the recall rate for BREAST (p=0.02) and non-BREAST readers (p=0.02) and in PPV (p=0.001, 0.01, respectively); however, improvements in detection rates also occurred exclusively in BREAST readers' performance for invasive cancer (p=0.04), DCIS (p=0.05), and all cancers (p=0.02); however, significant improvements in detection did not involve <15 mm invasive cancers in both periods. Meanwhile, non-BREAST readers demonstrated a decrease in sensitivity (p=0.02). CONCLUSION: Participation in test sets is linked to over-time improvements in most audit-measured cancer detection rates.

Mutual antagonism between glucocorticoid and canonical Wnt signaling pathways in B-cell acute lymphoblastic leukemia.

Glucocorticoids (GCs; i.e., steroids) are important chemotherapeutic agents in the treatment of B-cell precursor acute lymphoblastic leukemia (B-ALL) and de novo GC resistance predicts relapse and poor clinical outcome in patients. Glucocorticoids induce B-ALL cell apoptosis through activation of glucocorticoid receptor (GR), a ligand-induced nuclear receptor transcription factor (TF). We previously identified disruptions to glucocorticoid receptor (GR)-bound cis -regulatory elements controlling TLE1 expression in GC-resistant primary B-ALL cells from patients. TLE1 is a GC-response gene up-regulated by steroids and functions as a canonical Wnt signaling repressor. To better understand the mechanistic relationship between GC signaling and canonical Wnt signaling, we performed diverse functional analyses that identified extensive crosstalk and mutual antagonism between these two signaling pathways in B-ALL. We determined that crosstalk and antagonism was driven by the binding of GR and the canonical Wnt signaling TFs LEF1 and TCF7L2 to overlapping sets of cis -regulatory elements associated with genes impacting cell death and cell proliferation, and was further accompanied by overlapping and opposing transcriptional programs. Our data additionally suggest that cis -regulatory disruptions at TLE1 are linked to GC resistance through a dampening of the GC response and GC-mediated apoptosis via enhanced canonical Wnt signaling. As a result of the extensive genomic and gene regulatory connectivity between these two signaling pathways, our data supports the importance of canonical Wnt signaling in mediating GC resistance in B-ALL.

Briefings: what can surgical and minimally invasive interventional teams learn from airline flight deck practice?

While healthcare should not be compared to aviation or indeed other high reliability organisations (HROs), many lessons, attitudes, and transferable practices can be applied and, more importantly, adapted from them to improve patient safety and team morale. The team brief before any interventional list is one such process that can have a significant effect on the delivery and safety of patient care and effective team working. Due to NHS pressures and the perception by some in healthcare that the time taken to conduct a full team briefing has little importance, it can sometimes be rushed or regarded as a 'tick box' process that delays a list. However, when used appropriately, the briefing is a chance to lower authority gradients and thereby improve patient safety. It also reduces the likelihood of medical errors, builds and improves situational awareness by considering various 'what-if' scenarios and how they will be dealt with, and considers wider issues including potential distractions. An important outcome is its effect on team morale through empowerment, and it is an opportunity for learning. In this article, which has been written following a unique opportunity to observe a full team brief on an Airbus A380 flight deck, we consider how, through the thorough use of checklists, briefings can be used to best advantage for interventional teams. We raise the question 'would you engage differently with the briefing if your own life or procedure depended on it?'

Epigenomic profiling of glucocorticoid responses identifies cis-regulatory disruptions impacting steroid resistance in childhood acute lymphoblastic leukemia.

Glucocorticoids (GCs) are a mainstay of contemporary, multidrug chemotherapy in the treatment of childhood acute lymphoblastic leukemia (ALL), and resistance to GCs remains a major clinical concern. Resistance to GCs is predictive of ALL relapse and poor clinical outcome, and therefore represents a major hurdle limiting further improvements in survival rates. While advances have been made in identifying genes implicated in GC resistance, there remains an insufficient understanding of the impact of cis-regulatory disruptions in resistance. To address this, we mapped the gene regulatory response to GCs in two ALL cell lines using functional genomics and high-throughput reporter assays and identified thousands of GC-responsive changes to chromatin state, including the formation of over 250 GC-responsive super-enhancers and a depletion of AP-1 bound cis-regulatory elements implicated in cell proliferation and anti-apoptotic processes. By integrating our GC response maps with genetic and epigenetic datasets in primary ALL cells from patients, we further uncovered cis-regulatory disruptions at GC-responsive genes that impact GC resistance in childhood ALL. Overall, these data indicate that GCs initiate pervasive effects on the leukemia epigenome, and that alterations to the GC gene regulatory network contribute to GC resistance.