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Purpose: The ClinGen Actionability Working Group (AWG) developed an evidence-based framework to generate actionability reports and scores of gene-condition pairs in the context of secondary findings from genome sequencing. Here we describe the expansion of the framework to include actionability assertions., Methods: Initial development of the actionability rubric was based on previously scored adult gene-condition pairs and individual expert evaluation. Rubric refinement was iterative and based on evaluation, feedback, and discussion. The final rubric was pragmatically evaluated via integration into actionability assessments for 27 gene-condition pairs., Results: The resulting rubric has a 4-point scale (limited, moderate, strong, and definitive) and uses the highest-scoring outcome-intervention pair of each gene-condition pair to generate a preliminary assertion. During AWG discussions, predefined criteria and factors guide discussion to produce a consensus assertion for a gene-condition pair, which may differ from the preliminary assertion. The AWG has retrospectively generated assertions for all previously scored gene-condition pairs and are prospectively asserting on gene-condition pairs under assessment, having completed over 170 adult and 188 pediatric gene-condition pairs., Conclusion: The AWG expanded its framework to provide actionability assertions to enhance the clinical value of their resources and increase their utility as decision aids regarding return of secondary findings., Competing Interests: Conflict of Interest A. Buchanan has equity in MeTree and You, Inc. S. Rego is an employee and has options at BillionToOne, Inc. Dr Steiner is an employee with equity of PreventionGenetics, part of Exact Sciences, and reports consulting fees from Leadiant, Mirum, and PTC Therapeutics. All other authors declare no conflicts of interest., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

This study explores the impact of a novel phytogenic product containing citric acid, carvacrol, and cinnamaldehyde on buffel grass ( Cenchrus ciliaris ) seedling emergence. A dilution series of the phytogenic solution revealed a concentration range that promoted seedling emergence, with an optimal concentration of 0.5%. Transcriptomic analysis using RNA-seq was performed to investigate gene expression changes in seedlings under the influence of the phytogenic product. The results revealed that the phytogenic treatment significantly altered the gene expression, with a prevalent boost in transcriptional activity compared to the control. Functional analysis indicated the positive alteration of key metabolic pathways, including the tricarboxylic acid (TCA) cycle, glycolysis, and pentose phosphate pathways. Moreover, pathways related to amino acids, nucleotide biosynthesis, heme biosynthesis, and formyltetrahydrofolate biosynthesis showed substantial modulation. The study provides valuable insights into the molecular mechanisms underlying the phytogenic product's effects on grass seedling establishment and highlights its ability to promote energy metabolism and essential biosynthetic pathways for plant growth.

Sesame is an emerging crop of interest in Australia and has attracted widespread interest due to the health-benefitting properties of its bioactive compounds, including fatty acids, lignans, and polyphenols. This study aimed to investigate the impact of drought stress on these bioactive compounds, using eleven cultivars of black sesame seeds grown in Australia. Specific varieties responded positively to water deficit (WD) conditions, showing increased levels of TPC, FRAP, CUPRAC, and lignans. Varieties 1, 4, 7, and 12 showed significantly increased FRAP values ranging from 158.02 ± 10.43 to 195.22 ± 9.63 mg TE/100 g DW in the WD treatment compared to the well-watered (WW) treatment, whereas varieties 7, 10, 12, 13, and 18 demonstrated the highest CUPRAC values of all varieties (2584.86 ± 99.68-2969.56 ± 159.72 mg TE/100 g) across both WW and WD conditions, with no significant variations between irrigation regimes. Moreover, lignan contents (sesamin and sesamolin) were higher in varieties 1, 2, 5, and 8 grown in WD conditions. Compared to the optimal unsaturated to saturated fatty acid ratio (Σ UFA/Σ SFA ratio) of 0.45, all sesame genotypes showed superior ratios (ranging between 1.86 and 2.34). Moreover, the ω-6/ω-3 PUFA ratio varied from 33.7-65.5, with lower ratios in varieties 2, 4, 5, 8, and 18 under WD conditions. The high levels of phenolic compounds and healthy fats suggest the potential of black sesame to be incorporated into diets as a functional food. Furthermore, the enhanced phytochemistry of these cultivars in WD conditions is promising for widespread adoption. However, larger trial studies to confirm these findings across different geographic locations and seasons are warranted.

Adzuki bean has recently been proposed as a viable dual-purpose (grain-and-graze) crop for the Northern regions of Australia because of its successful use in semi-arid regions and its nitrogen fixation capacity to improve soil fertility and animal nutrition. However, there are very few studies on the phytochemical composition and nutritional value of the non-seed material. This study investigated the phenolic composition of the parts grown in the vegetative phase (leaves and stems) of nine Australian adzuki bean varieties for the first time. The total phenolic content (TPC) of the stem material (157-406 mg GAE/100 g) was 23-217% higher than that of commercial livestock feed, while the TPC of the leaf material (1158-1420 mg GAE/100 g) was 9-11 times higher. Using tandem liquid chromatography mass spectrometry (LC-MS), the major phenolic compounds identified were rutin, luteolin, salicylic acid, and quercetin-3-glucoside. The leaf and stem materials showed high levels of apparent in vitro dry matter digestibility, with no significant difference in total gas or methane production compared to lucerne hay. The results suggest that adzuki bean vegetative materials could be a high-value livestock fodder and support pursuing further in-depth studies into their nutritional value for livestock.

Pasture production is vital in cattle farming as it provides animals with food and nutrients. Australia, as a significant global beef producer, has been experiencing pasture dieback, a syndrome of deteriorating grassland that results in the loss of grass and the expansion of weeds. Despite two decades of research and many remediation attempts, there has yet to be a breakthrough in understanding the causes or mechanisms involved. Suggested causes of this phenomenon include soil and plant microbial pathogens, insect infestation, extreme heat stress, radiation, and others. Plants produce a range of phytomolecules with antifungal, antibacterial, antiviral, growth-promoting, and immunostimulant effects to protect themselves from a range of environmental stresses. These products are currently used more in human and veterinary health than in agronomy. In this study, we applied a phytogenic product containing citric acid, carvacrol, and cinnamaldehyde, to investigate its ability to alleviate pasture dieback. The phytogenic liquid-based solution was sprayed twice, one week apart, at 5.4 L per hectare. The soil microbial community was investigated longitudinally to determine long-term effects, and pasture productivity and plant morphometric improvements were explored. The phytogenic liquid significantly improved post-drought recovery of alpha diversity and altered temporal and spatial change in the community. The phytogenic liquid reduced biomarker genera associated with poor and polluted soils and significantly promoted plant and soil beneficial bacteria associated with plant rhizosphere and a range of soil benefits. Phytogenic liquid application produced plant morphology improvements and a consistent enhancement of pasture productivity extending beyond 18 months post-application. Our data show that phytogenic products used in the livestock market as an alternative to antibiotics may also have a beneficial role in agriculture, especially in the light of climate change-related soil maintenance and remediation.

Pasture dieback is a rapidly expanding decaying pasture syndrome that affects millions of hectares of agricultural land in Queensland, Australia, making it useless for the cattle industry and decimating farmers' income and welfare. Since the syndrome was first identified in the early 1990s, farmers and agronomists have tried various methods for pasture recovery, including slashing, burning, ploughing and resowing grass, fertilising, destocking, and overstocking. In most cases, after a minimal initial improvement, the grass reverts to dieback within a few weeks. Here, we present an application of potassium humate, a well-known plant growth stimulator, as a possible long-term recovery option. Humate was applied once at the rate of 12 ml per m 2 . Humate application did not alter the alpha or beta diversity of soil bacterial communities, nor did it change the mineral profile in the soil. However, humate application altered soil microbiota-mineral temporal interactions and introduced subtle changes in the microbial community that could assist pasture recovery. A single humate application increased paddock plant biomass significantly up to 20 weeks post-application. Eleven months after the single application, the paddock was grazed to the ground by the cattle just before the rainfall season. After pasture regrowth, the humate-treated plots significantly improved root morphometric indicators for both grass and dicots and increased the ratio of grass/weeds by 27.6% compared to the water-treated control. While this treatment will not resolve the dieback syndrome, our results invite more research to optimise the use of humate for maximum economic benefit in paddock use under pasture dieback syndrome conditions., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2023 The Authors.)

Advancements in therapies for Duchenne muscular dystrophy (DMD) have made diagnosis within the newborn period a high priority. We undertook a consortia approach to advance DMD newborn screening in the United States. This manuscript describes the formation of the Duchenne Newborn Screening Consortium, the development of the pilot protocols, data collection tools including parent surveys, and findings from the first year of a two-year pilot. The DMD pilot design is population-based recruitment of infants born in New York State. Data tools were developed to document the analytical and clinical validity of DMD NBS, capture parental attitudes, and collect longitudinal health information for diagnosed newborns. Data visualizations were updated monthly to inform the consortium on enrollment. After 12 months, 15,754 newborns were screened for DMD by the New York State Newborn Screening (NYS NBS) Program. One hundred and forty screened infants had borderline screening results, and sixteen infants were referred for molecular testing. Three male infants were diagnosed with dystrophinopathy. Data from the first year of a two-year NBS pilot for DMD demonstrate the feasibility of NBS for DMD. The consortia approach was found to be a useful model, and the Newborn Screening Translational Research Network's data tools played a key role in describing the NBS pilot findings and engaging stakeholders.

Purpose: Synthesis and curation of evidence regarding the clinical actionability of secondary findings (SFs) from genome-scale sequencing are needed to support decision-making on reporting of these findings. To assess actionability of SFs in children and adolescents, the Clinical Genome Resource established the Pediatric Actionability Working Group (AWG)., Methods: The Pediatric AWG modified the framework of the existing Adult AWG, which included production of summary reports of actionability for genes and associated conditions and consensus actionability scores for specific outcome-intervention pairs. Modification of the adult framework for the pediatric setting included accounting for special considerations for reporting presymptomatic or predictive genetic findings in the pediatric context, such as maintaining future autonomy by not disclosing conditions not actionable until adulthood. The Pediatric AWG then applied this new framework to genes and associated conditions with putative actionability., Results: As of September 2021, the Pediatric AWG applied the new framework to 70 actionability topics representing 143 genes. Reports and scores are publicly available at www.clinicalgenome.org., Conclusion: The Pediatric AWG continues to curate gene-condition topics and build an evidence-based resource, supporting clinical communities and decision-makers with policy development on the return of SFs in pediatric populations., Competing Interests: Conflict of Interest R.D.S. has equity interest in and has received consulting fees from Acer Inc and PTC Therapeutics. He has received consulting fees from Aeglea BioTherapeutics; Alexion Pharmaceuticals, Inc; Best Doctors; Health Advances LLC; Precision for Value; and Travere Therapeutics, Inc; and honoraria from Medscape/WebMD LLC and The France Foundation. R.D.S. is an employee of PreventionGenetics. He received research funding from Alexion Pharmaceuticals, Inc and the Smith Lemli Opitz Foundation. All other authors declare no conflicts of interest., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: The majority of colorectal carcinomas (CRCs) are insensitive to programmed death protein-1/programmed death-ligand 1 (anti-PD-1/PD-L1) immune checkpoint inhibitor (ICI) antibodies. While there are many causes for ICI insensitivity, recent studies suggest that suppression of innate immune gene expression in tumor cells could be a root cause of this insensitivity and an important factor in the evolution of tumor immunosuppression., Methods: We first assessed the reduction of mitochondrial antiviral signaling gene (MAVS) and related RIG-I pathway gene expression in several patient RNA expression datasets. We then engineered MAVS expressing tumor cells and tested their ability to elicit innate and adaptive anti-tumor immunity using both in vitro and in vivo approaches, which we then confirmed using MAVS expressing viral vectors. Finally, we observed that MAVS stimulated PD-L1 expression in multiple cell types and then assessed the combination of PD-L1 ICI antibodies with MAVS tumor expression in vivo., Results: MAVS was significantly downregulated in CRCs, but its re-expression could stimulate broad cellular interferon-related responses, in both murine and patient-derived CRCs. In vivo, local MAVS expression elicited significant anti-tumor responses in both immune-sensitive and insensitive CRC models, through the stimulation of an interferon responsive axis that provoked tumor antigen-specific adaptive immunity. Critically, we found that tumor-intrinsic MAVS expression triggered systemic adaptive immune responses that enabled abscopal CD8 +T cell cytotoxicity against distant CRCs. As MAVS also induced PD-L1 expression, we further found synergistic anti-tumor responses in combination with anti-PD-L1 ICIs., Conclusion: These data demonstrate that intratumoral MAVS expression results in local and systemic tumor antigen-specific T cell responses, which could be combined with PD-L1 ICI to permit effective anti-tumor immunotherapy in ICI resistant cancers., Competing Interests: Competing interests: A patent for the use of MAVS expression in cancer (US 2018/0092989) has been published through the Duke University’s Office of Licensing and Ventures and has been licensed as part of an agreement with Replicate Biosciences, LLC. Otherwise, the authors declare no potential conflicts of interest., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Subsyndromal delirium following surgery in older adults is related to increased lengths of hospital stay and increased admissions to long-term care. Impaired nutrition increases risk for delirium, but its relationship to subsyndromal delirium remains unclear., Purpose: This correlational study examined the relationship between nutritional status and subsyndromal delirium in older adults., Methods: Assessments for subsyndromal delirium in 53 adults 65 years or older were completed for three consecutive days following joint replacement surgery. Relationships between nutritional status and subsyndromal delirium were analyzed. Level of significance for all tests was set at p ≤ .05., Results: Participants' scores from the Mini Nutritional Assessment screen were significantly related (p = .05) to subsyndromal delirium severity after accounting for variability posed by age and cognition status., Conclusion: When preoperative risk assessment of older adults indicates nutritional risk, preoperative optimization may improve effectiveness of delirium prevention efforts.

Background: Whole breast irradiation delivered once per day over 3-5 weeks after breast conserving surgery reduces local recurrence with good cosmetic results. Accelerated partial breast irradiation (APBI) delivered over 1 week to the tumour bed was developed to provide a more convenient treatment. In this trial, we investigated if external beam APBI was non-inferior to whole breast irradiation., Methods: We did this multicentre, randomised, non-inferiority trial in 33 cancer centres in Canada, Australia and New Zealand. Women aged 40 years or older with ductal carcinoma in situ or node-negative breast cancer treated by breast conserving surgery were randomly assigned (1:1) to receive either external beam APBI (38·5 Gy in ten fractions delivered twice per day over 5-8 days) or whole breast irradiation (42·5 Gy in 16 fractions once per day over 21 days, or 50 Gy in 25 fractions once per day over 35 days). Patients and clinicans were not masked to treatment assignment. The primary outcome was ipsilateral breast tumour recurrence (IBTR), analysed by intention to treat. The trial was designed on the basis of an expected 5 year IBTR rate of 1·5% in the whole breast irradiation group with 85% power to exclude a 1·5% increase in the APBI group; non-inferiority was shown if the upper limit of the two-sided 90% CI for the IBTR hazard ratio (HR) was less than 2·02. This trial is registered with ClinicalTrials.gov, NCT00282035., Findings: Between Feb 7, 2006, and July 15, 2011, we enrolled 2135 women. 1070 were randomly assigned to receive APBI and 1065 were assigned to receive whole breast irradiation. Six patients in the APBI group withdrew before treatment, four more did not receive radiotherapy, and 16 patients received whole breast irradiation. In the whole breast irradiation group, 16 patients withdrew, and two more did not receive radiotherapy. In the APBI group, a further 14 patients were lost to follow-up and nine patients withdrew during the follow-up period. In the whole breast irradiation group, 20 patients were lost to follow-up and 35 withdrew during follow-up. Median follow-up was 8·6 years (IQR 7·3-9·9). The 8-year cumulative rates of IBTR were 3·0% (95% CI 1·9-4·0) in the APBI group and 2·8% (1·8-3·9) in the whole breast irradiation group. The HR for APBI versus whole breast radiation was 1·27 (90% CI 0·84-1·91). Acute radiation toxicity (grade ≥2, within 3 months of radiotherapy start) occurred less frequently in patients treated with APBI (300 [28%] of 1070 patients) than whole breast irradiation (484 [45%] of 1065 patients, p<0·0001). Late radiation toxicity (grade ≥2, later than 3 months) was more common in patients treated with APBI (346 [32%] of 1070 patients) than whole breast irradiation (142 [13%] of 1065 patients; p<0·0001). Adverse cosmesis (defined as fair or poor) was more common in patients treated with APBI than in those treated by whole breast irradiation at 3 years (absolute difference, 11·3%, 95% CI 7·5-15·0), 5 years (16·5%, 12·5-20·4), and 7 years (17·7%, 12·9-22·3)., Interpretation: External beam APBI was non-inferior to whole breast irradiation in preventing IBTR. Although less acute toxicity was observed, the regimen used was associated with an increase in moderate late toxicity and adverse cosmesis, which might be related to the twice per day treatment. Other approaches, such as treatment once per day, might not adversely affect cosmesis and should be studied., Funding: Canadian Institutes for Health Research and Canadian Breast Cancer Research Alliance., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Introduction: Physicians entering independent practice often express apprehension in managing the non-clinical aspects of practice. This study examined the perceived preparedness of radiation oncology (RO) residents for independent practice, identified education gaps, and discussed how these deficiencies could be addressed., Materials and Methods: Focus groups with senior RO residents, fellows, new-to-practice radiation oncologists (ROs), and residency program directors were conducted. Data were coded using the Canadian Medical Education Directives for Specialists (CanMEDS) competencies using thematic analysis., Results: Commonly reported gaps in the transition to practice (TtP) for ROs were lack of experience with: practice management, understanding the structure and function of the health care system and how it varies by jurisdiction, financial planning, effective communication and collaboration with other health care team members, creation of accurate and timely documentation, and radiotherapy problem-solving related to treatment planning and evaluation. Suggestions to address these challenges included use of mentorship, educational resources, courses, simulation-based medical education, improved graded responsibility, resident longitudinal clinics, and formal curricula in radiation therapy planning and evaluation., Conclusion: There are gaps in TtP education for RO trainees with opportunities for enrichment through the forthcoming implementation of a competency-based medical education framework in 2019. The gap in perceived competency in physician-related radiotherapy tasks may be caused by the complex interaction of clinical workflow processes, people and technology that has led to ineffective integration of trainees. The data are informative to medical education leaders for the development of comprehensive TtP curricula., (Crown Copyright © 2019. Published by Elsevier B.V. All rights reserved.)

Background: The burden oral anticoagulation is a limitation of mechanical valve prostheses., Objectives: The aim of this study was to test whether patients could be safely managed with dual-antiplatelet therapy (DAPT) (aspirin 325 mg and clopidogrel 75 mg) or lower warfarin after On-X mechanical aortic valve replacement (mAVR)., Methods: PROACT (Prospective Randomized On-X Anticoagulation Trial) (n = 576) is a multicenter (41 sites) noninferiority trial. From June 2006 through February 2014, 201 patients ≥18 years of age without thromboembolic risk factors undergoing mAVR were randomized to receive DAPT (n = 99) or standard warfarin plus aspirin (n = 102) 3 months after mAVR (low-risk arm). From June 2006 through October 2009, 375 patients with 1 or more thromboembolic risk factors were also randomized to lower intensity warfarin plus aspirin (international normalized ratio 1.5 to 2.0; n = 185) or standard warfarin plus aspirin (international normalized ratio 2.0 to 3.0; n = 190) 3 months after mAVR (high-risk arm)., Results: The low-risk arm was terminated for excess cerebral thromboembolic events (3.12% per patient-year vs. 0.29% per patient-year, p = 0.02) in the DAPT group at up to 8.8-year follow-up (631.6 patient-years), with no differences in bleeding or all-cause mortality. High-risk arm patients experienced significantly lower major (1.59% per patient-year vs. 3.94% per patient-year, p = 0.002) and minor (1.27% per patient-year vs. 3.49% per patient-year, p = 0.002) bleeding up to 8.7-year follow-up (2,035.2 patient-years), with no differences in thromboembolism (0.42% per patient-year vs. 0.09% per patient-year, p = 0.20) and all-cause mortality., Conclusions: DAPT was associated with higher rates of thromboembolism and valve thrombosis compared with control in the low-risk arm. International normalized ratios were safely maintained at 1.5 to 2.0 in high-risk patients, without differences in mortality or thromboembolic complications. (Randomized On-X Anticoagulation Trial [PROACT]; NCT00291525)., (Copyright © 2018. Published by Elsevier Inc.)

Duchenne muscular dystrophy (DMD/Duchenne) is one of the ten most severe and common pediatric genetic diseases and affects an estimated 1 in every 5000 male births. While Duchenne is a 100% fatal disease, the clinical community has demonstrated that immediate identification and early clinical interventions can add years, even decades to an individual's life span. In anticipation of the changing therapeutic landscape for the Duchenne community, Parent Project Muscular Dystrophy established a newborn screening (NBS) initiative. This initiative included a Bioethics and Legal Issues Workgroup to consider the bioethics and legal issues of NBS for Duchenne. The workgroup's discussion focused only on Duchenne NBS and met through conference calls over a one-year period of time seeking consensus on various identified issues. This article reports on the findings and recommendations from that workgroup., Competing Interests: Conflicts of InterestThe authors declare no conflicts of interest., (© 2018 by the authors.)

Background and Purpose: The need for radiation oncologists and other radiation oncology (RO) professionals to lead quality improvement activities and contribute to shaping the future of our specialty is self-evident. Leadership knowledge, skills and behaviours, like other competencies, can be learned (Blumenthal et al., 2012). The objective of this study was to define a globally applicable competency set specific to radiation oncology for the CanMEDS Leader Role (Frank et al., 2015)., Methods: A modified Delphi consensus process delivering two rounds of on-line surveys was used. Participants included trainees, radiation/clinical oncologists and other RO team members (radiation therapists, physicists, and nurses), professional educators and patients., Results: 72 of 95 (76%) invitees from nine countries completed the Round 1 (R1) survey. Of the 72 respondents to RI, 70 completed Round 2 (R2) (97%). In R1, 35 items were deemed for 'inclusion' and 21 for 'exclusion', leaving 41 'undetermined'. After review of items, informed by participant comments, 14 competencies from the 'inclusion' group went into the final curriculum; 12 from the 'undetermined' group went to R2. In R2, 6 items reached consensus for inclusion., Conclusion: This process resulted in 20 RO Leader Role competencies with apparent global applicability. This is the first step towards developing learning, teaching and assessment tools for this important area of training., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Family health history collection and genetic testing are core elements for the successful translation of genomics into primary care practice. Yet, little is known about how pediatric providers implement these elements in practice. We surveyed the membership of the American Academy of Pediatrics regarding family health history (FHH) collection and genetic testing in the primary care setting. Three hundred forty-nine (349) responses were analyzed with the initial response rate of 43.3%. Four principal findings were noted-(1) family health history is still recognized as a critical part of the medical evaluation; (2) perceived obstacles for FHH are time in obtaining the FHH and concerns about the family's knowledge of their FHH; (3) a 3-generation family history is out of the scope of routine care and alternate methods should be considered; (4) most primary care providers (PCPs) do not feel comfortable ordering, interpreting, and counseling regarding current genetic testing. Expanded genetic/genomic education at multiple levels (undergraduate medical education, graduate medical education, and maintenance of certification) is clearly indicated to allow PCPs to integrate these vital elements into a current evaluation (acute care or health maintenance) in the primary care setting.

Representatives from countries and regions world-wide who have implemented modern competency-based radiation- or clinical oncology curricula for training medical specialists, met to determine the feasibility and value of an ongoing international collaboration. In this forum, educational leaders from the ESTRO School, encompassing many European countries adopting the ESTRO Core Curriculum, and clinician educators from Canada, Denmark, the United Kingdom, Australia and New Zealand considered the training and educational arrangements within their jurisdictions, identifying similarities and challenges between programs. Common areas of educational interest and need were defined, which included development of new competency statements and assessment tools, and the application of the latter. The group concluded that such an international cooperation, which might expand to include others with similar goals, would provide a valuable vehicle to ensure training program currency, through sharing of resources and expertise, and enhance high quality radiation oncology education. Potential projects for the Global Radiation Oncology Collaboration in Education (GRaCE) were agreed upon, as was a strategy designed to maintain momentum. This paper describes the rationale for establishing this collaboration, presents a comparative view of training in the jurisdictions represented, and reports early goals and priorities., (Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.)

Purpose: To determine the employment status and location of recent Canadian radiation oncology (RO) graduates and to identify current workforce entry trends., Methods and Materials: A fill-in-the-blank spreadsheet was distributed to all RO program directors in December 2013 and June 2014, requesting the employment status and location of their graduates over the last 3 years. Visa trainee graduates were excluded., Results: Response rate from program directors was 100% for both survey administrations. Of 101 graduates identified, 99 (98%) had known employment status and location. In the December survey, 5 2013 graduates (16%), 17 2012 graduates (59%), and 18 2011 graduates (75%) had permanent staff employment. Six months later, 5 2014 graduates (29%), 15 2013 graduates (48%), 24 2012 graduates (83%), and 21 2011 graduates (88%) had secured staff positions. Fellowships and temporary locums were common for those without staff employment. The proportion of graduates with staff positions abroad increased from 22% to 26% 6 months later., Conclusions: Workforce entry for most RO graduates was delayed but showed steady improvement with longer time after graduation. High emigration rates for jobs abroad signify domestic employment challenges for newly certified, Canadian-trained radiation oncologists. Coordination on a national level is required to address and regulate radiation oncologist supply and demand disequilibrium in Canada., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Background: Aggressive medical management of cancer patients at the end of life (EOL) is an indicator of health services quality. We evaluated the variations in EOL cancer therapy utilization and in acute care hospital deaths across different types of cancer within the setting of a regionalized cancer program., Methods: Intravenous chemotherapy and radiotherapy use within the last 14 and 30 days of life was identified through the Alberta Cancer Registry and then verified by chart review for cancer decedents residing within 50 km of the Tom Baker Cancer Centre between 2003 and 2010. Multivariable logistic regression was used to examine variations in outcomes of interest by cancer, adjusting for age and other factors in prespecified models., Results: Of the 9863 decedents included in the study, 3.0 and 6.3 % received chemotherapy within the final 14 and 30 days of life, respectively. In multivariable model, breast, hematological, and gynecological cancers were at least 2.5 times more likely than other cancers to undergo EOL chemotherapy. Radiotherapy was given to 4.6 % of decedents within 14 days of death, but only 66 % (359/542 courses) were completed as prescribed. Acute care admission within 14 days of death was seen in 44 % of decedents and 34 % died in the hospital., Conclusions: In our regional cancer program, the intensity of cancer therapies near the end of life varied considerably across different cancer types. Such variations may be unwarranted. A substantial proportion of cancer deaths occurred in the acute care setting. Greater efforts to integrate palliative care in outpatient cancer services are needed.

Purpose: To evaluate factors associated with adverse cosmesis outcome in breast cancer patients randomized to accelerated partial breast irradiation (APBI) using 3-dimensional conformal radiation therapy or whole-breast irradiation in the RAPID (Randomized Trial of Accelerated Partial Breast Irradiation) trial., Methods and Materials: Subjects were trial participants with nurse-assessed global cosmetic scores at baseline and at 3 years. Adverse cosmesis was defined as a score of fair or poor. Cosmetic deterioration was defined as any adverse change in score from baseline to 3 years. The analysis is based on data from the previously reported interim analysis. Logistic regression models were used to assess the association of risk factors for these outcomes among all patients and those treated with APBI only., Results: Clinicopathologic characteristics were similar between subjects randomized to APBI (n=569) or whole-breast irradiation (n=539). For all subjects, factors associated with adverse cosmesis at 3 years were older age, central/inner tumor location, breast infection, smoking, seroma volume, breast volume, and use of APBI; factors associated with cosmetic deterioration were smoking, seroma volume, and use of APBI (P<.05). For APBI subjects, tumor location, smoking, age, and seroma volume were associated with adverse cosmesis (P<.05), and smoking was associated with cosmetic deterioration (P=.02). An independent association between the V95/whole-breast volume ratio and adverse cosmesis (P=.28) or cosmetic deterioration (P=.07) was not detected. On further exploration a V95/whole-breast volume ratio <0.15 was associated with a lower risk of cosmetic deterioration (p=.04), but this accounted for only 11% of patients., Conclusion: In the RAPID trial, a number of patient tumor and treatment-related factors, including the use of APBI, were associated with adverse cosmesis and cosmetic deterioration. For patients treated with APBI alone, the high-dose treatment volume was not independently associated with an adverse cosmetic outcome, and a useful clinical threshold could not be identified., (Copyright © 2015 Elsevier Inc. All rights reserved.)

With the recent expansion of genetic science, its evolving translation to clinical medicine, and the growing number of available resources for genomics in primary care, the primary care provider must increasingly integrate genetics and genomics into daily practice. Because primary care medicine combines the treatment of acute illness with disease prevention and anticipatory guidance, the primary care provider is in an ideal position to evaluate and treat patients for genetic disease. The notion that genetic knowledge is only rarely needed will have to be replaced with a comprehensive approach that integrates "genetic thinking" into every patient encounter. Genomic competencies will need to be added to the primary care provider's repertoire; such competencies include prevention, assessment, evaluation, and diagnosis of genetic conditions; the ordering and interpreting of genetic tests; communication with families; appropriate referrals; and the management or comanagement of care. The process of deciding when to order genetic tests, what tests to order, and how to interpret the results is complex, and the tests and their results have specific risks and benefits, especially for pediatric patients. The longitudinal nature of primary pediatric care provides the opportunity to obtain and continually update the family history, which is the most powerful initial genetic "test." The ongoing provider-family relationship, coupled with the astounding number of advances in genetic and genomic testing, also necessitates a constant re-evaluation of past diagnosis or nondiagnosis.

Purpose: To report interim cosmetic and toxicity results of a multicenter randomized trial comparing accelerated partial-breast irradiation (APBI) using three-dimensional conformal external beam radiation therapy (3D-CRT) with whole-breast irradiation (WBI)., Patients and Methods: Women age > 40 years with invasive or in situ breast cancer ≤ 3 cm were randomly assigned after breast-conserving surgery to 3D-CRT APBI (38.5 Gy in 10 fractions twice daily) or WBI (42.5 Gy in 16 or 50 Gy in 25 daily fractions ± boost irradiation). The primary outcome was ipsilateral breast tumor recurrence (IBTR). Secondary outcomes were cosmesis and toxicity. Adverse cosmesis was defined as a fair or poor global cosmetic score. After a planned interim cosmetic analysis, the data, safety, and monitoring committee recommended release of results. There have been too few IBTR events to trigger an efficacy analysis., Results: Between 2006 and 2011, 2,135 women were randomly assigned to 3D-CRT APBI or WBI. Median follow-up was 36 months. Adverse cosmesis at 3 years was increased among those treated with APBI compared with WBI as assessed by trained nurses (29% v 17%; P < .001), by patients (26% v 18%; P = .0022), and by physicians reviewing digital photographs (35% v 17%; P < .001). Grade 3 toxicities were rare in both treatment arms (1.4% v 0%), but grade 1 and 2 toxicities were increased among those who received APBI compared with WBI (P < .001)., Conclusion: 3D-CRT APBI increased rates of adverse cosmesis and late radiation toxicity compared with standard WBI. Clinicians and patients are cautioned against the use of 3D-CRT APBI outside the context of a controlled trial.

Many medical practitioners provide care to patients for whom radiotherapy [radiation oncology (RO)] is a recommended treatment or who have received radiotherapy treatment for cancer. A basic level of understanding about this modality is important to ensure a continuum of good patient care. This study aimed to explore the current teaching practices in RO across medical schools in Canada and understand the perception of RO as a career choice among final-year medical students. Ethics approval and/or consent was obtained from each medical school prior to sending an electronic survey to the Undergraduate Medical Education office and to the final-year medical school class. Only six of the 14 Canadian medical schools participated in the surveys. Four of the 14 refused external surveys. The response rate was 8 % (155/1,917) for all final-year medical students and 17 % (155/897) for students from participating medical schools. Didactic lectures are the primary means of delivering RO knowledge. One in five students reports that they did not receive any RO teaching, and 65 % received <2 h. The level of interest in RO as a career choice (scale of 1-5) was greater in students who received >2 h of RO teaching (2.85 vs. 3.18, p = 0.012) and those that took part in a RO elective (2.86 vs. 3.53, p < 0.001). This study confirms the underrepresentation of RO teaching within the Canadian undergraduate medical curriculum. Interest in this specialty is minimal but does appear to be influenced by exposure to RO teaching. It is important to highlight the limitations of conducting a survey study within the Canadian medical undergraduate system. Steps to conduct such studies in a more seamless fashion are required, in order to assist curriculum development in RO and enhance the understanding of the specialty as a career choice.

Purpose of the Study: To survey employment and training characteristics of Canadian radiation oncology training program graduates and foreign medical graduates with Canadian radiation oncology post-graduate education or specialist certification., Methods: A 38-question, web-based survey was distributed to radiation oncologists who completed specialty training between 2000-2010., Results: Out of 256 radiation oncologists contacted, 148 completed the survey (58% response rate). Thirty-two respondents (22%) were foreign MD graduates. One-hundred and fifteen respondents (78%) undertook fellowship training after residency. Many Canadian MD graduates (77%) and foreign MD graduates (34%) had staff positions in Canada, while 11% of all respondents had staff positions outside Canada, and 21% did not have a commitment for staff employment. Of the 31 respondents without a staff position, 22 graduated from Canadian residency training in 2009 or 2010, and 21 had completed medical school training in Canada., Conclusions: The majority of respondents were successful in securing staff positions in Canada. A sizeable proportion extended training with fellowships. New graduates may have more difficulty in finding Canadian staff positions in radiation oncology in the near future. Implications for specialty training programs and for an improved national strategy for physician resource planning are discussed.

Purpose: Statistics from the Canadian post-MD education registry show that numbers of Canadian radiation oncology (RO) trainees have risen from 62 in 1999 to approximately 150 per year between 2003 and 2009, contributing to the current perceived downturn in employment opportunities for radiation oncologists in Canada. When last surveyed in 2003, Canadian RO residents identified job availability as their main concern. Our objective was to survey current Canadian RO residents on their training and career plans., Methods and Materials: Trainees from the 13 Canadian residency programs using the national matching service were sought. Potential respondents were identified through individual program directors or chief resident and were e-mailed a secure link to an online survey. Descriptive statistics were used to report responses., Results: The eligible response rate was 53% (83/156). Similar to the 2003 survey, respondents generally expressed high satisfaction with their programs and specialty. The most frequently expressed perceived weakness in their training differed from 2003, with 46.5% of current respondents feeling unprepared to enter the job market. 72% plan on pursuing a postresidency fellowship. Most respondents intend to practice in Canada. Fewer than 20% of respondents believe that there is a strong demand for radiation oncologists in Canada., Conclusions: Respondents to the current survey expressed significant satisfaction with their career choice and training program. However, differences exist compared with the 2003 survey, including the current perceived lack of demand for radiation oncologists in Canada., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Primary cardiac lymphoma (PCL) is defined as a non-Hodgkin lymphoma involving only the heart or pericardium. PCL is extremely rare and often misdiagnosed. We report the case of a healthy 53-year-old male who originally presented with blurred vision secondary to a right intraocular mass. Enucleation of the eye confirmed a ciliary body melanoma and, upon further investigation, the patient was discovered to have a mass in the right atrium suspicious for a myxoma. However, resection of the atrial mass revealed a low-grade B-cell PCL. The occurrence of PCL in an immunocompetent patient being investigated for a visceral malignancy makes this a highly unusual presentation of a rare neoplasm., (© 2011 Wiley Periodicals, Inc.)

Breast cancer is the most common cancer diagnosed in women. The present study evaluated the family physicians' (FPs) understanding of adjuvant hormonal therapies for an early breast cancer. FPs were invited to attend teaching workshops on this topic, which utilized a pretest, didactic and interactive teaching, and posttest format. FPs (n = 23) showed an improvement (p < 0.001) in pretest to posttest score. It is clear that, with a targeted teaching, FPs can quickly become more knowledgeable on the topic of hormonal therapies in breast cancer, with the potential of applying this information in their own practice.

The Secretary's Advisory Committee on Heritable Disorders in Newborns and Children is charged with evaluating conditions nominated for addition to the uniform screening panel and consequently making recommendations to the secretary of the US Department of Health and Human Services. This report describes the framework by which the committee approaches its task. Key decision nodes include initial review of every nomination to determine whether conditions are amenable for systematic evidence review, review of systematic evidence reviews conducted by the committee's external review group, and deliberation and formal recommendation for addition or exclusion to the uniform panel. Data analyzed include the accuracy and specificity of screening and diagnostic tests for nominated disorders, the extent of predicted health benefits, harms impact on disease course, and cost from early diagnosis and treatment. The committee process is guided by approaches used by similar entities, but more flexible criteria are sometimes needed to accommodate data limitations stemming from the rarity of many of these conditions. Possible outcomes of committee review range from recommendation to add a nominated condition to the uniform panel; provide feedback on specific gaps in evidence that must be addressed before making a decision; or rejection of a nomination (e.g., because of identified harms). The committee's structured evidence-based assessment of nominated conditions supports a consistently rigorous, iterative and transparent approach to its making recommendations regarding broad population-based screening programs for rare conditions in infants and children.

Three intensity-modulated tangential beam radiotherapy plan types for breast cancer treatment were evaluated based on PTV homogeneity index (HI) and equivalent uniform dose (EUD), heart V30 and EUD, whole lung V20 and EUD, and typical planning time compared to conventional 2D plans. 20 early-stage breast cancer patients were CT-scanned in the supine position, and tangential field extent, gantry and collimator angles were chosen. Four treatment plans were created for each patient: conventional, dynamically wedged plan based on the dose distribution on the central axial slice; forward planned IMRT; surface compensated plan created using an Eclipse tool and hybrid IMRT plan combining open and inverse-optimized fields. All three IMRT planning techniques represent significant improvement in PTV HI and EUD compared to conventional plans. Among the IMRT plans, the hybrid IMRT plan produced the best HI. IMRT lowered heart V30 and lung V20, but no significant differences in heart or lung EUD were detected between IMRT techniques. The IMRT technique with the shortest planning time was the compensated plan, followed by the hybrid IMRT. IMRT planning provides dosimetric benefits in breast cancer patients. The selection of the most appropriate IMRT technique must include careful consideration of the resources available.

Introduction: The selective estrogen receptor modulator, Tamoxifen (TAM), is one of the most frequently prescribed drugs for the treatment of breast cancer; however, its effects on the cognition of users have not been adequately studied. Although TAM is an effective anti-estrogen that blocks tumour growth in the breast, it could also influence the activity of other target estrogen sites, including the brain. The exact nature of this interaction is unknown., Methods: A cross-sectional design was used to compare cognitive task performance of two treatment groups: 1) women using TAM for the treatment of early breast cancer (n = 23); and 2) age-matched, healthy women not using TAM (n = 23). All participants were pre-menopausal, and recipients of chemotherapy were excluded from the study., Results: It was found that TAM users scored significantly worse than controls on tasks of immediate and delayed visual memory, verbal fluency, immediate verbal memory, visuo-spatial ability, and processing speed., Discussions/conclusions: Although limited by the lack of baseline data and pre-morbid intelligence measures, the results of this exploratory study suggest that at least in pre-menopausal women, TAM may exert a widespread negative influence on cognitive abilities., Implications for Cancer Survivors: Larger, randomized, prospective trials are required to confirm these results; however, TAM use in pre-menopausal breast cancer may be associated with cognitive difficulties. Knowledge and understanding of these complications will be important for professionals in communicating both the benefits and risks of TAM use in breast cancer survivors.

Lentigo maligna (LM) and lentigo maligna melanoma (LMM) represent a character, histogenetic subclass of melanocytic malignancies. They often present with a prolonged phase of slow growth but once invasion has occurred, the prognostic features are identical to all other melanomas. These lesions occur primarily on the head and neck where they evolve from areas of pigmented staining to the more typical features identifiable with malignant melanomas on other skin surfaces. The treatment options and recent advances in management are reviewed., (Copyright 2004 Wiley-Liss, Inc.)

The comet assay is a single-cell gel electrophoresis technique that measures DNA damage in individual cells. Since radiation produces 3-4 times more DNA damage in well-oxygenated cells compared with hypoxic cells, this assay can quantify the fraction of radiation-resistant hypoxic cells found in many solid tumours. This paper summarizes our results with 73 accessible metastatic tumours irradiated with palliative intent. Hypoxic fractions ranged from 0.0 to 0.67 with a mean of 0.15; 62% of these advanced tumours showed a hypoxic fraction > 0.05. Comparisons between two sequential aspirates in 33 tumours gave a slope of 0.92 (r2 = 0.88), suggesting that a single aspirate is generally representative of the tumour. A limitation, however, is that the hypoxic fraction could not be measured in clinical samples given a conventional dose of 2 Gy.

Successful surgical repair of an unusual case of blunt trauma to the chest and abdomen is presented. The injury resulted in rupture of the pericardium, avulsion and rupture of the right coronary artery into the right atrium, complete disruption of the tricuspid valve, and acute right heart failure with complete heart block.

The alkaline comet assay has previously been used to estimate the fraction of radiobiologically hypoxic cells in tumours from patients undergoing palliative radiotherapy for advanced breast and head and neck cancer. Results obtained from fine needle aspirate biopsies (FNABs) using this method indicate considerable heterogeneity in hypoxic fraction between tumours. Heterogeneity between 3 aspirates taken from the same 10 tumours immediately following single doses of 3.5 to 5 Gy is now examined. Results indicate that a single fine needle aspirate is reasonably representative for DNA damage and DNA content. However, difficulties were encountered in obtaining an adequate sample of tumour cells after the final radiation treatment. The average hypoxic fraction decreased from 14% after the first dose to 9% after the last dose, and in 3 tumours which could be evaluated after both the first and last fraction, the hypoxic fraction decreased in two but increased in the third. Rejoining of DNA strand breaks was observed between sequential aspirates indicating that pooling of samples for analysis may not be advisable using this method.

We have examined the effect of alcohol on the gastric emptying rate of a liquid meal in 10 volunteers. Each volunteer was allocated randomly to receive, on three occasions, no alcohol, 3 units or 6 units of alcohol. Gastric emptying was measured using applied potential tomography. The rate of gastric emptying as measured by the time to 50% emptying (T50) was delayed significantly (P < 0.01) after alcohol 6 units (median 45.0 min (range 19-90 min)) compared with control (23.0 min (13-36 min)) and there was little change after alcohol 3 units (25.5 min (10-65 min)) [corrected].

Using continuous ambulatory electrocardiography, we have investigated the incidence of ST-segment changes occurring in patients undergoing elective Caesarean section under extradural, spinal or general anaesthesia. There was no evidence of significant perioperative ST-segment changes. The findings contrast with the results of other work published recently.