Equipping for risk: Lessons learnt from the UK shale-gas experience on assessing environmental risks for the future geoenergy use of the deep subsurface.

findings are presented from an investigation to improve understanding of the environmental risks associated with developing an unconventional-hydrocarbons industry in the UK. The EQUIPT4RISK project, funded by UK Research Councils, focused on investigations around Preston New Road (PNR), Fylde, Lancashire, and Kirby Misperton Site A (KMA), North Yorkshire, where operator licences to explore for shale gas by hydraulic fracturing (HF) were issued in 2016, although exploration only took place at PNR. EQUIPT4RISK considered atmospheric (greenhouse gases, air quality), water (groundwater quality) and solid-earth (seismicity) compartments to characterise and model local conditions and environmental responses to HF activities. Risk assessment was based on the source-pathway-receptor approach. Baseline monitoring of air around the two sites characterised the variability with meteorological conditions, and isotopic signatures were able to discriminate biogenic methane (cattle) from thermogenic (natural-gas) sources. Monitoring of a post-HF nitrogen-lift (well-cleaning) operation at PNR detected the release of atmospheric emissions of methane (4.2 ± 1.4 t CH4). Groundwater monitoring around KMA identified high baseline methane concentrations and detected ethane and propane at some locations. Dissolved methane was inferred from stable-isotopic evidence as overwhelmingly of biogenic origin. Groundwater-quality monitoring around PNR found no evidence of HF-induced impacts. Two approaches for modelling induced seismicity and associated seismic risk were developed using observations of seismicity and operational parameters from PNR in 2018 and 2019. Novel methodologies developed for monitoring include use of machine learning to identify fugitive atmospheric methane, Bayesian statistics to assess changes to groundwater quality, a seismicity forecasting model seeded by the HF-fluid injection rate and high-resolution monitoring of soil-gas methane. The project developed a risk-assessment framework, aligned with ISO 31000 risk-management principles, to assess the theoretical combined and cumulative environmental risks from operations over time. This demonstrated the spatial and temporal evolution of risk profiles: seismic and atmospheric impacts from the shale-gas operations are modelled to be localised and short-lived, while risk to groundwater quality is longer-term.

Trends and In-Hospital Mortality for Perioperative Myocardial Infarction After the Introduction of a Diagnostic Code for Type 2 Myocardial Infarction in the United States Between 2016 and 2018.

BACKGROUND: The frequency of perioperative myocardial infarction has been declining; however, previous studies have only described type 1 myocardial infarctions. Here, we evaluate the overall frequency of myocardial infarction with the addition of an International Classification of Diseases 10th revision (ICD-10-CM) code for type 2 myocardial infarction and the independent association with in-hospital mortality. METHODS: A longitudinal cohort study spanning the introduction of the ICD-10-CM diagnostic code for type 2 myocardial infarction using the National Inpatient Sample (NIS) from 2016 to 2018. Hospital discharges that included a primary surgical procedure code for intrathoracic, intraabdominal, or suprainguinal vascular surgery were included. Type 1 and type 2 myocardial infarctions were identified using ICD-10-CM codes. We used segmented logistic regression to estimate change in frequency of myocardial infarctions and multivariable logistic regression to determine the association with in-hospital mortality. RESULTS: A total of 360,264 unweighted discharges were included, representing 1,801,239 weighted discharges, with median age 59 and 56% female. The overall incidence of myocardial infarction was 0.76% (13,605/1,801,239). Before the introduction of type 2 myocardial infarction code, there was a small baseline decrease in the monthly frequency of perioperative myocardial infarctions (odds ratio [OR], 0.992; 95% confidence interval [CI], 0.984-1.000; P = .042), but no change in the trend after the introduction of the diagnostic code (OR, 0.998; 95% CI, 0.991-1.005; P = .50). In 2018, where there was an entire year where type 2 myocardial infarction was officially a diagnosis, the distribution of myocardial infarction type 1 was 8.8% (405/4580) ST elevation myocardial infarction (STEMI), 45.6% (2090/4580) non-ST elevation myocardial infarction (NSTEMI), and 45.5% (2085/4580) type 2 myocardial infarction. STEMI and NSTEMI were associated with increased in-hospital mortality (OR, 8.96; 95% CI, 6.20-12.96; P < .001 and OR, 1.59; 95% CI, 1.34-1.89; P < .001). A diagnosis of type 2 myocardial infarction was not associated with increased odds of in-hospital mortality (OR, 1.11; 95% CI, 0.81-1.53; P = .50) when accounting for surgical procedure, medical comorbidities, patient demographics, and hospital characteristics. CONCLUSIONS: The frequency of perioperative myocardial infarctions did not increase after the introduction of a new diagnostic code for type 2 myocardial infarctions. A diagnosis of type 2 myocardial infarction was not associated with increased in-patient mortality; however, few patients received invasive management that may have confirmed the diagnosis. Further research is needed to identify what type of intervention, if any, may improve outcomes in this patient population.

Preoperative ß-Blocker Therapy and Stroke or Major Adverse Cardiac Events in Major Abdominal Surgery: A Retrospective Cohort Study.

BACKGROUND: Perioperative ß-blocker therapy has been associated with increased risk of stroke. However, the association between ß-blocker initiation before the day of surgery and the risk of stroke is unknown. The authors hypothesized there would be no association between preoperative ß-blocker initiation within 60 days of surgery or chronic ß-blockade (more than 60 days) and the risk of stroke in patients undergoing major abdominal surgery. METHODS: Data on elective major abdominal surgery were obtained from the IBM (USA) Truven Health MarketScan 2005 to 2015 Commercial and Medicare Supplemental Databases. Patients were stratified by ß-blocker dispensing exposure: (1) ß-blocker-naïve, (2) preoperative ß-blocker initiation within 60 days of surgery, and (3) chronic ß-blocker dispensing (more than 60 days). The authors compared in-hospital stroke and major adverse cardiac events between the different ß-blocker therapy exposures. RESULTS: There were 204,981 patients who underwent major abdominal surgery. ß-Blocker exposure was as follows: perioperative initiation within 60 days of surgery for 4,026 (2.0%) patients, chronic ß-blocker therapy for 45,424 (22.2%) patients, and ß-blocker-naïve for 155,531 (75.9%) patients. The unadjusted frequency of stroke for patients with ß-blocker initiation (0.4%, 17 of 4,026) and chronic ß-blocker therapy (0.4%, 171 of 45,424) was greater than in ß-blocker-naïve patients (0.2%, 235 of 155,531; P < 0.001). After propensity score weighting, patients initiated on a ß-blocker within 60 days of surgery (odds ratio, 0.90; 95% CI, 0.31 to 2.04; P = 0.757) or on chronic ß-blocker therapy (odds ratio, 0.86; 95% CI, 0.65 to 1.15; P = 0.901) demonstrated similar stroke risk compared to ß-blocker-naïve patients. Patients on chronic ß-blocker therapy demonstrated lower adjusted risk of major adverse cardiac events compared to ß-blocker-naïve patients (odds ratio, 0.81; 95% CI, 0.72 to 0.91; P = 0.007), despite higher unadjusted absolute event rate (2.6% [1,173 of 45,424] vs. 0.6% [872 of 155,531]). CONCLUSIONS: Among patients undergoing elective major abdominal surgery, the authors observed no association between preoperative ß-blocker initiation within 60 days of surgery or chronic ß-blocker therapy and stroke.

TROG 14.04: Multicentre Study of Feasibility and Impact on Anxiety of DIBH in Breast Cancer Patients.

AIMS: The aim of TROG 14.04 was to assess the feasibility of deep inspiration breath hold (DIBH) and its impact on radiation dose to the heart in patients with left-sided breast cancer undergoing radiotherapy. Secondary end points pertained to patient anxiety and cost of delivering a DIBH programme. MATERIALS AND METHODS: The study comprised two groups - left-sided breast cancer patients engaging DIBH and right-sided breast cancer patients using free breathing through radiotherapy. The primary end point was the feasibility of DIBH, defined as left-sided breast cancer patients' ability to breath hold for 15 s, decrease in heart dose in DIBH compared with the free breathing treatment plan and reproducibility of radiotherapy delivery using mid-lung distance (MLD) assessed on electronic portal imaging as the surrogate. The time required for treatment delivery, patient-reported outcomes and resource requirement were compared between the groups. RESULTS: Between February and November 2018, 32 left-sided and 30 right-sided breast cancer patients from six radiotherapy centres were enrolled. Two left-sided breast cancer patients did not undergo DIBH (one treated in free breathing as per investigator choice, one withdrawn). The mean heart dose was reduced from 2.8 Gy (free breathing) to 1.5 Gy (DIBH). Set-up reproducibility in the first week of treatment assessed by MLD was 1.88 ± 1.04 mm (average ± 1 standard deviation) for DIBH and 1.59 ± 0.93 mm for free breathing patients. Using a reproducibility cut-off for MLD of 2 mm (1 standard deviation) as per study protocol, DIBH was feasible for 67% of DIBH patients. Radiotherapy delivery using DIBH took about 2 min longer than for free breathing. Anxiety was not significantly different in DIBH patients and decreased over the course of treatment in both groups. CONCLUSION: Although DIBH was shown to require about 2 min longer per treatment slot, it has the potential to reduce heart dose in left-sided breast cancer patients by nearly a half, provided careful assessment of breath hold reproducibility is carried out.

A simple intervention to improve the use of postoperative antibiotics and intra-abdominal drains in appendicectomy patients.

INTRODUCTION: Appendicitis remains the most common intra-abdominal surgical emergency, yet many patients receive postoperative antibiotics and intra-abdominal drains against recommended guidelines. This study assesses the impact of an educational poster on the appropriate use of postoperative antibiotics and intra-abdominal drains in appendicectomy patients. METHODS: Patients who underwent an appendicectomy between January and April 2019 ('Poster absent' group) as well as between November 2019 and February 2020 ('Poster present' group) were identified. Data were collected on patient demographics, the presence of complicating features (ie appendiceal abscesses, intraperitoneal pus, gangrene and/or perforation) as well as the use of postoperative antibiotics and intra-abdominal drains in accordance with World Society of Emergency Surgery guidelines. RESULTS: One hundred and thirty patients were included in the 'Poster absent' (73 patients) and 'Poster present' (57 patients) groups. After introducing the educational poster there was a significant reduction in the use of postoperative antibiotics (60.5% to 13.8%; p<0.0001) and an insignificant reduction in intra-abdominal drain use (15.2% to 13.2% p>0.05) that were contraindicated in simple appendicitis. There was a significant improvement in the use of postoperative antibiotics (71.9% to 100%; p=0.0019) and an insignificant increase in intra-abdominal drain use (58.8% to 64.3%; p>0.05) that were indicated in complicated appendicitis. The rates of wound infection (4.10% to 0%; p=0.2556) and ileus/obstruction (5.48% to 1.75%; p=0.3846) also reduced. CONCLUSION: This small study demonstrated that a simple and appropriately targeted intervention of an educational poster can significantly improve and reduce variation in the management of appendicectomy patients and may reduce postoperative complications.

Evaluation of Appropriate Use of Preoperative Echocardiography before Major Abdominal Surgery: A Retrospective Cohort Study.

BACKGROUND: Preoperative resting echocardiography is often performed before noncardiac surgery, but indications for preoperative resting echocardiography are limited. This study aimed to investigate appropriateness of preoperative resting echocardiography using the Appropriate Use Criteria for Echocardiography, which encompass indications from the guidelines on perioperative cardiovascular evaluation and management and nonperioperative indications independent of the perioperative period. The authors hypothesized that patients are frequently tested without an appropriate indication. METHODS: Records of patients in the Truven Health MarketScan Commercial and Medicare Supplemental Databases who underwent a major abdominal surgery from 2005 to 2017 were included. These databases contain de-identified records of health services for more than 250 million patients with primary or Medicare supplemental health insurance coverage through employer-based fee-for-service, point-of-service, or capitated plans. Patients were classified based on the presence of an outpatient claim for resting transthoracic echocardiography within 60 days of surgery. Appropriateness was determined via International Classification of Diseases, Ninth Revision-Clinical Modification, and International Classification of Diseases, Tenth Revision-Clinical Modification principal and secondary diagnosis codes associated with the claims, and classified as "appropriate," "rarely appropriate," or "unclassifiable" using the Appropriate Use Criteria for Echocardiography. RESULTS: Among 230,535 patients in the authors' cohort, preoperative resting transthoracic echocardiography was performed in 6.0% (13,936) of patients. There were 12,638 (91%) studies classifiable by the Appropriate Use Criteria for Echocardiography, and 1,298 (9%) were unable to be classified. Among the classifiable studies, 8,959 (71%) were deemed "appropriate," while 3,679 (29%) were deemed "rarely appropriate." Surveillance of chronic ischemic heart disease and uncomplicated hypertension accounted for 43% (1,588 of 3,679) of "rarely appropriate" echocardiograms. CONCLUSIONS: More than one in four preoperative resting echocardiograms were considered "rarely appropriate" according to the Appropriate Use Criteria for Echocardiography. A narrow set of patient characteristics accounts for a large proportion of "rarely appropriate" preoperative resting echocardiograms.

Frequency and Outcomes of Preoperative Stress Testing in Total Hip and Knee Arthroplasty from 2004 to 2017.

Importance: Cardiac stress testing is often performed prior to noncardiac surgery, although trends in use of preoperative stress testing and the effect of testing on cardiovascular outcomes are currently unknown. Objective: To describe temporal trends and outcomes of preoperative cardiac stress testing from 2004 to 2017. Design, Setting, and Participants: Cross-sectional study of patients undergoing elective total hip or total knee arthroplasty from 2004 to 2017. Trend analysis was conducted using Joinpoint and generalized estimating equation regression. The study searched IBM MarketScan Research Databases inpatient and outpatient health care claims for private insurers including supplemental Medicare coverage and included patients with a claim indicating an elective total hip or total knee arthroplasty from January 1, 2004, to December 31, 2017. Exposures: Elective total hip or knee arthroplasty. Main Outcomes and Measures: Trend in yearly frequency of preoperative cardiac stress testing. Results: The study cohort consisted of 801 396 elective total hip (27.9%; n = 246 168 of 801 396) and total knee (72.1%; 555 228 of 801 396) arthroplasty procedures, with a median age of 62 years (interquartile range, 57-70 years) and 58.1% women (n = 465 545 of 801 396). The overall rate of stress testing during the study period was 10.4% (n = 83 307 of 801 396). The rate of stress tests increased 0.65% (95% CI, 0.09-1.21; P = .03) annually from quarter (Q) 1 of 2004 until Q2 of 2006. A joinpoint was identified at Q3 of 2006 (95% CI, 2005 Q4 to 2007 Q4) when preoperative stress test use decreased by -0.71% (95% CI, -0.79% to 0.63%; P < .001) annually. A second joinpoint was identified at the Q4 of 2013 (95% CI, 2011 Q3 to 2015 Q3), when the decline in stress testing rates slowed to -0.40% (95% CI, -0.57% to -0.24%; P < .001) annually. The overall rate of myocardial infarction and cardiac arrest was 0.24% (n = 1677 of 686 067). Rates of myocardial infraction and cardiac arrest were not different in patients with at least 1 Revised Cardiac Risk Index condition who received a preoperative stress test and those who did not (0.60%; n = 221 of 36 554 vs 0.57%; n = 694 of 122 466; P = .51). Conclusions and Relevance: The frequency of preoperative stress testing declined annually from 2006 through 2017. Among patients with at least 1 Revised Cardiac Risk Index condition, no difference was observed in cardiovascular outcomes between patients who did and did not undergo preoperative testing.

Evaluation of implementation of risk management guidelines for carriers of pathogenic variants in mismatch repair genes: a nationwide audit of familial cancer clinics.

INTRODUCTION: This nationwide study assessed the impact of Lynch syndrome-related risk management guidelines on clinicians' recommendations of risk management strategies to carriers of pathogenic variants in mismatch repair genes and the extent to which carriers took up strategies in concordance with guidelines. MATERIALS AND METHODS: Clinic files of 464 carriers (with and without colorectal cancer) were audited for carriers who received their genetic testing results in July 2008-July 2009 (i.e. before guideline release), July 2010-July 2011 and July 2012-July 2013 (both after guideline release) at 12 familial cancer clinics (FCCs) to ascertain the extent to which carriers were informed about risk management in accordance with guidelines. All carriers captured by the audit were invited to participate in interviews; 215 were interviewed to assess adherence to recommended risk management guidelines. RESULTS: The rates of documentation in clinic files increased significantly from pre- to post-guideline for only two out of eight risk management strategies. The strategies with the highest compliance of carriers post-guidelines were: uptake of one or two-yearly colonoscopy (87%), followed by hysterectomy to prevent endometrial cancer (68%), aspirin as risk-reducing medication (67%) and risk-reducing salpingo-oophorectomy (63%). Interrater reliability check for all guidelines showed excellent agreement (k statistics = 0.89). CONCLUSION: These results indicate that there is scope to further increase provision of advice at FCCs to ensure that all carriers receive recommendations about evidence-based risk management. A multi-pronged behaviour change and implementation science approach tailored to specific barriers is likely to be needed to achieve optimal clinician behaviours and outcomes for carriers.

Women's views on screening for Type 2 diabetes after gestational diabetes: a systematic review, qualitative synthesis and recommendations for increasing uptake.

AIM: Many women do not attend recommended glucose testing following a pregnancy affected by gestational diabetes (GDM). We aimed to synthesize the literature regarding the views and experiences of women with a history of GDM on postpartum glucose testing, focusing on barriers and facilitators to attendance. METHODS: We systematically identified qualitative studies that examine women's experiences following GDM relating to glucose testing (diabetes screening) or experience of interventions to promote uptake of testing. We conducted a thematic synthesis to develop descriptive and then analytical themes, then developed recommendations to increase uptake based on the findings. We evaluated the quality of each study and the confidence that we had in the recommendations using published checklists. RESULTS: We included 16 articles after screening 23 160 citations and 129 full texts. We identified four themes of influences relating to the healthcare system and personal factors that affected both ability and motivation to attend: relationship with health care, logistics of appointments and tests, family-related practicalities and concern about diabetes. We developed 10 recommendations addressing diabetes risk information and education, and changes to healthcare systems to promote increased attendance at screening in this population, most with high or moderate confidence. CONCLUSIONS: We have identified a need to improve women's understanding about Type 2 diabetes and GDM, and to adjust healthcare provision during and after pregnancy to decrease barriers and increase motivation for testing. Encouraging higher uptake by incorporating these recommendations into practice will enable earlier management of diabetes and improve long-term outcomes.

On selecting quality indicators: preferences of patients with breast and colon cancers regarding hospital quality indicators.

BACKGROUND: There is an increasing number of quality indicators being reported publicly with aim to improve the transparency on hospital care quality. However, they are little used by patients. Knowledge on patients' preferences regarding quality may help to optimise the information presented to them. OBJECTIVE: To measure the preferences of patients with breast and colon cancers regarding publicly reported quality indicators of Dutch hospital care. METHODS: From the existing set of clinical quality indicators, participants of patient group discussions first assessed an indicator's suitability as choice information and then identified the most relevant ones. We used the final selection as attributes in two discrete choice experiments (DCEs). Questionnaires included choice vignettes as well as a direct ranking exercise, and were distributed among patient communities. Data were analysed using mixed logit models. RESULTS: Based on the patient group discussions, 6 of 52 indicators (breast cancer) and 5 of 21 indicators (colon cancer) were selected as attributes. The questionnaire was completed by 84 (breast cancer) and 145 respondents (colon cancer). In the patient group discussions and in the DCEs, respondents valued outcome indicators as most important: those reflecting tumour residual (breast cancer) and failure to rescue (colon cancer). Probability analyses revealed a larger range in percentage change of choice probabilities for breast cancer (10.9%-69.9%) relative to colon cancer (7.9%-20.9%). Subgroup analyses showed few differences in preferences across ages and educational levels. DCE findings partly matched with those of direct ranking. CONCLUSION: Study findings show that patients focused on a subset of indicators when making their choice of hospital and that they valued outcome indicators the most. In addition, patients with breast cancer were more responsive to quality information than patients with colon cancer.

Outcomes in patients ≥ 80 years with a diagnosis of a hepatopancreaticobiliary (HPB) malignancy.

Older patients are underrepresented in oncological clinical trials. The incidence of hepatopancreaticobiliary (HPB) malignancies is higher in older patients, but data on outcomes are lacking. This study assessed patient outcomes in those < 80 and ≥ 80 years with a HPB malignancy seen at a tertiary referral centre, The Christie NHS Foundation Trust. Data on patients with a HPB malignancy were collected retrospectively between 2012 and 2017 via on-line case-note review. Survival was calculated using the Kaplan-Meier method and prognostic factors using log-rank analysis. Of 1421 patients, 10% were ≥ 80 years. Of patients < 80 and ≥ 80 years, 56% and 57% had pancreas cancer, 39% and 36% biliary tract cancer, and 5% and 7% had hepatocellular carcinoma, respectively. Amongst patients ≥ 80 years, 75% had an Eastern Cooperative Oncology Group performance status (ECOG PS) 0-2. Patients ≥ 80 years had higher rates of comorbidity; 28% received systemic anti-cancer therapy (SACT), compared with 62% of patients < 80 years. Best supportive care (BSC) was instituted in 44% of older patients, compared with 13% in those < 80 years. Of patients ≥ 80 years who received SACT, 82% received monotherapy. Median overall survival (OS) for patients receiving palliative SACT was 10.07 months (95% CI 8.89-11.08) and 10.10 months (95% CI 6.30-12.30) in patients < 80 and ≥ 80 years, respectively, p 0.41; ECOG PS (p < 0.001) was prognostic for OS in older patients but Adult Comorbidity Evaluation-27 comorbidity score (p = 0.07, when comparing groups of ACE score ≤ 1 and > 1) was not. Baseline factors were similar in both age cohorts, but more comorbidities were present in older patients. Older patients were less likely to receive SACT, but when they did, they had an equivalent benefit in OS to younger patients.

Accuracy of Physical Function Questions to Predict Moderate-Vigorous Physical Activity as Measured by Hip Accelerometry.

BACKGROUND: Functional capacity assessment is a core component of current perioperative cardiovascular evaluation and management guidelines for noncardiac surgery. The authors investigated the ability of standardized physical function questions to predict whether participants engaged in moderate physical activity as measured by hip accelerometers. METHODS: Participant responses to physical functioning questions and whether they engaged in moderate physical activity were extracted from the National Health and Nutrition Examination Survey (2003 to 2004 and 2005 to 2006). Physical activity intensity was measured using hip accelerometers. Adult participants with at least one Revised Cardiac Risk Index condition were included in the analysis. Standardized physical function questions were evaluated using a classification and regression tree analysis. Training and test datasets were randomly generated to create and test the analysis. RESULTS: Five hundred and twenty-two participants were asked the physical functioning questions and 378 of 522 (72.4%) had a bout of moderate-vigorous activity. Classification and regression tree analysis identified a "no difficulty" response to walking up 10 stairs and the ability to walk two to three blocks as the most sensitive questions to predict the presence of a 2-min bout of moderate activity. Participants with positive responses to both questions had a positive likelihood ratio of 3.7 and a posttest probability greater than 90% of a 2-min bout of moderate-vigorous activity. The sensitivity and specificity of positive responses to physical functioning questions in the pruned tree were 0.97 (95% CI, 0.94 to 0.98) and 0.16 (95% CI, 0.10 to 0.23) for training data, and 0.88 (95% CI, 0.75 to 0.96) and 0.10 (95% CI, 0.00 to 0.45) for the test data. Participants with at least one 2-min bout of moderate activity had a greater percentage of overall daily active time (35.4 ± 0.5 vs. 26.7 ± 1.2; P = 0.001) than those without. CONCLUSIONS: Standardized physical function questions are highly sensitive but poorly specific to identify patients who achieve moderate physical activity. Additional strategies to evaluate functional capacity should be considered.

Health-related predictors of cancer registry-notified cancer of unknown primary site (CUP).

BACKGROUND: The relationship between comorbid disease and health service use and risk of cancer of unknown primary site (CUP) is uncertain. METHODS: A prospective cohort of 266,724 people aged 45 years and over in New South Wales, Australia. Baseline questionnaire data were linked to cancer registration, health service records 4-27 months prior to diagnosis, and mortality data. We compared individuals with incident registry-notified CUP (n = 327; 90% C80) to two sets of randomly selected controls (3:1): (i) incident metastatic cancer of known primary site (n = 977) and (ii) general cohort population (n = 981). We used conditional logistic regression to estimate adjusted odds ratios (ORs) and 95% confidence intervals (CIs). RESULTS: In fully adjusted models incorporating sociodemographic and lifestyle factors, people with cancer registry-notified CUP were more likely to have fair compared with excellent self-rated overall health (OR 1.78, 95% CI 1.01-3.14) and less likely to self-report anxiety (OR 0.48, 95% CI 0.24-0.97) than those registered with metastatic cancer of known primary. Compared to general cohort population controls, people registered with CUP were more likely to have poor rather than excellent self-rated overall health (OR 6.22, 95% CI 1.35-28.6), less likely to self-report anxiety (OR 0.28, 95% CI 0.12-0.63), and more likely to have a history of diabetes (OR 1.89, 95% CI 1.15-3.10) or cancer (OR 1.62, 95% CI 1.03-2.57). Neither tertiary nor community-based health service use independently predicted CUP risk. CONCLUSION: Low self-rated health may be a flag for undiagnosed cancer, and an investigation of its clinical utility in primary care appears warranted.

Demographic, social and lifestyle risk factors for cancer registry-notified cancer of unknown primary site (CUP).

BACKGROUND: Little is known about the risk factors for cancer of unknown primary site (CUP). We examined the demographic, social and lifestyle risk factors for CUP in a prospective cohort of 266,724 people aged 45 years and over in New South Wales, Australia. METHODS: Baseline questionnaire data were linked to cancer registration, hospitalisation, emergency department admission, and mortality data. We compared individuals with incident cancer registry-notified CUP (n = 327) to two sets of controls randomly selected (3:1) using incidence density sampling with replacement: (i) incident cancer registry-notified metastatic cancer of known primary site (n = 977) and (ii) general cohort population (n = 981). We used conditional logistic regression to estimate adjusted odds ratios (ORs) and 95% confidence intervals (CIs). RESULTS: In a fully adjusted model incorporating self-rated overall health and comorbidity, people diagnosed with CUP were more likely to be older (OR 1.05, 95% CI 1.04-1.07 per year) and more likely to have low educational attainment (OR 1.77, 95% CI 1.24-2.53) than those diagnosed with metastatic cancer of known primary. Similarly, compared to general cohort population controls, people diagnosed with CUP were older (OR 1.10, 95% CI 1.08-1.12 per year), of low educational attainment (OR 1.69, 95% CI 1.08-2.64), and current (OR 3.42, 95% CI 1.81-6.47) or former (OR 1.95, 95% CI 1.33-2.86) smokers. CONCLUSION: The consistent association with educational attainment suggests low health literacy may play a role in CUP diagnosis. These findings highlight the need to develop strategies to achieve earlier identification of diagnostically challenging malignancies in people with low health literacy.

Totally endoscopic robotic-assisted excision of right ventricular papillary fibroelastoma.

Although they comprise a small number of primary tumors of the heart, papillary fibroelastomas (PFEs) are the second most common type of benign cardiac tumor. PFEs of the right heart are uncommon, and those arising from the right-ventricular (RV) wall are extremely rare, with only a handful of reported cases in the literature. Removal of these tumors has been described, primarily through a median sternotomy approach, with only one report of using a right-sided mini-thoracotomy technique. The advantages of endoscopic robotic-assisted cardiac surgery have been demonstrated and described extensively. We report on a case of an incidentally found PFE in the RV that was successfully removed with a totally endoscopic robotic-assisted approach. The focus of our report is on the uniqueness of both the right-sided nonvalvular PFE and the treatment with a robotic totally endoscopic surgical approach.

High Prevalence of Clinically Important Echocardiographic Abnormalities in Patients with a Normal Electrocardiogram Referred for Transthoracic Echocardiography.

BACKGROUND: Normal electrocardiographic (ECG) results have been reported to be associated with a low prevalence of structural heart disease and thus may preclude the need for transthoracic echocardiographic (TTE) imaging. The goal of this study was to determine the prevalence of important TTE abnormalities in patients with a normal ECG referred for TTE imaging. METHODS: Consecutive electrocardiograms over 6 months were reviewed. Patients with a normal ECG who underwent TTE imaging within 30 days formed the study group. TTE indication and appropriateness designation were determined. TTE findings were noted, including a composite, "major TTE abnormalities" (Maj TTE ABNs). RESULTS: Of 26,254 electrocardiograms reviewed, 3,955 (15%) were normal, 522 with qualifying TTE studies. Maj TTE ABNs were common (27%). The most common TTE indication was signs or symptoms of congestive heart failure (17%), 35% of which had Maj TTE ABNs. Two echocardiographic indications were found to have significantly fewer of Maj TTE ABNs: palpitations (4%, P < .01) and preoperative evaluation before noncardiac surgery (6%, P < .01). A majority of TTE studies were appropriate (76%), with only 14% rarely appropriate. Maj TTE ABNs were less common in rarely appropriate compared with appropriate TTE studies (13% vs 30%, P < .01), with a very low prevalence of Maj TTE ABNs in outpatient rarely appropriate TTE studies (4%). CONCLUSIONS: Clinically important TTE abnormalities in patients with a normal ECG are common, suggesting that normal ECG results should not routinely preclude TTE imaging to identify structural heart disease. However, recognition of common clinical indications and application of the appropriate use criteria may identify patients with a normal ECG in whom TTE imaging is of very low yield.

Reduced nuclear DNA methylation and mitochondrial transcript changes in adenomas do not associate with mtDNA methylation.

BACKGROUND: Altered mitochondrial function and large-scale changes to DNA methylation patterns in the nuclear genome are both hallmarks of colorectal cancer (CRC). Mitochondria have multiple copies of a 16 kb circular genome that contains genes that are vital for their function. While DNA methylation is known to alter the nuclear genome in CRC, it is not clear whether it could have a similar influence in mtDNA; indeed, currently, the issue of whether mitochondrial genome (mtDNA) methylation occurs is controversial. Thus our goal here was to determine whether the methylation state of mtDNA is linked to mitochondrial gene transcription in colorectal adenomas, and to assess its suitability as a biomarker in CRC. METHODS: To investigate the relationship between DNA methylation and mitochondrial transcripts in adenomas, we performed RNA-sequencing and Whole Genome Bisulphite Sequencing (WGBS) of mtDNA-enriched DNA from normal mucosa and paired adenoma patient samples. RESULTS: Transcriptional profiling indicated that adenomas had reduced mitochondrial proton transport versus normal mucosa, consistent with altered mitochondrial function. The expression of 3 tRNAs that are transcribed from mtDNA were also decreased in adenoma. Overall methylation of CG dinucleotides in the nuclear genome was reduced in adenomas (68%) compared to normal mucosa (75%, P < 0.01). Methylation in mtDNA was low (1%) in both normal and adenoma tissue but we observed clusters of higher methylation at the ribosomal RNA genes. Levels of methylation within these regions did not differ between normal and adenoma tissue. CONCLUSIONS: We provide evidence that low-level methylation of specific sites does exist in the mitochondrial genome but that it is not associated with mitochondrial gene transcription changes in adenomas. Furthermore, as no large scale changes to mtDNA methylation were observed it is unlikely to be a suitable biomarker for early-stage CRC.

Towards a global cancer knowledge network: dissecting the current international cancer genomic sequencing landscape.

BACKGROUND: While next generation sequencing has enhanced our understanding of the biological basis of malignancy, current knowledge on global practices for sequencing cancer samples is limited. To address this deficiency, we developed a survey to provide a snapshot of current sequencing activities globally, identify barriers to data sharing and use this information to develop sustainable solutions for the cancer research community. METHODS: A multi-item survey was conducted assessing demographics, clinical data collection, genomic platforms, privacy/ethics concerns, funding sources and data sharing barriers for sequencing initiatives globally. Additionally, respondents were asked as to provide the primary intent of their initiative (clinical diagnostic, research or combination). RESULTS: Of 107 initiatives invited to participate, 59 responded (response rate = 55%). Whole exome sequencing (P = 0.03) and whole genome sequencing (P = 0.01) were utilized less frequently in clinical diagnostic than in research initiatives. Procedures to identify cancer-specific variants were heterogeneous, with bioinformatics pipelines employing different mutation calling/variant annotation algorithms. Measurement of treatment efficacy varied amongst initiatives, with time on treatment (57%) and RECIST (53%) being the most common; however, other parameters were also employed. Whilst 72% of initiatives indicated data sharing, its scope varied, with a number of restrictions in place (e.g. transfer of raw data). The largest perceived barriers to data harmonization were the lack of financial support (P < 0.01) and bioinformatics concerns (e.g. lack of interoperability) (P = 0.02). Capturing clinical data was more likely to be perceived as a barrier to data sharing by larger initiatives than by smaller initiatives (P = 0.01). CONCLUSIONS: These results identify the main barriers, as perceived by the cancer sequencing community, to effective sharing of cancer genomic and clinical data. They highlight the need for greater harmonization of technical, ethical and data capture processes in cancer sample sequencing worldwide, in order to support effective and responsible data sharing for the benefit of patients.

The relationship between meniscal pathology and osteoarthritis depends on the type of meniscal damage visible on magnetic resonance images: data from the Osteoarthritis Initiative.

OBJECTIVE: To determine the association of different types of meniscal pathology with knee pain, bone marrow lesion (BML) volume, and end-stage knee osteoarthritis (esKOA). DESIGN: Participants were selected from an ancillary project to the Osteoarthritis Initiative (OAI) who had at least one knee with symptomatic osteoarthritis. Baseline magnetic resonance images (MRI) were evaluated for meniscal pathology using a modified International Society of Arthroscopy, Knee Surgery, and Orthopaedic Sports Medicine (ISAKOS) classification system. We collapsed 10 types of meniscal pathology into five categories: normal, intrameniscal signal, morphological deformity/extrusion (altered meniscal shape and/or extrusion but no apparent substance loss), tear, and maceration. Outcomes included Western Ontario and McMaster Universities osteoarthritis index (WOMAC) knee pain and BML volume at baseline and after 2 years. We defined the prevalence of esKOA based on a validated algorithm. We performed logistic regression and adjusted for age, sex, and body mass index (BMI). RESULTS: The 463 participants (53% male) included in the analysis had mean age 63 (9.2) years, BMI 29.6 (4.6) kg/m2, and 71% had Kellgren-Lawrence grade ≥2. Morphological deformity/extrusion and maceration, but no other types of meniscal pathology, were associated with BML volume (morphological deformity/extrusion odds ratio [OR] = 2.47, 95% CI: 1.49, 4.09, maceration OR = 5.85, 95% CI: 3.40, 10.06) and change in BML volume (morphological deformity/extrusion OR = 2.17, 95% CI: 1.37, 3.45, maceration OR = 3.12, 95% CI: 1.87, 5.19). Only maceration was associated with baseline WOMAC knee pain (OR = 2.82, 95% CI: 1.79, 4.43) and prevalence of esKOA (OR = 7.53, 95% CI: 4.25, 13.31). CONCLUSIONS: Based on MRI, morphologic deformity/extrusion and maceration rather than intrameniscal signal or tear were associated with osteoarthritis severity and progression, which highlights the importance of differentiating distinct types of meniscal pathology.