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Autophagy is a housekeeping mechanism tasked with eliminating misfolded proteins and damaged organelles to maintain cellular homeostasis. Autophagy deficiency results in increased oxidative stress, DNA damage and chronic cellular injury. Among the core genes in the autophagy machinery, ATG7 is required for autophagy initiation and autophagosome formation. Based on the analysis of an extended pedigree of familial cholangiocarcinoma, we determined that all affected family members had a novel germline mutation (c.2000C>T p.Arg659* (p.R659*)) in ATG7. Somatic deletions of ATG7 were identified in the tumors of affected individuals. We applied linked-read sequencing to one tumor sample and demonstrated that the ATG7 somatic deletion and germline mutation were located on distinct alleles, resulting in two hits to ATG7. From a parallel population genetic study, we identified a germline polymorphism of ATG7 (c.1591C>G p.Asp522Glu (p.D522E)) associated with increased risk of cholangiocarcinoma. To characterize the impact of these germline ATG7 variants on autophagy activity, we developed an ATG7-null cell line derived from the human bile duct. The mutant p.R659* ATG7 protein lacked the ability to lipidate its LC3 substrate, leading to complete loss of autophagy and increased p62 levels. Our findings indicate that germline ATG7 variants have the potential to impact autophagy function with implications for cholangiocarcinoma development., (© 2022. The Author(s).)

Purpose: To accurately ascertain the frequency of pathogenic germline variants (PGVs) in a pan-cancer patient population with universal genetic testing and to assess the economic impact of receiving genetic testing on healthcare costs., Methods: In this prospective study, germline genetic testing using a 105-gene panel was administered to an unselected pan-cancer patient population irrespective of eligibility by current guidelines. Financial records of subjects were analyzed to assess the effect of PGV detection on cost of care one year from the date of testing., Results: A total of 284 patients participated in this study, of which 44 patients (15%) tested positive for a PGV in 14 different cancer types. Of the patients with PGVs, 23 patients (52%) were ineligible for testing by current guidelines. Identification of a PGV did not increase cost of care., Conclusion: Implementation of universal genetic testing for cancer patients in the clinic, beyond that specified by current guidelines, is necessary to accurately assess and treat hereditary cancer syndromes and does not increase healthcare costs.

Systemic inflammation is present during and serves as a diagnostic tool for cancer-associated cachexia and is detrimental to serum 25-hydroxyvitamin D (25(OH)D) concentrations in non-cancer conditions. The neutrophil-to-lymphocyte ratio (NLR) is a desirable measure of systemic inflammation because it is easily calculated from a routine complete blood cell count with differentials. We sought to determine if an elevation in the NLR associates with greater weight loss, cachexia, and lower serum 25-hydroxyvitamin D (25(OH)D) concentrations in patients with advanced cancer. Advanced colon, lung, and prostate cancer patients (stages III/IV; n = 50) were retrospectively studied and separated into one of two groups: 1) Above (n = 25) or 2) Below (n = 25) the median NLR of 3.15 determined at diagnosis. Around the time of diagnosis, serum 25(OH)D and body weight were assessed, while body weight was assessed again at a later date. Weight loss and cachexia were significantly (both p < 0.05) greater and there was a trend (p < 0.10) for lower serum 25(OH)D concentrations in the Above group. We conclude that an elevation in the NLR associates with greater weight loss and cachexia, and potentially, a lower serum 25(OH)D concentration in patients with advanced colon, lung, or prostate cancer.

DNA copy number aberrations (CNA) are frequently observed in colorectal cancers (CRC). There is an urgent need for CNA-based biomarkers in clinics,. n For Stage III CRC, if combined with imaging or pathologic evidence, these markers promise more precise care. We conducted this Stage III specific biomarker discovery with a cohort of 134 CRCs, and with a newly developed high-efficiency CNA profiling protocol. Specifically, we developed the profiling protocol for tumor-normal matched tissue samples based on low-coverage clinical whole-genome sequencing (WGS). We demonstrated the protocol's accuracy and robustness by a systematic benchmark with microarray, high-coverage whole-exome and -genome approaches, where the low-coverage WGS-derived CNA segments were highly accordant (PCC >0.95) with those derived from microarray, and they were substantially less variable if compared to exome-derived segments. A lasso-based model and multivariate cox regression analysis identified a chromosome 17p loss, containing the TP53 tumor suppressor gene, that was significantly associated with reduced survival (P = 0.0139, HR = 1.688, 95% CI = [1.112-2.562]), which was validated by an independent cohort of 187 Stage III CRCs. In summary, this low-coverage WGS protocol has high sensitivity, high resolution and low cost and the identified 17p-loss is an effective poor prognosis marker for Stage III patients.

Background: Sharing anonymised ED data with community agencies to reduce alcohol-related injury and assaults has been found effective in the UK. This protocol document outlines the design of an Australian multi-site trial using shared, anonymised ED data to reduce alcohol-related harm., Design and Method: Nine hospitals will participate in a 36 month stepped-wedge cluster randomised trial. After a 9 month baseline period, EDs will be randomised in five groups, clustered on geographic proximity, to commence the intervention at 3 monthly intervals. 'Last-drinks' data regarding alcohol use in the preceding 12 h, typical alcohol consumption amount, and location of alcohol purchase and consumption, are to be prospectively collected by ED triage nurses and clinicians at all nine EDs as a part of standard clinical process. Brief information flyers will be delivered to all ED patients who self-report risky alcohol consumption. Public Health Interventions to be conducted are: (i) information sharing with venues (via letter), and (ii) with police and other community agencies, and (iii) the option for public release of 'Top 5' venue lists., Outcomes: Primary outcomes will be: (i) the number and proportion of ED attendances among patients reporting recent alcohol use; and (ii) the number and proportion of ED attendances during high-alcohol hours (Friday and Saturday nights, 20.00-06.00 hours) assigned an injury diagnosis. Process measures will assess logistical and feasibility concerns, and clinical impacts of implementing this systems-change model in an Australian context. An economic cost-benefit analysis will evaluate the economic impact, or return on investment., (© 2019 Australasian College for Emergency Medicine.)

The impact of precision oncology on guiding treatment decisions of late-stage cancer patients was previously studied in a retrospective analysis. However, the overall survival and costs were not previously evaluated. We report the overall survival and healthcare costs associated with precision oncology in these patients with advanced cancer. Building on a matched cohort study of 44 patients with metastatic cancer who received all of their care within a single institution, we evaluated the overall survival and healthcare costs for each patient. We analyzed the outcomes of 22 patients who received genomic testing and targeted therapy (precision oncology) between July 1, 2013 and January 31, 2015, and compared to 22 historically controlled patients (control) who received standard chemotherapy ( N = 17) or best supportive care ( N = 5). The median overall survival was 51.7 weeks for the targeted treatment group and 25.8 weeks for the control group ( P = 0.008) when matching on age, gender, histological diagnosis and previous treatment lines. Average costs over the entire period were $2,720 per week for the targeted treatment group and $3,453 per week for the control group, ( P = 0.036). A separate analysis of 1,814 patients with late-stage cancer diagnoses found that those who received a targeted cancer treatment ( N = 93) had 6.9% lower costs in the last 3 months of life compared with those who did not. These findings suggest that precision oncology may improve overall survival for refractory cancer patients while lowering average per-week healthcare costs, resource utilization and end-of-life costs., Competing Interests: CONFLICTS OF INTEREST None.

Purpose: The advent of genomic diagnostic technologies such as next-generation sequencing has recently enabled the use of genomic information to guide targeted treatment in patients with cancer, an approach known as precision medicine. However, clinical outcomes, including survival and the cost of health care associated with precision cancer medicine, have been challenging to measure and remain largely unreported., Patients and Methods: We conducted a matched cohort study of 72 patients with metastatic cancer of diverse subtypes in the setting of a large, integrated health care delivery system. We analyzed the outcomes of 36 patients who received genomic testing and targeted therapy (precision cancer medicine) between July 1, 2013, and January 31, 2015, compared with 36 historical control patients who received standard chemotherapy (n = 29) or best supportive care (n = 7)., Results: The average progression-free survival was 22.9 weeks for the precision medicine group and 12.0 weeks for the control group ( P = .002) with a hazard ratio of 0.47 (95% CI, 0.29 to 0.75) when matching on age, sex, histologic diagnosis, and previous lines of treatment. In a subset analysis of patients who received all care within the Intermountain Healthcare system (n = 44), per patient charges per week were $4,665 in the precision treatment group and $5,000 in the control group ( P = .126)., Conclusion: These findings suggest that precision cancer medicine may improve survival for patients with refractory cancer without increasing health care costs. Although the results of this study warrant further validation, this precision medicine approach may be a viable option for patients with advanced cancer.

Emergency medicine in the highly advanced world is traditionally performed in two different ways. The first is the well-known Anglo-American system with skilled EDs, and a pre-hospital emergency medical service utilizing paramedics. The second is the so-called Franco-German system, with a highly developed pre-hospital emergency physician service, but only a basic organization of hospital-based emergency medicine. This gap is now closing fast because of the rapid advancement of hospital-based emergency medicine in Europe. Four criteria might be used to measure this: the recognition as a specialty, the specialist training programme, the professional organization of emergency physicians and the presence of academic centres in Europe. Eleven of the 27 European countries recognize hospital-based emergency medicine as a specialty already. These include Belgium, Czech Republic, Estonia, Hungary, Ireland, Italy, Malta, Poland, Romania, Slovenia and the United Kingdom. Other nations are striving to do so, for example Sweden, France, Germany and Greece. There is no doubt that emergency medicine is gaining momentum and other countries will follow. Training for the specialty of emergency medicine is advanced already. Several curricula presently exist in the respective European countries. A task force, governed by the European Society for Emergency Medicine has been working hard to create a model curriculum for all of Europe, which is expected to be published in 2007. This comprises a 5-year specialty training, with three of them spent in an ED. The curriculum follows a symptom-oriented approach to emergency medicine, and includes a skilled description of the key competencies of the future trained emergency physicians. Given the century-long history of the pre-hospital emergency physician service in some European countries, a number of professional bodies exist representing pre-hospital emergency doctors. Within the last few years, ED physicians followed suit forming organizations of their own. In some countries, the next step of amalgamation has occurred, with the merger of EMS and ED emergency physician organizations, although no country has abolished the pre-hospital emergency physician service. The last milestone, the development of academic emergency centres, has only just started. This process will take some time. The present paper describes the present and future of emergency medicine in some European countries using these criteria.

Objective: To describe the planning and implementation of health care provision at a mass gathering, and to describe the conditions treated at such an event., Setting: When approximately 93,000 fans gathered outdoors in Sydney's Centennial Park, a natural reserve, for Australasia's largest ever outdoor rock concert, there was an obvious potential for medical disaster., Patients: At most disasters or mass gatherings, accurate patient numbers and details are not available, but an organised patient data collection system allowed the case load at this event to be clearly defined. This showed that 450 patients were attended to by the first aid teams. Triage identified 36 of these as having conditions serious enough to require admission to the medical area. Seven of these patients were ultimately transferred to hospital., Results: A brief practical outline is provided of the medical planning for the concert, detailing the staff and equipment, how to avoid potential problems, the use of voluntary organisations, and specific site organisation. Key points in the medical planning, organisation and practicalities, especially those which are vital to any disaster response, are highlighted., Conclusion: Solutions to recurrent problems experienced by medical personnel involved with mass gatherings or disasters are suggested. The lack of practice in implementing a multiple casualty or disaster plan may be remedied by organised responses to mass events.

Objective: A case of severe acute peripheral arterial insufficiency secondary to ergotamine toxicity treated successfully with intravenously administered prostaglandin is presented to highlight the features of this condition and to demonstrate the efficacy of treatment with prostaglandin infusion., Clinical Features: A 35-year-old unemployed Caucasian woman with a background of polypharmacy abuse and recurrent migraines presented to St Vincent's Hospital Emergency Department with limb-threatening ischaemia of both legs secondary to chronic ergotamine overuse., Intervention and Outcome: A prostaglandin infusion was started and a dramatic and rapid improvement of her peripheral circulation occurred within six hours., Conclusion: Ergotamine toxicity is an uncommon but well documented cause of peripheral vascular insufficiency that should be recognised and treated aggressively because its sequelae can be disastrous. Intravenously administered prostaglandin proved to be successful in this case and is a logical choice as first-line therapy for ergotamine toxicity.

An experimental technique designed to predict theophylline doses needed to attain therapeutic theophylline concentrations in 43 emergency department (ED) patients was compared with a standard conventional regimen in 46 ED patients. The experimental protocol utilized a computer-assisted dosage prediction program that incorporated baseline theophylline concentration rapidly obtained using a bedside assay. The standard protocol used conventional loading and infusion rates, as well as an estimate of time of last theophylline dose based on patient history. Plasma theophylline concentrations, estimated 1 and 6 hours after commencement of aminophylline therapy in each regimen, were compared. The experimental protocol was equally rapid but much more accurate in achieving targeted theophylline concentrations. Experimental dosage prediction was associated with a higher proportion of theophylline concentrations in the therapeutic range at 1 (81 percent vs 26 percent; p less than 0.001) and 6 hours (91 percent vs 37 percent; p less than 0.001). There was a trend toward fewer toxic concentrations recorded at 1 (0 percent vs 7 percent; p = 0.27) and 6 hours (0 percent vs 10 percent; p = 0.08). This protocol, which was performed quickly and without difficulty by residents in a busy hospital ED, offers an opportunity to improve the efficacy and decrease the toxicity of theophylline use in asthma emergencies.

Lightning strike is a natural phenomenon with potentially devastating effects. The physics of lightning strike and the physiology of lightning injury are discussed. Three cases are reported and the clinical features are described. Aspects of the management of such patients are discussed with particular emphasis on assessment and resuscitation in the Emergency Department.

A rare occurrence of serious envenomation by a sea snake in the waters of a popular Sydney beach is reported. A 19-year-old man was bitten while swimming, then quickly developed major proximal neuromuscular complications. Prompt, effective first aid (firm limb bandaging and splinting), transport to hospital, and administration of antivenom led to the rapid, full recovery of the patient who was discharged from hospital on the following day.

The purpose of this review is to highlight the toxicity of chloral hydrate and to review the management of overdoses with chloral hydrate. Three patients are presented in whom life-threatening cardiac arrhythmias dominated the clinical presentation. These arrhythmias were resistant to standard antiarrhythmic therapy. Also, we have reviewed selected features in eight patients who took overdoses of chloral hydrate who were admitted to an intensive care unit between 1981 and 1988. The pharmacology and toxicology of chloral hydrate are discussed with particular reference to the cardiac arrhythmias that are seen with overdosage. A proposed management scheme is detailed, including intravenously-administered propranolol as the preferred first-line antiarrhythmic agent. A case may be made for the discontinuation of the usage of chloral hydrate.